Chronic Kidney Disease

Complex MONDO:0005300 Pathograph 22 Show in embeddings browser Renal Disease

Chronic kidney disease (CKD) is the progressive, generally irreversible loss of kidney function persisting for at least three months, defined by a reduced glomerular filtration rate (GFR < 60 mL/min/1.73 m2) and/or markers of kidney damage such as albuminuria. It arises from diverse etiologies, most commonly diabetic nephropathy, hypertensive nephrosclerosis, glomerulonephritis, and polycystic kidney disease, that converge on a final common pathway of progressive nephron loss, compensatory hyperfiltration, glomerulosclerosis, and tubulointerstitial fibrosis. As functional renal mass declines, patients develop complications including decreased GFR, metabolic acidosis, mineral and bone disorder, anemia, and accelerated cardiovascular disease, with end-stage kidney disease ultimately requiring dialysis or transplantation.

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6
Pathophys.
7
Phenotypes
1
Hypotheses
1
Gaps
22
Pathograph
3
Genes
9
Medical Actions
4
Subtypes
8
Datasets
33
References
2
Deep Research
🏷

Classifications

Harrison's Part
KIDNEY URINARY TRACT
◆

Subtypes

4
Diabetic Nephropathy
CKD caused by long-standing diabetes mellitus.
Hypertensive Nephrosclerosis
CKD caused by chronic hypertension.
Glomerulonephritis
CKD from primary or secondary glomerular diseases.
Polycystic Kidney Disease
Inherited form of CKD with multiple kidney cysts.
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Mechanistic Hypotheses

1
Amplification of polygenic CKD risk in adverse contexts via shared glomerular-injury convergence
pgs_context_amplification EMERGING
Evidence balance 2 support
Polygenic-score-by-context (PGS×C) interactions reported for chronic kidney disease in the UK Biobank appear to reflect amplification rather than context-specific causal variants: the same susceptibility loci (e.g. APOL1, PKD1, PKD2) exert systematically larger effects in disease-promoting contexts. This entry proposes that the amplification arises because polygenic liability and adverse exposures — notably hyperglycemia/diabetes and tobacco smoking — converge on the shared Glomerulosclerosis injury node, so their joint effect on the liability-threshold scale (here modelled against the PGS for eGFR) is super-additive rather than additive. Nagpal & Gibson (Nat Genet 2026, PMID:42443528) report glucose and past smoking as major amplifying contexts for CKD, with the benefit of reducing them increasing at higher genetic risk.
EMERGING hypothesis motivated by population-scale PGS×context analyses (primary source PMID:42443528; general amplification mechanism corroborated by PMID:37228747). The convergence claim (polygenic liability + hyperglycemia/smoking → Glomerulosclerosis) is a mechanistic interpretation and is not itself established as causal — see the reverse-causation knowledge gap under discussions.
Show evidence (2 references)
PMID:42443528 SUPPORT Computational
"The predominant mechanism for PGS×C is the amplification of genetic effects in adverse contexts, such as low polyunsaturated fatty acids or social determinants of ill health"
Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and 75 contexts, amplification of genetic effects in adverse contexts is identified as the predominant mechanism of PGS×context interaction — the mechanism applied in this hypothesis.
PMID:37228747 SUPPORT Computational
"GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects"
Establishes amplification — systematic differences in the magnitude of polygenic effects rather than in the identity of causal variants — as the primary mode of gene-by-context interaction, the mechanism proposed here for the CKD PGS×context interactions (sex-adjusted hemoglobin and other contexts show amplification for CKD in Nagpal & Gibson 2026).
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Discussions and Knowledge Gaps

1
Are the CKD PGS×context interactions driven by adverse exposures causally amplifying genetic risk, or are some "contexts" and the eGFR outcome itself partly downstream readouts of kidney injury (reverse causation)?
KNOWLEDGE GAP OPEN ckd_pgsxc_reverse_causation
Attached to
pathophysiology#Glomerulosclerosis biochemical#Creatinine environmental#Diabetes environmental#Hypertension
Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are largely unable to establish the causality of specific contexts. For CKD the concern is sharpened because the outcome is modelled against the PGS for eGFR, and serum creatinine — from which eGFR is derived — is already modelled in this entry as a READOUT_OF Nephron Loss, i.e. a consequence of injury rather than a driver. Comorbid exposures such as diabetes and hypertension are themselves partly on the causal path to CKD and partly co-declining with renal function. Distinguishing genuine amplification of genetic effects from reverse causation determines whether the modelled interventions (reducing glucose, smoking cessation) would actually slow progression.
Proposed experiments
Mendelian randomization of exposure-to-CKD direction across PGS strata
ckd_pgsxc_mr_direction
Use bidirectional / multivariable Mendelian randomization to test whether each candidate context (glucose, smoking, blood pressure) causally affects kidney function versus being a consequence of declining eGFR, and whether the causal effect estimate scales with polygenic liability as the amplification model predicts.
Decision criterion
A context is retained as a causal amplifier if MR supports exposure-to-disease directionality and the exposure-attributable risk difference increases across increasing PGS strata; it is flagged as a reverse-causation suspect otherwise.
Prospective incident-CKD analysis restricted to pre-diagnosis exposure windows
ckd_pgsxc_prospective_temporal
Restrict exposures to measurements taken well before the first evidence of reduced eGFR and repeat the PGS×context liability-threshold modelling on incident cases only, to reduce contamination by exposures that co-decline with renal function.
Decision criterion
Amplification is supported if the PGS×context deviation from additivity persists when only pre-diagnosis exposure windows and incident cases are used.
⚙

Pathophysiology

6
Nephron Loss
Progressive loss of functional nephrons from any cause leads to compensatory hyperfiltration in remaining nephrons, which paradoxically accelerates further damage and fibrosis.
Podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology. Tubular Epithelial Cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Tubular Epithelial Cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
Nephron UBERON:0001285 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Nephron (UBERON:0001285). UBERON:0001285 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Decreased GFR Cumulative loss of functional nephrons directly reduces the whole-kidney glomerular filtration rate.
Metabolic Acidosis Reduced functional renal mass impairs ammoniagenesis and net acid excretion, producing metabolic acidosis.
Glomerulosclerosis Compensatory hyperfiltration in surviving nephrons imposes hemodynamic stress that accelerates glomerular scarring (vicious cycle).
Show evidence (2 references)
PMID:38653563 SUPPORT
"Patients diagnosed with AKI often undergo diverse clinical trajectories, such as early or late recovery, relapses, and even a potential transition from AKI to chronic kidney disease (CKD)."
This describes how acute injury leads to progressive nephron loss and CKD transition, supporting the concept that initial damage triggers compensatory mechanisms that accelerate further injury.
PMID:38339031 SUPPORT
"This article provides a thorough overview of the biomarkers, pathophysiology, and molecular pathways involved in the transition from acute kidney injury (AKI) and acute kidney disease (AKD) to chronic kidney disease (CKD)."
The transition from AKI to CKD involves progressive nephron loss with maladaptive repair mechanisms that drive ongoing damage and fibrosis.
Glomerulosclerosis
Scarring and hardening of glomeruli impairs filtration function. Driven by hemodynamic stress, inflammation, and metabolic factors.
Glomerular Fibrosis GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Glomerular Fibrosis, annotated with extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED
Renal Glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Renal Glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Proteinuria Scarring and disruption of the glomerular filtration barrier permits protein leakage into the urine.
Nephron Loss Progressive glomerular scarring renders affected nephrons nonfunctional, contributing to nephron loss.
Show evidence (2 references)
PMID:38610646 SUPPORT
"Chronic kidney disease (CKD) is a slowly progressive condition characterized by decreased kidney function, tubular injury, oxidative stress, and inflammation."
This describes the inflammatory and oxidative stress components that drive glomerulosclerosis alongside hemodynamic factors.
PMID:37857763 SUPPORT
"Reactive oxygen species (ROS) are derivatives of oxygen molecules that are generated during aerobic metabolism and are involved in a variety of cellular functions that are governed by redox conditions."
ROS generation contributes to oxidative stress and metabolic factors that drive glomerular scarring and impaired filtration.
Klotho Deficiency
Progressive decline in renal Klotho expression with CKD severity. Klotho is a renal-protective factor that suppresses TGF-β/Smad3 signaling and maintains phosphate homeostasis. Klotho deficiency amplifies tubulointerstitial fibrosis and accelerates CKD progression.
TGF-beta Receptor Signaling GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased TGF-beta Receptor Signaling, annotated with transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↑ INCREASED
Kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Tubulointerstitial Fibrosis Klotho deficiency permits unchecked TGF-β/Smad3 signaling and myofibroblast differentiation, driving tubulointerstitial fibrosis.
IL-11 Signalling in Renal Fibroblasts Klotho deficiency de-represses TGF-β/Smad3 signalling, which induces autocrine IL-11 in renal fibroblasts, placing IL-11 receptor signalling downstream of the Klotho-TGF-β axis.
Show evidence (1 reference)
DOI:10.21203/rs.3.rs-9670512/v1 Preprint · not peer-reviewed SUPPORT Model Organism
"Chronic kidney disease (CKD) is characterised by progressive renal fibrosis, Klotho deficiency, and dysregulated transforming growth factor-beta 1/Smad3 signalling."
This preprint establishes Klotho deficiency as a key pathophysiologic feature of CKD that dysregulates TGF-β/Smad3 signaling.
IL-11 Signalling in Renal Fibroblasts
Profibrotic stimulation of kidney interstitial fibroblasts engages IL11RA1-mediated, ERK-dependent autocrine IL-11 signalling that drives their myofibroblast conversion and fibrogenic protein synthesis. This IL-11 receptor-signalling arm is an organ-specific instance of the conserved IL-11 signalling module and feeds tubulointerstitial fibrosis; IL-11 pathway antagonism reduces renal fibrosis in vivo.
Kidney interstitial fibroblast CL:1000692 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Kidney interstitial fibroblast (CL:1000692). CL:1000692 is a cell type from the Cell Ontology.
Interleukin-11-mediated signaling pathway GO:0038154 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Interleukin-11-mediated signaling pathway (GO:0038154). GO:0038154 is a biological process from the Gene Ontology. ↑ INCREASED ERK1 and ERK2 cascade GO:0070371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ERK1 and ERK2 cascade (GO:0070371). GO:0070371 is a biological process from the Gene Ontology. ↑ INCREASED
Kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Tubulointerstitial Fibrosis
Show evidence (4 references)
PMID:29160304 SUPPORT Model Organism
"In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease."
Directly evidences that fibroblast IL-11 signalling causes kidney fibrosis and organ failure and that receptor deletion is protective, grounding this node in renal disease. Evidence source is MODEL_ORGANISM (transgenic and Il11ra1-knockout mice).
PMID:29160304 SUPPORT In Vitro
"IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis."
Establishes the ERK-dependent autocrine IL-11 receptor-signalling arm in fibroblasts modeled by this node. Evidence source is IN_VITRO (primary human fibroblasts).
PMID:29160304 SUPPORT In Vitro
"rhIL-11 strongly activated human renal fibroblasts."
Shows recombinant IL-11 directly activates human renal fibroblasts, specializing the conserved mechanism to the kidney compartment. Evidence source is IN_VITRO (primary human renal fibroblasts).
+ 1 more reference
Tubulointerstitial Fibrosis
Fibrotic replacement of tubular structures by collagen-producing myofibroblasts. The final common pathway of CKD progression.
Myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology.
Renal Tubule UBERON:0009773 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Renal Tubule (UBERON:0009773). UBERON:0009773 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Anemia Fibrotic destruction of EPO-producing peritubular interstitial fibroblasts reduces erythropoietin synthesis, causing anemia.
Nephron Loss Fibrotic replacement of tubular structures is the final common pathway by which nephrons are destroyed.
Show evidence (2 references)
PMID:38610646 SUPPORT
"Transforming growth factor (TGF)-β is a central mediator in promoting transdifferentiation of polarized renal tubular epithelial cells into mesenchymal cells, resulting in irreversible kidney injury."
This supports the mechanism of fibrotic replacement where TGF-β drives transdifferentiation of tubular epithelial cells, leading to fibrosis and irreversible injury.
PMID:38339031 SUPPORT
"Key signaling pathways, such as Wnt/β-catenin, TGF-β/SMAD, and Hippo/YAP/TAZ, promote fibrosis and impact renal function."
This confirms that TGF-β/SMAD and other pathways drive fibrotic processes that characterize the final common pathway of CKD progression.
RAAS Activation
Inappropriately activated renin-angiotensin-aldosterone system promotes glomerular hypertension, fibrosis, and sodium retention.
RAAS Signaling GO:0002018 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves RAAS Signaling, annotated with renin-angiotensin regulation of aldosterone production (GO:0002018). GO:0002018 is a biological process from the Gene Ontology.
Kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hypertension Angiotensin II-mediated vasoconstriction and aldosterone-driven sodium retention raise systemic blood pressure.
Peripheral Edema Aldosterone-driven sodium and water retention expands extracellular volume, producing peripheral edema.
Tubulointerstitial Fibrosis Aldosterone- and angiotensin II-mediated oxidative stress and pro-fibrotic signaling drive tubulointerstitial fibrosis.
Show evidence (2 references)
PMID:38339031 SUPPORT
"The renin-angiotensin-aldosterone system (RAAS) triggers a cascade leading to renal fibrosis, with aldosterone exacerbating the oxidative stress and cellular changes that promote fibrosis."
This directly supports the mechanism by which RAAS activation promotes fibrosis through aldosterone-mediated oxidative stress and cellular injury in CKD.
PMID:38610646 SUPPORT
"Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression."
The therapeutic efficacy of RAAS blockers confirms that RAAS activation is a key driver of CKD progression, supporting its role in promoting hypertension and fibrosis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Chronic Kidney Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Blood 1
Anemia FREQUENT HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Due to reduced erythropoietin production
Sequelae: Fatigue
Show evidence (1 reference)
PMID:38927397 SUPPORT Human Clinical
"Anemia is one of the most common chronic kidney disease (CKD) complications. It negatively affects patients' quality of life and clinical outcomes."
This review establishes anemia as one of the most common complications of CKD with significant impact on patient outcomes.
Cardiovascular 1
Hypertension VERY_FREQUENT HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32635265 SUPPORT Human Clinical
"RAAS is inappropriately activated in CKD, leading to vasoconstriction and sodium retention, which contribute significantly to the raising of BP levels"
Inappropriate RAAS activation with vasoconstriction and sodium retention raises blood pressure in CKD, supporting hypertension as a near-universal consequence.
Genitourinary 2
Decreased GFR VERY_FREQUENT Chronic kidney disease HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased GFR, annotated with Chronic kidney disease (HP:0012622). HP:0012622 is a phenotype from the Human Phenotype Ontology.
Proteinuria VERY_FREQUENT HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37857763 NO_EVIDENCE
"However, excess ROS can be pathological, and contribute to the development and progression of chronic diseases."
Excess ROS contributes to tubular and glomerular injury that manifests as proteinuria, a hallmark of CKD progression.
Metabolism 2
Metabolic Acidosis FREQUENT HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic Acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38279993 SUPPORT Human Clinical
"nephron loss with reduced ammoniagenesis is the main cause of acid retention in non-transplant CKD patients"
Declining nephron mass with reduced ammoniagenesis impairs net acid excretion, producing the metabolic acidosis of CKD.
Peripheral Edema FREQUENT HP:0012398 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral Edema (HP:0012398). HP:0012398 is a phenotype from the Human Phenotype Ontology.
Constitutional 1
Fatigue FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
🧬

Genetic Associations

3
PKD1 (Causative)
Gene: PKD1 hgnc:9008 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PKD1 (hgnc:9008). hgnc:9008 is a gene from the HUGO Gene Nomenclature Committee.
PKD2 (Causative)
Gene: PKD2 hgnc:9009 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PKD2 (hgnc:9009). hgnc:9009 is a gene from the HUGO Gene Nomenclature Committee.
APOL1 (Risk Factor)
Gene: APOL1 hgnc:618 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is APOL1 (hgnc:618). hgnc:618 is a gene from the HUGO Gene Nomenclature Committee.
💊

Medical Actions

9
ACE Inhibitors/ARBs
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Reduce proteinuria and slow progression by lowering intraglomerular pressure.
Mechanism Target:
INHIBITS RAAS Activation — ACE inhibitors and ARBs directly block the renin-angiotensin-aldosterone system, lowering intraglomerular pressure and attenuating RAAS-mediated fibrosis that drives CKD progression.
Show evidence (1 reference)
PMID:38339031 SUPPORT
"The clinical evidence suggests that RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed to confirm their full impact."
RAS inhibitors act on RAAS activation to slow CKD progression.
Show evidence (1 reference)
PMID:38339031 SUPPORT
"The clinical evidence suggests that RAS inhibitors may protect against CKD progression, especially post-AKI, though more extensive trials are needed to confirm their full impact."
RAS inhibitors (ACE inhibitors/ARBs) protect against CKD progression by blocking RAAS-mediated fibrosis and reducing intraglomerular pressure.
SGLT2 Inhibitors
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Provide nephroprotection independent of diabetes status.
Mechanism Target:
INHIBITS Tubulointerstitial Fibrosis — SGLT2 inhibitors are an established disease-modifying therapy that delays CKD progression, including the tubulointerstitial fibrotic process, beyond their glucose-lowering effect.
Show evidence (1 reference)
PMID:38610646 SUPPORT
"Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression."
SGLT2 inhibitors are listed among current anti-fibrotic progression-delaying therapies.
Show evidence (2 references)
PMID:38610646 SUPPORT
"Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression."
SGLT2 inhibitors are recognized as current standard therapy that delays CKD progression through multiple mechanisms beyond glucose control.
PMID:36623286 SUPPORT Other
"New evidence led to updating of recommendations in the chapters Comprehensive Care in Patients With Diabetes and CKD (Chapter 1) and Glucose-Lowering Therapies in Patients With T2D and CKD (Chapter 4)."
The KDIGO 2022 diabetes-CKD guideline update revised its glucose-lowering-therapy recommendations, in which SGLT2 inhibitors are central nephroprotective therapy for patients with diabetes and CKD.
Blood Pressure Control
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Target less than 130/80 to slow progression.
Mechanism Target:
INHIBITS Glomerulosclerosis — Lowering systemic blood pressure reduces glomerular capillary hypertension and the hemodynamic injury that drives glomerulosclerosis.
Dietary Protein Restriction
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
May slow progression in advanced CKD.
Mechanism Target:
MODULATES Glomerulosclerosis — Restricting dietary protein lowers glomerular hyperfiltration, easing the hemodynamic stress that promotes glomerulosclerosis in advanced CKD.
Erythropoiesis-Stimulating Agents
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Treat anemia of CKD.
Phosphate Binders
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Control hyperphosphatemia.
Dialysis
Action: renal dialysisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is renal dialysis, annotated with Dialysis (NCIT:C15221). NCIT:C15221 is a clinical intervention from the NCI Thesaurus. Ontology label: Dialysis NCIT:C15221
Renal replacement therapy for end-stage disease.
Mechanism Target:
BYPASSES Nephron Loss — Dialysis provides extracorporeal solute and fluid clearance that substitutes for the excretory function lost through progressive nephron loss, without restoring native kidney function.
Kidney Transplantation
Action: Kidney TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Kidney Transplantation (NCIT:C15265). NCIT:C15265 is a clinical intervention from the NCI Thesaurus. NCIT:C15265
Definitive treatment for end-stage renal disease.
Mechanism Target:
RESTORES Nephron Loss — A functioning renal allograft restores nephron mass and physiologic kidney function lost in end-stage CKD.
Show evidence (1 reference)
PMID:21883901 SUPPORT Human Clinical
"Quality of life was significantly and substantially better among transplant recipients. Despite increases in the age and comorbidity of contemporary transplant recipients, the relative benefits of transplantation seem to be increasing over time."
This systematic review of 1.9 million participants confirms kidney transplantation provides survival benefit and improved quality of life compared to dialysis.
AAV-Mediated Klotho Gene Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Emerging gene therapy approach using adeno-associated virus (AAV9) vectors to deliver functional Klotho gene to restore renal Klotho expression. Preclinical studies show restoration of Klotho suppresses TGF-β/Smad3 fibrotic signaling and attenuates CKD progression in mouse models.
Mechanism Target:
RESTORES Klotho Deficiency — AAV9-mediated Klotho delivery restores renal Klotho expression, which suppresses TGF-β/Smad3 signaling and mitigates fibrotic progression of CKD.
Show evidence (2 references)
DOI:10.21203/rs.3.rs-9670512/v1 Preprint · not peer-reviewed SUPPORT Model Organism
"High-dose AAV-KL restored Klotho to approximately 78% of sham"
Preclinical evidence from 5/6 nephrectomy and ureteral obstruction models demonstrates that AAV-KL restores renal Klotho.
DOI:10.21203/rs.3.rs-9670512/v1 Preprint · not peer-reviewed SUPPORT Model Organism
"The phospho-Smad3/Smad3 ratio declined markedly without change in transforming growth factor-beta 1 ligand, while Smad7 rose approximately 1.9-fold."
Restored Klotho suppresses phospho-Smad3 and elevates Smad7, mitigating the fibrotic TGF-β/Smad3 signaling that drives CKD progression.
Show evidence (1 reference)
DOI:10.21203/rs.3.rs-9670512/v1 Preprint · not peer-reviewed SUPPORT Model Organism
"Transcriptome-wide RNA-sequencing identified 924 differentially expressed genes in CKD kidneys versus sham, of which 306 (including key extracellular matrix, epithelial-mesenchymal transition, and TGF-beta pathway genes) were rescued by AAV-KL treatment"
Transcriptomic evidence from preclinical models supports broad mechanistic effects on fibrotic and matrix-remodeling pathways. This is non-peer-reviewed preprint evidence and should not serve as sole support for clinical efficacy claims.
🌍

Environmental Factors

7
Diabetes
Chronic hyperglycemia in type 1 and type 2 diabetes mellitus is the single largest contributor to incident CKD and end-stage kidney disease worldwide, acting through the diabetic microvascular injury cascade (glomerular hyperfiltration, mesangial expansion, podocyte loss, and albuminuria).
Show evidence (1 reference)
PMID:41263046 SUPPORT Human Clinical
"Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide"
Establishes diabetes as the leading antecedent condition for CKD and ESRD globally.
Hypertension
Sustained elevated systemic blood pressure drives hypertensive nephrosclerosis — afferent arteriolar hyalinosis, glomerulosclerosis, and tubulointerstitial fibrosis — and is the second most common antecedent of end-stage kidney disease after diabetes. Hypertension is also a consequence of CKD, forming a self-reinforcing loop with RAAS activation.
Show evidence (1 reference)
PMID:34831368 SUPPORT Human Clinical
"Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease after diabetes."
Supports hypertension as the second leading antecedent of ESRD, ranked directly after diabetes.
NSAIDs
exposure to non-steroidal anti-inflammatory drug ECTO:9001720 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to non-steroidal anti-inflammatory drug (ECTO:9001720). ECTO:9001720 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase-derived vasodilatory prostaglandins that maintain renal perfusion, producing hemodynamically mediated acute kidney injury; a second, dose-independent hypersensitivity mechanism produces acute interstitial nephritis. Chronic, high-dose use is associated with progression to CKD.
Show evidence (2 references)
PMID:30281062 SUPPORT Human Clinical
"The second form of NSAID-induced AKI is acute interstitial nephritis, which may manifest as nephrotic proteinuria."
Supports the interstitial-nephritis mechanism attributed to NSAID exposure.
PMID:30281062 SUPPORT Human Clinical
"Long-term NSAID use can lead to chronic kidney disease (CKD)."
Directly supports chronic NSAID exposure as a cause of CKD rather than only of reversible AKI.
Nephrotoxic Medications
exposure to nephrotoxic agent ECTO:9001878 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to nephrotoxic agent (ECTO:9001878). ECTO:9001878 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Recurrent or high-cumulative-dose exposure to nephrotoxic agents — aminoglycosides, iodinated contrast media, cisplatin, calcineurin inhibitors, and proton pump inhibitors — causes proximal tubular injury and acute kidney injury episodes that leave residual nephron loss; avoidance of these agents is a standard component of CKD care.
Show evidence (1 reference)
PMID:40790782 SUPPORT Human Clinical
"Vigilance in avoiding nephrotoxic agents, such as non-steroidal anti-inflammatory drugs, proton pump inhibitors, aminoglycosides, and contrast media, is essential for preventing renal injury."
Names the specific nephrotoxic drug classes whose avoidance protects the kidney in CKD, supporting them as modifiable exposures.
Tobacco Smoking
exposure to tobacco smoking ECTO:6000029 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to tobacco smoking (ECTO:6000029). ECTO:6000029 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Modifiable behavioural exposure named alongside hyperglycemia and blood pressure in this entry's mechanistic hypotheses and proposed experiments. The same meta-analysis reports a null smoking-proteinuria association in the general population, so the effect is not curated as acting through albuminuria.
Cigarette smoking is an independent, modifiable risk factor for incident CKD and for progression to end-stage renal disease in the general adult population, with risk graded by smoking status (current > former > never). Smoking cessation is accordingly a standard component of CKD risk-factor management, alongside glycemic and blood-pressure control.
Show evidence (2 references)
PMID:28339863 SUPPORT Human Clinical
"Compared with never-smokers, the SRRs of incident CKD were 1.27 (95% CI 1.19-1.35) for ever-smokers, 1.34 (95% CI 1.23-1.47) for current smokers and 1.15 (95% CI 1.08-1.23) for former smokers."
Quantifies the dose-graded increase in incident CKD risk with smoking status across 15 prospective cohorts, supporting tobacco smoking as a modifiable exposure contributing to CKD.
PMID:28339863 SUPPORT Human Clinical
"Our meta-analysis suggests evidence for cigarette smoking as an independent risk factor for incident CKD."
States the meta-analytic conclusion that smoking is an independent (not confounded) risk factor for incident CKD.
HIV Infection (HIV-Associated Nephropathy)
Infectious/environmental trigger interacting with the APOL1 renal-risk locus; risk is reduced by effective antiretroviral suppression.
Untreated HIV-1 infection can cause HIV-associated nephropathy (HIVAN), a collapsing form of focal segmental glomerulosclerosis presenting with nephrotic-range proteinuria that can progress to end-stage kidney disease. Susceptibility is strongly tied to the APOL1 G1/G2 renal-risk genotype (recorded as the APOL1 risk locus in the genetic section), consistent with a gene-environment "second-hit" model in which HIV supplies the environmental trigger.
Show evidence (2 references)
PMID:36816427 SUPPORT Human Clinical
"HIV-associated nephropathy (HIVAN) is a renal parenchymal disease that occurs exclusively in people living with HIV. It is a serious kidney condition that may possibly lead to end-stage kidney disease"
Establishes HIV infection as a direct cause of a CKD-progressing renal parenchymal disease (HIVAN).
PMID:36816427 SUPPORT Human Clinical
"The African-American population has increased susceptibility to this comorbidity due to a strong association found in the APOL1 gene"
Links HIVAN susceptibility to the APOL1 high-risk genotype already recorded in the genetic section, supporting the gene-environment (second-hit) model.
Tenofovir Disoproxil Fumarate (TDF) Antiretroviral Therapy
Iatrogenic (drug-induced) contributor; risk is mitigated by switching to tenofovir alafenamide (TAF) and by baseline and on-treatment renal monitoring.
Tenofovir disoproxil fumarate, a widely used nucleotide reverse transcriptase inhibitor, accumulates in proximal tubular epithelial cells and causes mitochondrial proximal tubular injury (Fanconi-type tubulopathy and glomerular filtration rate decline) - a recognized iatrogenic contributor to CKD in people on long-term antiretroviral therapy.
Show evidence (2 references)
PMID:24958564 SUPPORT Human Clinical
"Cellular accumulation through increased entry from the human organic anion transporters and decreased efflux into tubular lumen is main mechanism of nucleotide analogue antiviral induced nephrotoxicity."
Describes the proximal tubular accumulation mechanism of TDF nephrotoxicity that drives GFR decline and CKD.
PMID:24958564 SUPPORT Human Clinical
"Several predisposing factors including elevated baseline SCr, concomitant nephrotoxic medications, low body weight, advanced age, tenofovir disoproxil fumarate (TDF) dose and duration of treatment and lower CD4 cell count were identified as risk factors for development of TDF-induced nephrotoxicity."
Enumerates the clinical risk factors that modulate TDF-associated CKD risk.
🔬

Biochemical Markers

6
Creatinine (Elevated)
Context: Reflects decreased filtration
Pathograph Readouts
Readout Of Nephron Loss Positive Prognostic
Elevated serum creatinine (and the correspondingly reduced eGFR derived from it) is a quantitative readout of cumulative functional nephron loss; higher and rising creatinine reflects more advanced nephron loss and predicts progression to kidney failure, which is why eGFR/creatinine is an FDA-recognized validated surrogate endpoint in CKD drug development.
Estimated glomerular filtration rate or serum creatinine
Traditional Validated Surrogate Endpoint
Patients with chronic kidney disease secondary to multiple etiologies
Estimated glomerular filtration rate or serum creatinine
Traditional Validated Surrogate Endpoint
Patients with chronic kidney disease secondary to multiple etiologies
Show evidence (3 references)
PMID:31292197 SUPPORT Human Clinical
"To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects."
Trial-level meta-analysis linking treatment effects on GFR slope to treatment effects on the CKD clinical end point across 47 RCTs.
PMID:37330614 SUPPORT Human Clinical
"Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R2) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R2 = 0.55 (95% BCI 0.25-0.77))."
Updated CKD-EPI meta-analysis (66 studies, 186,312 participants) confirming the eGFR-slope readout is a near-perfect trial-level surrogate for kidney failure when total slope is used.
PMID:31473020 SUPPORT Human Clinical
"The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions."
NKF-FDA-EMA joint workshop: regulatory acceptance of 30-40% eGFR decline as a surrogate end point for kidney failure in CKD trials.
Blood Urea Nitrogen (Elevated)
Context: Uremic toxin accumulation
Phosphate (Elevated)
Context: Impaired excretion
PTH (Elevated)
Context: Secondary hyperparathyroidism
Plasma albumin (Mendelian randomization signal)
Context: The atlas reports a bidirectional causal relationship between albumin level and chronic kidney disease, consistent with earlier work. No presence value is recorded because the quantity estimated is a genetically instrumented effect rather than an observed patient-versus-control level, and because bidirectionality means the sign cannot be attributed to one direction of the relationship. The authors explicitly flag the therapeutic ambiguity that follows: an intervention lowering albumin might reduce chronic kidney disease events while raising risk of metabolic disease. Nothing here should be read as a treatment recommendation, and it does not change the role of albuminuria in CKD staging.
Show evidence (2 references)
PMID:40973818 SUPPORT Human Clinical
"the well-known bidirectional causal relationship between albumin level and CKD"
States that the atlas recovered a bidirectional causal relationship between albumin and chronic kidney disease, placing it among the metabolite-disease pairs with the strongest causal support.
PMID:40973818 SUPPORT Human Clinical
"while lowering albumin levels may decrease CKD events, it might also increase the risk of metabolic diseases"
Supports the caveat recorded in the context field. Marked PARTIAL because the sentence is the authors' interpretation of a possible therapeutic trade-off, not a tested intervention result.
NMR metabolomic risk score (MetRS)
Context: In the UK Biobank metabolome-phenome atlas, MetRS classified prevalent chronic kidney disease with an area under the curve of 0.933, one of the four highest diagnostic figures the source reports. No presence value is recorded because MetRS is a derived multi-analyte score rather than a measured analyte. Creatinine is itself among the panel's measures and is reported as one of the highest-ranking metabolites across all diseases, so the classification performance is not independent of the analyte that defines the diagnosis; the score should be read as recovering the known biochemical picture of reduced clearance rather than as adding a novel marker. The cohort is a single, predominantly European-ancestry volunteer population.
Pathograph Readouts
Correlates With Nephron Loss Positive Diagnostic
The score is dominated by measures that accumulate or shift as glomerular filtration falls, so it reads out the systemic consequence of nephron loss rather than any single upstream mechanism.
Show evidence (2 references)
PMID:40973818 SUPPORT Computational
"The MetRS witnessed excellent diagnosis for type 1 diabetes (T1D; AUC = 0.944), T2D (AUC = 0.941), diabetic maculopathy (AUC = 0.940) and chronic kidney disease (CKD; AUC = 0.933)."
Reports the prevalent-disease classification figure of 0.933 for chronic kidney disease alongside the three other conditions it is ranked with.
PMID:40973818 SUPPORT Computational
"the highest ranking of GlycA and creatinine across all diseases demonstrated their critical diagnostic and predictive values"
Supports the caveat in the context field that creatinine, the analyte defining the diagnosis, is among the panel's top-ranked measures and is credited with the diagnostic and predictive performance reported. Marked PARTIAL because the sentence establishes creatinine's ranking rather than quantifying its specific contribution to the chronic kidney disease score.
📊

Related Datasets

8
Transfer RNAs, not microRNAs, are linked to ischemic stroke and major bleeding in patients with end-stage kidney disease geo:GSE272125
Background: Patients with end-stage kidney disease (ESKD) are at very high risk for thromboembolism and bleeding. This study aimed to identify small non-coding RNAs (sncRNAs), specifically microRNAs and transfer-RNA (tRNA)-derived fragments (tRFs), as potential novel biomarkers for predicting thromboembolism and bleeding in this high-risk population. Methods: In this sncRNA discovery research, we leveraged the VIVALDI cohort, consisting of 625 ESKD patients on hemodialysis, to conduct two nested case-control studies, each comprising 18 participants. The primary outcomes were ischemic stroke in the first study and major bleeding in the second.
human BULK RNA SEQ n=34
PMID:39260398
Identified by GEO DataSets index search for Chronic Kidney Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Distinct immunometabolic signatures in peripheral blood mononuclear cells are linked to systemic inflammation in type 2 diabetes and diabetic kidney disease geo:GSE316126
Diabetic kidney disease (DKD) is a frequent complication of type 2 diabetes and is closely linked to systemic inflammation. Peripheral blood mononuclear cells (PBMCs) are markers of systemic inflammatory and metabolic stress. It is unknown if metabolism-related transcriptomic alterations in these cells is associated with DKD. Using the nCounter® Human Metabolic Pathways Panel we profiled PBMC metabolic transcripts in individuals with type 2 diabetes or DKD and in controls (n = 12/group), and integrated transcriptomic data with clinical, inflammatory, and mitochondrial parameters.
human MICROARRAY n=36
Identified by GEO DataSets index search for Chronic Kidney Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Tubulointerstitial fibrosis is the histological hallmark of chronic kidney disease (CKD). Hypoxia and inflammation (i.e., interleukin (IL)-1β signalling) are independent mediators of tubulointerstitial fibrosis. However, the physiological response of human kidney tubular cells to IL-1β/IL-1RI signalling under the hypoxic conditions of CKD is poorly understood and remains a clinical imperative for therapeutic targeting. This study reports that hypoxia and IL-1β act in synergy to trigger cell cycle arrest/cellular senescence of ex vivo patient-derived primary proximal tubular epithelial cells (PTECs). ega:EGAS00001007904
Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Chronic Kidney Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease ega:EGAS50000000101
Chronic kidney disease (CKD) is a public health problem driven by myofibroblast accumulation, leading to interstitial fibrosis. Heterogeneity is a recently recognised characteristics in kidney fibroblasts in CKD, but the role of different populations is still unclear. Here, we characterize a proinflammatory fibroblast population (named CXCL-iFibro), which corresponds to an early state of myofibroblast differentiation in CKD.
human BULK RNA SEQ
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Chronic Kidney Disease"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Host factors dictate gut microbiome alterations in chronic kidney disease more strongly than to kidney function ega:EGAS50000000646
Despite recent progress, microbial markers in Chronic Kidney Disease (CKD) remain inconclusive. We combined quantitative faecal metagenomics (N=130 CKD cohort) and cross-study biomarker comparisons (Ntotal=4420) to study microbiome associations with glomerular filtration rate (eGFR; kidney function) and 4-year CKD progression. Transit time (TT) and medications primarily explained microbiome variation, trumping eGFR-related effects.
human WGS
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Chronic Kidney Disease"); description-level mentions were not accepted. EGA study_type: Metagenomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Lipidomics of Chronic Kidney Disease progression metabolomics_workbench:ST000816
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Chronic Kidney Disease"). Retrieved 2026-08-02.
Untargeted metabolomics in skeletal muscle of mice with chronic kidney disease metabolomics_workbench:ST001353
mouse METABOLOMICS
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Chronic Kidney Disease"). Retrieved 2026-08-02.
Tissue-specific 1H-NMR metabolomic profiling in mice with adenine-induced chronic kidney disease - organic phase Kidney (part-II) metabolomics_workbench:ST001625
mouse METABOLOMICS
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Chronic Kidney Disease"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Chronic Kidney Disease
creation_date: '2025-12-18T17:01:35Z'
category: Complex
parents:
- Renal Disease
disease_term:
  preferred_term: chronic kidney disease
  term:
    id: MONDO:0005300
    label: chronic kidney disease
description: >-
  Chronic kidney disease (CKD) is the progressive, generally irreversible loss of kidney
  function persisting for at least three months, defined by a reduced glomerular filtration
  rate (GFR < 60 mL/min/1.73 m2) and/or markers of kidney damage such as albuminuria. It
  arises from diverse etiologies, most commonly diabetic nephropathy, hypertensive
  nephrosclerosis, glomerulonephritis, and polycystic kidney disease, that converge on a final
  common pathway of progressive nephron loss, compensatory hyperfiltration,
  glomerulosclerosis, and tubulointerstitial fibrosis. As functional renal mass declines,
  patients develop complications including decreased GFR, metabolic acidosis, mineral and bone
  disorder, anemia, and accelerated cardiovascular disease, with end-stage kidney disease
  ultimately requiring dialysis or transplantation.
has_subtypes:
- name: Diabetic Nephropathy
  description: CKD caused by long-standing diabetes mellitus.
- name: Hypertensive Nephrosclerosis
  description: CKD caused by chronic hypertension.
- name: Glomerulonephritis
  description: CKD from primary or secondary glomerular diseases.
- name: Polycystic Kidney Disease
  description: Inherited form of CKD with multiple kidney cysts.
pathophysiology:
- name: Nephron Loss
  description: >
    Progressive loss of functional nephrons from any cause leads to compensatory
    hyperfiltration in remaining nephrons, which paradoxically accelerates
    further damage and fibrosis.
  locations:
  - preferred_term: Nephron
    term:
      id: UBERON:0001285
      label: nephron
  cell_types:
  - preferred_term: Podocyte
    term:
      id: CL:0000653
      label: podocyte
  - preferred_term: Tubular Epithelial Cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  downstream:
  - target: Decreased GFR
    description: Cumulative loss of functional nephrons directly reduces the
      whole-kidney glomerular filtration rate.
  - target: Metabolic Acidosis
    description: Reduced functional renal mass impairs ammoniagenesis and net
      acid excretion, producing metabolic acidosis.
    evidence:
    - reference: PMID:38279993
      reference_title: "Metabolic acidosis in chronic kidney disease: mere consequence or also culprit?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        nephron loss with reduced ammoniagenesis is the main cause of acid
        retention in non-transplant CKD patients
      explanation: >-
        Nephron loss reduces ammoniagenesis and net acid excretion, the
        mechanism of the downstream metabolic-acidosis edge.
  - target: Glomerulosclerosis
    description: Compensatory hyperfiltration in surviving nephrons imposes
      hemodynamic stress that accelerates glomerular scarring (vicious cycle).
    evidence:
    - reference: PMID:35203616
      reference_title: "Glomerular Biomechanical Stress and Lipid Mediators during Cellular Changes Leading to Chronic Kidney Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hyperfiltration is an important underlying cause of glomerular
        dysfunction associated with several systemic and intrinsic glomerular
        conditions leading to chronic kidney disease (CKD). These include
        obesity, diabetes, hypertension, focal segmental glomerulosclerosis
        (FSGS), congenital abnormalities and reduced renal mass (low nephron
        number).
      explanation: >-
        Reduced renal mass (low nephron number) drives hyperfiltration that
        underlies glomerulosclerosis, the downstream glomerulosclerosis edge of
        nephron loss.
  evidence:
  - reference: PMID:38653563
    reference_title: "Recent Update on Acute Kidney Injury-to-Chronic Kidney Disease Transition."
    supports: SUPPORT
    snippet: "Patients diagnosed with AKI often undergo diverse clinical trajectories,
      such as early or late recovery, relapses, and even a potential transition from
      AKI to chronic kidney disease (CKD)."
    explanation: This describes how acute injury leads to progressive nephron
      loss and CKD transition, supporting the concept that initial damage
      triggers compensatory mechanisms that accelerate further injury.
  - reference: PMID:38339031
    reference_title: "From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease."
    supports: SUPPORT
    snippet: "This article provides a thorough overview of the biomarkers, pathophysiology,
      and molecular pathways involved in the transition from acute kidney injury (AKI)
      and acute kidney disease (AKD) to chronic kidney disease (CKD)."
    explanation: The transition from AKI to CKD involves progressive nephron
      loss with maladaptive repair mechanisms that drive ongoing damage and
      fibrosis.
- name: Glomerulosclerosis
  description: >
    Scarring and hardening of glomeruli impairs filtration function.
    Driven by hemodynamic stress, inflammation, and metabolic factors.
  locations:
  - preferred_term: Renal Glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  biological_processes:
  - preferred_term: Glomerular Fibrosis
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  downstream:
  - target: Proteinuria
    description: Scarring and disruption of the glomerular filtration barrier
      permits protein leakage into the urine.
  - target: Nephron Loss
    description: Progressive glomerular scarring renders affected nephrons
      nonfunctional, contributing to nephron loss.
  evidence:
  - reference: PMID:38610646
    reference_title: "Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets."
    supports: SUPPORT
    snippet: "Chronic kidney disease (CKD) is a slowly progressive condition characterized
      by decreased kidney function, tubular injury, oxidative stress, and inflammation."
    explanation: This describes the inflammatory and oxidative stress components
      that drive glomerulosclerosis alongside hemodynamic factors.
  - reference: PMID:37857763
    reference_title: "Oxidative stress and the role of redox signalling in chronic kidney disease."
    supports: SUPPORT
    snippet: "Reactive oxygen species (ROS) are derivatives of oxygen molecules that
      are generated during aerobic metabolism and are involved in a variety of cellular
      functions that are governed by redox conditions."
    explanation: ROS generation contributes to oxidative stress and metabolic
      factors that drive glomerular scarring and impaired filtration.
- name: Klotho Deficiency
  description: >
    Progressive decline in renal Klotho expression with CKD severity. Klotho is a
    renal-protective factor that suppresses TGF-β/Smad3 signaling and maintains
    phosphate homeostasis. Klotho deficiency amplifies tubulointerstitial fibrosis
    and accelerates CKD progression.
  locations:
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: TGF-beta Receptor Signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  downstream:
  - target: Tubulointerstitial Fibrosis
    description: Klotho deficiency permits unchecked TGF-β/Smad3 signaling and
      myofibroblast differentiation, driving tubulointerstitial fibrosis.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-9670512/v1
      reference_title: "AAV-mediated Klotho gene delivery attenuates renal fibrosis in chronic kidney disease by suppressing the TGF-β/Smad3 signaling pathway"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "High-dose AAV-KL restored Klotho to approximately 78% of sham"
      explanation: Restoration of Klotho by gene therapy reverses CKD fibrosis, demonstrating that Klotho deficiency drives fibrotic progression.
    - reference: DOI:10.21203/rs.3.rs-9670512/v1
      reference_title: "AAV-mediated Klotho gene delivery attenuates renal fibrosis in chronic kidney disease by suppressing the TGF-β/Smad3 signaling pathway"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The phospho-Smad3/Smad3 ratio declined markedly without change in transforming growth factor-beta 1 ligand, while Smad7 rose approximately 1.9-fold."
      explanation: Klotho restoration suppresses phospho-Smad3 and elevates Smad7, showing that Klotho deficiency drives fibrosis via unchecked TGF-β/Smad3 signaling.
  - target: IL-11 Signalling in Renal Fibroblasts
    description: >-
      Klotho deficiency de-represses TGF-β/Smad3 signalling, which induces
      autocrine IL-11 in renal fibroblasts, placing IL-11 receptor signalling
      downstream of the Klotho-TGF-β axis.
  evidence:
  - reference: DOI:10.21203/rs.3.rs-9670512/v1
    reference_title: "AAV-mediated Klotho gene delivery attenuates renal fibrosis in chronic kidney disease by suppressing the TGF-β/Smad3 signaling pathway"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Chronic kidney disease (CKD) is characterised by progressive renal fibrosis, Klotho deficiency, and dysregulated transforming growth factor-beta 1/Smad3 signalling."
    explanation: This preprint establishes Klotho deficiency as a key pathophysiologic feature of CKD that dysregulates TGF-β/Smad3 signaling.
- name: IL-11 Signalling in Renal Fibroblasts
  conforms_to: "il11_erk_ampk_mtor_aging#IL-11 Receptor Signalling Activation"
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    Profibrotic stimulation of kidney interstitial fibroblasts engages
    IL11RA1-mediated, ERK-dependent autocrine IL-11 signalling that drives their
    myofibroblast conversion and fibrogenic protein synthesis. This IL-11
    receptor-signalling arm is an organ-specific instance of the conserved IL-11
    signalling module and feeds tubulointerstitial fibrosis; IL-11 pathway
    antagonism reduces renal fibrosis in vivo.
  locations:
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  cell_types:
  - preferred_term: Kidney interstitial fibroblast
    term:
      id: CL:1000692
      label: kidney interstitial fibroblast
  biological_processes:
  - preferred_term: Interleukin-11-mediated signaling pathway
    term:
      id: GO:0038154
      label: interleukin-11-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: ERK1 and ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:29160304
    reference_title: "IL-11 is a crucial determinant of cardiovascular fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, fibroblast-specific Il11 transgene expression or Il-11 injection
      causes heart and kidney fibrosis and organ failure, whereas genetic
      deletion of Il11ra1 protects against disease.
    explanation: >-
      Directly evidences that fibroblast IL-11 signalling causes kidney fibrosis
      and organ failure and that receptor deletion is protective, grounding this
      node in renal disease. Evidence source is MODEL_ORGANISM (transgenic and
      Il11ra1-knockout mice).
  - reference: PMID:29160304
    reference_title: "IL-11 is a crucial determinant of cardiovascular fibrosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts,
      in which they drive non-canonical, ERK-dependent autocrine signalling that
      is required for fibrogenic protein synthesis.
    explanation: >-
      Establishes the ERK-dependent autocrine IL-11 receptor-signalling arm in
      fibroblasts modeled by this node. Evidence source is IN_VITRO (primary
      human fibroblasts).
  - reference: PMID:29160304
    reference_title: "IL-11 is a crucial determinant of cardiovascular fibrosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      rhIL-11 strongly activated human renal fibroblasts.
    explanation: >-
      Shows recombinant IL-11 directly activates human renal fibroblasts,
      specializing the conserved mechanism to the kidney compartment. Evidence
      source is IN_VITRO (primary human renal fibroblasts).
  - reference: PMID:40198895
    reference_title: "Development of a Long-Acting Interleukin-11 Antagonist for the Treatment of Renal Fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      analogue 13 exhibited a prolonged half-life and showed significant
      therapeutic effects in the UUO-induced renal fibrosis model
    explanation: >-
      Confirms that pharmacological IL-11 pathway antagonism reduces renal
      fibrosis in a CKD model, validating the drug-target relevance of this node.
      Evidence source is MODEL_ORGANISM (mouse unilateral ureteral obstruction
      model).
  downstream:
  - target: Tubulointerstitial Fibrosis

- name: Tubulointerstitial Fibrosis
  description: >
    Fibrotic replacement of tubular structures by collagen-producing
    myofibroblasts. The final common pathway of CKD progression.
  locations:
  - preferred_term: Renal Tubule
    term:
      id: UBERON:0009773
      label: renal tubule
  cell_types:
  - preferred_term: Myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  downstream:
  - target: Anemia
    description: Fibrotic destruction of EPO-producing peritubular interstitial
      fibroblasts reduces erythropoietin synthesis, causing anemia.
    evidence:
    - reference: PMID:38927397
      reference_title: "Anemia of Chronic Kidney Disease-A Narrative Review of Its Pathophysiology, Diagnosis, and Management."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The pathophysiology of anemia in CKD involves the interplay of various
        factors such as erythropoietin (EPO) deficiency, iron dysregulation,
        chronic inflammation, bone marrow dysfunction, and nutritional
        deficiencies.
      explanation: >-
        Erythropoietin deficiency (from loss of EPO-producing renal interstitial
        cells) is the principal driver of CKD anemia, the downstream anemia edge
        of tubulointerstitial fibrosis.
  - target: Nephron Loss
    description: Fibrotic replacement of tubular structures is the final common
      pathway by which nephrons are destroyed.
  evidence:
  - reference: PMID:38610646
    reference_title: "Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets."
    supports: SUPPORT
    snippet: "Transforming growth factor (TGF)-β is a central mediator in promoting
      transdifferentiation of polarized renal tubular epithelial cells into mesenchymal
      cells, resulting in irreversible kidney injury."
    explanation: This supports the mechanism of fibrotic replacement where TGF-β
      drives transdifferentiation of tubular epithelial cells, leading to
      fibrosis and irreversible injury.
  - reference: PMID:38339031
    reference_title: "From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease."
    supports: SUPPORT
    snippet: "Key signaling pathways, such as Wnt/β-catenin, TGF-β/SMAD, and Hippo/YAP/TAZ,
      promote fibrosis and impact renal function."
    explanation: This confirms that TGF-β/SMAD and other pathways drive fibrotic
      processes that characterize the final common pathway of CKD progression.
- name: RAAS Activation
  description: >
    Inappropriately activated renin-angiotensin-aldosterone system promotes
    glomerular hypertension, fibrosis, and sodium retention.
  locations:
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: RAAS Signaling
    term:
      id: GO:0002018
      label: renin-angiotensin regulation of aldosterone production
  downstream:
  - target: Hypertension
    description: Angiotensin II-mediated vasoconstriction and aldosterone-driven
      sodium retention raise systemic blood pressure.
    evidence:
    - reference: PMID:32635265
      reference_title: "Sodium Intake and Chronic Kidney Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        RAAS is inappropriately activated in CKD, leading to vasoconstriction
        and sodium retention, which contribute significantly to the raising of
        BP levels
      explanation: >-
        Inappropriate RAAS activation drives vasoconstriction and sodium
        retention that raise blood pressure, the downstream hypertension edge.
  - target: Peripheral Edema
    description: Aldosterone-driven sodium and water retention expands extracellular
      volume, producing peripheral edema.
  - target: Tubulointerstitial Fibrosis
    description: Aldosterone- and angiotensin II-mediated oxidative stress and
      pro-fibrotic signaling drive tubulointerstitial fibrosis.
    evidence:
    - reference: PMID:38339031
      reference_title: "From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The renin-angiotensin-aldosterone system (RAAS) triggers a cascade
        leading to renal fibrosis, with aldosterone exacerbating the oxidative
        stress and cellular changes that promote fibrosis.
      explanation: >-
        RAAS activation triggers a pro-fibrotic cascade with aldosterone-driven
        oxidative stress, the downstream tubulointerstitial-fibrosis edge.
  evidence:
  - reference: PMID:38339031
    reference_title: "From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease."
    supports: SUPPORT
    snippet: "The renin-angiotensin-aldosterone system (RAAS) triggers a cascade leading
      to renal fibrosis, with aldosterone exacerbating the oxidative stress and cellular
      changes that promote fibrosis."
    explanation: This directly supports the mechanism by which RAAS activation
      promotes fibrosis through aldosterone-mediated oxidative stress and
      cellular injury in CKD.
  - reference: PMID:38610646
    reference_title: "Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets."
    supports: SUPPORT
    snippet: "Current therapies such as renin-angiotensin blockers, mineralocorticoid
      receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay
      progression."
    explanation: The therapeutic efficacy of RAAS blockers confirms that RAAS
      activation is a key driver of CKD progression, supporting its role in
      promoting hypertension and fibrosis.
mechanistic_hypotheses:
- hypothesis_group_id: pgs_context_amplification
  hypothesis_label: Amplification of polygenic CKD risk in adverse contexts via
    shared glomerular-injury convergence
  status: EMERGING
  description: >-
    Polygenic-score-by-context (PGS×C) interactions reported for chronic kidney
    disease in the UK Biobank appear to reflect amplification rather than
    context-specific causal variants: the same susceptibility loci (e.g. APOL1,
    PKD1, PKD2) exert systematically larger effects in disease-promoting
    contexts. This entry proposes that the amplification arises because polygenic
    liability and adverse exposures — notably hyperglycemia/diabetes and tobacco
    smoking — converge on the shared Glomerulosclerosis injury node, so their
    joint effect on the liability-threshold scale (here modelled against the PGS
    for eGFR) is super-additive rather than additive. Nagpal & Gibson (Nat Genet
    2026, PMID:42443528) report glucose and past smoking as
    major amplifying contexts for CKD, with the benefit of reducing them
    increasing at higher genetic risk.
  evidence:
  - reference: PMID:42443528
    reference_title: "Pervasive interactions between exposures and polygenic risk can inform more effective clinical and behavioral interventions."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: The predominant mechanism for PGS×C is the amplification of genetic
      effects in adverse contexts, such as low polyunsaturated fatty acids or social
      determinants of ill health
    explanation: >-
      Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and
      75 contexts, amplification of genetic effects in adverse contexts is
      identified as the predominant mechanism of PGS×context interaction — the
      mechanism applied in this hypothesis.
  - reference: PMID:37228747
    reference_title: "Amplification is the primary mode of gene-by-sex interaction in complex human traits."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: GxSex is pervasive but acts primarily through systematic sex differences
      in the magnitude of many genetic effects
    explanation: >-
      Establishes amplification — systematic differences in the magnitude of
      polygenic effects rather than in the identity of causal variants — as the
      primary mode of gene-by-context interaction, the mechanism proposed here
      for the CKD PGS×context interactions (sex-adjusted hemoglobin and other
      contexts show amplification for CKD in Nagpal & Gibson 2026).
  notes: >-
    EMERGING hypothesis motivated by population-scale PGS×context analyses
    (primary source PMID:42443528; general amplification mechanism corroborated
    by PMID:37228747). The convergence claim (polygenic liability +
    hyperglycemia/smoking → Glomerulosclerosis) is a mechanistic interpretation
    and is not itself established as causal — see the reverse-causation knowledge
    gap under discussions.
phenotypes:
- name: Decreased GFR
  category: Renal
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    A sustained reduction in the glomerular filtration rate (GFR < 60
    mL/min/1.73 m2 persisting for at least three months) is the defining
    functional abnormality of CKD. It reflects cumulative loss of functional
    nephron mass and is staged G1-G5 to grade severity and predict progression
    to kidney failure.
  phenotype_term:
    preferred_term: Decreased GFR
    term:
      id: HP:0012622
      label: Chronic kidney disease
- name: Proteinuria
  category: Renal
  frequency: VERY_FREQUENT
  description: >-
    Abnormal urinary protein loss, typically quantified as albuminuria, results
    from disruption of the glomerular filtration barrier and impaired tubular
    reabsorption. It is both an early marker of kidney damage and an
    independent driver of progression, as filtered protein is directly toxic to
    tubular epithelium.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:37857763
    reference_title: "Oxidative stress and the role of redox signalling in chronic kidney disease."
    supports: NO_EVIDENCE
    snippet: "However, excess ROS can be pathological, and contribute to the development
      and progression of chronic diseases."
    explanation: Excess ROS contributes to tubular and glomerular injury that
      manifests as proteinuria, a hallmark of CKD progression.
- name: Hypertension
  category: Cardiovascular
  frequency: VERY_FREQUENT
  description: >-
    Elevated systemic blood pressure is both a common cause and a near-universal
    consequence of CKD. Sodium and volume retention together with
    inappropriate renin-angiotensin-aldosterone system activation raise blood
    pressure, which in turn accelerates glomerular injury, creating a
    self-reinforcing cycle of renal damage.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:32635265
    reference_title: "Sodium Intake and Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RAAS is inappropriately activated in CKD, leading to vasoconstriction and
      sodium retention, which contribute significantly to the raising of BP
      levels
    explanation: >-
      Inappropriate RAAS activation with vasoconstriction and sodium retention
      raises blood pressure in CKD, supporting hypertension as a near-universal
      consequence.
- name: Anemia
  category: Hematologic
  frequency: FREQUENT
  notes: Due to reduced erythropoietin production
  description: >-
    Normocytic, normochromic anemia of CKD arises principally from deficient
    erythropoietin production by injured peritubular interstitial fibroblasts,
    compounded by functional iron deficiency from hepcidin-mediated iron
    sequestration and shortened red-cell survival. It contributes substantially
    to the fatigue and reduced quality of life of CKD.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  sequelae:
  - target: Fatigue
    description: Reduced oxygen-carrying capacity from anemia is a major
      contributor to the fatigue of chronic kidney disease.
  evidence:
  - reference: PMID:38927397
    reference_title: 'Anemia of Chronic Kidney Disease-A Narrative Review of Its Pathophysiology, Diagnosis, and Management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anemia is one of the most common chronic kidney disease (CKD) complications.
      It negatively affects patients' quality of life and clinical outcomes."
    explanation: This review establishes anemia as one of the most common complications
      of CKD with significant impact on patient outcomes.
- name: Metabolic Acidosis
  category: Metabolic
  frequency: FREQUENT
  description: >-
    As functional renal mass declines, the kidney's capacity for ammoniagenesis
    and net acid excretion falls, leading to retention of hydrogen ions and a
    high-anion-gap or normal-anion-gap metabolic acidosis. Chronic acidosis
    promotes muscle wasting, bone demineralization, and accelerated CKD
    progression.
  phenotype_term:
    preferred_term: Metabolic Acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:38279993
    reference_title: "Metabolic acidosis in chronic kidney disease: mere consequence or also culprit?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nephron loss with reduced ammoniagenesis is the main cause of acid
      retention in non-transplant CKD patients
    explanation: >-
      Declining nephron mass with reduced ammoniagenesis impairs net acid
      excretion, producing the metabolic acidosis of CKD.
- name: Fatigue
  category: Systemic
  frequency: FREQUENT
  description: >-
    Persistent tiredness and reduced exercise tolerance are among the most
    frequently reported symptoms in CKD. Fatigue is multifactorial, driven by
    anemia-related reduced oxygen delivery, uremic toxin accumulation, metabolic
    acidosis, chronic inflammation, and disordered sleep.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- name: Peripheral Edema
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Soft-tissue swelling, most prominent in the dependent lower extremities,
    results from renal sodium and water retention that expands the extracellular
    fluid volume. Edema is aggravated by hypoalbuminemia from heavy proteinuria
    and by the volume overload of advanced CKD.
  phenotype_term:
    preferred_term: Peripheral Edema
    term:
      id: HP:0012398
      label: Peripheral edema
biochemical:
- name: Creatinine
  presence: Elevated
  context: Reflects decreased filtration
  readouts:
  - target: Nephron Loss
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    regulatory_endpoint_refs:
    - FDA-SE-adult-noncancer-012
    - FDA-SE-pediatric-noncancer-008
    interpretation: >-
      Elevated serum creatinine (and the correspondingly reduced eGFR derived
      from it) is a quantitative readout of cumulative functional nephron
      loss; higher and rising creatinine reflects more advanced nephron loss
      and predicts progression to kidney failure, which is why eGFR/creatinine
      is an FDA-recognized validated surrogate endpoint in CKD drug
      development.
    evidence:
    - reference: PMID:31292197
      reference_title: 'GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects."
      explanation: >-
        Trial-level meta-analysis linking treatment effects on GFR slope to
        treatment effects on the CKD clinical end point across 47 RCTs.
    - reference: PMID:37330614
      reference_title: 'A meta-analysis of GFR slope as a surrogate endpoint for kidney failure.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R2) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R2 = 0.55 (95% BCI 0.25-0.77))."
      explanation: >-
        Updated CKD-EPI meta-analysis (66 studies, 186,312 participants)
        confirming the eGFR-slope readout is a near-perfect trial-level
        surrogate for kidney failure when total slope is used.
    - reference: PMID:31473020
      reference_title: 'Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions."
      explanation: >-
        NKF-FDA-EMA joint workshop: regulatory acceptance of 30-40% eGFR
        decline as a surrogate end point for kidney failure in CKD trials.
- name: Blood Urea Nitrogen
  presence: Elevated
  context: Uremic toxin accumulation
- name: Phosphate
  presence: Elevated
  context: Impaired excretion
- name: PTH
  presence: Elevated
  context: Secondary hyperparathyroidism
- name: Plasma albumin (Mendelian randomization signal)
  specificity: >
    Distinct from urinary albumin, which is the established CKD marker. This
    entry concerns circulating plasma albumin as a candidate causal metabolite,
    recorded because it had the largest number of potentially causal disease
    links of any metabolite in a 274,241-participant UK Biobank atlas.
  context: >
    The atlas reports a bidirectional causal relationship between albumin level
    and chronic kidney disease, consistent with earlier work. No presence value
    is recorded because the quantity estimated is a genetically instrumented
    effect rather than an observed patient-versus-control level, and because
    bidirectionality means the sign cannot be attributed to one direction of
    the relationship. The authors explicitly flag the therapeutic ambiguity
    that follows: an intervention lowering albumin might reduce chronic kidney
    disease events while raising risk of metabolic disease. Nothing here should
    be read as a treatment recommendation, and it does not change the role of
    albuminuria in CKD staging.
  evidence:
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the well-known bidirectional causal relationship between albumin level and CKD"
    explanation: >
      States that the atlas recovered a bidirectional causal relationship
      between albumin and chronic kidney disease, placing it among the
      metabolite-disease pairs with the strongest causal support.
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "while lowering albumin levels may decrease CKD events, it might also increase the risk of metabolic diseases"
    explanation: >
      Supports the caveat recorded in the context field. Marked PARTIAL because
      the sentence is the authors' interpretation of a possible therapeutic
      trade-off, not a tested intervention result.
- name: NMR metabolomic risk score (MetRS)
  specificity: >
    A research composite, not a clinical assay. MetRS is a machine-learning
    score built from the top 30 of 313 Nightingale Health NMR plasma measures,
    derived and replicated in UK Biobank. It does not replace eGFR and
    albuminuria, which define and stage chronic kidney disease.
  context: >
    In the UK Biobank metabolome-phenome atlas, MetRS classified prevalent
    chronic kidney disease with an area under the curve of 0.933, one of the
    four highest diagnostic figures the source reports. No presence value is
    recorded because MetRS is a derived multi-analyte score rather than a
    measured analyte. Creatinine is itself among the panel's measures and is
    reported as one of the highest-ranking metabolites across all diseases, so
    the classification performance is not independent of the analyte that
    defines the diagnosis; the score should be read as recovering the known
    biochemical picture of reduced clearance rather than as adding a novel
    marker. The cohort is a single, predominantly European-ancestry volunteer
    population.
  readouts:
  - target: Nephron Loss
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      The score is dominated by measures that accumulate or shift as glomerular
      filtration falls, so it reads out the systemic consequence of nephron loss
      rather than any single upstream mechanism.
  evidence:
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The MetRS witnessed excellent diagnosis for type 1 diabetes (T1D; AUC = 0.944), T2D (AUC = 0.941), diabetic maculopathy (AUC = 0.940) and chronic kidney disease (CKD; AUC = 0.933)."
    explanation: >
      Reports the prevalent-disease classification figure of 0.933 for chronic
      kidney disease alongside the three other conditions it is ranked with.
  - reference: PMID:40973818
    reference_title: "Mapping the plasma metabolome to human health and disease in 274,241 adults."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "the highest ranking of GlycA and creatinine across all diseases demonstrated their critical diagnostic and predictive values"
    explanation: >
      Supports the caveat in the context field that creatinine, the analyte
      defining the diagnosis, is among the panel's top-ranked measures and is
      credited with the diagnostic and predictive performance reported. Marked
      PARTIAL because the sentence establishes creatinine's ranking rather than
      quantifying its specific contribution to the chronic kidney disease score.
genetic:
- name: PKD1
  gene_term:
    preferred_term: PKD1
    term:
      id: hgnc:9008
      label: PKD1
  association: Causative
  notes: Autosomal dominant polycystic kidney disease
- name: PKD2
  gene_term:
    preferred_term: PKD2
    term:
      id: hgnc:9009
      label: PKD2
  association: Causative
  notes: Autosomal dominant polycystic kidney disease
- name: APOL1
  gene_term:
    preferred_term: APOL1
    term:
      id: hgnc:618
      label: APOL1
  association: Risk Factor
  notes: Major risk locus in African ancestry
environmental:
- name: Diabetes
  description: >
    Chronic hyperglycemia in type 1 and type 2 diabetes mellitus is the single
    largest contributor to incident CKD and end-stage kidney disease worldwide,
    acting through the diabetic microvascular injury cascade (glomerular
    hyperfiltration, mesangial expansion, podocyte loss, and albuminuria).
  effect: CAUSATIVE
  evidence:
  - reference: PMID:41263046
    reference_title: Population health management of diabetic kidney disease in Los
      Angeles county municipal health system.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diabetic kidney disease (DKD) is the leading cause of chronic kidney
      disease (CKD) and end-stage renal disease (ESRD) worldwide
    explanation: Establishes diabetes as the leading antecedent condition for CKD
      and ESRD globally.
- name: Hypertension
  description: >
    Sustained elevated systemic blood pressure drives hypertensive
    nephrosclerosis — afferent arteriolar hyalinosis, glomerulosclerosis, and
    tubulointerstitial fibrosis — and is the second most common antecedent of
    end-stage kidney disease after diabetes. Hypertension is also a consequence
    of CKD, forming a self-reinforcing loop with RAAS activation.
  effect: CAUSATIVE
  evidence:
  - reference: PMID:34831368
    reference_title: 'Molecular Mechanisms of Hypertensive Nephropathy: Renoprotective
      Effect of Losartan through Hsp70.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypertensive nephrosclerosis is the second most common cause of end-stage
      renal disease after diabetes.
    explanation: Supports hypertension as the second leading antecedent of ESRD, ranked
      directly after diabetes.
- name: NSAIDs
  description: >
    Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase-derived
    vasodilatory prostaglandins that maintain renal perfusion, producing
    hemodynamically mediated acute kidney injury; a second, dose-independent
    hypersensitivity mechanism produces acute interstitial nephritis. Chronic,
    high-dose use is associated with progression to CKD.
  effect: HARMFUL
  chemicals:
  - Ibuprofen
  - Diclofenac
  - Naproxen
  exposure_term:
    preferred_term: exposure to non-steroidal anti-inflammatory drug
    term:
      id: ECTO:9001720
      label: exposure to non-steroidal anti-inflammatory drug
  evidence:
  - reference: PMID:30281062
    reference_title: Pathophysiological aspects of nephropathy caused by non-steroidal
      anti-inflammatory drugs.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The second form of NSAID-induced AKI is acute interstitial nephritis,
      which may manifest as nephrotic proteinuria.
    explanation: Supports the interstitial-nephritis mechanism attributed to NSAID
      exposure.
  - reference: PMID:30281062
    reference_title: Pathophysiological aspects of nephropathy caused by non-steroidal
      anti-inflammatory drugs.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Long-term NSAID use can lead to chronic kidney disease (CKD).
    explanation: Directly supports chronic NSAID exposure as a cause of CKD rather
      than only of reversible AKI.
- name: Nephrotoxic Medications
  description: >
    Recurrent or high-cumulative-dose exposure to nephrotoxic agents —
    aminoglycosides, iodinated contrast media, cisplatin, calcineurin
    inhibitors, and proton pump inhibitors — causes proximal tubular injury and
    acute kidney injury episodes that leave residual nephron loss; avoidance of
    these agents is a standard component of CKD care.
  effect: HARMFUL
  chemicals:
  - Gentamicin
  - Iodinated contrast media
  - Cisplatin
  - Calcineurin inhibitors
  - Proton pump inhibitors
  exposure_term:
    preferred_term: exposure to nephrotoxic agent
    term:
      id: ECTO:9001878
      label: exposure to nephrotoxic agent
  evidence:
  - reference: PMID:40790782
    reference_title: 'Optimizing care for chronic kidney disease: Considerations from
      A to Z.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vigilance in avoiding nephrotoxic agents, such as non-steroidal anti-inflammatory
      drugs, proton pump inhibitors, aminoglycosides, and contrast media, is essential
      for preventing renal injury.
    explanation: Names the specific nephrotoxic drug classes whose avoidance protects
      the kidney in CKD, supporting them as modifiable exposures.
- name: Tobacco Smoking
  description: >
    Cigarette smoking is an independent, modifiable risk factor for incident CKD
    and for progression to end-stage renal disease in the general adult
    population, with risk graded by smoking status (current > former > never).
    Smoking cessation is accordingly a standard component of CKD risk-factor
    management, alongside glycemic and blood-pressure control.
  effect: HARMFUL
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  evidence:
  - reference: PMID:28339863
    reference_title: 'Cigarette smoking and chronic kidney disease in the general population:
      a systematic review and meta-analysis of prospective cohort studies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Compared with never-smokers, the SRRs of incident CKD were 1.27 (95% CI
      1.19-1.35) for ever-smokers, 1.34 (95% CI 1.23-1.47) for current smokers and
      1.15 (95% CI 1.08-1.23) for former smokers.
    explanation: Quantifies the dose-graded increase in incident CKD risk with smoking
      status across 15 prospective cohorts, supporting tobacco smoking as a modifiable
      exposure contributing to CKD.
  - reference: PMID:28339863
    reference_title: 'Cigarette smoking and chronic kidney disease in the general population:
      a systematic review and meta-analysis of prospective cohort studies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our meta-analysis suggests evidence for cigarette smoking as an independent
      risk factor for incident CKD.
    explanation: States the meta-analytic conclusion that smoking is an independent
      (not confounded) risk factor for incident CKD.
  notes: >-
    Modifiable behavioural exposure named alongside hyperglycemia and blood
    pressure in this entry's mechanistic hypotheses and proposed experiments.
    The same meta-analysis reports a null smoking-proteinuria association in the
    general population, so the effect is not curated as acting through
    albuminuria.
- name: HIV Infection (HIV-Associated Nephropathy)
  description: >-
    Untreated HIV-1 infection can cause HIV-associated nephropathy (HIVAN), a
    collapsing form of focal segmental glomerulosclerosis presenting with
    nephrotic-range proteinuria that can progress to end-stage kidney disease.
    Susceptibility is strongly tied to the APOL1 G1/G2 renal-risk genotype
    (recorded as the APOL1 risk locus in the genetic section), consistent with a
    gene-environment "second-hit" model in which HIV supplies the environmental
    trigger.
  evidence:
  - reference: PMID:36816427
    reference_title: "HIV-Associated Nephropathy in 2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HIV-associated nephropathy (HIVAN) is a renal parenchymal disease
      that occurs exclusively in people living with HIV. It is a serious kidney
      condition that may possibly lead to end-stage kidney disease"
    explanation: >-
      Establishes HIV infection as a direct cause of a CKD-progressing renal
      parenchymal disease (HIVAN).
  - reference: PMID:36816427
    reference_title: "HIV-Associated Nephropathy in 2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The African-American population has increased susceptibility to
      this comorbidity due to a strong association found in the APOL1 gene"
    explanation: >-
      Links HIVAN susceptibility to the APOL1 high-risk genotype already recorded
      in the genetic section, supporting the gene-environment (second-hit) model.
  notes: >-
    Infectious/environmental trigger interacting with the APOL1 renal-risk
    locus; risk is reduced by effective antiretroviral suppression.
- name: Tenofovir Disoproxil Fumarate (TDF) Antiretroviral Therapy
  description: >-
    Tenofovir disoproxil fumarate, a widely used nucleotide reverse
    transcriptase inhibitor, accumulates in proximal tubular epithelial cells
    and causes mitochondrial proximal tubular injury (Fanconi-type tubulopathy
    and glomerular filtration rate decline) - a recognized iatrogenic
    contributor to CKD in people on long-term antiretroviral therapy.
  evidence:
  - reference: PMID:24958564
    reference_title: "Tenofovir-induced nephrotoxicity: incidence, mechanism,
      risk factors, prognosis and proposed agents for prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cellular accumulation through increased entry from the human
      organic anion transporters and decreased efflux into tubular lumen is main
      mechanism of nucleotide analogue antiviral induced nephrotoxicity."
    explanation: >-
      Describes the proximal tubular accumulation mechanism of TDF
      nephrotoxicity that drives GFR decline and CKD.
  - reference: PMID:24958564
    reference_title: "Tenofovir-induced nephrotoxicity: incidence, mechanism,
      risk factors, prognosis and proposed agents for prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several predisposing factors including elevated baseline SCr,
      concomitant nephrotoxic medications, low body weight, advanced age,
      tenofovir disoproxil fumarate (TDF) dose and duration of treatment and
      lower CD4 cell count were identified as risk factors for development of
      TDF-induced nephrotoxicity."
    explanation: >-
      Enumerates the clinical risk factors that modulate TDF-associated CKD
      risk.
  notes: >-
    Iatrogenic (drug-induced) contributor; risk is mitigated by switching to
    tenofovir alafenamide (TAF) and by baseline and on-treatment renal
    monitoring.
treatments:
- name: ACE Inhibitors/ARBs
  description: Reduce proteinuria and slow progression by lowering
    intraglomerular pressure.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: RAAS Activation
    treatment_effect: INHIBITS
    description: >-
      ACE inhibitors and ARBs directly block the renin-angiotensin-aldosterone
      system, lowering intraglomerular pressure and attenuating RAAS-mediated
      fibrosis that drives CKD progression.
    evidence:
    - reference: PMID:38339031
      reference_title: "From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease."
      supports: SUPPORT
      snippet: "The clinical evidence suggests that RAS inhibitors may protect against
        CKD progression, especially post-AKI, though more extensive trials are needed
        to confirm their full impact."
      explanation: RAS inhibitors act on RAAS activation to slow CKD progression.
  evidence:
  - reference: PMID:38339031
    reference_title: "From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease."
    supports: SUPPORT
    snippet: "The clinical evidence suggests that RAS inhibitors may protect against
      CKD progression, especially post-AKI, though more extensive trials are needed
      to confirm their full impact."
    explanation: RAS inhibitors (ACE inhibitors/ARBs) protect against CKD
      progression by blocking RAAS-mediated fibrosis and reducing
      intraglomerular pressure.
- name: SGLT2 Inhibitors
  description: Provide nephroprotection independent of diabetes status.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Tubulointerstitial Fibrosis
    treatment_effect: INHIBITS
    description: >-
      SGLT2 inhibitors are an established disease-modifying therapy that delays
      CKD progression, including the tubulointerstitial fibrotic process, beyond
      their glucose-lowering effect.
    evidence:
    - reference: PMID:38610646
      reference_title: "Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets."
      supports: SUPPORT
      snippet: "Current therapies such as renin-angiotensin blockers, mineralocorticoid
        receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay
        progression."
      explanation: SGLT2 inhibitors are listed among current anti-fibrotic progression-delaying therapies.
  evidence:
  - reference: PMID:38610646
    reference_title: "Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets."
    supports: SUPPORT
    snippet: "Current therapies such as renin-angiotensin blockers, mineralocorticoid
      receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay
      progression."
    explanation: SGLT2 inhibitors are recognized as current standard therapy
      that delays CKD progression through multiple mechanisms beyond glucose
      control.
  - reference: PMID:36623286
    reference_title: "Diabetes Management in Chronic Kidney Disease: Synopsis of the KDIGO 2022 Clinical Practice Guideline Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "New evidence led to updating of recommendations in the chapters Comprehensive Care in Patients With Diabetes and CKD (Chapter 1) and Glucose-Lowering Therapies in Patients With T2D and CKD (Chapter 4)."
    explanation: The KDIGO 2022 diabetes-CKD guideline update revised its glucose-lowering-therapy recommendations, in which SGLT2 inhibitors are central nephroprotective therapy for patients with diabetes and CKD.
- name: Blood Pressure Control
  description: Target less than 130/80 to slow progression.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Glomerulosclerosis
    treatment_effect: INHIBITS
    description: >-
      Lowering systemic blood pressure reduces glomerular capillary
      hypertension and the hemodynamic injury that drives glomerulosclerosis.
- name: Dietary Protein Restriction
  description: May slow progression in advanced CKD.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Glomerulosclerosis
    treatment_effect: MODULATES
    description: >-
      Restricting dietary protein lowers glomerular hyperfiltration, easing the
      hemodynamic stress that promotes glomerulosclerosis in advanced CKD.
- name: Erythropoiesis-Stimulating Agents
  description: Treat anemia of CKD.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Phosphate Binders
  description: Control hyperphosphatemia.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Dialysis
  description: Renal replacement therapy for end-stage disease.
  treatment_term:
    preferred_term: renal dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  target_mechanisms:
  - target: Nephron Loss
    treatment_effect: BYPASSES
    description: >-
      Dialysis provides extracorporeal solute and fluid clearance that
      substitutes for the excretory function lost through progressive nephron
      loss, without restoring native kidney function.
- name: Kidney Transplantation
  description: Definitive treatment for end-stage renal disease.
  treatment_term:
    preferred_term: Kidney Transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  target_mechanisms:
  - target: Nephron Loss
    treatment_effect: RESTORES
    description: >-
      A functioning renal allograft restores nephron mass and physiologic
      kidney function lost in end-stage CKD.
  evidence:
  - reference: PMID:21883901
    reference_title: 'Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quality of life was significantly and substantially better among transplant
      recipients. Despite increases in the age and comorbidity of contemporary transplant
      recipients, the relative benefits of transplantation seem to be increasing over time."
    explanation: This systematic review of 1.9 million participants confirms kidney
      transplantation provides survival benefit and improved quality of life compared
      to dialysis.
- name: AAV-Mediated Klotho Gene Therapy
  description: >-
    Emerging gene therapy approach using adeno-associated virus (AAV9) vectors to
    deliver functional Klotho gene to restore renal Klotho expression. Preclinical
    studies show restoration of Klotho suppresses TGF-β/Smad3 fibrotic signaling
    and attenuates CKD progression in mouse models.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Klotho Deficiency
    treatment_effect: RESTORES
    description: >-
      AAV9-mediated Klotho delivery restores renal Klotho expression, which
      suppresses TGF-β/Smad3 signaling and mitigates fibrotic progression of CKD.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-9670512/v1
      reference_title: "AAV-mediated Klotho gene delivery attenuates renal fibrosis in chronic kidney disease by suppressing the TGF-β/Smad3 signaling pathway"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "High-dose AAV-KL restored Klotho to approximately 78% of sham"
      explanation: Preclinical evidence from 5/6 nephrectomy and ureteral obstruction models demonstrates that AAV-KL restores renal Klotho.
    - reference: DOI:10.21203/rs.3.rs-9670512/v1
      reference_title: "AAV-mediated Klotho gene delivery attenuates renal fibrosis in chronic kidney disease by suppressing the TGF-β/Smad3 signaling pathway"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The phospho-Smad3/Smad3 ratio declined markedly without change in transforming growth factor-beta 1 ligand, while Smad7 rose approximately 1.9-fold."
      explanation: Restored Klotho suppresses phospho-Smad3 and elevates Smad7, mitigating the fibrotic TGF-β/Smad3 signaling that drives CKD progression.
  evidence:
  - reference: DOI:10.21203/rs.3.rs-9670512/v1
    reference_title: "AAV-mediated Klotho gene delivery attenuates renal fibrosis in chronic kidney disease by suppressing the TGF-β/Smad3 signaling pathway"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transcriptome-wide RNA-sequencing identified 924 differentially expressed genes in CKD kidneys versus sham, of which 306 (including key extracellular matrix, epithelial-mesenchymal transition, and TGF-beta pathway genes) were rescued by AAV-KL treatment"
    explanation: Transcriptomic evidence from preclinical models supports broad mechanistic effects on fibrotic and matrix-remodeling pathways. This is non-peer-reviewed preprint evidence and should not serve as sole support for clinical efficacy claims.
classifications:
  harrisons_chapter:
  - classification_value: KIDNEY_URINARY_TRACT
discussions:
- discussion_id: ckd_pgsxc_reverse_causation
  prompt: >-
    Are the CKD PGS×context interactions driven by adverse exposures causally
    amplifying genetic risk, or are some "contexts" and the eGFR outcome itself
    partly downstream readouts of kidney injury (reverse causation)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Glomerulosclerosis
  - biochemical#Creatinine
  - environmental#Diabetes
  - environmental#Hypertension
  rationale: >-
    Population PGS×context analyses (Nagpal & Gibson 2026,
    PMID:42443528) are largely unable to establish the causality
    of specific contexts. For CKD the concern is sharpened because the outcome is
    modelled against the PGS for eGFR, and serum creatinine — from which eGFR is
    derived — is already modelled in this entry as a READOUT_OF Nephron Loss,
    i.e. a consequence of injury rather than a driver. Comorbid exposures such as
    diabetes and hypertension are themselves partly on the causal path to CKD and
    partly co-declining with renal function. Distinguishing genuine amplification
    of genetic effects from reverse causation determines whether the modelled
    interventions (reducing glucose, smoking cessation) would actually slow
    progression.
  proposed_experiments:
  - experiment_id: ckd_pgsxc_mr_direction
    name: Mendelian randomization of exposure-to-CKD direction across PGS strata
    description: >-
      Use bidirectional / multivariable Mendelian randomization to test whether
      each candidate context (glucose, smoking, blood pressure) causally affects
      kidney function versus being a consequence of declining eGFR, and whether
      the causal effect estimate scales with polygenic liability as the
      amplification model predicts.
    decision_criterion: >-
      A context is retained as a causal amplifier if MR supports
      exposure-to-disease directionality and the exposure-attributable risk
      difference increases across increasing PGS strata; it is flagged as a
      reverse-causation suspect otherwise.
  - experiment_id: ckd_pgsxc_prospective_temporal
    name: Prospective incident-CKD analysis restricted to pre-diagnosis exposure
      windows
    description: >-
      Restrict exposures to measurements taken well before the first evidence of
      reduced eGFR and repeat the PGS×context liability-threshold modelling on
      incident cases only, to reduce contamination by exposures that co-decline
      with renal function.
    decision_criterion: >-
      Amplification is supported if the PGS×context deviation from additivity
      persists when only pre-diagnosis exposure windows and incident cases are
      used.
datasets:
- accession: geo:GSE272125
  title: Transfer RNAs, not microRNAs, are linked to ischemic stroke and major bleeding in patients with end-stage kidney disease
  description: 'Background: Patients with end-stage kidney disease (ESKD) are at very high risk for thromboembolism and bleeding. This study aimed to identify small non-coding RNAs (sncRNAs), specifically microRNAs and transfer-RNA (tRNA)-derived fragments (tRFs), as potential novel biomarkers for predicting thromboembolism and bleeding in this high-risk population. Methods: In this sncRNA discovery research, we leveraged the VIVALDI cohort, consisting of 625 ESKD patients on hemodialysis, to conduct two nested case-control studies, each comprising 18 participants. The primary outcomes were ischemic stroke in the first study and major bleeding in the second.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 34
  publication: PMID:39260398
  notes: Identified by GEO DataSets index search for Chronic Kidney Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE316126
  title: Distinct immunometabolic signatures in peripheral blood mononuclear cells are linked to systemic inflammation in type 2 diabetes and diabetic kidney disease
  description: Diabetic kidney disease (DKD) is a frequent complication of type 2 diabetes and is closely linked to systemic inflammation. Peripheral blood mononuclear cells (PBMCs) are markers of systemic inflammatory and metabolic stress. It is unknown if metabolism-related transcriptomic alterations in these cells is associated with DKD. Using the nCounter® Human Metabolic Pathways Panel we profiled PBMC metabolic transcripts in individuals with type 2 diabetes or DKD and in controls (n = 12/group), and integrated transcriptomic data with clinical, inflammatory, and mitochondrial parameters.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 36
  notes: Identified by GEO DataSets index search for Chronic Kidney Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001007904
  title: Tubulointerstitial fibrosis is the histological hallmark of chronic kidney disease (CKD). Hypoxia and inflammation (i.e., interleukin (IL)-1β signalling) are independent mediators of tubulointerstitial fibrosis. However, the physiological response of human kidney tubular cells to IL-1β/IL-1RI signalling under the hypoxic conditions of CKD is poorly understood and remains a clinical imperative for therapeutic targeting. This study reports that hypoxia and IL-1β act in synergy to trigger cell cycle arrest/cellular senescence of ex vivo patient-derived primary proximal tubular epithelial cells (PTECs).
  description: Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Chronic Kidney Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000101
  title: WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease
  description: Chronic kidney disease (CKD) is a public health problem driven by myofibroblast accumulation, leading to interstitial fibrosis. Heterogeneity is a recently recognised characteristics in kidney fibroblasts in CKD, but the role of different populations is still unclear. Here, we characterize a proinflammatory fibroblast population (named CXCL-iFibro), which corresponds to an early state of myofibroblast differentiation in CKD.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Chronic Kidney Disease"); description-level mentions were not accepted. EGA study_type: Transcriptome Analysis. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000646
  title: Host factors dictate gut microbiome alterations in chronic kidney disease more strongly than to kidney function
  description: Despite recent progress, microbial markers in Chronic Kidney Disease (CKD) remain inconclusive. We combined quantitative faecal metagenomics (N=130 CKD cohort) and cross-study biomarker comparisons (Ntotal=4420) to study microbiome associations with glomerular filtration rate (eGFR; kidney function) and 4-year CKD progression. Transit time (TT) and medications primarily explained microbiome variation, trumping eGFR-related effects.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WGS
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Chronic Kidney Disease"); description-level mentions were not accepted. EGA study_type: Metagenomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST000816
  title: Lipidomics of Chronic Kidney Disease progression
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Chronic Kidney Disease"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST001353
  title: Untargeted metabolomics in skeletal muscle of mice with chronic kidney disease
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: METABOLOMICS
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Chronic Kidney Disease"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST001625
  title: Tissue-specific 1H-NMR metabolomic profiling in mice with adenine-induced chronic kidney disease - organic phase Kidney (part-II)
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: METABOLOMICS
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Chronic Kidney Disease"). Retrieved 2026-08-02.
references:
- reference: DOI:10.1038/s41581-023-00775-0
  title: Oxidative stress and the role of redox signalling in chronic kidney
    disease
  findings: []
- reference: DOI:10.1080/0886022x.2024.2313864
  title: 'Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase
    inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic
    review and meta-analysis'
  findings: []
- reference: DOI:10.1093/ckj/sfad143
  title: 'Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors
    in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled
    trials'
  findings: []
- reference: DOI:10.1182/hematology.2024000655
  title: 'Hypoxia-inducible factor activators: a novel class of oral drugs for the
    treatment of anemia of chronic kidney disease'
  findings: []
- reference: DOI:10.3349/ymj.2023.0306
  title: Recent Update on Acute Kidney Injury-to-Chronic Kidney Disease
    Transition
  findings: []
- reference: DOI:10.3390/biomedicines13061424
  title: 'Pathogenesis and Therapeutic Perspectives of Tubular Injury in Diabetic
    Kidney Disease: An Update'
  findings: []
- reference: DOI:10.3390/ijms25031518
  title: Mitochondrial Signaling, the Mechanisms of AKI-to-CKD Transition and
    Potential Treatment Targets
  findings: []
- reference: DOI:10.3390/ijms25031755
  title: 'From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the
    Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney
    Disease'
  findings: []
- reference: DOI:10.3390/jcm13071881
  title: 'Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets'
  findings: []
- reference: DOI:10.34067/kid.0000000000000425
  title: 'SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular
    Feedback'
  findings: []
- reference: PMID:37330614
  title: "A meta-analysis of GFR slope as a surrogate endpoint for kidney failure."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:31473020
  title: "Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:24206459
  title: "Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:30149958
  title: "The Validity of Drug Effects on Proteinuria, Albuminuria, Serum Creatinine, and Estimated GFR as Surrogate End Points for ESKD: A Systematic Review."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:31292197
  title: "GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:25441437
  title: "GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration."
  findings:
  - statement: "2014 NKF-FDA workshop: a confirmed 30% eGFR decline over 2-3 years may serve as an acceptable surrogate end point in some circumstances, with careful attention to acute eGFR effects."
    supporting_text: "the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR"
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:24892770
  title: "Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality."
  findings:
  - statement: "CKD Prognosis Consortium meta-analysis of 1.7 million participants from 35 cohorts: adjusted hazards of ESRD and mortality increase with larger eGFR decline, establishing the individual-level surrogate-outcome link."
    supporting_text: "The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:33009129
  title: "GFR slope as a surrogate endpoint for CKD progression in clinical trials."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:25441438
  title: "GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials."
  findings:
  - statement: "Inker 2014 meta-analysis of 37 RCTs (9,488 participants): lesser eGFR decline thresholds work as alternative end points, with stronger support for the 40% than 30% decline."
    supporting_text: "These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:41177216
  title: "Effects of Empagliflozin on Urine Biomarkers in EMPA-KIDNEY."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:35508594
  title: "Dose-Exposure-Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR: An Analysis from FIDELIO-DKD."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:25604450
  title: "Joint modelling of repeated measurement and time-to-event data: an introductory tutorial."
  findings:
  - statement: "Asar 2015 tutorial: joint longitudinal-survival models give less biased estimates of the eGFR-ESRD relationship than Cox models treating eGFR as a time-varying covariate, because joint models account for measurement error in eGFR."
    supporting_text: "the relationship between kidney function as measured by eGFR and the hazard for initiation of RRT was significantly underestimated by the Cox model"
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:38540235
  title: "An Approach for Personalized Dynamic Assessment of Chronic Kidney Disease Progression Using Joint Model."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:24898299
  title: "Synergism between circulating tumor necrosis factor receptor 2 and HbA(1c) in determining renal decline during 5-18 years of follow-up in patients with type 1 diabetes and proteinuria."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:31071186
  title: "Predicting kidney failure from longitudinal kidney function trajectory: A comparison of models."
  findings:
  - statement: "van den Brand 2019 comparison of joint longitudinal-survival models against last-eGFR Cox models for kidney-failure prediction, supporting eGFR trajectory as the prognostic readout."
    supporting_text: "Predicting kidney failure from longitudinal kidney function trajectory"
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:34013739
  title: "Clinical Implications of Estimated Glomerular Filtration Rate Dip Following Sodium-Glucose Cotransporter-2 Inhibitor Initiation on Cardiovascular and Kidney Outcomes."
  findings:
  - statement: "Xie 2021 (US Veterans cohort): the magnitude of the kidney/CV benefit of SGLT2 inhibitors mediated by the acute eGFR dip is small, so the dip is not the mechanistic driver of long-term outcomes."
    supporting_text: "the magnitude of the association reduced by eGFR dipping was small for both outcomes"
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:37343533
  title: "Practical Utilization of Prediction Equations in Chronic Kidney Disease."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:32518870
  title: "Randomized Clinical Trial on the Effect of Bardoxolone Methyl on GFR in Diabetic Kidney Disease Patients (TSUBAKI Study)."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:31292198
  title: "Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation."
  findings:
  - statement: "Greene 2019 statistical-simulation companion to the Inker meta-analysis: characterises the statistical performance of GFR slope as a surrogate, complementing the empirical meta-analytic R^2 estimate."
    supporting_text: "Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials"
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:31495881
  title: "Choice of endpoint in kidney outcome trials: considerations from the EMPA-REG OUTCOME trial."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:37931634
  title: "Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:32970396
  title: "Dapagliflozin in Patients with Chronic Kidney Disease."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
- reference: PMID:36002026
  title: "Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: design and baseline characteristics of the AYAME study."
  found_in:
  - research/surrogacy/Chronic_Kidney_Disease-surrogacy-estimated_glomerular_filtration_rate-deep-research-openscientist.md
📚

References & Deep Research

References

33
DOI:10.1038/s41581-023-00775-0
Oxidative stress and the role of redox signalling in chronic kidney disease
No top-level findings curated for this source.
DOI:10.1080/0886022x.2024.2313864
Cardiovascular and renal safety outcomes of hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat for anemia patients with chronic kidney disease: a systematic review and meta-analysis
No top-level findings curated for this source.
DOI:10.1093/ckj/sfad143
Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials
No top-level findings curated for this source.
DOI:10.1182/hematology.2024000655
Hypoxia-inducible factor activators: a novel class of oral drugs for the treatment of anemia of chronic kidney disease
No top-level findings curated for this source.
DOI:10.3349/ymj.2023.0306
Recent Update on Acute Kidney Injury-to-Chronic Kidney Disease Transition
No top-level findings curated for this source.
DOI:10.3390/biomedicines13061424
Pathogenesis and Therapeutic Perspectives of Tubular Injury in Diabetic Kidney Disease: An Update
No top-level findings curated for this source.
DOI:10.3390/ijms25031518
Mitochondrial Signaling, the Mechanisms of AKI-to-CKD Transition and Potential Treatment Targets
No top-level findings curated for this source.
DOI:10.3390/ijms25031755
From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease
No top-level findings curated for this source.
DOI:10.3390/jcm13071881
Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets
No top-level findings curated for this source.
DOI:10.34067/kid.0000000000000425
SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular Feedback
No top-level findings curated for this source.
PMID:37330614
A meta-analysis of GFR slope as a surrogate endpoint for kidney failure.
No top-level findings curated for this source.
PMID:31473020
Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency.
No top-level findings curated for this source.
PMID:24206459
Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.
No top-level findings curated for this source.
PMID:30149958
The Validity of Drug Effects on Proteinuria, Albuminuria, Serum Creatinine, and Estimated GFR as Surrogate End Points for ESKD: A Systematic Review.
No top-level findings curated for this source.
PMID:31292197
GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials.
No top-level findings curated for this source.
PMID:25441437
GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.
1 finding
2014 NKF-FDA workshop: a confirmed 30% eGFR decline over 2-3 years may serve as an acceptable surrogate end point in some circumstances, with careful attention to acute eGFR effects.
"the workshop concluded that a confirmed decline in estimated GFR of 30% over 2 to 3 years may be an acceptable surrogate end point in some circumstances, but the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR"
PMID:24892770
Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.
1 finding
CKD Prognosis Consortium meta-analysis of 1.7 million participants from 35 cohorts: adjusted hazards of ESRD and mortality increase with larger eGFR decline, establishing the individual-level surrogate-outcome link.
"The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline."
PMID:33009129
GFR slope as a surrogate endpoint for CKD progression in clinical trials.
No top-level findings curated for this source.
PMID:25441438
GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials.
1 finding
Inker 2014 meta-analysis of 37 RCTs (9,488 participants): lesser eGFR decline thresholds work as alternative end points, with stronger support for the 40% than 30% decline.
"These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline."
PMID:41177216
Effects of Empagliflozin on Urine Biomarkers in EMPA-KIDNEY.
No top-level findings curated for this source.
PMID:35508594
Dose-Exposure-Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR: An Analysis from FIDELIO-DKD.
No top-level findings curated for this source.
PMID:25604450
Joint modelling of repeated measurement and time-to-event data: an introductory tutorial.
1 finding
Asar 2015 tutorial: joint longitudinal-survival models give less biased estimates of the eGFR-ESRD relationship than Cox models treating eGFR as a time-varying covariate, because joint models account for measurement error in eGFR.
"the relationship between kidney function as measured by eGFR and the hazard for initiation of RRT was significantly underestimated by the Cox model"
PMID:38540235
An Approach for Personalized Dynamic Assessment of Chronic Kidney Disease Progression Using Joint Model.
No top-level findings curated for this source.
PMID:24898299
Synergism between circulating tumor necrosis factor receptor 2 and HbA(1c) in determining renal decline during 5-18 years of follow-up in patients with type 1 diabetes and proteinuria.
No top-level findings curated for this source.
PMID:31071186
Predicting kidney failure from longitudinal kidney function trajectory: A comparison of models.
1 finding
van den Brand 2019 comparison of joint longitudinal-survival models against last-eGFR Cox models for kidney-failure prediction, supporting eGFR trajectory as the prognostic readout.
"Predicting kidney failure from longitudinal kidney function trajectory"
PMID:34013739
Clinical Implications of Estimated Glomerular Filtration Rate Dip Following Sodium-Glucose Cotransporter-2 Inhibitor Initiation on Cardiovascular and Kidney Outcomes.
1 finding
Xie 2021 (US Veterans cohort): the magnitude of the kidney/CV benefit of SGLT2 inhibitors mediated by the acute eGFR dip is small, so the dip is not the mechanistic driver of long-term outcomes.
"the magnitude of the association reduced by eGFR dipping was small for both outcomes"
PMID:37343533
Practical Utilization of Prediction Equations in Chronic Kidney Disease.
No top-level findings curated for this source.
PMID:32518870
Randomized Clinical Trial on the Effect of Bardoxolone Methyl on GFR in Diabetic Kidney Disease Patients (TSUBAKI Study).
No top-level findings curated for this source.
PMID:31292198
Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation.
1 finding
Greene 2019 statistical-simulation companion to the Inker meta-analysis: characterises the statistical performance of GFR slope as a surrogate, complementing the empirical meta-analytic R^2 estimate.
"Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials"
PMID:31495881
Choice of endpoint in kidney outcome trials: considerations from the EMPA-REG OUTCOME trial.
No top-level findings curated for this source.
PMID:37931634
Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial.
No top-level findings curated for this source.
PMID:32970396
Dapagliflozin in Patients with Chronic Kidney Disease.
No top-level findings curated for this source.
PMID:36002026
Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: design and baseline characteristics of the AYAME study.
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Chronic Kidney Disease
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 21

Key Pathophysiology Nodes

  • Nephron Loss
  • Glomerulosclerosis
  • Tubulointerstitial Fibrosis
  • RAAS Activation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1038/s41581-023-00775-0
  • DOI:10.1080/0886022x.2024.2313864
  • DOI:10.1093/ckj/sfad143
  • DOI:10.1182/hematology.2024000655
  • DOI:10.3349/ymj.2023.0306
  • DOI:10.3390/biomedicines13061424
  • DOI:10.3390/ijms25031518
  • DOI:10.3390/ijms25031755
  • DOI:10.3390/jcm13071881
  • DOI:10.34067/kid.0000000000000425
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 31 citations 2025-12-17T18:46:31.876442

Disease Pathophysiology Research Report

Target Disease

  • Disease Name: Chronic Kidney Disease (CKD)
  • MONDO ID: Not specified
  • Category: Complex

Pathophysiology description (narrative)

Chronic kidney disease progresses through intertwined mechanisms of persistent injury, maladaptive epithelial repair, inflammation, and fibrosis that culminate in nephron loss and functional decline. Kidney fibrosis is the final common pathway of CKD. Canonical TGF-β/Smad signaling activates myofibroblasts and drives extracellular matrix deposition; Smad2/3 activation with Smad7 downregulation induces profibrotic transcription (collagen, α-SMA, fibronectin) in mesangial and interstitial cells, while matricellular proteins (CTGF, tenascin-C) amplify the fibrotic niche (doi:10.3390/jcm13071881; 2024-03-26) (reiss2024fibrosisinchronic pages 5-6). Oxidative stress and mitochondrial dysfunction are central amplifiers: mitochondrial ROS, mtDNA release, and organelle crosstalk at mitochondria–ER contact sites activate innate sensors (NLRP3, AIM2; cGAS–STING), NF-κB, and Wnt–β-catenin, promoting albuminuria, endothelial/tubular injury, and interstitial fibrosis; RAAS–NOX signaling further increases ROS and inflammation (doi:10.1038/s41581-023-00775-0; 2024-10-01) (kishi2024oxidativestressand pages 10-12).

Transitions from acute kidney injury (AKI) to CKD illustrate the maladaptive repair paradigm: proximal tubular epithelial cells (PTECs) that arrest in G2/M and acquire senescent/SASP phenotypes secrete TGF-β and chemokines, activate pericytes to fibroblasts, and fail to redifferentiate, linking epithelial injury to chronic fibrosis (doi:10.3349/ymj.2023.0306; 2024-05-01) (koh2024recentupdateon pages 5-7). Single-cell and transcriptomic work identifies injury-associated epithelial states (oxidative stress/hypoxia, inflammation/translation, EMT-like) that recruit leukocytes and fibroblasts and correlate with eGFR decline (2024; details and mechanistic ligands SPP1, C3, NECTIN2–CD226) (hinze2024decipheringinjuryassociatedrenal pages 7-9). Pathways reactivated after injury include Wnt/β-catenin, PI3K/AKT, PDGF, CTGF, and Sonic hedgehog, acting alongside TGF-β to sustain fibroblast activation and matrix accumulation (doi:10.3390/ijms25031518; 2024-01-24) (chang2024mitochondrialsignalingthe pages 2-4). Persistent hypoxia (HIF-1/2α activity) intersects with TGF-β, NF-κB, and PI3K/Akt signaling and has context-dependent roles in fibrosis versus protection; pharmacologic HIF modulation (HIF–PHD inhibition) alters inflammation, mitochondrial injury, and erythropoiesis (doi:10.3390/ijms25031755; 2024-02-01) (yeh2024fromacuteto pages 8-10).

Therapeutically, SGLT2 inhibitors lessen hyperfiltration injury, improve renal energetics, autophagy and microvascular function, and reduce oxidative/inflammatory signaling, providing kidney protection beyond tubuloglomerular feedback (doi:10.34067/kid.0000000000000425; 2024-03-14) (kishi2024oxidativestressand pages 10-12). For CKD anemia, HIF–PHD inhibitors (e.g., daprodustat, vadadustat, roxadustat) increase hemoglobin and improve iron handling without excess major adverse cardiovascular events relative to ESAs in phase 3 trials, though vigilance for hypertension and hyperkalemia is warranted (doi:10.1182/hematology.2024000655; 2024-12-01; doi:10.1093/ckj/sfad143; 2024-06-01; doi:10.1080/0886022x.2024.2313864; 2024-02-05) (kishi2024oxidativestressand pages 10-12).

Mechanism Key pathways (GO) Principal genes / proteins (HGNC) Primary cell types (CL) Anatomical sites (UBERON) Representative clinical phenotypes (HP)
Fibrosis (TGF-β / Wnt) GO:TGF-β receptor signaling; GO:Wnt/β-catenin signaling TGFB1, SMAD3, CTGF, CTNNB1 CL:interstitial_fibroblast; CL:mesangial_cell; CL:proximal_tubular_epithelial_cell UBERON:renal_interstitium; UBERON:glomerulus HP:interstitial_fibrosis; HP:proteinuria (reiss2024fibrosisinchronic pages 5-6, yeh2024fromacuteto pages 8-10)
Inflammation / innate immunity (NF-κB, NLRP3 / pyroptosis) GO:NF-κB signaling; GO:inflammasome activation NLRP3, CASP1, IL1B, NFKB1 CL:macrophage; CL:neutrophil; CL:dendritic_cell UBERON:renal_interstitium; UBERON:glomerulus HP:renal_inflammation; HP:albuminuria (yeh2024fromacuteto pages 12-14, hinze2024decipheringinjuryassociatedrenal pages 7-9)
Oxidative stress & mitochondria (Nrf2 / mtDNA → cGAS-STING) GO:cellular_response_to_oxidative_stress; GO:mitochondrial_dysfunction NFE2L2 (Nrf2), KEAP1, NOX4, PPARGC1A (PGC-1α) CL:proximal_tubular_epithelial_cell; CL:endothelial_cell UBERON:proximal_tubule; UBERON:peritubular_capillary HP:albuminuria; HP:decreased_eGFR (kishi2024oxidativestressand pages 10-12, geng2025pathogenesisandtherapeutic pages 7-9)
Hypoxia / HIF GO:cellular_response_to_hypoxia; GO:HIF-1 signaling HIF1A, EGLN1 (PHD2), EPO CL:proximal_tubular_epithelial_cell; CL:endothelial_cell UBERON:renal_cortex; UBERON:renal_medulla HP:anemia_of_CKD; HP:interstitial_hypoxia (yeh2024fromacuteto pages 8-10, kishi2024oxidativestressand pages 10-12)
Maladaptive repair / cellular senescence (G2/M arrest, SASP) GO:cellular_senescence; GO:DNA_damage_response CDKN1A (p21), CDKN2A (p16), IL6 (SASP) CL:proximal_tubular_epithelial_cell; CL:senescent_cell UBERON:renal_tubule; UBERON:interstitium HP:tubulointerstitial_fibrosis; HP:progressive_eGFR_loss (koh2024recentupdateon pages 5-7, yeh2024fromacuteto pages 12-14, hinze2024decipheringinjuryassociatedrenal pages 7-9)
RAAS / Hemodynamics (Ang II → NOX / ROS) GO:renin-angiotensin system signaling; GO:regulation_of_blood_pressure AGT, ACE, AGTR1, NOX4 CL:glomerular_endothelial_cell; CL:vascular_smooth_muscle_cell UBERON:glomerulus; UBERON:afferent_arteriole HP:hypertension; HP:hyperfiltration; HP:proteinuria (yeh2024fromacuteto pages 12-14, kishi2024oxidativestressand pages 10-12)
Therapeutic mechanisms: SGLT2 inhibitors & HIF-PHIs GO:glucose_transport; GO:regulation_of_HIF_signaling SLC5A2 (SGLT2), HIF1A, EGLN1 (PHDs) CL:proximal_tubular_epithelial_cell UBERON:proximal_tubule HP:reduced_albuminuria; HP:slower_GFR_decline (kishi2024oxidativestressand pages 10-12, chang2024mitochondrialsignalingthe pages 2-4)

Table: Compact mapping of major CKD pathophysiology mechanisms to pathways (GO), genes/proteins (HGNC), cell types (CL), anatomical sites (UBERON) and clinical phenotypes (HP); citations link source evidence from the gathered context (yeh2024fromacuteto pages 8-10, koh2024recentupdateon pages 5-7).

Gene/protein annotations with ontology terms

  • TGFB1 (HGNC:11766) – GO:0007179 (TGF-β receptor signaling pathway); promotes Smad2/3 phosphorylation and ECM gene induction in kidney fibrosis (reiss2024fibrosisinchronic pages 5-6)
  • SMAD3 (HGNC:6769) – GO:0007179; mediates canonical TGF-β profibrotic transcription in mesangial/interstitial cells (reiss2024fibrosisinchronic pages 5-6)
  • CTGF (HGNC:2503) – GO:0030198 (ECM organization); matricellular amplifier of fibrosis (reiss2024fibrosisinchronic pages 5-6)
  • NLRP3 (HGNC:16400) – GO:0140186 (inflammasome complex assembly); activates caspase-1, IL-1β/IL-18 and pyroptosis in renal inflammation (kishi2024oxidativestressand pages 10-12)
  • NFE2L2/Nrf2 (HGNC:7782) – GO:0034599 (cellular response to oxidative stress); coordinates antioxidant defenses; dysregulation linked to CKD oxidative stress (kishi2024oxidativestressand pages 10-12)
  • PPARGC1A/PGC-1α (HGNC:9237) – GO:0009889 (regulation of biosynthetic process); mitochondrial biogenesis regulator protective in PTECs (yeh2024fromacuteto pages 12-14)
  • HIF1A (HGNC:4910) – GO:0071456 (cellular response to hypoxia); context-dependent in fibrosis; targeted by HIF–PHD inhibitors in CKD anemia (yeh2024fromacuteto pages 8-10)
  • SLC5A2 (HGNC:11036) – GO:0005355 (glucose transmembrane transporter activity); proximal tubular SGLT2 blockade yields nephroprotection (kishi2024oxidativestressand pages 10-12)
  • AGTR1 (HGNC:336) – GO:0009755 (hormone-mediated signaling); Ang II–NOX–ROS axis drives oxidative stress and hemodynamic injury (kishi2024oxidativestressand pages 10-12)

Biological processes (GO terms) disrupted

  • Fibrotic signaling: GO:0007179 TGF-β receptor signaling; GO:0016055 Wnt signaling; GO:0001932 regulation of protein phosphorylation (reiss2024fibrosisinchronic pages 5-6, yeh2024fromacuteto pages 8-10)
  • Inflammation/innate immunity: GO:0006954 inflammatory response; GO:0140186 inflammasome assembly; GO:0007249 I-κB/NF-κB signaling (kishi2024oxidativestressand pages 10-12, yeh2024fromacuteto pages 12-14)
  • Oxidative stress and mitochondrial quality control: GO:0034599 cellular response to oxidative stress; GO:0007005 mitochondrion organization; GO:0000422 mitophagy (kishi2024oxidativestressand pages 10-12, yeh2024fromacuteto pages 12-14)
  • Hypoxia: GO:0071456 cellular response to hypoxia; GO:0032412 regulation of ion transmembrane transport (intersecting with hemodynamics) (yeh2024fromacuteto pages 8-10, kishi2024oxidativestressand pages 10-12)
  • Maladaptive repair and senescence: GO:0007050 cell cycle arrest (G2/M); GO:0090398 cellular senescence; GO:0030198 ECM organization (koh2024recentupdateon pages 5-7, yeh2024fromacuteto pages 12-14)
  • Hemodynamics/RAAS: GO:0003018 vascular process in circulatory system; GO:0007204 elevation of cytosolic calcium ion concentration (yeh2024fromacuteto pages 12-14, kishi2024oxidativestressand pages 10-12)

Cellular components (where processes occur)

  • ECM and interstitium: extracellular region, basement membrane (GO:0005576; GO:0005604) – matrix deposition by myofibroblasts (reiss2024fibrosisinchronic pages 5-6)
  • Mitochondria and MAMs: mitochondrial matrix/membrane (GO:0005739; GO:0005743); ER–mitochondria contact sites (MAM) for lipid/Ca2+ handling (kishi2024oxidativestressand pages 10-12)
  • Inflammasome complex: cytosol/perinuclear area (GO:0061702) (kishi2024oxidativestressand pages 10-12)
  • Nucleus: Smad2/3/4 transcriptional complexes, HIF-1/2α activity (GO:0005634) (reiss2024fibrosisinchronic pages 5-6, yeh2024fromacuteto pages 8-10)

Cell type involvement (CL terms)

  • Proximal tubular epithelial cells (CL:0002306): central to injury, maladaptive repair, senescence, mitochondrial dysfunction (koh2024recentupdateon pages 5-7, yeh2024fromacuteto pages 12-14)
  • Interstitial fibroblasts/pericytes (CL:0002553/CL:0000669): sources of myofibroblasts and ECM (chang2024mitochondrialsignalingthe pages 2-4, reiss2024fibrosisinchronic pages 5-6)
  • Mesangial cells (CL:0000650): glomerular ECM producers under TGF-β/diabetic stimuli (reiss2024fibrosisinchronic pages 5-6)
  • Endothelial cells (CL:0000115): hypoxia/ROS injury, microvascular rarefaction (kishi2024oxidativestressand pages 10-12, hinze2024decipheringinjuryassociatedrenal pages 7-9)
  • Macrophages (CL:0000235): M1→M2 shifts, inflammasome activity, cytokine production; MMT contributes to myofibroblasts (yeh2024fromacuteto pages 12-14, hinze2024decipheringinjuryassociatedrenal pages 7-9)

Anatomical locations (UBERON terms)

  • Kidney interstitium (UBERON:0008761): site of fibroblast activation and matrix accumulation (reiss2024fibrosisinchronic pages 5-6)
  • Glomerulus (UBERON:0000108): mesangial matrix expansion, endothelial/podocyte injury (reiss2024fibrosisinchronic pages 5-6, kishi2024oxidativestressand pages 10-12)
  • Proximal tubule (UBERON:0001285): locus of metabolic stress, SGLT2 action, maladaptive repair (koh2024recentupdateon pages 5-7, kishi2024oxidativestressand pages 10-12)
  • Peritubular capillaries (UBERON:0002227): hypoxia and endothelial dysfunction (kishi2024oxidativestressand pages 10-12)

Chemical entities (CHEBI) and interventions

  • SGLT2 inhibitors (CHEBI:142996, class): reduce intraglomerular pressure; improve oxidative and inflammatory profiles and cellular homeostasis (2024-03-14; 2024-06-30) (kishi2024oxidativestressand pages 10-12)
  • HIF–PHD inhibitors (roxadustat CHEBI:135996; daprodustat CHEBI:143545; vadadustat CHEBI:143546): treat CKD anemia by stabilizing HIF and improving iron handling; safety broadly comparable to ESA, though BP monitoring is advised (2024-12-01; 2024-06-01; 2024-02-05) (kishi2024oxidativestressand pages 10-12)

Disease progression

Initial epithelial injury (ischemia, toxins, metabolic stress) induces oxidative stress, hypoxia signaling, and inflammatory cascades. PTECs fail to fully redifferentiate, arrest in G2/M, and become senescent, secreting SASP factors that attract macrophages and activate pericyte-derived fibroblasts. Profibrotic pathways (TGF-β/Smad, Wnt/β-catenin, CTGF) reinforce myofibroblast activation and ECM deposition. Mitochondrial dysfunction and RAAS–NOX–ROS perpetuate injury. Microvascular rarefaction and persistent hypoxia consolidate fibrosis and nephron loss, manifesting clinically as progressive albuminuria and eGFR decline (doi:10.3349/ymj.2023.0306; 2024-05-01; doi:10.3390/ijms25031755; 2024-02-01; doi:10.3390/jcm13071881; 2024-03-26; doi:10.1038/s41581-023-00775-0; 2024-10-01) (koh2024recentupdateon pages 5-7, yeh2024fromacuteto pages 8-10, reiss2024fibrosisinchronic pages 5-6, kishi2024oxidativestressand pages 10-12).

Phenotype associations (HP terms)

  • HP:0000093 Proteinuria/Albuminuria – from glomerular and tubular injury, oxidative stress, and endothelial dysfunction (kishi2024oxidativestressand pages 10-12)
  • HP:0004789 Interstitial renal fibrosis – from TGF-β/Smad and Wnt activation and myofibroblast accumulation (reiss2024fibrosisinchronic pages 5-6)
  • HP:0000120 Decreased eGFR – correlates with injury-state burden and fibrosis advancement (hinze2024decipheringinjuryassociatedrenal pages 7-9)
  • HP:0001892 Anemia – due to reduced EPO and iron dysregulation; improved by HIF–PHD inhibitors (kishi2024oxidativestressand pages 10-12)
  • HP:0030975 Chronic kidney disease–mineral bone disorder – linked to chronic inflammation and oxidative stress (contextual linkage via redox review) (kishi2024oxidativestressand pages 10-12)

Evidence items (quotes with sources)

  • “Transforming growth factor (TGF)-β is a central mediator… TGFBR2→TGFBR1… Smad3-driven transcription of profibrotic genes (fibronectin, α-SMA, collagen) leading to… tubulointerstitial fibrosis.” (doi:10.3390/jcm13071881; URL: https://doi.org/10.3390/jcm13071881; 2024-03-26) (reiss2024fibrosisinchronic pages 5-6)
  • “Mitochondrial ROS promote cytosolic release of mtDNA… activate innate immune sensors (NLRP3, AIM2)… cGAS–STING signalling… RAAS (ANGII → NAD(P)H oxidase) amplifies ROS and inflammation.” (doi:10.1038/s41581-023-00775-0; URL: https://doi.org/10.1038/s41581-023-00775-0; 2024-10-01) (kishi2024oxidativestressand pages 10-12)
  • “Maladaptive tubular repair… G2/M cell-cycle arrest… activates… TGF-β… leading to fibrosis” and “epigenetic reprogramming… PCAF… pharmacologic inhibition reduced… fibrosis.” (doi:10.3349/ymj.2023.0306; URL: https://doi.org/10.3349/ymj.2023.0306; 2024-05-01) (koh2024recentupdateon pages 5-7)
  • “Injury-associated epithelial states… hypoxia/oxidative stress… inflammation/translation, EMT… recruit leukocytes/fibroblasts… correlate with eGFR decline.” (2024; single-cell/transcriptomic synthesis) (hinze2024decipheringinjuryassociatedrenal pages 7-9)
  • “Hypoxia signalling… HIF-1/2α… has context-dependent roles in fibrosis… PHD inhibitors modulate inflammation, mitochondrial injury… and erythropoiesis.” (doi:10.3390/ijms25031755; URL: https://doi.org/10.3390/ijms25031755; 2024-02-01) (yeh2024fromacuteto pages 8-10)
  • “SGLT2 inhibitors… mechanisms beyond tubuloglomerular feedback… optimization of energy substrate use, regulation of autophagy, attenuation of sympathetic hyperactivity, improvement in microvascular function.” (doi:10.34067/kid.0000000000000425; URL: https://doi.org/10.34067/kid.0000000000000425; 2024-03-14) (kishi2024oxidativestressand pages 10-12)
  • “HIF-PHIs… effective at improving and maintaining hemoglobin… stimulate endogenous EPO… lower hepcidin… with safety broadly comparable to ESA across phase 3 trials” (doi:10.1182/hematology.2024000655; https://doi.org/10.1182/hematology.2024000655; 2024-12-01; and doi:10.1093/ckj/sfad143; https://doi.org/10.1093/ckj/sfad143; 2024-06-01; and doi:10.1080/0886022x.2024.2313864; https://doi.org/10.1080/0886022x.2024.2313864; 2024-02-05) (kishi2024oxidativestressand pages 10-12)

Expert opinions and analysis (authoritative sources)

  • Nature Reviews Nephrology (2024) underscores oxidative stress–mitochondria–innate immunity coupling (mtDNA→inflammasomes; RAAS–NOX) as central to CKD and highlights why non-specific antioxidants have disappointed clinically, steering interest to pathway-level interventions and SGLT2i (doi:10.1038/s41581-023-00775-0; 2024-10-01) (kishi2024oxidativestressand pages 10-12).
  • Yonsei Medical Journal (2024) emphasizes maladaptive epithelial repair, cell cycle arrest, epigenetics (PCAF), and mitochondrial/autophagy insufficiency as actionable drivers of AKI→CKD, suggesting targets beyond hemodynamics (doi:10.3349/ymj.2023.0306; 2024-05-01) (koh2024recentupdateon pages 5-7).

Current applications and real-world implementations

  • SGLT2 inhibitors are guideline-directed therapy for CKD with and without diabetes, slowing eGFR decline and reducing albuminuria via hemodynamic, metabolic, and anti-inflammatory/oxidative mechanisms (doi:10.34067/kid.0000000000000425; 2024-03-14) (kishi2024oxidativestressand pages 10-12).
  • HIF–PHD inhibitors are approved in many countries for CKD anemia; recent meta-analyses and narrative reviews show efficacy on hemoglobin and iron metrics with safety comparable to ESAs (careful BP monitoring required) (doi:10.1093/ckj/sfad143; 2024-06-01; doi:10.1182/hematology.2024000655; 2024-12-01; doi:10.1080/0886022x.2024.2313864; 2024-02-05) (kishi2024oxidativestressand pages 10-12).

Relevant statistics and data

  • The oxidative stress review links ROS–NO imbalance to albuminuria and GFR loss and summarizes mechanistic and translational data on mtDNA–inflammasome and cGAS–STING activation in kidney models (doi:10.1038/s41581-023-00775-0; 2024-10-01) (kishi2024oxidativestressand pages 10-12).
  • Phase 3 meta-analysis across 24,387 patients shows HIF–PHD inhibitors raise hemoglobin slightly more than ESAs, lower hepcidin and ferritin, increase serum iron/TIBC, with no significant differences in cancer, MACE, thrombotic events, AVF thrombosis, or death versus ESAs (doi:10.1093/ckj/sfad143; 2024-06-01) (kishi2024oxidativestressand pages 10-12).

References (with URLs and dates)

  • Reiss AB et al. Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets. Journal of Clinical Medicine. 2024-03-26. https://doi.org/10.3390/jcm13071881 (reiss2024fibrosisinchronic pages 5-6)
  • Kishi S et al. Oxidative stress and the role of redox signalling in chronic kidney disease. Nat Rev Nephrol. 2024-10-01. https://doi.org/10.1038/s41581-023-00775-0 (kishi2024oxidativestressand pages 10-12)
  • Koh ES, Chung S. Recent Update on AKI-to-CKD Transition. Yonsei Med J. 2024-05-01. https://doi.org/10.3349/ymj.2023.0306 (koh2024recentupdateon pages 5-7)
  • Yeh T-H et al. From AKI to CKD progression. Int J Mol Sci. 2024-02-01. https://doi.org/10.3390/ijms25031755 (yeh2024fromacuteto pages 8-10)
  • Chang L-Y et al. Mitochondrial signaling in AKI-to-CKD. Int J Mol Sci. 2024-01-24. https://doi.org/10.3390/ijms25031518 (chang2024mitochondrialsignalingthe pages 2-4)
  • Upadhyay A. SGLT2 inhibitors and kidney protection: mechanisms beyond TGF. Kidney360. 2024-03-14. https://doi.org/10.34067/kid.0000000000000425 (kishi2024oxidativestressand pages 10-12)
  • Haase VH et al. HIF activators for CKD anemia. Hematology. 2024-12-01. https://doi.org/10.1182/hematology.2024000655 (kishi2024oxidativestressand pages 10-12)
  • Minutolo R et al. HIF-PHI meta-analysis. Clin Kidney J. 2024-06-01. https://doi.org/10.1093/ckj/sfad143 (kishi2024oxidativestressand pages 10-12)
  • Tian L-R et al. Roxadustat safety meta-analysis. Renal Failure. 2024-02-05. https://doi.org/10.1080/0886022x.2024.2313864 (kishi2024oxidativestressand pages 10-12)
  • Hinze C et al. Injury-associated epithelial states and fibrosis link. 2024 (preprint/unknown journal) (hinze2024decipheringinjuryassociatedrenal pages 7-9)

References

  1. (reiss2024fibrosisinchronic pages 5-6): Allison B. Reiss, Berlin Jacob, Aarij Zubair, Ankita Srivastava, Maryann Johnson, and Joshua De Leon. Fibrosis in chronic kidney disease: pathophysiology and therapeutic targets. Journal of Clinical Medicine, 13:1881, Mar 2024. URL: https://doi.org/10.3390/jcm13071881, doi:10.3390/jcm13071881. This article has 67 citations and is from a poor quality or predatory journal.

  2. (kishi2024oxidativestressand pages 10-12): Seiji Kishi, Hajime Nagasu, Kengo Kidokoro, and Naoki Kashihara. Oxidative stress and the role of redox signalling in chronic kidney disease. Nature Reviews Nephrology, 20:101-119, Oct 2024. URL: https://doi.org/10.1038/s41581-023-00775-0, doi:10.1038/s41581-023-00775-0. This article has 177 citations and is from a domain leading peer-reviewed journal.

  3. (koh2024recentupdateon pages 5-7): Eun Sil Koh and Sungjin Chung. Recent update on acute kidney injury-to-chronic kidney disease transition. Yonsei medical journal, 65 5:247-256, May 2024. URL: https://doi.org/10.3349/ymj.2023.0306, doi:10.3349/ymj.2023.0306. This article has 33 citations and is from a peer-reviewed journal.

  4. (hinze2024decipheringinjuryassociatedrenal pages 7-9): C Hinze, S Lovric, and PF Halloran. Deciphering injury-associated renal epithelial cell states and their role in kidney transplantation. Unknown journal, 2024.

  5. (chang2024mitochondrialsignalingthe pages 2-4): Li-Yun Chang, Yu-Lin Chao, Chien-Chih Chiu, Phang-Lang Chen, and Hugo Y.-H. Lin. Mitochondrial signaling, the mechanisms of aki-to-ckd transition and potential treatment targets. International Journal of Molecular Sciences, 25:1518, Jan 2024. URL: https://doi.org/10.3390/ijms25031518, doi:10.3390/ijms25031518. This article has 14 citations and is from a poor quality or predatory journal.

  6. (yeh2024fromacuteto pages 8-10): Tzu-Hsuan Yeh, Kuan-Chieh Tu, Hsien-Yi Wang, and Jui-Yi Chen. From acute to chronic: unraveling the pathophysiological mechanisms of the progression from acute kidney injury to acute kidney disease to chronic kidney disease. International Journal of Molecular Sciences, Feb 2024. URL: https://doi.org/10.3390/ijms25031755, doi:10.3390/ijms25031755. This article has 57 citations and is from a poor quality or predatory journal.

  7. (yeh2024fromacuteto pages 12-14): Tzu-Hsuan Yeh, Kuan-Chieh Tu, Hsien-Yi Wang, and Jui-Yi Chen. From acute to chronic: unraveling the pathophysiological mechanisms of the progression from acute kidney injury to acute kidney disease to chronic kidney disease. International Journal of Molecular Sciences, Feb 2024. URL: https://doi.org/10.3390/ijms25031755, doi:10.3390/ijms25031755. This article has 57 citations and is from a poor quality or predatory journal.

  8. (geng2025pathogenesisandtherapeutic pages 7-9): Jiamian Geng, Sijia Ma, Hui Tang, and Chun-di Zhang. Pathogenesis and therapeutic perspectives of tubular injury in diabetic kidney disease: an update. Biomedicines, 13:1424, Jun 2025. URL: https://doi.org/10.3390/biomedicines13061424, doi:10.3390/biomedicines13061424. This article has 2 citations and is from a poor quality or predatory journal.