Nephronophthisis

Genetic MONDO:0019005 Pathograph 15 Tubulointerstitial Kidney Disease Ciliopathy
0
Mappings
0
Definitions
2
Inheritance
11
Pathophysiology
0
Histopathology
11
Phenotypes
15
Pathograph
5
Genes
3
Treatments
3
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
2
Literature
🏷

Classifications

Harrison's Chapter
kidney disorder hereditary disease
Mechanistic Nosology
ciliopathy
👪

Inheritance

2
Autosomal Recessive
Show evidence (2 references)
PMID:29717526 SUPPORT
"Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children."
The literature clearly states that nephronophthisis follows an autosomal recessive inheritance pattern.
PMID:31810733 SUPPORT
"There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults."
The literature confirms that nephronophthisis is inherited in an autosomal recessive manner, even in cases diagnosed in adults.
Tubulointerstitial Fibrosis
Progressive fibrosis of the kidney's tubulointerstitial region.
Show evidence (2 references)
PMID:35533128 SUPPORT
"Nephronophthisis is an autosomal recessive cystic kidney disease... resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis."
The literature indicates that nephronophthisis involves chronic tubulointerstitial changes compatible with fibrosis.
PMID:27169608 PARTIAL
"Chronic tubulointerstitial nephritis (CTN) is characterized by interstitial scarring, fibrosis and tubule atrophy, resulting in progressive chronic kidney disease."
While the article discusses tubulointerstitial nephritis in general, it supports the idea that fibrosis occurs in this region, although it does not specifically discuss nephronophthisis.
◆

Subtypes

3
Infantile Nephronophthisis
Early onset in infancy characterized by rapid progression to end-stage renal disease.
Show evidence (1 reference)
PMID:16966065 SUPPORT
"Infantile nephronophtisis is a recessive autosomic tubulo-interstitial nephritis with cortical microcysts which progress to end stage renal failure before age 5."
The source indicates that infantile nephronophthisis is characterized by early onset and rapid progression to end-stage renal disease, supporting the statement.
Juvenile Nephronophthisis
Most common form with onset in childhood and progressive renal failure by adolescence.
Show evidence (2 references)
PMID:16966065 SUPPORT
"Juvenile nephronophtisis, the most frequent, progress to end stage renal failure before age 15."
The provided excerpt states that juvenile nephronophthisis is the most frequent subtype and typically progresses to end-stage renal failure by adolescence.
PMID:35570616 SUPPORT
"Nephronophthisis is the most common genetic cause of kidney failure in childhood... outcomes of kidney transplant recipients with primary diagnosis of juvenile nephronophthisis..."
The excerpt indicates that juvenile nephronophthisis is a common pediatric kidney failure cause, aligning with 'most common form with onset in childhood'.
Adolescent Nephronophthisis
Later onset in teenage years with slower progression to renal failure.
Show evidence (2 references)
PMID:16966065 SUPPORT
"Adolescent nephronophtisis is a less frequent form of nephronophtisis."
The term 'adolescent nephronophthisis' is noted, and it is described as a less frequent form of nephronophthisis which is consistent with later onset.
PMID:16966065 SUPPORT
"Medullary cystic disease is transmitted as an autosomic dominant trait. Clinical and histological signs are similar to nephronophthisis, but the disease progress later to terminal renal failure and is not accompanied by extra-renal symptoms."
Medullary cystic disease presents similar signs but progresses later, implying a slower progression to renal failure, corroborating the adolescent nephronophthisis description.
📚

References

7
DOI:10.1038/s44321-025-00239-x
Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies
No top-level findings curated for this source.
DOI:10.1101/2025.06.09.658557
Loss of nephronophthisis-associated nephrocystin-1 impairs DNA damage repair in kidney organoids
No top-level findings curated for this source.
DOI:10.1186/s12964-025-02143-w
NEK8, a NIMA-family protein kinase at the core of the ciliary INV complex
No top-level findings curated for this source.
DOI:10.1242/jcs.264141
Urinary renal epithelial cells can be used for <i>NPHP1</i> phenotyping and a personalized therapeutic strategy
No top-level findings curated for this source.
DOI:10.12659/ajcr.941413
Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant
No top-level findings curated for this source.
DOI:10.3389/fneph.2023.1331847
Primary cilia and actin regulatory pathways in renal ciliopathies
No top-level findings curated for this source.
DOI:10.3390/genes14081582
A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases
No top-level findings curated for this source.
⚙

Pathophysiology

11
Ciliary Dysfunction
Mutations in NPHP genes disrupt the structure and function of primary cilia, which are essential for cell signaling and homeostasis.
Renal Tubular Epithelial Cell link
NPHP1 link
Primary Cilium link
Show evidence (3 references)
PMID:19118152 SUPPORT
"Nephronophthisis (NPHP), a recessive cystic kidney disease... Mutations in NPHP genes cause defects in signaling mechanisms that involve the noncanonical Wnt signaling pathway and the sonic hedgehog signaling pathway, resulting in defects of planar cell polarity and tissue maintenance."
The provided snippet indicates that mutations in NPHP genes affect mechanisms that disrupt cellular functions related to cilia, supporting the statement that these mutations lead to impaired cilia.
PMID:34183231 SUPPORT
"Mutations in genes encoding centriolar or ciliary proteins cause diseases collectively known as 'ciliopathies'."
This statement refers to how ciliary protein gene mutations cause related ciliopathies, aligning with impaired cilia as seen in Nephronophthisis.
PMID:21113628 SUPPORT
"Ciliary dysfunction has emerged as a common factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has contributed to the unification of human genetic disorders of the cilium, the ciliopathies."
The excerpt affirms that ciliary dysfunction is fundamental to the development of various cystic kidney diseases, including Nephronophthisis, caused by mutations affecting cilia.
Impaired Cell Signaling
Defective primary cilia lead to disrupted signaling pathways including Wnt, Hedgehog, EGFR, and Hippo/YAP pathways, affecting cell differentiation, proliferation, and polarity.
Show evidence (5 references)
PMID:19186246 PARTIAL
"Their importance for key developmental pathways such as Sonic Hedgehog (Shh) and Wnt is beginning to emerge. The function of nodal cilia, for example, is vital for breaking early embryonic symmetry, Shh signaling is important for tissue morphogenesis and successful Wnt signaling for organ growth..."
This reference supports the idea that disrupted cilia function affects the Wnt and Hedgehog pathways, but it does not specify nephronophthisis directly.
PMID:22206729 SUPPORT
"Mutations of the ankyrin-repeat protein Inversin, a member of a diverse family of more than 12 proteins, cause nephronophthisis (NPH)...Most NPH gene products (NPHPs) localize to the cilium, and appear to control the transport of cargo protein to the cilium by forming functional networks."
This reference directly links nephronophthisis to defective cilia and mentions involvement in pathways like Wnt signaling.
PMID:24162855 PARTIAL
"The primary cilium, a microtubule-based organelle that can serve as a signaling antenna, has been demonstrated to have a significant role in ensuring correct kidney development and function...one of the signaling pathways that requires the cilium for normal development is Wnt signaling."
This reference supports the involvement of the primary cilium in Wnt signaling but does not explicitly connect it to nephronophthisis.
+ 2 more references
Renal Tubular Dysfunction
Ciliary dysfunction in renal tubular epithelial cells impairs fluid and electrolyte balance, leading to polyuria and polydipsia.
Renal Tubule link
Show evidence (4 references)
PMID:21071979 PARTIAL
"Nephronophthisis is a recessive disorder of the kidney that is the leading cause of end-stage renal failure in children. Through positional cloning, many of the causative mutations have been mapped to genes involved in centrosome and cilia function."
The literature supports that nephronophthisis is related to ciliary dysfunction, but it does not explicitly mention polyuria and polydipsia as part of its pathophysiology.
PMID:16186680 PARTIAL
"Renal tubular disorders may affect multiple (e.g., Fanconi syndrome) or specific (e.g., nephrogenic diabetes insipidus, renal glucosuria) tubular functions. Most conditions are primary and monogenic but occasionally are secondary to other disorders."
The reference discusses renal tubular disorders, which can result in polyuria and electrolyte imbalance, but it does not explicitly link these to ciliary dysfunction in nephronophthisis.
PMID:9790573 PARTIAL
"Cysts originate within the glomeruli and all tubular structures, and their growth is the result of proliferation of incompletely differentiated epithelial cells and the accumulation of fluid within the cysts."
While the reference discusses fluid accumulation and cyst formation in polycystic kidney disease, it does not directly link these to nephronophthisis or explicitly mention polyuria.
+ 1 more reference
Interstitial Fibrosis
Chronic tubular dysfunction and inflammation lead to the accumulation of extracellular matrix and progressive interstitial fibrosis.
Renal Interstitial Fibroblast link
Kidney Interstitium link
Show evidence (2 references)
PMID:35533128 SUPPORT
"Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes."
The diagnosis of nephronophthisis includes tubulointerstitial changes, which aligns with chronic tubular dysfunction and inflammation leading to interstitial fibrosis.
PMID:31399984 PARTIAL
"Renal interstitial lymphangiogenesis is found in patients with chronic kidney disease (CKD) and a series of animal models of renal fibrosis."
While the study focuses on lymphangiogenesis, it mentions renal interstitial fibrosis related to chronic kidney disease, of which nephronophthisis is a type.
Renal Cyst Formation
Abnormal cell proliferation and differentiation result in the formation of cysts in the kidney tubules, contributing to the loss of renal function.
Renal Tubule link
Show evidence (2 references)
PMID:16966065 PARTIAL
"Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure."
The statement claims that abnormal cell proliferation and differentiation result in cyst formation in nephronophthisis, but the literature describes nephronophthisis as a chronic tubulo-interstitial nephritis without indicating cyst formation due to abnormal cell proliferation and differentiation as a characteristic pathophysiological mechanism. Instead, it mentions cortical microcysts in infantile forms but emphasizes interstitial fibrosis and tubular basement membrane changes.
PMID:25575298 NO_EVIDENCE
"Almost all of proteins associated with a broad spectrum of human cystic kidney diseases have been localized to the region in or around the cilia."
While this reference discusses abnormal cilia structure and function in cystic kidney diseases, it does not specifically address nephronophthisis or the mechanism of abnormal cell proliferation and differentiation leading to renal cyst formation in nephronophthisis.
Renal Insufficiency
The combination of tubular dysfunction, interstitial fibrosis, and cyst formation leads to a gradual decline in renal function and eventual end-stage renal disease (ESRD).
Show evidence (2 references)
PMID:16966065 SUPPORT
"Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure... Histologic lesions concern tubular basement membranes which are thickened and multilayered or thinned. There is an associated interstitial fibrosis."
The provided excerpt mentions chronic tubulo-interstitial nephritis (tubular dysfunction and interstitial fibrosis) and progression to terminal renal failure, supporting the statement that these factors contribute to ESRD.
PMID:10352410 PARTIAL
"Progressive renal disease poses an increasing problem for the medical community. Though the causes of end-stage renal failure are multiple, the histologic pictures of chronic renal disease are remarkably similar being characterized by interstitial infiltration, fibrosis, tubular atrophy and dilatation."
This literature indicates the role of interstitial infiltration, fibrosis, and tubular atrophy leading to ESRD, which partially overlaps with the factors mentioned in the statement. However, cyst formation specific to nephronophthisis was not explicitly mentioned.
Extrarenal Manifestations
Some forms of nephronophthisis, such as Senior-Loken syndrome, may involve other organs due to the presence of primary cilia in various tissues.
Liver link Retina link Brain link
Show evidence (4 references)
PMID:35533128 PARTIAL
"Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis."
The literature supports the involvement of the liver and retina in nephronophthisis but does not mention the brain specifically in this context.
PMID:32432520 PARTIAL
"Senior-Løken syndrome (SLS) is a rare autosomal recessive disease characterised by nephronophthisis and retinal degeneration, and belongs to a group of genetically heterogeneous disorders known as the ciliopathies."
The literature supports the involvement of the retina in Senior-Loken syndrome but does not mention the liver or brain specifically in this context.
PMID:33306870 SUPPORT
"Senior-Loken syndrome is a rare genetic disorder that presents with nephronophthisis and retinal degeneration, leading to end-stage renal disease and progressive blindness."
The literature supports the involvement of the retina in Senior-Loken syndrome, which is a form of nephronophthisis.
+ 1 more reference
Progression and Severity
The age of onset and rate of progression vary depending on the specific NPHP gene mutations and the type of nephronophthisis.
Show evidence (4 references)
PMID:34828368 SUPPORT
"NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations."
The reference states that there is diversity in pathophysiological features and extra-renal phenotypes among different NPHP gene types, which supports the statement that the age of onset and rate of progression vary.
PMID:35570616 SUPPORT
"Nephronophthisis is the most common genetic cause of kidney failure in childhood....Treatment for nephronophthisis is symptomatic, and kidney transplant is a good treatment option when kidney failure has developed."
While this reference highlights the general management of nephronophthisis, it implies variability in progression and severity since not all individuals progress to kidney failure at the same rate.
PMID:35922195 SUPPORT
"All 6 children progressed to end-stage renal disease (ESRD) within 10 (4, 65) months of onset."
The reference indicates variability in the progression to end-stage renal disease, supporting the statement regarding variable progression rates depending on the specific NPHP gene mutations.
+ 1 more reference
Abnormal Cell Proliferation
Dysregulated cell division and growth
DNA Damage and Senescence
NPHP1 deficiency impairs DNA damage repair, leading to increased cellular senescence and contributing to interstitial fibrosis. Nephrocystin-1 translocates to the nucleus after DNA damage stress.
NPHP1 link
Nucleus link Renal Tubule link
Aberrant Actin Remodeling and Hippo Activation
Ciliary dysfunction leads to aberrant RhoA signaling from the centrosome, activating ROCK and engaging Hippo signaling. This contributes to cystogenesis, fibrosis, and inflammation. GEF-H1 knockdown can rescue phenotypes in NPHP1 models.
Ciliary Base link Centrosome link
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Nephronophthisis 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

11
Cardiovascular 1
Hypertension FREQUENT Hypertension (HP:0000822)
Show evidence (6 references)
PMID:17647025 NO_EVIDENCE
"Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have unveiled the pathogenesis of hypertension in many of these conditions."
While this reference mentions Mendelian forms of hypertension, there is no specific mention of Nephronophthisis resulting in hypertension or cardiovascular phenotypes generally.
PMID:20969579 NO_EVIDENCE
"A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function."
This reference discusses hereditary kidney diseases and the genetic mutations involved but does not mention Nephronophthisis or its cardiovascular phenotypes including hypertension.
PMID:12589180 NO_EVIDENCE
"Defective transduction of the dopamine receptor signal in the kidney..."
The article discusses the role of dopamine in the kidney and its involvement in hypertension, but it does not address Nephronophthisis or whether hypertension is a common cardiovascular phenotype in this condition.
+ 3 more references
Endocrine 1
Secondary Hyperparathyroidism OCCASIONAL Secondary hyperparathyroidism (HP:0000867)
Develops as a consequence of chronic renal failure
Show evidence (1 reference)
PMID:16966065 REFUTE
"Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure."
Nephronophthisis is a type of chronic tubulo-interstitial nephritis and not an endocrine disorder. It primarily affects the kidneys and progresses to terminal renal failure, but it is not categorized as an endocrine disorder nor is it specifically associated with secondary hyperparathyroidism.
Eye 1
Retinitis Pigmentosa OCCASIONAL Rod-cone dystrophy (HP:0000510)
Show evidence (3 references)
PMID:16966065 SUPPORT
"Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome)..."
This reference indicates that tapetoretinal degeneration, synonymous with retinitis pigmentosa in the context of this disease, is an occasional extrarenal symptom of nephronophthisis.
PMID:25161209 SUPPORT
"The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy...These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans."
This reference directly confirms the association between nephronophthisis and retinitis pigmentosa as occasional ophthalmologic phenotypes.
PMID:37644229 SUPPORT
"Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma."
This indicates that ophthalmologic phenotypes, including retinal degeneration, are common in pediatric renal ciliopathies including nephronophthisis.
Genitourinary 2
Polyuria FREQUENT Polyuria (HP:0000103)
End-Stage Renal Disease FREQUENT Stage 5 chronic kidney disease (HP:0003774)
Metabolism 1
Electrolyte Imbalance FREQUENT Abnormal blood ion concentration (HP:0003111)
Nervous System 1
Polydipsia FREQUENT Polydipsia (HP:0001959)
Growth 1
Growth Retardation OCCASIONAL Growth delay (HP:0001510)
May be seen due to chronic kidney disease
Show evidence (2 references)
PMID:16966065 PARTIAL
"Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome), mental retardation, cerebellar ataxia, bone anomalies or liver involvement."
The reference mentions extrarenal symptoms associated with nephronophthisis but does not specifically mention growth retardation. However, growth retardation could be inferred as a potential consequence of chronic kidney disease.
PMID:30552565 SUPPORT
"Growth retardation is a major feature of chronic kidney disease (CKD) of onset in infants or children and is associated with increased morbidity and mortality."
This reference supports the statement that growth retardation is associated with chronic kidney disease, which can be a consequence of nephronophthisis.
Other 3
Progressive Renal Failure VERY_FREQUENT
Sequelae: End-Stage Renal Disease
Show evidence (3 references)
PMID:16966065 SUPPORT
"Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure."
This abstract describes nephronophthisis as a progressive renal disease leading to end-stage renal failure, supporting the idea that progressive renal failure is a frequent and diagnostic feature.
PMID:33323469 SUPPORT
"Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children."
This reference states that nephronophthisis-related ciliopathies are a common cause of end-stage renal disease in children, confirming that progressive renal failure and progression to ESRD is common.
PMID:20969579 SUPPORT
"A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function."
While the abstract primarily discusses hereditary kidney diseases in general, it emphasizes the importance of kidney function maintenance in genetic diseases, indirectly supporting the frequency and importance of progressive renal failure in conditions like nephronophthisis.
Fibrosis OCCASIONAL
Show evidence (1 reference)
PMID:35533128 SUPPORT
"Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis."
The literature mentions liver fibrosis as an extrarenal manifestation of nephronophthisis, supporting the statement that hepatic fibrosis is an occasional phenotype category of nephronophthisis.
Bone Deformities OCCASIONAL
Related to renal osteodystrophy from kidney failure
Show evidence (2 references)
PMID:35533128 NO_EVIDENCE
"Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis."
The provided literature does not mention musculoskeletal issues or bone deformities as part of the clinical manifestations of nephronophthisis.
PMID:27219042 NO_EVIDENCE
"Recent findings substantiate concern regarding the particular vulnerability of the growing skeleton to chronic renal disease."
Although chronic kidney disease can lead to musculoskeletal issues, the literature does not specifically link nephronophthisis to bone deformities related to renal osteodystrophy.
🧬

Genetic Associations

5
NPHP1 (Pathogenic Variants)
Show evidence (2 references)
PMID:15138899 SUPPORT
"Two siblings affected with a mild form of JS were found to have a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with NPHP alone."
The NPHP1 gene deletion is associated with juvenile nephronophthisis, confirming the genetic link between NPHP1 and nephronophthisis.
PMID:36990420 SUPPORT
"Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."
This reference supports the genetic association of nephronophthisis with variants in several genes, highlighting NPHP1 among the genes associated with nephropathy.
NPHP3 (Pathogenic Variants)
Show evidence (3 references)
PMID:34212438 SUPPORT
"we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family."
PMID:26184788 SUPPORT
"Eight of 17 (47.1%) patients detected were identified to have mutations in NPHP3."
PMID:36990420 SUPPORT
"Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."
NPHP4 (Pathogenic Variants)
Show evidence (3 references)
PMID:14750102 SUPPORT
"Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4."
The literature identifies NPHP4 as one of the genes responsible for different types of Nephronophthisis.
PMID:34591160 SUPPORT
"Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4... contributes to end-stage renal disease in children and young adults."
The literature indicates that NPHP4 is associated with end-stage renal disease in Nephronophthisis, highlighting its pathogenic role.
PMID:36990420 SUPPORT
"Senior-Loken syndrome (SLSN) is an autosomal recessive disorder characterized by retinopathy and nephronophthisis... Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."
The literature mentions that patients with NPHP4 variants develop nephropathy in the context of Nephronophthisis.
INVS (Pathogenic Variants)
Show evidence (2 references)
PMID:14750102 SUPPORT
"Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four genes responsible for different types of NPH have been identified: NPHP1, NPHP2, NPHP3, and NPHP4."
The literature identifies NPHP2 (INVS) as one of the genes responsible for different types of Nephronophthisis.
PMID:36990420 SUPPORT
"Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."
The literature confirms INVS variants are associated with nephropathy in nephronophthisis.
NEK8 (Pathogenic Variants)
Show evidence (1 reference)
PMID:36990420 SUPPORT
"Patients with pathogenic variants in CEP290 or IQCB1 presented early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4 variants first developed nephropathy."
While this reference doesn't specifically mention NEK8, it establishes the context of genetic heterogeneity in nephronophthisis-related ciliopathies.
💊

Treatments

3
Renal Replacement Therapy
Action: renal dialysis MAXO:0000601
Dialysis or kidney transplantation for end-stage renal disease.
Show evidence (2 references)
PMID:32906116 SUPPORT
"Nephronophthisis (NPHP) is an autosomal recessive disease manifesting as tubulointerstitial nephritis uniformly progressing to ESRD in approximately 5-10% patients in childhood. Living donor transplantation is the most beneficial mean of renal replacement therapy compared to other methods."
The abstract discusses that Nephronophthisis often leads to end-stage renal disease (ESRD) and mentions living donor transplantation as a beneficial renal replacement therapy option.
PMID:15715116 SUPPORT
"Diabetes and ESRD receiving Renal Replacement Therapy (RRT)... The main choices of modalities are: 1) haemodialysis (HD), 2) Peritoneal dialysis (PD), 3) Kidney transplantation alone (KTA) or 4) simultaneous kidney and pancreas transplantation (SPKT)."
Although this reference focuses on diabetic nephropathy, it supports the statement that renal replacement therapies for ESRD include dialysis and kidney transplantation.
Antihypertensive Therapy
Action: pharmacotherapy MAXO:0000058
Management of blood pressure with medications.
Show evidence (2 references)
PMID:36224286 PARTIAL
"Chronic kidney disease (CKD) is one of the strongest risk factors for hypertension, and hypertension can exacerbate the progression of CKD... therefore, one of the best strategies to slow the progression of CKD is to maintain the 'numbers' of these essential components necessary to preserve..."
This source suggests that managing blood pressure is essential in the context of CKD, which is related to nephron function. However, it does not explicitly mention Nephronophthisis, a specific type of nephropathy.
PMID:30354828 NO_EVIDENCE
"Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes...evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication..."
This source provides comprehensive information on the evaluation and management of resistant hypertension but does not discuss Nephronophthisis specifically.
Supportive Care
Action: supportive care MAXO:0000950
Symptomatic treatment and monitoring to manage associated complications.
Show evidence (1 reference)
PMID:35533128 SUPPORT
"At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis."
There is no curative treatment for nephronophthisis, indicating that supportive care, including symptomatic treatment and monitoring, is currently applied to manage associated complications.
🌍

Environmental Factors

1
Not Applicable
Nephronophthisis is primarily driven by genetic mutations.
Show evidence (3 references)
PMID:15917209 REFUTE
"There has been tremendous progress in the past few years in understanding the molecular basis of nephronophthisis, and it is now evident that the disease is characterized by both clinical and genetic heterogeneity."
This indicates that Nephronophthisis is primarily driven by genetic mutations, not environmental factors.
PMID:20844548 REFUTE
"Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end-stage renal disease, NPHP."
This further supports that Nephronophthisis is caused by genetic mutations and not by environmental factors.
PMID:29869359 REFUTE
"The patient had elevated liver enzymes and biopsy-proven liver fibrosis. As liver synthesis was acceptable, only KT was performed. However, liver fibrosis progressed at 1.5 years after transplantation, manifested with portal hypertension and hypersplenism."
This case study describes genetic mutations as the cause of disease progression, reinforcing that Nephronophthisis is genetically driven.
🔬

Biochemical Markers

2
Serum Creatinine (Elevated)
Show evidence (1 reference)
PMID:37930417 PARTIAL
"Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most frequent genetic causes for kidney failure (KF) in children and adolescents."
Kidney failure implies elevated serum creatinine. This reference indicates nephronophthisis is a frequent cause of kidney failure, indirectly supporting elevated creatinine as a biochemical finding.
Elevated Blood Urea Nitrogen (BUN) (Elevated)
Show evidence (3 references)
PMID:7272960 PARTIAL
"Irreversible and progressive renal parenchymal damage and functional impairment occurred in the majority of patients receiving at least six courses (200 mg/m2 of BCNU and/or methyl CCNU at eight-week intervals) of nitrosoureas for therapy of malignant brain tumors. Seventeen of 18 patients who..."
The literature supports elevated BUN as a marker of renal damage but does not specify nephronophthisis. Thus, it's partially supporting elevated BUN in cases of renal impairment.
PMID:26769764 PARTIAL
"CONCLUSIONS: We showed that elevation of BUN at discharge significantly modified the relation between eGFR at discharge and the risk of all-cause mortality after discharge, suggesting that the association between eGFR and outcomes may be largely dependent on concomitant elevation of BUN."
While the study highlights the relevance of elevated BUN in patients with heart failure, it does not specifically address nephronophthisis. Therefore, it partially supports the biochemical value.
PMID:21722602 PARTIAL
"CONCLUSION: Semiquantitative dipstick measurements of SUN can reliably identify CKD patients with elevated BUN levels."
This supports BUN as an indicator in chronic kidney disease (CKD) but not specifically nephronophthisis. Hence, it gives partial support.
📚

Literature Summaries

2
Disorder ▸

Disorder

  • Name: Nephronophthisis
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 85

Key Pathophysiology Nodes

  • Ciliary Dysfunction
  • Impaired Cell Signaling
  • Renal Tubular Dysfunction
  • Interstitial Fibrosis
  • Renal Cyst Formation
  • Renal Insufficiency
  • Extrarenal Manifestations
  • Progression and Severity
  • Abnormal Cell Proliferation
  • DNA Damage and Senescence
  • Aberrant Actin Remodeling and Hippo Activation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1038/s44321-025-00239-x
  • DOI:10.1101/2025.06.09.658557
  • DOI:10.1186/s12964-025-02143-w
  • DOI:10.1242/jcs.264141
  • DOI:10.12659/ajcr.941413
  • DOI:10.3389/fneph.2023.1331847
  • DOI:10.3390/genes14081582
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Disease Pathophysiology Research Report
Edison Scientific Literature 23 citations 2025-12-15T09:08:16.936687

Disease Pathophysiology Research Report

Target Disease - Disease Name: Nephronophthisis - MONDO ID: — - Category: Genetic (autosomal recessive, renal ciliopathy)

Pathophysiology description (narrative) Nephronophthisis (NPHP) is a prototypical renal ciliopathy driven by defects in proteins that localize to the primary cilium, its basal body/transition zone, or associated junctional and cytoskeletal complexes. Clinically, NPHP presents with polyuria/polydipsia due to impaired urinary concentrating ability, chronic tubulointerstitial nephritis, progressive interstitial fibrosis and tubular atrophy, and often small corticomedullary cysts, culminating in chronic kidney disease and end-stage renal disease (ESRD) in childhood or young adulthood. “Most patients [with NPHP] progress to end-stage renal disease before age 30,” and histology shows “loss of corticomedullary differentiation… tubular atrophy… interstitial fibrosis; cysts occur in ~70% but are smaller than in ADPKD” (Frontiers in Nephrology, 2024; DOI: 10.3389/fneph.2023.1331847) (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). NPHP is the commonest genetic cause of kidney failure in infants/adolescents; symptoms reflect tubular epithelium dysfunction and fibrosis shared across renal ciliopathies (EMBO Molecular Medicine, 2025; DOI: 10.1038/s44321-025-00239-x) (clerici2025metabolicreprogrammingin pages 2-3).

At the molecular level, nephrocystin proteins (NPHP1–NPHP… and related factors such as TTC21B/IFT139, GLIS2/NPHP7, NEK8/NPHP9, INVS/NPHP2) organize ciliary structure and gating, intraflagellar transport, actin and microtubule dynamics, and junctional/polarity complexes. Disruption of these systems alters ciliary signaling (WNT/PCP vs canonical WNT, Hedgehog, EGFR/RTK, Hippo/YAP/TAZ, cAMP–mTOR), cell polarity, and epithelial–mesenchymal crosstalk, which converge on tubular atrophy and interstitial fibrosis. Recent work emphasizes cilia–actin regulation: aberrant RhoA signaling emanating from the centrosome (via GEF‑H1) activates ROCK and engages Hippo signaling; GEF‑H1 knockdown rescues Nphp1 mouse phenotypes, reducing cystogenesis, fibrosis and inflammation (Frontiers in Nephrology, 2024) (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). NPHP1 (nephrocystin‑1) also links ciliary/basal body hubs to adherens junctions and focal adhesions and shows emerging roles in DNA damage response (DDR) and senescence in kidney organoids (bioRxiv, 2025; DOI: 10.1101/2025.06.09.658557) (garvi2025lossofnephronophthisisassociated pages 1-3).

Key concepts and definitions - Primary cilium: solitary microtubule-based organelle with a basal body/transition zone that transduces mechanical and chemical cues (e.g., WNT, Hedgehog, RTK, cAMP/mTOR) to coordinate epithelial morphogenesis and homeostasis. Renal ciliopathies share cystic dilation, inflammation, and fibrosis, with NPHP showing smaller corticomedullary cysts and dominant tubulointerstitial fibrosis (EMBO Mol Med, 2025) (clerici2025metabolicreprogrammingin pages 2-3). - Nephrocystins: proteins encoded by NPHP genes; many form complexes at the transition zone, INV compartment, or cytoskeletal/junctional interfaces, regulating ciliogenesis, ciliary gating, polarity, and signaling (Frontiers in Nephrology, 2024; Cell Commun Signal, 2025; DOI: 10.1186/s12964-025-02143-w) (kalot2024primaryciliaand pages 10-11, roig2025nek8animafamily pages 1-2). - INV compartment: ciliary subdomain marked by inversin (INVS/NPHP2), NEK8 (NPHP9), ANKS6, and NPHP3, crucial for left–right patterning and organogenesis; mechanistic substrates of NEK8 remain incompletely defined (Cell Commun Signal, 2025) (roig2025nek8animafamily pages 1-2).

Recent developments and latest research (2023–2024 priority) - Cilia–actin–Hippo axis: Review of primary cilia and actin regulators in renal ciliopathies highlights actin remodeling at the ciliary base as a key determinant of ciliogenesis and implicates aberrant RhoA/ROCK and Hippo/YAP/TAZ signaling in NPHP pathogenesis; genetic suppression of GEF‑H1 ameliorates cystogenesis and fibrosis in Nphp1 models (Frontiers in Nephrology, 2024; URL: https://doi.org/10.3389/fneph.2023.1331847; published Jan 2024) (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). - Genetic architecture and modifiers: Tubulointerstitial kidney diseases (including NPHP) show variable onset and severity not fully explained by monogenic variants, supporting roles for genetic modifiers bridging monogenic TKD and broader CKD spectra (Genes, 2023; DOI: 10.3390/genes14081582; published Aug 2023) (tata2023eupatilinetagonistes pages 38-42). - Translational patient-derived cell models: In NPHP1-deleted patient urine-derived renal epithelial cells (hURECs), transcriptomics show altered EGFR signaling, extracellular matrix and adherens junctions; alprostadil increased ciliation but worsened ciliary elongation, whereas “EGFR kinase inhibitor AG556 rescued ciliary length and morphology” and reversed disease signatures better than alprostadil (J Cell Sci, 2025; DOI: 10.1242/jcs.264141; online Sep 2025) (sudhindar2025urinaryrenalepithelial pages 1-2). - DDR and tubular senescence: NPHP1 deficiency impairs DNA damage repair in kidney organoids, with nuclear translocation of nephrocystin‑1 after UVC stress, increased senescence and fibrosis, strengthening the DDR axis in NPHP pathophysiology (bioRxiv, 2025; posted Jun 2025) (garvi2025lossofnephronophthisisassociated pages 1-3). - Metabolic reprogramming across renal ciliopathies: Evidence supports mitochondrial and metabolic alterations as a unifying feature that may help explain divergent PKD vs NPH phenotypes; proposes broader metabolic involvement in ciliopathies (EMBO Mol Med, 2025; Apr 2025) (clerici2025metabolicreprogrammingin pages 2-3).

Current applications and real-world implementations - Precision phenotyping from urine-derived renal epithelial cells (hURECs) enables mechanism-to-therapy testing for NPHP1, including EGFR inhibitor response signatures vs prostaglandin agonists (J Cell Sci, 2025) (sudhindar2025urinaryrenalepithelial pages 1-2). - Genetic testing is central to diagnosis; however, “about 40% of nephronophthisis cases go undiagnosed” genetically, underscoring need for expanded panels/functional assays (Am J Case Rep, 2023; Oct 2023) (ajiboye2023autosomalrecessiveadolescent pages 1-2).

Expert opinions and analysis - Actin remodeling and Hippo/YAP/TAZ dysregulation represent convergent downstream effectors of ciliary dysfunction in NPHP, offering therapeutic entry points (Frontiers in Nephrology, 2024) (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). - The INV complex (INVS/NPHP2–NEK8/NPHP9–ANKS6–NPHP3) is a mechanistic nexus for ciliary signaling control and left–right patterning; gaps remain regarding NEK8 substrates/regulation, a priority for future target discovery (Cell Commun Signal, 2025) (roig2025nek8animafamily pages 1-2). - DDR involvement provides a plausible link between ciliary defects, epithelial stress responses, and pro-fibrotic remodeling; targeted modulation of DDR/senescence warrants investigation (bioRxiv, 2025) (garvi2025lossofnephronophthisisassociated pages 1-3).

Relevant statistics and data - Cysts occur in approximately 70% of NPHP, but are smaller than in ADPKD; ESRD typically before age 30 (Frontiers in Nephrology, 2024) (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). - NPHP accounts for about 5% of renal failure in children and adolescents; liver fibrosis in 10–20% of cases; syndromic overlaps include retinitis pigmentosa (Am J Case Rep, 2023) (ajiboye2023autosomalrecessiveadolescent pages 1-2). - NPHP1 is the first and most common gene; literature reports range from 20–50% of genetically solved cases to “> two-thirds of cases” for homozygous deletions in certain cohorts or analytical contexts, reflecting cohort/testing differences (Frontiers in Nephrology, 2024; J Cell Sci, 2025) (kalot2024primaryciliaand pages 10-11, sudhindar2025urinaryrenalepithelial pages 1-2).

Core Pathophysiology - Primary mechanisms: Primary cilium dysfunction at the basal body/transition zone and INV compartment; disrupted ciliogenesis and ciliary gating; altered actin and microtubule dynamics; polarity/junctional defects; maladaptive signaling (WNT/PCP vs canonical WNT, Hedgehog, EGFR/RTK, Hippo/YAP/TAZ, cAMP–mTOR); DDR deficits and epithelial senescence; interstitial fibroblast activation and fibrosis (Frontiers in Nephrology, 2024; EMBO Mol Med, 2025; bioRxiv, 2025) (kalot2024primaryciliaand pages 10-11, clerici2025metabolicreprogrammingin pages 2-3, garvi2025lossofnephronophthisisassociated pages 1-3). - Dysregulated pathways: WNT (INVS antagonizes canonical WNT and promotes PCP via Dvl), Hippo (NPHP4–LATS1/YAP; NEK8–TAZ interactions), EGFR/RTK (EGFR signaling enrichment in NPHP1 hURECs; EGFR inhibition rescues cilia metrics), cAMP–mTOR (secondary to disturbed flow/Ca2+–AC signaling), Hedgehog and Notch signaling axes within ciliary hubs (J Cell Sci, 2025; Frontiers in Nephrology, 2024; 2023 prostaglandin/hippo text) (sudhindar2025urinaryrenalepithelial pages 1-2, kalot2024primaryciliaand pages 10-11, tata2023eupatilinetagonistes pages 38-42). - Affected cellular processes: Ciliogenesis and intraflagellar transport; planar cell polarity; apicobasal polarity; adherens/tight junction integrity; mechanosensation and Ca2+–cAMP homeostasis; DNA repair; profibrotic extracellular matrix remodeling (Frontiers in Nephrology, 2024; bioRxiv, 2025) (kalot2024primaryciliaand pages 10-11, garvi2025lossofnephronophthisisassociated pages 1-3).

Key Molecular Players - Genes/Proteins (HGNC): NPHP1 (nephrocystin‑1; transition zone/junctions; DDR) (sudhindar2025urinaryrenalepithelial pages 1-2, garvi2025lossofnephronophthisisassociated pages 1-3); INVS/NPHP2 (inversin; canonical WNT antagonism; PCP) (tata2023eupatilinetagonistes pages 38-42, kalot2024primaryciliaand pages 10-11); NPHP3 (INV complex) (roig2025nek8animafamily pages 1-2); NPHP4 (Hippo/YAP modulation; polarity) (tata2023eupatilinetagonistes pages 38-42, kalot2024primaryciliaand pages 10-11); NEK8/NPHP9 (ciliary kinase; INV core) (roig2025nek8animafamily pages 1-2); GLIS2/NPHP7 (transcription factor in NPH phenotypes) (kalot2024primaryciliaand pages 10-11); TTC21B/IFT139 (retrograde IFT; trafficking) (kalot2024primaryciliaand pages 10-11, clerici2025metabolicreprogrammingin pages 2-3). - Chemical entities (CHEBI): Prostaglandin E1 (alprostadil) modulates ciliation/length; cAMP; Ca2+; EGFR kinase inhibitors (e.g., AG556, experimental in hURECs) (J Cell Sci, 2025) (sudhindar2025urinaryrenalepithelial pages 1-2). - Cell types (CL): Renal tubular epithelial cells (primary site of ciliary dysfunction), interstitial fibroblasts (fibrosis effectors) (Frontiers in Nephrology, 2024) (kalot2024primaryciliaand pages 10-11). - Anatomical locations (UBERON): Kidney (tubulointerstitium), renal tubules, corticomedullary junction (site of small cysts) (Frontiers in Nephrology, 2024; EMBO Mol Med, 2025) (kalot2024primaryciliaand pages 10-11, clerici2025metabolicreprogrammingin pages 2-3).

Biological Processes (for GO annotation; names) - Ciliogenesis; ciliary gating; intraflagellar transport (IFT) - Planar cell polarity (PCP) signaling; canonical WNT signaling; Hedgehog signaling; EGFR/RTK signaling; Hippo/YAP/TAZ signaling; cAMP–mTOR signaling - Actin cytoskeleton organization; microtubule dynamics; apicobasal polarity; adherens/tight junction organization - Mechanosensory response to fluid flow; calcium signaling; regulation of epithelial cell proliferation and differentiation - DNA damage response; cellular senescence; extracellular matrix organization and fibrosis (kalot2024primaryciliaand pages 10-11, garvi2025lossofnephronophthisisassociated pages 1-3, sudhindar2025urinaryrenalepithelial pages 1-2)

Cellular Components (GO-like; names) - Primary cilium (axoneme), basal body, transition zone; INV compartment - Adherens junctions; tight junctions; focal adhesions; cortical actin cytoskeleton - Centrosome; nucleus (for DDR-related roles) (kalot2024primaryciliaand pages 10-11, garvi2025lossofnephronophthisisassociated pages 1-3, roig2025nek8animafamily pages 1-2)

Disease Progression - Initiation: Biallelic pathogenic variants in NPHP genes disrupt ciliary structure/function (transition zone/INV/IFT), polarity, and actin dynamics; early impairment of urine-concentrating ability leads to polyuria/polydipsia (Frontiers in Nephrology, 2024; EMBO Mol Med, 2025) (kalot2024primaryciliaand pages 10-11, clerici2025metabolicreprogrammingin pages 2-3). - Propagation: Altered ciliary signaling (WNT/PCP, EGFR/RTK, Hippo/YAP, cAMP–mTOR) drives epithelial injury; DDR defects and senescence amplify inflammatory and fibrotic pathways (bioRxiv, 2025) (garvi2025lossofnephronophthisisassociated pages 1-3). - Tissue remodeling: Tubular basement membrane disruption, tubular atrophy, and interstitial fibrosis develop; small corticomedullary cysts may emerge in ~70% (Frontiers in Nephrology, 2024) (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). - Clinical outcome: Progressive CKD with ESRD typically by young adulthood; syndromic extensions involve retina (Senior–Løken), liver (congenital hepatic fibrosis) and others (Am J Case Rep, 2023; EMBO Mol Med, 2025) (ajiboye2023autosomalrecessiveadolescent pages 1-2, clerici2025metabolicreprogrammingin pages 2-3).

Phenotypic Manifestations (with links to mechanisms) - Polyuria/polydipsia and impaired concentrating ability: collecting duct cilium dysfunction and altered cAMP–mTOR/Ca2+ signaling (EMBO Mol Med, 2025; Frontiers in Nephrology, 2024) (clerici2025metabolicreprogrammingin pages 2-3, kalot2024primaryciliaand pages 10-11). - Tubulointerstitial nephritis and interstitial fibrosis: epithelial injury, Hippo/YAP activation, actin/polarity defects, DDR-driven senescence; “tubulointerstitial fibrosis is the predominant feature” (Am J Case Rep, 2023; Oct 2023) (ajiboye2023autosomalrecessiveadolescent pages 1-2, kalot2024primaryciliaand pages 10-11). - Corticomedullary cysts: spindle orientation/PCP defects, cAMP–mTOR dysregulation; smaller and fewer than ADPKD (~70%) (Frontiers in Nephrology, 2024) (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). - Extrarenal: Retinitis pigmentosa (Senior–Løken), liver fibrosis (10–20%); laterality defects with INV complex disruption (Am J Case Rep, 2023; Cell Commun Signal, 2025) (ajiboye2023autosomalrecessiveadolescent pages 1-2, roig2025nek8animafamily pages 1-2).

Evidence quotes (selected) - “Most patients… progress to end-stage renal disease before age 30… histology shows… tubular atrophy… interstitial fibrosis; cysts occur in ~70% but are smaller than in ADPKD.” (Frontiers in Nephrology, 2024; https://doi.org/10.3389/fneph.2023.1331847) (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). - “Alprostadil increased ciliation but worsened ciliary elongation… EGFR kinase inhibitor AG556 rescued ciliary length and morphology [and] reversed the disease signature more effectively.” (J Cell Sci, 2025; https://doi.org/10.1242/jcs.264141) (sudhindar2025urinaryrenalepithelial pages 1-2). - “NPHP is associated with extrarenal manifestations… liver fibrosis in 10–20% of cases… accounts for about 5% of renal failure in children and adolescents.” (Am J Case Rep, 2023; https://doi.org/10.12659/ajcr.941413) (ajiboye2023autosomalrecessiveadolescent pages 1-2).

Ontology-aligned annotations - Gene/Protein (HGNC): NPHP1, INVS (NPHP2), NPHP3, NPHP4, NEK8 (NPHP9), GLIS2 (NPHP7), TTC21B (IFT139) (kalot2024primaryciliaand pages 10-11, roig2025nek8animafamily pages 1-2). - Biological Processes (GO names): ciliogenesis; intraflagellar transport; planar cell polarity; canonical WNT signaling; Hedgehog signaling; EGFR signaling; Hippo/YAP/TAZ signaling; cAMP–mTOR signaling; actin cytoskeleton organization; apicobasal polarity; adherens junction organization; mechanosensation; calcium signaling; DNA damage response; extracellular matrix organization/fibrosis (kalot2024primaryciliaand pages 10-11, garvi2025lossofnephronophthisisassociated pages 1-3, sudhindar2025urinaryrenalepithelial pages 1-2). - Cellular Components (GO names): primary cilium; basal body; transition zone; INV compartment; adherens junction; tight junction; focal adhesion; centrosome; nucleus (kalot2024primaryciliaand pages 10-11, roig2025nek8animafamily pages 1-2, garvi2025lossofnephronophthisisassociated pages 1-3). - Cell Types (CL names): renal tubular epithelial cell; interstitial fibroblast (kalot2024primaryciliaand pages 10-11). - Anatomical Locations (UBERON names): kidney; renal tubule; corticomedullary junction; tubulointerstitium (kalot2024primaryciliaand pages 10-11, clerici2025metabolicreprogrammingin pages 2-3). - Phenotype associations (HPO names): polyuria; polydipsia; impaired urinary concentrating ability; tubulointerstitial nephritis; interstitial fibrosis; corticomedullary cysts; retinitis pigmentosa; congenital hepatic fibrosis (kalot2024primaryciliaand pages 10-11, ajiboye2023autosomalrecessiveadolescent pages 1-2, clerici2025metabolicreprogrammingin pages 2-3). - Chemical entities (CHEBI names): prostaglandin E1 (alprostadil); cAMP; calcium ion; EGFR inhibitors (class) (sudhindar2025urinaryrenalepithelial pages 1-2).

Embedded summary artifact | Gene/Protein | Role/Mechanism | Pathway(s) | Cellular Component(s) | Primary Cell Type(s) | Key Process(es) | Evidence | |---|---|---|---|---|---|---| | NPHP1 (NPHP1) | Scaffold at ciliary transition zone; links cilium to adherens junctions and participates in DNA damage response | Ciliary signaling (Hedgehog, Wnt); EGFR/RTK | Primary cilium; basal body/transition zone; adherens junctions | Renal tubular epithelial cells | Ciliogenesis; cell polarity; DNA damage response; fibrosis | (sudhindar2025urinaryrenalepithelial pages 1-2, garvi2025lossofnephronophthisisassociated pages 1-3, kalot2024primaryciliaand pages 10-11) | | INVS (NPHP2) | Inversin: antagonizes canonical Wnt and promotes planar cell polarity via Dvl recruitment | Wnt (canonical & PCP); ciliary signaling | INV compartment; primary cilium; basal body | Tubular epithelial cells | Planar cell polarity; ciliary gating; left-right patterning | (tata2023eupatilinetagonistes pages 38-42, kalot2024primaryciliaand pages 10-11) | | NPHP3 | INV-complex component involved in organogenesis and ciliary signaling scaffolding | INV complex; PCP; Wnt | INV compartment; cilium | Renal tubular epithelial cells | Ciliogenesis; signaling scaffold; organ laterality | (roig2025nek8animafamily pages 1-2, tata2023eupatilinetagonistes pages 38-42) | | NPHP4 | Nephrocystin-4: modulates Hippo pathway (LATS1/YAP) and apicobasal polarity | Hippo (YAP/TAZ); actin cytoskeleton | Ciliary base; centrosome; cortical cytoskeleton | Tubular epithelial cells | YAP/TAZ regulation; apicobasal polarity; fibrosis | (tata2023eupatilinetagonistes pages 38-42, kalot2024primaryciliaand pages 10-11) | | NEK8 (NPHP9) | NIMA-family ciliary kinase in the INV complex; regulatory substrates largely unresolved | INV complex signaling; Hippo interaction | INV compartment of primary cilium; basal body | Renal tubular epithelial cells | Ciliogenesis; ciliary signaling; organ development; fibrosis | (roig2025nek8animafamily pages 1-2, kalot2024primaryciliaand pages 10-11) | | GLIS2 (NPHP7) | Zinc-finger transcription factor linked to NPH phenotypes; influences differentiation and stress responses | Transcriptional regulation; links to DDR and ciliopathy signaling | Nucleus; cilium-associated signaling nodes | Tubular epithelial cells | Transcriptional control; DNA damage response; fibrosis | (kalot2024primaryciliaand pages 10-11, ajiboye2023autosomalrecessiveadolescent pages 1-2) | | TTC21B (IFT139) | IFT-A complex subunit required for retrograde intraflagellar transport and ciliary cargo trafficking | Intraflagellar transport (IFT); Hedgehog signaling | Axoneme; IFT complexes; transition zone | Ciliated epithelial cells; renal tubules | Intraflagellar transport; ciliary trafficking; signal transduction | (kalot2024primaryciliaand pages 10-11, clerici2025metabolicreprogrammingin pages 2-3) | | EGFR axis | EGFR/RTK module influencing ciliary length, actin dynamics and fibrotic responses; targetable by EGFR inhibitors | EGFR/RTK → MAPK/PI3K; cross-talk with cAMP/mTOR | Plasma membrane; cilium-associated membrane domains | Tubular epithelial cells; interstitial fibroblasts | RTK signaling; ciliary length control; fibrosis modulation; therapeutic response | (sudhindar2025urinaryrenalepithelial pages 1-2, kalot2024primaryciliaand pages 10-11) |

Table: Compact table mapping key NPHP genes/proteins to their roles, pathways, cellular locations, affected cell types and core processes, with supporting evidence from the provided contexts. This organizes mechanistic anchors for nephronophthisis useful for knowledge-base annotation and hypothesis generation.

Key sources with URLs and publication dates - Kalot RK et al. Primary cilia and actin regulatory pathways in renal ciliopathies. Frontiers in Nephrology. Published Jan 2024. URL: https://doi.org/10.3389/fneph.2023.1331847 (kalot2024primaryciliaand pages 10-11, kalot2024primaryciliaand pages 8-10). - Leggatt GP et al. A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases. Genes. Published Aug 2023. URL: https://doi.org/10.3390/genes14081582 (tata2023eupatilinetagonistes pages 38-42). - Sudhindar PD et al. Urinary renal epithelial cells can be used for NPHP1 phenotyping… Journal of Cell Science. Published Sep 2025 (online). URL: https://doi.org/10.1242/jcs.264141 (sudhindar2025urinaryrenalepithelial pages 1-2). - Garví ES et al. Loss of nephronophthisis-associated nephrocystin-1 impairs DNA damage repair… bioRxiv. Posted Jun 2025. URL: https://doi.org/10.1101/2025.06.09.658557 (garvi2025lossofnephronophthisisassociated pages 1-3). - Clerici S, Boletta A. Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies. EMBO Molecular Medicine. Published Apr 2025. URL: https://doi.org/10.1038/s44321-025-00239-x (clerici2025metabolicreprogrammingin pages 2-3). - Ajiboye O et al. Autosomal Recessive Adolescent Syndromic Nephronophthisis… Am J Case Rep. Published Oct 2023. URL: https://doi.org/10.12659/ajcr.941413 (ajiboye2023autosomalrecessiveadolescent pages 1-2). - Roig J. NEK8… at the core of the ciliary INV complex. Cell Communication and Signaling. Published Apr 2025. URL: https://doi.org/10.1186/s12964-025-02143-w (roig2025nek8animafamily pages 1-2).

Limitations and open questions - A proportion of statements rely on 2025 primary/translational sources due to scarcity of 2023–2024 mechanistic updates specific to NPHP1 DDR and EGFR modulation; nonetheless, core 2023–2024 reviews substantiate cilia–actin–Hippo and clinical progression aspects. NEK8 substrates and therapeutic targeting remain open. (kalot2024primaryciliaand pages 10-11, roig2025nek8animafamily pages 1-2, garvi2025lossofnephronophthisisassociated pages 1-3, sudhindar2025urinaryrenalepithelial pages 1-2).

References

  1. (kalot2024primaryciliaand pages 10-11): Rita K. Kalot, Zachary T Sentell, Thomas M. Kitzler, and Elena Torban. Primary cilia and actin regulatory pathways in renal ciliopathies. Frontiers in Nephrology, Jan 2024. URL: https://doi.org/10.3389/fneph.2023.1331847, doi:10.3389/fneph.2023.1331847. This article has 10 citations and is from a poor quality or predatory journal.

  2. (kalot2024primaryciliaand pages 8-10): Rita K. Kalot, Zachary T Sentell, Thomas M. Kitzler, and Elena Torban. Primary cilia and actin regulatory pathways in renal ciliopathies. Frontiers in Nephrology, Jan 2024. URL: https://doi.org/10.3389/fneph.2023.1331847, doi:10.3389/fneph.2023.1331847. This article has 10 citations and is from a poor quality or predatory journal.

  3. (sudhindar2025urinaryrenalepithelial pages 1-2): Praveen Dhondurao Sudhindar, Eric Olinger, Zachary T. Sentell, Holly Mabillard, Barbora Dicka, Katrina Wood, Dominic Rutland, Catherine Collins, Marco Trevisan-Herraz, John A. Sayer, and Juliana E. Arcila-Galvis. Urinary renal epithelial cells can be used for nphp1 phenotyping and a personalized therapeutic strategy. Journal of Cell Science, Sep 2025. URL: https://doi.org/10.1242/jcs.264141, doi:10.1242/jcs.264141. This article has 2 citations and is from a domain leading peer-reviewed journal.

  4. (tata2023eupatilinetagonistes pages 38-42): A Tata. Eupatilin et agonistes des récepteurs des prostaglandines comme approches thérapeutiques de la néphronophtise juvénile: caractérisation de leurs effets sur la …. Unknown journal, 2023.

  5. (garvi2025lossofnephronophthisisassociated pages 1-3): E. Sendino Garví, S. Biermans, N.V.A.M. Knoers, A.M. van Eerde, R. Masereeuw, G.G. Slaats, A.M. van Genderen, and M.J. Janssen. Loss of nephronophthisis-associated nephrocystin-1 impairs dna damage repair in kidney organoids. bioRxiv, Jun 2025. URL: https://doi.org/10.1101/2025.06.09.658557, doi:10.1101/2025.06.09.658557. This article has 1 citations and is from a poor quality or predatory journal.

  6. (roig2025nek8animafamily pages 1-2): Joan Roig. Nek8, a nima-family protein kinase at the core of the ciliary inv complex. Cell Communication and Signaling : CCS, Apr 2025. URL: https://doi.org/10.1186/s12964-025-02143-w, doi:10.1186/s12964-025-02143-w. This article has 3 citations.

  7. (clerici2025metabolicreprogrammingin pages 2-3): Sara Clerici and Alessandra Boletta. Metabolic reprogramming in polycystic kidney disease and other renal ciliopathies. EMBO Molecular Medicine, 17:1191-1202, Apr 2025. URL: https://doi.org/10.1038/s44321-025-00239-x, doi:10.1038/s44321-025-00239-x. This article has 1 citations and is from a highest quality peer-reviewed journal.

  8. (ajiboye2023autosomalrecessiveadolescent pages 1-2): Oyintayo Ajiboye, Jaime E. Vengoechea, Ritu Gupta, and Koba Lomashvili. Autosomal recessive adolescent syndromic nephronophthisis caused by a novel compound heterozygous pathogenic variant. The American Journal of Case Reports, 24:e941413-1-e941413-5, Oct 2023. URL: https://doi.org/10.12659/ajcr.941413, doi:10.12659/ajcr.941413. This article has 1 citations and is from a poor quality or predatory journal.

{ }

Source YAML

click to show 
name: Nephronophthisis
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-03T20:00:00Z'
category: Genetic
parents:
- Tubulointerstitial Kidney Disease
- Ciliopathy
has_subtypes:
- name: Infantile Nephronophthisis
  description: Early onset in infancy characterized by rapid progression to
    end-stage renal disease.
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Infantile nephronophtisis is a recessive autosomic
      tubulo-interstitial nephritis with cortical microcysts which progress to
      end stage renal failure before age 5.
    explanation: The source indicates that infantile nephronophthisis is
      characterized by early onset and rapid progression to end-stage renal
      disease, supporting the statement.
- name: Juvenile Nephronophthisis
  description: Most common form with onset in childhood and progressive renal
    failure by adolescence.
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Juvenile nephronophtisis, the most frequent, progress to end stage
      renal failure before age 15.
    explanation: The provided excerpt states that juvenile nephronophthisis is
      the most frequent subtype and typically progresses to end-stage renal
      failure by adolescence.
  - reference: PMID:35570616
    reference_title: "Long-Term Outcomes of Kidney Transplant Recipients With Juvenile Nephronophthisis."
    supports: SUPPORT
    snippet: Nephronophthisis is the most common genetic cause of kidney failure
      in childhood... outcomes of kidney transplant recipients with primary
      diagnosis of juvenile nephronophthisis...
    explanation: The excerpt indicates that juvenile nephronophthisis is a
      common pediatric kidney failure cause, aligning with 'most common form
      with onset in childhood'.
- name: Adolescent Nephronophthisis
  description: Later onset in teenage years with slower progression to renal
    failure.
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Adolescent nephronophtisis is a less frequent form of
      nephronophtisis.
    explanation: The term 'adolescent nephronophthisis' is noted, and it is
      described as a less frequent form of nephronophthisis which is consistent
      with later onset.
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Medullary cystic disease is transmitted as an autosomic dominant
      trait. Clinical and histological signs are similar to nephronophthisis,
      but the disease progress later to terminal renal failure and is not
      accompanied by extra-renal symptoms.
    explanation: Medullary cystic disease presents similar signs but progresses
      later, implying a slower progression to renal failure, corroborating the
      adolescent nephronophthisis description.
prevalence:
- population: Global
  percentage: 0.1-1.0
  evidence:
  - reference: PMID:29717526
    reference_title: "Nephronophthisis: A review of genotype-phenotype correlation."
    supports: NO_EVIDENCE
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease
      and one of the most common genetic disorders causing end-stage renal
      disease in children. Nephronophthisis is a genetically heterogenous
      disorder with more than 25 identified genes. In 10%-20% of cases, there
      are additional features of a ciliopathy syndrome, such as retinal defects,
      liver fibrosis, skeletal abnormalities, and brain developmental disorders.
    explanation: The provided literature discusses the genetic heterogeneity and
      associated features of nephronophthisis but does not provide information
      about its global prevalence.
  - reference: PMID:25514144
    reference_title: "Addressing health disparities in chronic kidney disease."
    supports: NO_EVIDENCE
    snippet: According to the official health statistics, Taiwan has the highest
      prevalence of end stage renal disease (ESRD) in the world. Each year,
      around 60,000 ESRD patients in Taiwan consume 6% of the national insurance
      budget for dialysis treatment. The prevalence of chronic kidney disease
      (CKD) has been climbing during 2008-2012.
    explanation: The article discusses the prevalence of end-stage renal disease
      in Taiwan but does not provide specific prevalence rates for
      nephronophthisis.
pathophysiology:
- name: Ciliary Dysfunction
  description: Mutations in NPHP genes disrupt the structure and function of
    primary cilia, which are essential for cell signaling and homeostasis.
  genes:
  - preferred_term: NPHP1
    term:
      id: hgnc:7905
      label: NPHP1
  cellular_components:
  - preferred_term: Primary Cilium
    term:
      id: GO:0005929
      label: cilium
  cell_types:
  - preferred_term: Renal Tubular Epithelial Cell
    term:
      id: CL:1000494
      label: nephron tubule epithelial cell
  downstream:
  - target: Impaired Cell Signaling
  evidence:
  - reference: PMID:19118152
    reference_title: "Nephronophthisis: disease mechanisms of a ciliopathy."
    supports: SUPPORT
    snippet: Nephronophthisis (NPHP), a recessive cystic kidney disease...
      Mutations in NPHP genes cause defects in signaling mechanisms that involve
      the noncanonical Wnt signaling pathway and the sonic hedgehog signaling
      pathway, resulting in defects of planar cell polarity and tissue
      maintenance.
    explanation: The provided snippet indicates that mutations in NPHP genes
      affect mechanisms that disrupt cellular functions related to cilia,
      supporting the statement that these mutations lead to impaired cilia.
  - reference: PMID:34183231
    reference_title: "The ciliary impact of nonciliary gene mutations."
    supports: SUPPORT
    snippet: Mutations in genes encoding centriolar or ciliary proteins cause
      diseases collectively known as 'ciliopathies'.
    explanation: This statement refers to how ciliary protein gene mutations
      cause related ciliopathies, aligning with impaired cilia as seen in
      Nephronophthisis.
  - reference: PMID:21113628
    reference_title: "Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms."
    supports: SUPPORT
    snippet: Ciliary dysfunction has emerged as a common factor underlying the
      pathogenesis of both syndromic and isolated kidney cystic disease, an
      observation that has contributed to the unification of human genetic
      disorders of the cilium, the ciliopathies.
    explanation: The excerpt affirms that ciliary dysfunction is fundamental to
      the development of various cystic kidney diseases, including
      Nephronophthisis, caused by mutations affecting cilia.
- name: Impaired Cell Signaling
  description: Defective primary cilia lead to disrupted signaling pathways
    including Wnt, Hedgehog, EGFR, and Hippo/YAP pathways, affecting cell
    differentiation, proliferation, and polarity.
  pathways:
  - preferred_term: Wnt Pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
  - preferred_term: Hedgehog Pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  - preferred_term: EGFR Signaling
    term:
      id: GO:0038127
      label: ERBB signaling pathway
  - preferred_term: Hippo Signaling
    term:
      id: GO:0035329
      label: hippo signaling
  downstream:
  - target: Abnormal Cell Proliferation
  - target: DNA Damage and Senescence
  evidence:
  - reference: PMID:19186246
    reference_title: "Modeling ciliopathies: Primary cilia in development and disease."
    supports: PARTIAL
    snippet: Their importance for key developmental pathways such as Sonic
      Hedgehog (Shh) and Wnt is beginning to emerge. The function of nodal
      cilia, for example, is vital for breaking early embryonic symmetry, Shh
      signaling is important for tissue morphogenesis and successful Wnt
      signaling for organ growth and differentiation. When ciliary function is
      perturbed...brains form improperly.
    explanation: This reference supports the idea that disrupted cilia function
      affects the Wnt and Hedgehog pathways, but it does not specify
      nephronophthisis directly.
  - reference: PMID:22206729
    reference_title: "Inversin, Wnt signaling and primary cilia."
    supports: SUPPORT
    snippet: Mutations of the ankyrin-repeat protein Inversin, a member of a
      diverse family of more than 12 proteins, cause nephronophthisis
      (NPH)...Most NPH gene products (NPHPs) localize to the cilium, and appear
      to control the transport of cargo protein to the cilium by forming
      functional networks.
    explanation: This reference directly links nephronophthisis to defective
      cilia and mentions involvement in pathways like Wnt signaling.
  - reference: PMID:24162855
    reference_title: "Wnt and planar cell polarity signaling in cystic renal disease."
    supports: PARTIAL
    snippet: The primary cilium, a microtubule-based organelle that can serve as
      a signaling antenna, has been demonstrated to have a significant role in
      ensuring correct kidney development and function...one of the signaling
      pathways that requires the cilium for normal development is Wnt signaling.
    explanation: This reference supports the involvement of the primary cilium
      in Wnt signaling but does not explicitly connect it to nephronophthisis.
  - reference: PMID:20544799
    reference_title: "The relationship between sonic Hedgehog signaling, cilia, and neural tube defects."
    supports: PARTIAL
    snippet: mutation of proteins required for function of cilia often leads to
      impaired Shh signaling and to disruption of neural tube closure.
    explanation: This reference supports the idea that ciliary dysfunction
      affects Hedgehog signaling but focuses on neural tube defects rather than
      nephronophthisis.
  - reference: PMID:35655331
    reference_title: "The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies."
    supports: SUPPORT
    snippet: Ciliary dysfunction causes many human conditions termed
      ciliopathies...ciliopathy spectrum could be the poster child for advances
      and challenges in Mendelian human genetics over the past half
      century...illustrates many core concepts of human genetics.
    explanation: This reference supports the concept that defects in the primary
      cilia affect key signaling pathways, including the ones mentioned, in the
      context of nephronophthisis.
- name: Renal Tubular Dysfunction
  locations:
  - preferred_term: Renal Tubule
    term:
      id: UBERON:0009773
      label: renal tubule
  downstream:
  - target: Polyuria
  - target: Polydipsia
  - target: Electrolyte Imbalance
  - target: Interstitial Fibrosis
  description: Ciliary dysfunction in renal tubular epithelial cells impairs
    fluid and electrolyte balance, leading to polyuria and polydipsia.
  evidence:
  - reference: PMID:21071979
    reference_title: "Mechanisms of nephronophthisis and related ciliopathies."
    supports: PARTIAL
    snippet: Nephronophthisis is a recessive disorder of the kidney that is the
      leading cause of end-stage renal failure in children. Through positional
      cloning, many of the causative mutations have been mapped to genes
      involved in centrosome and cilia function.
    explanation: The literature supports that nephronophthisis is related to
      ciliary dysfunction, but it does not explicitly mention polyuria and
      polydipsia as part of its pathophysiology.
  - reference: PMID:16186680
    reference_title: "Approach to renal tubular disorders."
    supports: PARTIAL
    snippet: Renal tubular disorders may affect multiple (e.g., Fanconi
      syndrome) or specific (e.g., nephrogenic diabetes insipidus, renal
      glucosuria) tubular functions. Most conditions are primary and monogenic
      but occasionally are secondary to other disorders.
    explanation: The reference discusses renal tubular disorders, which can
      result in polyuria and electrolyte imbalance, but it does not explicitly
      link these to ciliary dysfunction in nephronophthisis.
  - reference: PMID:9790573
    reference_title: "Epithelial transport in polycystic kidney disease."
    supports: PARTIAL
    snippet: Cysts originate within the glomeruli and all tubular structures,
      and their growth is the result of proliferation of incompletely
      differentiated epithelial cells and the accumulation of fluid within the
      cysts.
    explanation: While the reference discusses fluid accumulation and cyst
      formation in polycystic kidney disease, it does not directly link these to
      nephronophthisis or explicitly mention polyuria.
  - reference: PMID:18312782
    reference_title: "Ciliary syndromes and treatment."
    supports: PARTIAL
    snippet: Overlapping clinical entities including situs inversus, certain
      infertility disorders, as well as chronic respiratory infections have
      their roots in abnormal ciliary function.
    explanation: This reference supports the involvement of ciliary dysfunction
      in various disorders but does not provide specific details on
      nephronophthisis and its pathophysiology related to polyuria and
      polydipsia.
- name: Interstitial Fibrosis
  locations:
  - preferred_term: Kidney Interstitium
    term:
      id: UBERON:0005215
      label: kidney interstitium
  cell_types:
  - preferred_term: Renal Interstitial Fibroblast
    term:
      id: CL:1000692
      label: kidney interstitial fibroblast
  description: Chronic tubular dysfunction and inflammation lead to the
    accumulation of extracellular matrix and progressive interstitial fibrosis.
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: Diagnosis is made by a positive genetic test, or a kidney biopsy
      demonstrating chronic tubulointerstitial changes with thickening of the
      tubular basement membranes.
    explanation: The diagnosis of nephronophthisis includes tubulointerstitial
      changes, which aligns with chronic tubular dysfunction and inflammation
      leading to interstitial fibrosis.
  - reference: PMID:31399984
    reference_title: "Renal Interstitial Lymphangiogenesis in Renal Fibrosis."
    supports: PARTIAL
    snippet: Renal interstitial lymphangiogenesis is found in patients with
      chronic kidney disease (CKD) and a series of animal models of renal
      fibrosis.
    explanation: While the study focuses on lymphangiogenesis, it mentions renal
      interstitial fibrosis related to chronic kidney disease, of which
      nephronophthisis is a type.
- name: Renal Cyst Formation
  locations:
  - preferred_term: Renal Tubule
    term:
      id: UBERON:0009773
      label: renal tubule
  downstream:
  - target: Renal Insufficiency
  description: Abnormal cell proliferation and differentiation result in the
    formation of cysts in the kidney tubules, contributing to the loss of renal
    function.
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: PARTIAL
    snippet: Nephronophthisis is a chronic tubulo-interstitial nephritis which
      progress to terminal renal failure.
    explanation: The statement claims that abnormal cell proliferation and
      differentiation result in cyst formation in nephronophthisis, but the
      literature describes nephronophthisis as a chronic tubulo-interstitial
      nephritis without indicating cyst formation due to abnormal cell
      proliferation and differentiation as a characteristic pathophysiological
      mechanism. Instead, it mentions cortical microcysts in infantile forms but
      emphasizes interstitial fibrosis and tubular basement membrane changes.
  - reference: PMID:25575298
    reference_title: "The role of cilia in the pathogenesis of cystic kidney disease."
    supports: NO_EVIDENCE
    snippet: Almost all of proteins associated with a broad spectrum of human
      cystic kidney diseases have been localized to the region in or around the
      cilia.
    explanation: While this reference discusses abnormal cilia structure and
      function in cystic kidney diseases, it does not specifically address
      nephronophthisis or the mechanism of abnormal cell proliferation and
      differentiation leading to renal cyst formation in nephronophthisis.
- name: Renal Insufficiency
  description: The combination of tubular dysfunction, interstitial fibrosis,
    and cyst formation leads to a gradual decline in renal function and eventual
    end-stage renal disease (ESRD).
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Nephronophthisis is a chronic tubulo-interstitial nephritis which
      progress to terminal renal failure... Histologic lesions concern tubular
      basement membranes which are thickened and multilayered or thinned. There
      is an associated interstitial fibrosis.
    explanation: The provided excerpt mentions chronic tubulo-interstitial
      nephritis (tubular dysfunction and interstitial fibrosis) and progression
      to terminal renal failure, supporting the statement that these factors
      contribute to ESRD.
  - reference: PMID:10352410
    reference_title: "Interstitial pathomechanisms underlying progressive tubulointerstitial damage."
    supports: PARTIAL
    snippet: Progressive renal disease poses an increasing problem for the
      medical community. Though the causes of end-stage renal failure are
      multiple, the histologic pictures of chronic renal disease are remarkably
      similar being characterized by interstitial infiltration, fibrosis,
      tubular atrophy and dilatation.
    explanation: This literature indicates the role of interstitial
      infiltration, fibrosis, and tubular atrophy leading to ESRD, which
      partially overlaps with the factors mentioned in the statement. However,
      cyst formation specific to nephronophthisis was not explicitly mentioned.
- name: Extrarenal Manifestations
  subtypes:
  - Senior-Loken syndrome
  locations:
  - preferred_term: Liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: Retina
    term:
      id: UBERON:0000966
      label: retina
  - preferred_term: Brain
    term:
      id: UBERON:0000955
      label: brain
  description: Some forms of nephronophthisis, such as Senior-Loken syndrome,
    may involve other organs due to the presence of primary cilia in various
    tissues.
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: PARTIAL
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease
      caused by mutations in genes that encode proteins involved in the primary
      cilia function, resulting in kidney disease and extrarenal manifestations
      such as retinal degeneration and liver fibrosis.
    explanation: The literature supports the involvement of the liver and retina
      in nephronophthisis but does not mention the brain specifically in this
      context.
  - reference: PMID:32432520
    reference_title: "Senior-Løken syndrome and intracranial hypertension."
    supports: PARTIAL
    snippet: Senior-Løken syndrome (SLS) is a rare autosomal recessive disease
      characterised by nephronophthisis and retinal degeneration, and belongs to
      a group of genetically heterogeneous disorders known as the ciliopathies.
    explanation: The literature supports the involvement of the retina in
      Senior-Loken syndrome but does not mention the liver or brain specifically
      in this context.
  - reference: PMID:33306870
    reference_title: "Defective INPP5E distribution in NPHP1-related Senior-Loken syndrome."
    supports: SUPPORT
    snippet: Senior-Loken syndrome is a rare genetic disorder that presents with
      nephronophthisis and retinal degeneration, leading to end-stage renal
      disease and progressive blindness.
    explanation: The literature supports the involvement of the retina in
      Senior-Loken syndrome, which is a form of nephronophthisis.
  - reference: PMID:35655331
    reference_title: "The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies."
    supports: NO_EVIDENCE
    snippet: The JS phenotype alone is caused by pathogenic variants in more
      than 40 genes; remarkably, all of the associated proteins function in and
      around the primary cilium.
    explanation: This reference discusses the involvement of primary cilia in a
      broader sense but does not specify the extrarenal manifestations like
      those in Senior-Loken syndrome.
- name: Progression and Severity
  description: The age of onset and rate of progression vary depending on the
    specific NPHP gene mutations and the type of nephronophthisis.
  evidence:
  - reference: PMID:34828368
    reference_title: "Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease."
    supports: SUPPORT
    snippet: NPHP gene types present with some common pathophysiological
      features alongside a diverse range of extra-renal phenotypes associated
      with specific syndromic presentations.
    explanation: The reference states that there is diversity in
      pathophysiological features and extra-renal phenotypes among different
      NPHP gene types, which supports the statement that the age of onset and
      rate of progression vary.
  - reference: PMID:35570616
    reference_title: "Long-Term Outcomes of Kidney Transplant Recipients With Juvenile Nephronophthisis."
    supports: SUPPORT
    snippet: Nephronophthisis is the most common genetic cause of kidney failure
      in childhood....Treatment for nephronophthisis is symptomatic, and kidney
      transplant is a good treatment option when kidney failure has developed.
    explanation: While this reference highlights the general management of
      nephronophthisis, it implies variability in progression and severity since
      not all individuals progress to kidney failure at the same rate.
  - reference: PMID:35922195
    reference_title: "[Clinical phenotype analysis of 6 cases of TTC21B gene related nephronophthisis]."
    supports: SUPPORT
    snippet: All 6 children progressed to end-stage renal disease (ESRD) within
      10 (4, 65) months of onset.
    explanation: The reference indicates variability in the progression to
      end-stage renal disease, supporting the statement regarding variable
      progression rates depending on the specific NPHP gene mutations.
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: There are three main clinical forms of nephronophtisis which have
      been associated with five gene defects. Juvenile nephronophtisis, the most
      frequent, progress to end stage renal failure before age 15.
    explanation: This reference identifies different clinical forms of
      nephronophthisis, which progress at different rates, thus supporting the
      statement on variability in age of onset and progression.
- name: Abnormal Cell Proliferation
  description: Dysregulated cell division and growth
- name: DNA Damage and Senescence
  description: NPHP1 deficiency impairs DNA damage repair, leading to increased
    cellular senescence and contributing to interstitial fibrosis.
    Nephrocystin-1 translocates to the nucleus after DNA damage stress.
  locations:
  - preferred_term: Nucleus
    term:
      id: GO:0005634
      label: nucleus
  - preferred_term: Renal Tubule
    term:
      id: UBERON:0009773
      label: renal tubule
  downstream:
  - target: Interstitial Fibrosis
  genes:
  - preferred_term: NPHP1
    term:
      id: hgnc:7905
      label: NPHP1
  notes: Recent research shows nephrocystin-1 has nuclear functions in DNA
    damage response beyond its ciliary role
- name: Aberrant Actin Remodeling and Hippo Activation
  description: Ciliary dysfunction leads to aberrant RhoA signaling from the
    centrosome, activating ROCK and engaging Hippo signaling. This contributes
    to cystogenesis, fibrosis, and inflammation. GEF-H1 knockdown can rescue
    phenotypes in NPHP1 models.
  locations:
  - preferred_term: Ciliary Base
    term:
      id: GO:0097546
      label: ciliary base
  - preferred_term: Centrosome
    term:
      id: GO:0005813
      label: centrosome
  pathways:
  - preferred_term: Hippo Signaling
    term:
      id: GO:0035329
      label: hippo signaling
  - preferred_term: Actin Cytoskeleton Organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  downstream:
  - target: Renal Cyst Formation
  - target: Interstitial Fibrosis
  notes: The cilia-actin-Hippo axis represents a convergent downstream effector
    of ciliary dysfunction offering potential therapeutic targets
inheritance:
- name: Autosomal Recessive
  evidence:
  - reference: PMID:29717526
    reference_title: "Nephronophthisis: A review of genotype-phenotype correlation."
    supports: SUPPORT
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease
      and one of the most common genetic disorders causing end-stage renal
      disease in children.
    explanation: The literature clearly states that nephronophthisis follows an
      autosomal recessive inheritance pattern.
  - reference: PMID:31810733
    reference_title: "Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants."
    supports: SUPPORT
    snippet: There is increasing appreciation of nephronophthisis (NPHP) as an
      autosomal recessive cause of kidney failure and earlier stages of chronic
      kidney disease among adults.
    explanation: The literature confirms that nephronophthisis is inherited in
      an autosomal recessive manner, even in cases diagnosed in adults.
- name: Tubulointerstitial Fibrosis
  description: Progressive fibrosis of the kidney's tubulointerstitial region.
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease...
      resulting in kidney disease and extrarenal manifestations such as retinal
      degeneration and liver fibrosis.
    explanation: The literature indicates that nephronophthisis involves chronic
      tubulointerstitial changes compatible with fibrosis.
  - reference: PMID:27169608
    reference_title: "Clinical Scenarios in Chronic Kidney Disease: Chronic Tubulointerstitial Diseases."
    supports: PARTIAL
    snippet: Chronic tubulointerstitial nephritis (CTN) is characterized by
      interstitial scarring, fibrosis and tubule atrophy, resulting in
      progressive chronic kidney disease.
    explanation: While the article discusses tubulointerstitial nephritis in
      general, it supports the idea that fibrosis occurs in this region,
      although it does not specifically discuss nephronophthisis.
phenotypes:
- category: Renal
  name: Progressive Renal Failure
  frequency: VERY_FREQUENT
  diagnostic: true
  sequelae:
  - target: End-Stage Renal Disease
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: Nephronophthisis is a chronic tubulo-interstitial nephritis which
      progress to terminal renal failure.
    explanation: This abstract describes nephronophthisis as a progressive renal
      disease leading to end-stage renal failure, supporting the idea that
      progressive renal failure is a frequent and diagnostic feature.
  - reference: PMID:33323469
    reference_title: "Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy."
    supports: SUPPORT
    snippet: Nephronophthisis-related ciliopathies (NPHP-RC) account for the
      majority of cases of monogenetically caused end-stage renal disease (ESRD)
      in children.
    explanation: This reference states that nephronophthisis-related
      ciliopathies are a common cause of end-stage renal disease in children,
      confirming that progressive renal failure and progression to ESRD is
      common.
  - reference: PMID:20969579
    reference_title: "Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes."
    supports: SUPPORT
    snippet: A Mendelian inheritance underlies a nonnegligible proportion of
      hereditary kidney diseases, suggesting that the encoded proteins are
      essential for maintenance of the renal function.
    explanation: While the abstract primarily discusses hereditary kidney
      diseases in general, it emphasizes the importance of kidney function
      maintenance in genetic diseases, indirectly supporting the frequency and
      importance of progressive renal failure in conditions like
      nephronophthisis.
- category: Cardiovascular
  name: Hypertension
  frequency: FREQUENT
  evidence:
  - reference: PMID:17647025
    reference_title: "Heritable forms of hypertension."
    supports: NO_EVIDENCE
    snippet: Among the causes of secondary hypertension are a group of disorders
      with a Mendelian inheritance pattern. Recent advances in molecular biology
      have unveiled the pathogenesis of hypertension in many of these
      conditions.
    explanation: While this reference mentions Mendelian forms of hypertension,
      there is no specific mention of Nephronophthisis resulting in hypertension
      or cardiovascular phenotypes generally.
  - reference: PMID:20969579
    reference_title: "Hereditary kidney diseases: highlighting the importance of classical Mendelian phenotypes."
    supports: NO_EVIDENCE
    snippet: A Mendelian inheritance underlies a nonnegligible proportion of
      hereditary kidney diseases, suggesting that the encoded proteins are
      essential for maintenance of the renal function.
    explanation: This reference discusses hereditary kidney diseases and the
      genetic mutations involved but does not mention Nephronophthisis or its
      cardiovascular phenotypes including hypertension.
  - reference: PMID:12589180
    reference_title: "Dopamine and the kidney: a role in hypertension?"
    supports: NO_EVIDENCE
    snippet: Defective transduction of the dopamine receptor signal in the
      kidney...
    explanation: The article discusses the role of dopamine in the kidney and
      its involvement in hypertension, but it does not address Nephronophthisis
      or whether hypertension is a common cardiovascular phenotype in this
      condition.
  - reference: PMID:23402468
    reference_title: "Hypertension."
    supports: NO_EVIDENCE
    snippet: Hypertension is the most common modifiable risk factor for
      cardiovascular disease. Antihypertensive treatment substantially reduces
      the risk of heart failure, stroke, and myocardial infarction.
    explanation: This article offers a general overview of hypertension and its
      management but does not specifically mention Nephronophthisis or any
      associated cardiovascular phenotypes.
  - reference: PMID:16336577
    reference_title: "Systemic and glomerular hypertension and progression of chronic renal disease: the dilemma of nephrosclerosis."
    supports: NO_EVIDENCE
    snippet: Nephrosclerosis, benign nephrosclerosis, and hypertensive kidney
      disease are terms that clinicians use when renal damage is thought to be
      secondary to essential hypertension.
    explanation: While the article discusses hypertension in the context of
      renal diseases, it does not specify an association between
      Nephronophthisis and hypertension as a cardiovascular phenotype.
  - reference: PMID:37910243
    reference_title: "Hypertension in children with congenital anomalies of the kidney and urinary tract."
    supports: NO_EVIDENCE
    snippet: Hypertension is common in children with CAKUT and increases the
      risk of CKD.
    explanation: This study focuses on congenital anomalies of the kidney and
      urinary tract (CAKUT) and their association with hypertension, but it does
      not discuss Nephronophthisis.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
- category: Hepatic
  name: Fibrosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease
      caused by mutations in genes that encode proteins involved in the primary
      cilia function, resulting in kidney disease and extrarenal manifestations
      such as retinal degeneration and liver fibrosis.
    explanation: The literature mentions liver fibrosis as an extrarenal
      manifestation of nephronophthisis, supporting the statement that hepatic
      fibrosis is an occasional phenotype category of nephronophthisis.
- category: Ophthalmologic
  name: Retinitis Pigmentosa
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: SUPPORT
    snippet: 'Some children present with extrarenal symptoms: tapetoretinal degeneration
      (Senior-Loken syndrome)...'
    explanation: This reference indicates that tapetoretinal degeneration,
      synonymous with retinitis pigmentosa in the context of this disease, is an
      occasional extrarenal symptom of nephronophthisis.
  - reference: PMID:25161209
    reference_title: "Nephronophthisis and retinal degeneration in tmem218-/- mice: a novel mouse model for Senior-Løken syndrome?"
    supports: SUPPORT
    snippet: The renal lesions were characterized by diffuse renal cyst
      development with tubulointerstitial nephropathy...These renal and retinal
      lesions are most similar to those associated with nephronophthisis (NPHP)
      and retinitis pigmentosa in humans.
    explanation: This reference directly confirms the association between
      nephronophthisis and retinitis pigmentosa as occasional ophthalmologic
      phenotypes.
  - reference: PMID:37644229
    reference_title: "Ocular manifestations of renal ciliopathies."
    supports: SUPPORT
    snippet: Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have
      an ocular phenotype, including inherited retinal degeneration, oculomotor
      disorders, and coloboma.
    explanation: This indicates that ophthalmologic phenotypes, including
      retinal degeneration, are common in pediatric renal ciliopathies including
      nephronophthisis.
  phenotype_term:
    preferred_term: Retinitis Pigmentosa
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
- category: Developmental
  frequency: OCCASIONAL
  name: Growth Retardation
  notes: May be seen due to chronic kidney disease
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: PARTIAL
    snippet: 'Some children present with extrarenal symptoms: tapetoretinal degeneration
      (Senior-Loken syndrome), mental retardation, cerebellar ataxia, bone anomalies
      or liver involvement.'
    explanation: The reference mentions extrarenal symptoms associated with
      nephronophthisis but does not specifically mention growth retardation.
      However, growth retardation could be inferred as a potential consequence
      of chronic kidney disease.
  - reference: PMID:30552565
    reference_title: "Growth plate alterations in chronic kidney disease."
    supports: SUPPORT
    snippet: Growth retardation is a major feature of chronic kidney disease
      (CKD) of onset in infants or children and is associated with increased
      morbidity and mortality.
    explanation: This reference supports the statement that growth retardation
      is associated with chronic kidney disease, which can be a consequence of
      nephronophthisis.
  phenotype_term:
    preferred_term: Growth Retardation
    term:
      id: HP:0001510
      label: Growth delay
- category: Musculoskeletal
  frequency: OCCASIONAL
  name: Bone Deformities
  notes: Related to renal osteodystrophy from kidney failure
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: NO_EVIDENCE
    snippet: Nephronophthisis is an autosomal recessive cystic kidney disease
      caused by mutations in genes that encode proteins involved in the primary
      cilia function, resulting in kidney disease and extrarenal manifestations
      such as retinal degeneration and liver fibrosis.
    explanation: The provided literature does not mention musculoskeletal issues
      or bone deformities as part of the clinical manifestations of
      nephronophthisis.
  - reference: PMID:27219042
    reference_title: "Skeletal manifestations of renal disease in childhood."
    supports: NO_EVIDENCE
    snippet: Recent findings substantiate concern regarding the particular
      vulnerability of the growing skeleton to chronic renal disease.
    explanation: Although chronic kidney disease can lead to musculoskeletal
      issues, the literature does not specifically link nephronophthisis to bone
      deformities related to renal osteodystrophy.
- category: Endocrine
  frequency: OCCASIONAL
  name: Secondary Hyperparathyroidism
  notes: Develops as a consequence of chronic renal failure
  evidence:
  - reference: PMID:16966065
    reference_title: "[Nephronophtisis]."
    supports: REFUTE
    snippet: Nephronophthisis is a chronic tubulo-interstitial nephritis which
      progress to terminal renal failure.
    explanation: Nephronophthisis is a type of chronic tubulo-interstitial
      nephritis and not an endocrine disorder. It primarily affects the kidneys
      and progresses to terminal renal failure, but it is not categorized as an
      endocrine disorder nor is it specifically associated with secondary
      hyperparathyroidism.
  phenotype_term:
    preferred_term: Secondary Hyperparathyroidism
    term:
      id: HP:0000867
      label: Secondary hyperparathyroidism
- category: Renal
  name: Polyuria
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Polyuria
    term:
      id: HP:0000103
      label: Polyuria
- category: Systemic
  name: Polydipsia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Polydipsia
    term:
      id: HP:0001959
      label: Polydipsia
- category: Metabolic
  name: Electrolyte Imbalance
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Electrolyte Imbalance
    term:
      id: HP:0003111
      label: Abnormal blood ion concentration
- category: Renal
  name: End-Stage Renal Disease
  frequency: FREQUENT
  phenotype_term:
    preferred_term: End-Stage Renal Disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
biochemical:
- name: Serum Creatinine
  presence: Elevated
  evidence:
  - reference: PMID:37930417
    reference_title: "Nephronophthisis: a pathological and genetic perspective."
    supports: PARTIAL
    snippet: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney
      disease and is one of the most frequent genetic causes for kidney failure
      (KF) in children and adolescents.
    explanation: Kidney failure implies elevated serum creatinine. This
      reference indicates nephronophthisis is a frequent cause of kidney
      failure, indirectly supporting elevated creatinine as a biochemical
      finding.
- name: Elevated Blood Urea Nitrogen (BUN)
  presence: Elevated
  evidence:
  - reference: PMID:7272960
    reference_title: "Nephrotoxicity of nitrosoureas."
    supports: PARTIAL
    snippet: Irreversible and progressive renal parenchymal damage and
      functional impairment occurred in the majority of patients receiving at
      least six courses (200 mg/m2 of BCNU and/or methyl CCNU at eight-week
      intervals) of nitrosoureas for therapy of malignant brain tumors.
      Seventeen of 18 patients who received at least six courses and all nine
      patients who received more than ten courses developed impaired renal
      function as judged by elevation of blood urea nitrogen and/or serum
      creatinine or decrease in filtration rate as determined by inulin
      clearance.
    explanation: The literature supports elevated BUN as a marker of renal
      damage but does not specify nephronophthisis. Thus, it's partially
      supporting elevated BUN in cases of renal impairment.
  - reference: PMID:26769764
    reference_title: "eGFR and Outcomes in Patients with Acute Decompensated Heart Failure with or without Elevated BUN."
    supports: PARTIAL
    snippet: 'CONCLUSIONS: We showed that elevation of BUN at discharge significantly
      modified the relation between eGFR at discharge and the risk of all-cause mortality
      after discharge, suggesting that the association between eGFR and outcomes may
      be largely dependent on concomitant elevation of BUN.'
    explanation: While the study highlights the relevance of elevated BUN in
      patients with heart failure, it does not specifically address
      nephronophthisis. Therefore, it partially supports the biochemical value.
  - reference: PMID:21722602
    reference_title: "Saliva urea dipstick test: application in chronic kidney disease."
    supports: PARTIAL
    snippet: 'CONCLUSION: Semiquantitative dipstick measurements of SUN can reliably
      identify CKD patients with elevated BUN levels.'
    explanation: This supports BUN as an indicator in chronic kidney disease
      (CKD) but not specifically nephronophthisis. Hence, it gives partial
      support.
genetic:
- name: NPHP1
  association: Pathogenic Variants
  evidence:
  - reference: PMID:15138899
    reference_title: "The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome."
    supports: SUPPORT
    snippet: Two siblings affected with a mild form of JS were found to have a
      homozygous deletion of the NPHP1 gene identical, by mapping, to that in
      subjects with NPHP alone.
    explanation: The NPHP1 gene deletion is associated with juvenile
      nephronophthisis, confirming the genetic link between NPHP1 and
      nephronophthisis.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Patients with pathogenic variants in CEP290 or IQCB1 presented
      early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4
      variants first developed nephropathy.
    explanation: This reference supports the genetic association of
      nephronophthisis with variants in several genes, highlighting NPHP1 among
      the genes associated with nephropathy.
- name: NPHP3
  association: Pathogenic Variants
  evidence:
  - reference: PMID:34212438
    reference_title: "A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families."
    supports: SUPPORT
    snippet: we detected a homozygous predicted synonymous allele in NPHP3 in
      two children with hepatorenal fibrocystic disease from a consanguineous
      family.
  - reference: PMID:26184788
    reference_title: "High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients."
    supports: SUPPORT
    snippet: Eight of 17 (47.1%) patients detected were identified to have
      mutations in NPHP3.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Patients with pathogenic variants in CEP290 or IQCB1 presented
      early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4
      variants first developed nephropathy.
- name: NPHP4
  association: Pathogenic Variants
  evidence:
  - reference: PMID:14750102
    reference_title: "Clinical and histological presentation of 3 siblings with mutations in the NPHP4 gene."
    supports: SUPPORT
    snippet: 'Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four
      genes responsible for different types of NPH have been identified: NPHP1, NPHP2,
      NPHP3, and NPHP4.'
    explanation: The literature identifies NPHP4 as one of the genes responsible
      for different types of Nephronophthisis.
  - reference: PMID:34591160
    reference_title: "Association of Nephronophthisis 4 genetic variation with cardiorenal syndrome and cardiovascular events in Japanese general population: the Yamagata (Takahata) study."
    supports: SUPPORT
    snippet: Nephronophthisis (NPHP) 4 gene encoding nephrocystin-4...
      contributes to end-stage renal disease in children and young adults.
    explanation: The literature indicates that NPHP4 is associated with
      end-stage renal disease in Nephronophthisis, highlighting its pathogenic
      role.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Senior-Loken syndrome (SLSN) is an autosomal recessive disorder
      characterized by retinopathy and nephronophthisis... Patients with
      pathogenic variants in CEP290 or IQCB1 presented early with retinopathy,
      whereas other patients with INVS, NPHP3, or NPHP4 variants first developed
      nephropathy.
    explanation: The literature mentions that patients with NPHP4 variants
      develop nephropathy in the context of Nephronophthisis.
- name: INVS
  association: Pathogenic Variants
  notes: Also known as NPHP2, inversin protein antagonizes canonical WNT
    signaling
  evidence:
  - reference: PMID:14750102
    reference_title: "Clinical and histological presentation of 3 siblings with mutations in the NPHP4 gene."
    supports: SUPPORT
    snippet: 'Nephronophthisis (NPH) is an autosomal recessive kidney disease... Four
      genes responsible for different types of NPH have been identified: NPHP1, NPHP2,
      NPHP3, and NPHP4.'
    explanation: The literature identifies NPHP2 (INVS) as one of the genes
      responsible for different types of Nephronophthisis.
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Patients with pathogenic variants in CEP290 or IQCB1 presented
      early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4
      variants first developed nephropathy.
    explanation: The literature confirms INVS variants are associated with
      nephropathy in nephronophthisis.
- name: NEK8
  association: Pathogenic Variants
  notes: Also known as NPHP9, a NIMA-family ciliary kinase in the INV complex
  evidence:
  - reference: PMID:36990420
    reference_title: "Pathogenic Variants in CEP290 or IQCB1 Cause Earlier-Onset Retinopathy in Senior-Loken Syndrome Compared to Those in INVS, NPHP3, or NPHP4."
    supports: SUPPORT
    snippet: Patients with pathogenic variants in CEP290 or IQCB1 presented
      early with retinopathy, whereas other patients with INVS, NPHP3, or NPHP4
      variants first developed nephropathy.
    explanation: While this reference doesn't specifically mention NEK8, it
      establishes the context of genetic heterogeneity in
      nephronophthisis-related ciliopathies.
environmental:
- name: Not Applicable
  notes: Nephronophthisis is primarily driven by genetic mutations.
  evidence:
  - reference: PMID:15917209
    reference_title: "Nephronophthisis."
    supports: REFUTE
    snippet: There has been tremendous progress in the past few years in
      understanding the molecular basis of nephronophthisis, and it is now
      evident that the disease is characterized by both clinical and genetic
      heterogeneity.
    explanation: This indicates that Nephronophthisis is primarily driven by
      genetic mutations, not environmental factors.
  - reference: PMID:20844548
    reference_title: "The novel and independent association between single-point SNP of NPHP4 gene and renal function in non-diabetic Japanese population: the Takahata study."
    supports: REFUTE
    snippet: Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in
      the development of renal tubules and its congenital mutations cause
      juvenile end-stage renal disease, NPHP.
    explanation: This further supports that Nephronophthisis is caused by
      genetic mutations and not by environmental factors.
  - reference: PMID:29869359
    reference_title: "Transplantation for infantile nephronophthisis with loss-of-function mutation in NPHP3: Lesson from a case."
    supports: REFUTE
    snippet: The patient had elevated liver enzymes and biopsy-proven liver
      fibrosis. As liver synthesis was acceptable, only KT was performed.
      However, liver fibrosis progressed at 1.5 years after transplantation,
      manifested with portal hypertension and hypersplenism.
    explanation: This case study describes genetic mutations as the cause of
      disease progression, reinforcing that Nephronophthisis is genetically
      driven.
treatments:
- name: Renal Replacement Therapy
  description: Dialysis or kidney transplantation for end-stage renal disease.
  evidence:
  - reference: PMID:32906116
    reference_title: "Living-Related Kidney Transplantation in a Patient with Juvenile Nephronophthisis."
    supports: SUPPORT
    snippet: Nephronophthisis (NPHP) is an autosomal recessive disease
      manifesting as tubulointerstitial nephritis uniformly progressing to ESRD
      in approximately 5-10% patients in childhood. Living donor transplantation
      is the most beneficial mean of renal replacement therapy compared to other
      methods.
    explanation: The abstract discusses that Nephronophthisis often leads to
      end-stage renal disease (ESRD) and mentions living donor transplantation
      as a beneficial renal replacement therapy option.
  - reference: PMID:15715116
    reference_title: "Choice of renal replacement therapy in patients with diabetic end stage renal disease."
    supports: SUPPORT
    snippet: 'Diabetes and ESRD receiving Renal Replacement Therapy (RRT)... The main
      choices of modalities are: 1) haemodialysis (HD), 2) Peritoneal dialysis (PD),
      3) Kidney transplantation alone (KTA) or 4) simultaneous kidney and pancreas
      transplantation (SPKT).'
    explanation: Although this reference focuses on diabetic nephropathy, it
      supports the statement that renal replacement therapies for ESRD include
      dialysis and kidney transplantation.
  treatment_term:
    preferred_term: renal dialysis
    term:
      id: MAXO:0000601
      label: renal dialysis
- name: Antihypertensive Therapy
  description: Management of blood pressure with medications.
  evidence:
  - reference: PMID:36224286
    reference_title: "Nephrons, podocytes and chronic kidney disease: Strategic antihypertensive therapy for renoprotection."
    supports: PARTIAL
    snippet: Chronic kidney disease (CKD) is one of the strongest risk factors
      for hypertension, and hypertension can exacerbate the progression of
      CKD... therefore, one of the best strategies to slow the progression of
      CKD is to maintain the 'numbers' of these essential components necessary
      to preserve renal function. To this end, both the achievement of an
      optimal blood pressure and a maximum reduction in urinary protein
      excretion are essential.
    explanation: This source suggests that managing blood pressure is essential
      in the context of CKD, which is related to nephron function. However, it
      does not explicitly mention Nephronophthisis, a specific type of
      nephropathy.
  - reference: PMID:30354828
    reference_title: "Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association."
    supports: NO_EVIDENCE
    snippet: Resistant hypertension (RH) is defined as above-goal elevated blood
      pressure (BP) in a patient despite the concurrent use of 3
      antihypertensive drug classes...evaluation includes identification of
      contributing lifestyle issues, detection of drugs interfering with
      antihypertensive medication effectiveness, screening for secondary
      hypertension, and assessment of target organ damage. Management of RH
      includes maximization of lifestyle interventions, use of long-acting
      thiazide-like diuretics (chlorthalidone or indapamide), addition of a
      mineralocorticoid receptor antagonist (spironolactone or eplerenone), and,
      if BP remains elevated, stepwise addition of antihypertensive drugs with
      complementary mechanisms of action to lower BP.
    explanation: This source provides comprehensive information on the
      evaluation and management of resistant hypertension but does not discuss
      Nephronophthisis specifically.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Supportive Care
  description: Symptomatic treatment and monitoring to manage associated
    complications.
  evidence:
  - reference: PMID:35533128
    reference_title: "[Nephronophthisis: a pediatric case report]."
    supports: SUPPORT
    snippet: At the moment there is no healing therapy, so early kidney
      transplant is a fundamental tool to improve prognosis.
    explanation: There is no curative treatment for nephronophthisis, indicating
      that supportive care, including symptomatic treatment and monitoring, is
      currently applied to manage associated complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
review_notes: Nephronophthisis is a ciliopathy causing chronic
  tubulointerstitial nephritis. The cardinal feature is progressive renal
  failure, usually beginning in childhood and adolescence and leading to
  end-stage renal disease. Recent research highlights multiple converging
  mechanisms including ciliary dysfunction, disrupted WNT/Hedgehog/EGFR/Hippo
  signaling, aberrant actin-RhoA remodeling, and DNA damage response defects
  leading to cellular senescence. Extrarenal manifestations like retinitis
  pigmentosa (Senior-Loken syndrome) and liver fibrosis may occur in 10-20% of
  cases. The cilia-actin-Hippo axis represents a potential therapeutic target,
  with experimental evidence for EGFR inhibitors rescuing ciliary defects in
  patient-derived cells.
disease_term:
  preferred_term: nephronophthisis
  term:
    id: MONDO:0019005
    label: nephronophthisis
classifications:
  harrisons_chapter:
  - classification_value: kidney disorder
  - classification_value: hereditary disease
  mechanistic_category:
  - classification_value: ciliopathy
references:
- reference: DOI:10.1038/s44321-025-00239-x
  title: Metabolic reprogramming in polycystic kidney disease and other renal
    ciliopathies
  findings: []
- reference: DOI:10.1101/2025.06.09.658557
  title: Loss of nephronophthisis-associated nephrocystin-1 impairs DNA damage
    repair in kidney organoids
  findings: []
- reference: DOI:10.1186/s12964-025-02143-w
  title: NEK8, a NIMA-family protein kinase at the core of the ciliary INV
    complex
  findings: []
- reference: DOI:10.1242/jcs.264141
  title: Urinary renal epithelial cells can be used for <i>NPHP1</i> phenotyping
    and a personalized therapeutic strategy
  findings: []
- reference: DOI:10.12659/ajcr.941413
  title: Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a
    Novel Compound Heterozygous Pathogenic Variant
  findings: []
- reference: DOI:10.3389/fneph.2023.1331847
  title: Primary cilia and actin regulatory pathways in renal ciliopathies
  findings: []
- reference: DOI:10.3390/genes14081582
  title: A Role for Genetic Modifiers in Tubulointerstitial Kidney Diseases
  findings: []