Nephronophthisis and Related Renal Ciliopathies (incl. Senior-Løken)

Autosomal recessive chronic tubulointerstitial nephropathy caused by defects of the primary cilium, with infantile, juvenile and adolescent/adult forms, and extrarenal associations that include Senior-Løken syndrome (nephronophthisis with retinal dystrophy) and Senior-Boichis syndrome (nephronophthisis with hepatic fibrosis).

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

The following table brings together the entities within scope: nephronophthisis (NPH) as an overall category and its age-based subtypes, Senior-Løken syndrome (SLS) and Senior-Boichis syndrome. Joubert syndrome, Leber congenital amaurosis (LCA) and Meckel-Gruber syndrome, which share genes with NPH, are included here only as differential diagnoses or bridging entities.

The following table lists the genes of the spectrum with their identifiers, the MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcripts validated in VariantValidator, the approximate fraction of NPH explained by each gene and the extrarenal manifestations described. The percentages come from Table 1 of GeneReviews, which adapts them from Barroso-Gil 2021 and Van De Weghe 2022; extrarenal manifestations are not obligatory and may appear over time [1].

Sources for the gene table: GeneReviews (percentages, subtypes and manifestations) [1], OMIM phenotypic series PS256100 and PS266900 (MIM numbers and inheritance) [10, 12] and VariantValidator (MANE transcripts, GRCh38) [31]. "Not consulted" indicates that the MANE transcript of that gene was not validated in the sources for this article; the variants described in the text always use the stated transcript.

1. Introduction

1.1. Definition and place of nephronophthisis among the ciliopathies

Nephronophthisis (NPH) is an autosomal recessive chronic tubulointerstitial nephropathy that manifests as polyuria and polydipsia secondary to a urinary concentrating defect, chronic tubulointerstitial nephritis and progression to end-stage kidney disease (ESKD), usually before 30 years of age, although later presentations have been described. Treatment-resistant chronic anaemia and growth restriction frequently accompany the picture. GeneReviews proposes suspecting NPH in chronic kidney disease (CKD) without congenital anomalies of the kidney and urinary tract (CAKUT) and without signs or symptoms of glomerular disease [1]. NPH belongs to the group of ciliopathies, diseases caused by defects in the formation or function of primary cilia, signalling organelles present on the surface of almost all cell types [1]. The Oxford Desk Reference describes primary cilia, usually one per cell, as sensory "antennae" that coordinate signalling pathways such as Sonic hedgehog (SHH) and Wnt and that take part in the early breaking of embryonic symmetry; this explains the multiorgan involvement of the ciliopathies, whose common core includes retinal degeneration, kidney disease, brain malformation, situs inversus and infertility, to which many of them add congenital fibrocystic liver disease, polydactyly, obesity, diabetes and skeletal dysplasias [3].

GeneReviews groups isolated NPH, NPH with non-syndromic extrarenal manifestations and the syndromic forms under the designation "nephronophthisis-related ciliopathies" (NPH-RC) and limits its review to the 21 genes classified as NPHP, acknowledging that more than 90 genetic causes of syndromic NPH-RC lie outside that set [1]. At initial presentation, about 80–90% of people with NPH appear to have isolated disease, with all findings explainable by kidney dysfunction, and 10–20% have extrarenal manifestations suggestive of a syndrome; over time, some people with apparently isolated NPH develop syndromic features [1]. A 2024 review estimates the fraction of patients with extrarenal symptoms at 15–20% and lists the main associations: retina (SLS), central nervous system (Joubert), liver (Boichis and Arima syndromes) and skeleton (Mainzer-Saldino and Sensenbrenner) [32].

1.2. Founding descriptions

The name "nephronophthisis" was established in 1951 by Fanconi, Hanhart, von Albertini, Uhlinger, Dolivo and Prader, in a 49-page article published in Helvetica Paediatrica Acta, whose indexed English title is "Familial, juvenile nephronophthisis (idiopathic parenchymal contracted kidney)" [2]. In 1961 two independent descriptions of the association between familial juvenile nephropathy and retinal degeneration appeared: Senior, Friedmann and Braudo published "Juvenile familial nephropathy with tapetoretinal degeneration. A new oculorenal dystrophy" in the American Journal of Ophthalmology, and Løken, Hanssen, Halvorsen and Jølster published "Hereditary renal dysplasia and blindness" in Acta Paediatrica [4, 5]. The eponym Senior-Løken syndrome (SLS) derives from these two works. In 1973 Boichis, Passwell, David and Miller described a family study of congenital hepatic fibrosis associated with nephronophthisis in the Quarterly Journal of Medicine, the origin of the designation Boichis or Senior-Boichis syndrome [6].

For decades, recessive juvenile NPH was confused with dominantly inherited "medullary cystic disease", because both produce small kidneys with cysts at the corticomedullary junction. OMIM records the debate and the later separation of the two entities, with distinct loci (2q13 for NPH and 1q21 for the dominant form, now autosomal dominant tubulointerstitial kidney disease associated with MUC1, ADTKD-MUC1); it also records the observation by Strauss and Sommers, in 1967, that calling the disease "medullary cysts" focused on "the hole of the doughnut rather than the mass", and Steele's 1980 series of 21 patients, in which renal cysts were uncommon [12, 33]. The Finnish study by Ala-Mello and colleagues, published in 1999, still brought together under the same national survey 37 patients from 28 families with a recessive pattern and 17 patients from 4 families with a dominant pattern, distinguishing them by age at first symptoms, at start of dialysis and at transplantation [16].

1.3. Milestones of molecular discovery

In 1993 Antignac and colleagues linked "pure" familial juvenile NPH to the short arm of chromosome 2 (region D2S48–D2S51; maximum lod score 4.78) in 22 multiplex families, 18 without and 4 with ocular anomalies, and excluded this linkage in families with SLS, the first demonstration of genetic heterogeneity between NPH and SLS; the authors then attributed 15% of paediatric ESKD to NPH and the association with Leber amaurosis to 16% of cases [34]. The localisation was later refined to 2q13. In 1996 Konrad and colleagues showed that large homozygous rearrangements of the 2q13 region, mostly deletions of about 250 kb involving an inverted duplication of about 100 kb, were present in 80% of patients from consanguineous or multiplex families linked to the NPH1 locus and in 65% of sporadic cases, which for the first time allowed diagnosis without kidney biopsy in most patients [35]. In 1997 two groups identified the gene in parallel: Hildebrandt and colleagues cloned NPHP1, which encodes a protein with an SH3 (Src homology 3) domain and spans most of the common deletion, finding point mutations in patients hemizygous for the deletion [36]; Saunier and colleagues, at the Necker Hospital, defined the minimal deletion interval and identified the same candidate gene, with null mutations on the other allele in two hemizygous patients [37]. In the same year, Hildebrandt's German series set the median age at "renal death" in NPH type 1 at 13.1 years and proposed creatinine-by-age curves for future trials [38]. In 2000 Saunier and colleagues characterised the mechanism of the 290 kb deletion, mediated by flanking repeats [39].

The other main genes followed. In 2002 Schuermann and colleagues mapped the NPH type 4 locus and an SLS locus in the same interval to 1p36 [40], and two groups identified NPHP4: Otto and colleagues named the protein nephroretinin and described loss-of-function variants in families with NPH and with SLS [41], and Mollet and colleagues demonstrated its interaction with nephrocystin-1 [42]. In 2003 Otto and colleagues showed that INVS (inversin) causes infantile NPH type 2, with and without situs inversus, and that nephrocystin, inversin and β-tubulin co-localise in the primary cilia of tubular cells, which definitively linked NPH, cystic kidney disease, the primary cilium and left-right axis determination [43]; in the same issue of Nature Genetics, Olbrich and colleagues described NPHP3 in adolescent NPH, isolated and associated with hepatic fibrosis or tapetoretinal degeneration [11]. In 2005 Otto and colleagues cloned IQCB1 (nephrocystin-5), the most frequent cause of SLS in their series, in which all patients with variants in this gene had RP [44]; in 2006 Sayer and colleagues showed that CEP290 (nephrocystin-6) is mutated in NPH and in Joubert syndrome [45]. The following decade added GLIS2 [46], ZNF423 and CEP164, which linked the renal ciliopathies to the DNA damage response [47], ANKS6 [48], CEP83 [49], TRAF3IP1/IFT54 [28], MAPKBP1 [50] and ADAMTS9 [51].

1.4. Nomenclature and reclassifications

The historical classification distinguished three types: juvenile NPH type 1, infantile type 2 and adolescent type 3, as still appears in the ciliopathy table of the Oxford Desk Reference, which also uses the old gene notation (NPHP2 for INV, NPHP5 for IQCB1, NPHP6 for CEP290) [3]. GeneReviews and current series treat the juvenile, adolescent and adult forms as a continuum, keeping the infantile form as a distinct clinical and histological entity [1]. Orphanet keeps three subtypes under ORPHA:655: infantile NPH (ORPHA:93591), juvenile (ORPHA:93592) and late-onset (ORPHA:93589) [7–9]. The expression "renal dysplasia", used by Løken in 1961 and taken up in the Oxford Desk Reference for SLS, is terminologically imprecise, because NPH is not a dysplasia [1, 3, 5]. The Oxford Desk Reference also includes SLS among the cerebello-oculo-renal syndromes (Arima, Senior-Løken, COACH), following Satran and colleagues [52, 53]; the current definition in GeneReviews and OMIM restricts SLS to the association of NPH with retinal dystrophy (LCA or RP), without the molar tooth sign that defines Joubert syndrome [1, 10].

The OMIM series reflect reclassification by gene. Phenotypic series PS256100 "Nephronophthisis" includes the entries NPHP1 to NPHP20 that have a predominantly renal phenotype and the two nephronophthisis-like nephropathies (XPNPEP3 and SLC41A1); the forms due to IQCB1, CEP290, RPGRIP1L and SDCCAG8 appear in the SLS or Joubert series [12]. Series PS266900 "Senior-Loken syndrome" contains eight entries (SLSN1 and SLSN3 to SLSN9); there is no SLSN2 in the current series, and SLSN3 corresponds to a locus mapped by linkage to 3q22, with no gene identified [10]. The text of OMIM entry #256100 contains two factual errors that should not be reproduced: in describing the Halbritter study it assigns the number 609237 to CEP290 and 610743 to IQCB1, whereas the phenotypic series gives IQCB1 *609237 and CEP290 *610142; and it links the Boichis 1973 reference to PMID 13804544, which corresponds to another article, the correct PMID being 4688793 [6, 12].

1.5. Entities within scope

Infantile NPH begins in utero or in the first months of life, with moderately enlarged cystic kidneys, severe HTN and progression to ESKD in the first years; it is mainly caused by variants in genes of the inversin compartment (INVS, NPHP3, NEK8, ANKS6) and of the intraflagellar transport complex A (IFT-A) [1, 54]. Juvenile NPH is the classic form, with polyuria, polydipsia, anaemia and growth delay at school age and ESKD at a median of about 13 years; NPHP1 is the predominant gene [1, 17]. Late-onset NPH, adolescent or adult, is defined by ESKD after 15 years of age and is frequently classified as CKD of unknown cause, chronic interstitial nephritis or nephrosclerosis [18, 54]. Senior-Løken syndrome is the association of NPH with LCA or RP and corresponds to the OMIM entries SLSN1–9 [1, 10]. Senior-Boichis syndrome is the association of NPH with congenital hepatic fibrosis, described with NPHP3, TMEM67 and DCDC2 [6, 11, 13]. NPH with Cogan oculomotor apraxia, described with the NPHP1 deletion and with NPHP4, is covered within the NPHP1 spectrum [22, 42]. Joubert syndrome and its forms with renal and hepatic involvement (including COACH), CEP290-related LCA and early-onset retinal dystrophies without kidney disease, and Meckel-Gruber syndrome are part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The primary cilium and the functional modules of the nephrocystins

The proteins encoded by the NPHP genes are located mainly in the ciliary transition zone and in the basal body, where they regulate ciliary structure and signalling; loss of ciliary function disturbs epithelial polarity, intracellular trafficking and signal transduction, with tubular injury and fibrosis as the end result [55]. The review by Wolf and colleagues lists the pathways involved: planar cell polarity, Sonic hedgehog, DNA damage response, Hippo, mTOR (mechanistic target of rapamycin) and cyclic adenosine monophosphate (cAMP) [32]. The large cohort of the Institut Imagine and the Necker Hospital, in Paris, found alterations in all the ciliary modules defined by structural or functional subdomains and showed that the module affected is related to age at onset: infantile forms cluster in variants of the inversin compartment or the IFT-A complex, whereas late-onset forms depend mainly on variants of the transition zone module; hypomorphic variants in genes of the early phases of ciliogenesis are associated with juvenile and late forms [54].

The transition zone module comprises nephrocystin-1, nephrocystin-4 and the protein encoded by RPGRIP1L. Nephrocystin-1 is a protein with an SH3 domain and no assayable enzymatic activity [36, 37]; nephrocystin-4, or nephroretinin, was identified through its interaction with nephrocystin-1 [41, 42]. Immunofluorescence of nasal epithelial cells from 86 individuals with genetically defined renal ciliopathy demonstrated in vivo the mutual dependence of the two proteins: nephrocystin-1 and nephrocystin-4 were absent in all patients with causal variants in NPHP1, and patients with an NPHP4 genotype had complete absence of nephrocystin-4 and marked reduction of nephrocystin-1, whereas variants in other genes did not alter staining [56]. The inversin compartment is organised by ANKS6, which links the kinase NEK8 to inversin and nephrocystin-3 [48]; inversin connects cystic kidney disease with left-right axis determination, which explains the situs inversus of some patients with INVS, NPHP3, NEK8 and ANKS6 [43]. Intraflagellar transport depends on two complexes: IFT-A, which includes the proteins encoded by WDR19 (IFT144) and TTC21B, and IFT-B, with IFT172 and TRAF3IP1 (IFT54); variants in TRAF3IP1 revealed a role of IFT proteins in microtubule stabilisation [28]. CEP164 and CEP83 encode proteins of the distal centriole and its appendages [47, 49]. CEP164 and ZNF423 link the renal ciliopathies to DNA damage response signalling [47]. Loss of GLIS2 causes NPH through increased apoptosis and fibrosis in humans and mice [46]. CEP290 encodes a centrosomal protein of the photoreceptor connecting cilium, which modulates the transcription factor ATF4, involved in cAMP-dependent cyst formation [45]. MAPKBP1 is an exception: the protein does not localise to the primary cilium and patients' fibroblasts have no ciliogenesis defect, so the authors described a "cilia-independent" NPH [50]. XPNPEP3, responsible for nephronophthisis-like nephropathy type 1, encodes a mitochondrial aminopeptidase [29, 57].

2.2. Tissue and physiological mechanisms

The histology of juvenile and adult NPH shows tubulointerstitial fibrosis, thickened and disrupted tubular basement membranes and sporadic cysts at the corticomedullary junction; focal segmental glomerulosclerosis appears as a non-specific finding of advanced disease [1]. In infantile NPH cortical cysts predominate, without thickening of tubular basement membranes and with minimal fibrosis [1, 58]. Proteinuria results from secondary glomerulosclerosis and, like HTN, appears late in the juvenile form [1, 22]. The urinary concentrating defect may reflect dysfunction of the vasopressin V2 receptor and aquaporin-2 pathway or loss of tubular architecture and of the medullary gradient [25]. Chronic polyuria can dilate the bladder without any urinary tract malformation [1]. Imbalanced signalling in several organs explains the extrarenal manifestations: the retina depends on transport through the connecting cilium between the inner and outer segments of the photoreceptors, where nephrocystin-5 (which interacts with RPGR and calmodulin) and nephrocystin-6 act [44, 45]; the liver develops congenital hepatic fibrosis in Senior-Boichis syndrome [6, 11]; and the genes involved in early patterning produce situs inversus, heart defects and polydactyly when function is completely lost [59].

2.3. Genetic architecture and diagnostic yield

GeneReviews classifies 21 genes as NPHP and estimates that biallelic pathogenic variants in these genes account for 50–60% of people with NPH; the remaining 40–50% remain without a molecular diagnosis with this set of genes [1]. Estimates vary with method and cohort. Sequencing of 13 genes (NPHP1 to NPHP13) in a worldwide cohort of 1056 patients with NPH-RC, without targeted testing for the NPHP1 deletion, gave a diagnosis in 127 (12.0%) and a single heterozygous truncating variant in 31 (2.9%) [60]. In the Necker cohort, with a targeted panel and exome, a diagnosis was obtained in 600 patients from 496 families (71% per family), with 788 pathogenic variants in 40 ciliopathy genes and 53% of patients with biallelic variants in NPHP1 [54, 61]. In the German, Austrian and Dutch NEPHREG registry, 97 of 152 children (64%) had a monogenic diagnosis, 89 of them in NPHP genes; the homozygous NPHP1 deletion was the most frequent defect (60/152; 39%), with possible bias because several centres tested only this gene [22]. The European cohort of König and colleagues (2022) estimates that about 40% of patients remain without a genetic diagnosis, that the homozygous deletion encompassing the whole of NPHP1 explains 20–40% of cases and that each of the remaining genes accounts for no more than 3% [17]. The 2026 systematic review by the IPNA (International Pediatric Nephrology Association) reports 20–60% homozygous NPHP1 deletion among genetically identified patients and ≤1% for each of the other genes [19].

2.4. The recurrent NPHP1 deletion

The homozygous deletion of about 290 kb encompassing the whole of NPHP1 is the most frequent single cause of NPH, with about 25% of all cases according to GeneReviews [1, 39]. Saunier and colleagues showed that NPHP1 is flanked by two large inverted repeats of about 330 kb and that a 45 kb sequence next to the proximal repeat is directly repeated 250 kb further on; the breakpoints lie within this 45 kb repeat, indicating unequal recombination between homologous copies. The same work found a non-pathogenic rearrangement, an inversion between the 330 kb repeats, in 11 patients and in the homozygous state in 2 controls (1.3%) [39]. In the French series of that time, predating the discovery of the other genes, NPHP1 explained about 85% of purely renal NPH and the homozygous deletion about 80% of these patients [35, 39]. There is no single description of the deletion according to the Human Genome Variation Society (HGVS) nomenclature: ClinVar pathogenic records have coordinates that vary with laboratory and platform, for example GRCh38 chr2:110104900-110207160 with zero copies (VCV000032789) or chr2:110091573-110212811 (VCV004851971), and boundaries measured by microarray underestimate the classical extent [62]. In the study by Snoek and colleagues, the single nucleotide polymorphism (SNP) array estimated the deletion at about 96 kb, with all NPHP1 exons included, and confirmation by multiplex ligation-dependent probe amplification (MLPA) was concordant in 11 of 11 samples [18]. In the remaining NPH genes no recurrent whole-gene deletion is known [18].

2.5. Variant spectrum and nomenclature

The following table brings together the recurrent or informative variants cited in the article, with the transcript used. Conversions between transcripts were made in VariantValidator; when the variant has only been described on a transcript other than MANE, the published notation is kept and the transcript is indicated.

2.6. Gene-by-gene distinction

NPHP1. Most disease alleles are the whole-gene deletion, which eliminates the protein; missense and point truncating variants occur in compound heterozygosity with the deletion [36, 37]. The dominant phenotype is isolated juvenile NPH, but 23% (14/60) of patients with NPHP1 in the NEPHREG registry had extrarenal manifestations [22], and 15 of 116 in the 2022 cohort (7 SLS, 3 Joubert, 4 Cogan oculomotor apraxia, 1 Bardet-Biedl) [17]. The retina of patients with the homozygous deletion is frequently affected subclinically: 15 of 16 patients studied by optical coherence tomography (OCT) and electroretinography had mild cone-predominant retinopathy with relative foveal sparing, usually without fundus changes, termed "occult retinopathy" [68].

NPHP3. The allelic spectrum illustrates the relationship between residual function and phenotype. Hypomorphic alleles cause NPH, sometimes of late onset, whereas complete loss of nephrocystin-3 causes embryonic lethality, situs inversus and heart disease in mice, and in humans a spectrum of early patterning defects that includes Meckel-Gruber-like phenotypes (Meckel 7) and renal-hepatic-pancreatic dysplasia [59]. In the 2022 cohort, the presence of at least one truncating variant was associated with ESKD before 2 years in more than half of patients, and two missense variants with longer renal survival (p<0.0001), although 24 of the 27 patients with two missense variants belonged to the same Venezuelan pedigree in which NPHP3 was described [11, 17]. A rare synonymous NPHP3 variant, discarded by the usual filters, explained hepatorenal fibrocystic disease in six families by activating a cryptic splice donor [67].

NPHP4. It causes juvenile and adult NPH, isolated or with RP (SLSN4) [10, 41, 42]. In the 2022 cohort, only the combination of two truncating variants was associated with a worse renal prognosis (p=0.0021) [17]; in a consanguineous Filipino family with two missense variants, ESKD occurred at a median of 36.2 years [17]. In Korean patients, carriers under 20 years had moderate or end-stage CKD with normal visual fields, and those over 30 years had severe retinopathy with an extinguished electroretinogram (ERG) [21].

IQCB1. All people with biallelic variants have RP, according to GeneReviews and the original series [1, 44]. Visual failure generally precedes the renal diagnosis: in the NEPHREG registry, the five patients with IQCB1 had visual impairment in the 1st year of life, renal cysts and ESKD at the end of adolescence, without liver disease [22]. Structural variants that are difficult to detect are frequent in this gene: a 5.8 kb intronic deletion in two Korean siblings, the whole-gene deletion in the case in section 10 and the insertion of a mobile element into intron 6 in a Dutch patient [21, 63, 64].

CEP290. It is one of the most pleiotropic ciliary genes, with phenotypes ranging from isolated LCA (LCA10) to Joubert syndrome, SLS (SLSN6), Bardet-Biedl syndrome and lethal Meckel-Gruber syndrome (Meckel 4) [1, 45]. In the NEPHREG registry, the five patients with CEP290 had Joubert syndrome, four blind from birth, with CKD in three and ESKD in two (at 7 and 21 years) [22]. In a Chinese ophthalmology-based series, CEP290 was the most frequent gene among patients with biallelic variants in SLS genes (61.4%), and NPH was present in only 11.4% at the time of nephrology referral [20]. The deep intronic variant c.2991+1655A>G is the target of retina-directed trials.

TMEM67. It is associated with NPH with hepatic fibrosis (NPHP11), Joubert syndrome, COACH and Meckel-Gruber syndrome [12, 26]. In the NEPHREG registry, all six patients with TMEM67 had hepatic fibrosis [22]; in the 2022 cohort, renal survival did not depend on variant type or on location in exons 8–15 (ESKD at 11.8 and 11.3 years, respectively) [17].

INVS, NEK8 and ANKS6. These are the typical genes of infantile NPH, with enlarged cystic kidneys, situs inversus and, in the case of NEK8, pancreatic anomalies and renal-hepatic-pancreatic dysplasia [1, 43, 48]. OMIM classifies NPHP2 as infantile, but GeneReviews assigns infantile and juvenile forms to INVS, and Halbritter described two patients with truncating INVS variants with neither infantile presentation nor extrarenal manifestations [1, 12, 60]. A family with a homozygous INVS variant had early-presenting renal cysts [58].

WDR19, TTC21B and IFT172. The IFT-A genes cause a spectrum that includes isolated NPH, SLS (SLSN8, WDR19), Sensenbrenner cranioectodermal dysplasia, short-rib thoracic dysplasias and Caroli disease [60, 69]. Analysis of 94 patients with biallelic variants in WDR19 (93 published and a 32-year-old woman) showed renal, ocular, skeletal and hepatic involvement as the most frequent; the presence of at least one truncating variant was associated with more skeletal and less hepatobiliary involvement, and, among patients with missense variants only, variants outside the repeat domains were associated with onset before 16 years and ocular involvement [70]. The TTC21B variant p.(Pro209Leu) is associated with early-onset HTN, arteriolar thrombotic microangiopathy and proteinuria [65, 66]. IFT172 causes NPH with skeletal anomalies and RP, within the spectrum of Mainzer-Saldino syndrome [1, 71].

SDCCAG8 and TRAF3IP1. SDCCAG8 causes SLS (SLSN7) and Bardet-Biedl syndrome 16, with obesity and hypogenitalism in some patients [1, 10]. TRAF3IP1 (IFT54) was described in eight patients from five families, all with early-onset NPH and retinal degeneration, with variable hepatic and skeletal involvement and obesity (SLSN9) [28].

MAPKBP1. The original series described eight patients from five families with juvenile or late NPH, extensive renal fibrosis and no extrarenal manifestations [50]. A 2026 systematic review, with 19 eligible patients and a mean age of 24.9 years at last follow-up, found at least one extrarenal manifestation in 14 (73.7%), mainly skeletal (scoliosis in 8 of 19, short stature, patellar subluxation, long fingers and feet), as well as craniofacial dysmorphism and cardiovascular anomalies, which contradicts the initial description of a purely renal disease [27].

Other rare genes. CEP83 causes infantile NPH with intellectual disability [49]; CEP164 and ZNF423 cause NPH with retinal, hepatic or neurological involvement [47]; GLIS2 causes juvenile NPH without known extrarenal manifestations [46]; ADAMTS9 causes NPH-RC with deafness, short stature and developmental delay [51]; DCDC2 causes juvenile NPH with liver disease and deafness [1].

2.7. Genotype-phenotype correlations, penetrance and expressivity

The most robust correlation is the relationship between gene, variant type and age at ESKD, described in section 11. For NPHP1, the 2022 cohort found no difference between the homozygous deletion (n=97) and the other biallelic genotypes (n=19) (p=0.20), but genotypes with two truncating variants, including the deletion, fared worse than genotypes with at least one missense variant (p=0.03) [17]. The renal penetrance of biallelic NPHP1 variants is described as complete by Snoek and colleagues [18], but age at onset varies between childhood and the seventh decade. Inter- and intrafamilial variability in the rate of progression is considerable [1]; in the two consanguineous families with XPNPEP3, severity and organs affected varied between families but were concordant within each family [57]. The Oxford Desk Reference records, in Bardet-Biedl syndrome, cases of "triallelic" inheritance in which a third variant at another locus may modify severity [3].

2.8. Modifiers, atypical inheritance and allelic disorders

OMIM summarises the study by Louie and colleagues, in which the hypomorphic AHI1 variant p.(Arg830Trp) was found in 25% of alleles of 153 Italian patients with NPH and retinal degeneration compared with 1.8% of controls (p=5.36×10⁻⁶; relative risk 7.5), with no association in 155 patients with Joubert [12]. A patient with a homozygous NPHP1 deletion and an additional variant in CEP290 had more severe retinal degeneration than the others in Birtel's series, suggesting a modifier effect [68]. NPH-RC is typically autosomal recessive; OFD1-related Joubert syndrome is X-linked, and dominant inheritance has rarely been described in Joubert with variants in SLC30A7, SUFU and ZNF423, with insufficient evidence according to GeneReviews [1]. OMIM records AD or AR inheritance for the entries NPHP12 (TTC21B) and NPHP14 (ZNF423) [12]. The allelic disorders of the NPHP genes include Joubert syndrome (NPHP1, CEP290, TMEM67, RPGRIP1L, ZNF423), Meckel-Gruber syndrome (CEP290, TMEM67, RPGRIP1L, NPHP3), LCA and other isolated retinal dystrophies (CEP290, IQCB1, IFT172), Bardet-Biedl syndrome (CEP290, SDCCAG8), short-rib thoracic dysplasias and cranioectodermal dysplasia (WDR19, TTC21B, IFT172), renal-hepatic-pancreatic dysplasia (NPHP3, NEK8) and DFNB66 deafness and neonatal sclerosing cholangitis (DCDC2) [10, 12, 59, 69].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Age-based classification and distribution of the forms

Clinical classification is based on age at ESKD. König and colleagues, citing earlier literature, describe the infantile form with ESKD before 5 years (mean 8 months), the juvenile form with a median of 13 years and the adolescent form with a mean of 19 years [17]. GeneReviews places ESKD in the infantile form before 3 years [1], and the IPNA review reports kidney replacement therapy (KRT) before 4 years, typically at around the 8th month [19]; the differences reflect the source series and do not alter the separation between a rapidly progressive infantile form and a juvenile–adult continuum. In the Necker cohort, 76% of patients with a molecular diagnosis had progressed to kidney failure: 18% with the infantile form (before 5 years), 48% juvenile (5–15 years) and 34% late-onset (after 15 years) [54]. More than 85% of infantile forms had extrarenal manifestations, compared with about half of juvenile and late forms; the eye was the predominant extrarenal organ, followed by cerebellar hypoplasia and other brain anomalies, the liver and the skeleton [54].

3.2. Infantile nephronophthisis

Infantile NPH may manifest in utero with the oligohydramnios sequence (limb contractures, pulmonary hypoplasia and facial dysmorphism) or after birth with severe HTN and renal manifestations that progress to ESKD in the first years [1]. Ultrasound shows moderately enlarged cystic kidneys with cortical hyperechogenicity, and histology shows cortical cysts without the tubular basement membrane thickening typical of the juvenile form [1, 58]. In the NEPHREG registry, 7 of the 90 patients without NPHP1 (8%) had infantile NPH, with ESKD at 2.1±1.07 years [22]. The four patients with NPHP3 had NPH with congenital hepatic fibrosis and early cysts, with ESKD at 0.7, 4, 8 and 10 years [22]. In the 2022 cohort, about half of patients with NPHP3 had infantile NPH with ESKD before 4 years [17]. In the first year of life, the presenting signs of patients without NPHP1 included dysmorphism (11%), failure to thrive (18%), developmental delay (18%), visual impairment (12%) and fetal or neonatal tachypnoea (10%) [22].

3.3. Juvenile nephronophthisis

The juvenile form is the most frequent. The classic picture begins at around 6 years with polyuria, polydipsia and secondary enuresis, and ESKD appears at around 13 years [18]. GeneReviews adds growth restriction, iron-resistant chronic anaemia and the manifestations of advanced CKD (mineral and bone disorder, metabolic acidosis and uraemic symptoms such as nausea, anorexia and weakness) as modes of presentation, and stresses that proteinuria and HTN are late [1]. The disease is silent for years: there is no oedema, macroscopic haematuria or nephritic syndrome, and urine and blood pressure may be normal during progression [1, 22].

The NEPHREG registry describes 152 children from 22 paediatric nephrology centres in Germany, Austria and the Netherlands, followed for 7.5±6.1 years [22]. The initial presentation in patients with NPHP1 was polyuria (54%) or CKD (46%); signs of a concentrating defect rarely appeared before 4–6 years. Polyuria (defined as urine output above 2000 ml/m²/day) was recorded in only 38 of 60 patients with NPHP1 (63%), proteinuria in up to 32%, almost only in ESKD, and haematuria was rare. Anaemia occurred in 104 of 152 patients (68%), in 90 of them associated with advanced CKD (mean estimated glomerular filtration rate, GFR, of 25 ml/min/1.73 m²); 14 patients (6 with NPHP1 and 6 with Joubert or COACH) had anaemia with an estimated GFR (eGFR) above 45 ml/min/1.73 m², that is, disproportionate to kidney function [22]. Of the patients with NPHP1, 38 (63%) reached ESKD at 11.4±2.4 years, only 5 after 15 years and none before 5; 90% had a rapid decline in function between 8 and 16 years [22]. In the 2022 cohort of 116 patients with NPHP1, 52% were hypertensive (mean age at diagnosis of HTN 11.2 years), 26% had proteinuria above 300 mg/24 h and 34% had growth delay (height below the 3rd centile or crossing that centile); in 14 of the 62 hypertensive patients, HTN was diagnosed already in ESKD, and the mean time between diagnosis of HTN and ESKD was 1.52 years [17].

3.4. Adolescent and adult nephronophthisis

Late-onset NPH is underdiagnosed. In the iGeneTRAiN consortium, which brought together 5606 patients with adult-onset ESKD (first KRT at 18 years or older) in five transplant cohorts from the USA, the Netherlands and Austria, 26 (0.5%; 1 in 200) had the homozygous NPHP1 deletion, compared with none of 3311 control donors [18]. Prevalence was 0.9% (24/2794) among patients starting KRT at 18–50 years and 2.1% at 18–29 years; the median age at first KRT was 30 years (range 18 to 61), and 14 of the 26 were 30 years or older [18]. Only 3 of the 26 (12%) had a clinical diagnosis of NPH; the rest were classified as CKD of unknown cause (11), cystic disease (2), hypertensive nephrosclerosis (2), tubulointerstitial disease (2), glomerular disease or glomerulonephritis (2), reflux, vascular nephropathy, uric acid nephropathy and autosomal dominant polycystic kidney disease without a variant in PKD1 or PKD2 (1 each); one patient labelled as hypertensive nephrosclerosis had congenital blindness, compatible with SLS [18]. Before this study only 6 patients from 4 families with NPHP1 and ESKD after 30 years had been described, the oldest aged 56 years [18].

In a Japanese series of 18 sporadic adults with histological suspicion of NPH (median age at biopsy 52 years, median eGFR 18.4 ml/min/1.73 m², HTN in 61% and proteinuria in 78%), a 69-gene panel with CNV analysis found pathogenic variants in 7 (NPHP1, NPHP3, NPHP4, CEP164); patients with a genetic diagnosis were younger (median 26 versus 63 years; p=0.01), and no patient over 50 years at biopsy had a variant [72]. Two non-consanguineous Belgian families show the presentation as "non-specific" chronic interstitial nephritis: in the first, the younger brother had CKD discovered at 21 years, proteinuria of 1 g/day and kidney failure at 27, and the 31-year-old brother, evaluated as a potential donor, had an eGFR of 50 ml/min/1.73 m² and proteinuria of 250 mg/day, both with NPHP1 c.1027G>A on NM_000272.5 (c.859G>A on MANE) in trans with the gene deletion; in the second, a patient transplanted at 36 years with polyuria since childhood and a brother on dialysis at 57 years, with a presumed diagnosis of lithium-induced interstitial nephritis, had biallelic variants in NPHP4 [23].

At the Pitié-Salpêtrière Hospital, in Paris, exome sequencing offered to all patients with CKD of onset before 45 years without a clear cause identified, among 200 index cases studied from September 2018 to May 2020, 18 ciliopathies, 7 of them with a severe hypertensive phenotype: 6 with homozygous TTC21B p.(Pro209Leu) and 1 with homozygous WDR19 p.(Asp98Tyr) [65]. HTN began at a mean age of 23 years, in 3 patients before any kidney dysfunction, with left ventricular hypertrophy and hypertensive retinopathy; the 4 biopsies showed severe hypertensive nephrosclerosis and arteriolar thrombotic microangiopathy, without cysts or tubular basement membrane changes; 5 of the 7 had abnormal liver tests, and all were classified as hypertensive kidney disease [65]. The authors named this phenotype "nephroangiophthisis". In a Chinese series of 21 children with NPH, 9 had moderate to severe proteinuria, associated with more family history, HTN and oedema, and 3 of the 4 patients with TTC21B belonged to this group; the median age at symptom onset was 7.4 years and 20 patients reached ESKD at a median of 9.8 years [66]. Moderate or nephrotic-range proteinuria does not exclude NPH [61, 66].

3.5. Phenotype by gene in the European paediatric registry

The following table summarises the frequencies by gene in the NEPHREG registry. Denominators are small outside the NPHP1 group, so the percentages for the rare genes describe series of 4 to 6 patients and do not estimate population frequencies [22].

The differences between NPHP1 and the other genes were significant for hepatic involvement (8% versus 41%; p<0.001), neurological involvement (25% versus 47%; p<0.01) and visual loss (23% versus 41%; p=0.02) [22]. Of all 152 children, 77 (51%) had isolated NPH, 26 (17%) Joubert syndrome or COACH, 17 (11%) SLS, 7 (5%) congenital oculomotor apraxia, 4 (3%) Bardet-Biedl syndrome, 6 (4%) skeletal disease and 1 Meckel-Gruber syndrome; NPH was isolated in 77% of patients with NPHP1 and in 34% of the others [22]. Eight patients with NPHP1 first presented with isolated neurological signs (3 with Joubert and 5 with oculomotor apraxia), and all progressed to ESKD [22].

3.6. Ocular manifestations and Senior-Løken syndrome

SLS is defined by the association of NPH with LCA or with RP; the genes of the OMIM series are NPHP1, NPHP4, IQCB1, CEP290, SDCCAG8, WDR19 and TRAF3IP1, and Orphanet adds CEP164, INVS and NPHP3 [10, 15]. Otto and colleagues estimated the fraction of patients with NPH who have RP at about 10% [44]. The retinal phenotype and the order of appearance of signs depend on the gene. In a Chinese ophthalmology-based series of 74 patients from 70 families, CEP290 explained 61.4%, IQCB1 28.6%, NPHP1 4.2%, NPHP4 2.9% and WDR19 2.9%; the median age at onset of retinopathy was about 1 month, nystagmus was the first sign in 63.6% of patients with CEP290 and in 86.4% of patients with IQCB1, and cone and rod responses were extinguished in 53 of 55 (96.4%) [20]. Of the 70 patients referred to nephrology, 62 (88.6%) did not have NPH at a median of 6 years and 8 (11.4%) had it at around 9 years; patients with CEP290 or IQCB1 manifested retinopathy first, and patients with INVS, NPHP3 or NPHP4 nephropathy first [20]. Because this is an ophthalmology-based cohort, frequencies are biased towards the genes with early retinopathy.

In the Korean series of 17 patients with SLS and a genetic diagnosis (mean age at diagnosis 18.3±11.4 years), NPHP1 explained 6 patients (35.3%), NPHP4 5 (29.4%), IQCB1 5 (29.4%) and SDCCAG8 1 (5.9%), with no case due to CEP290 [21]. Patients with NPHP1 had RP sine pigmento or retinal dystrophy with preserved central vision, an initially preserved ERG and worsening with age; patients with NPHP4 under 20 years had normal visual fields and those over 30 years severe retinopathy; IQCB1 was associated with early and severe degeneration, with LCA in 3 patients, but two siblings with a large intronic deletion had RP sine pigmento and normal kidney function at diagnosis; the patient with SDCCAG8 had ESKD and congenital blindness [21]. Wide-field autofluorescence in the younger patients showed perifoveal and peripapillary hypoautofluorescence with a perifoveal hyperautofluorescent ring. The authors concluded that renal and retinal severity are not aligned, so the kidney and the eye should be assessed simultaneously and independently in all patients with SLS [21].

Retinopathy due to the NPHP1 deletion is frequently subclinical. Birtel and colleagues found in 15 of 16 patients a mild cone-predominant retinopathy with relative foveal sparing, sometimes with early night blindness; OCT showed reduced reflectivity and a granular appearance of the ellipsoid zone, effacement of the interdigitation zone and mild thinning of the outer retina, with fundus and autofluorescence usually normal, and the degeneration may progress with age [68]. CEP290-associated retinopathy with LCA and retinal dystrophies without kidney disease have their own natural history.

3.7. Hepatic involvement and Senior-Boichis syndrome

Senior-Boichis syndrome combines NPH with congenital hepatic fibrosis. The description by Boichis and colleagues in 1973 was a family study [6]; NPHP3 was later identified in adolescent NPH with hepatic fibrosis [11], and Orphanet links this entity to the OMIM entries NPHP11 (TMEM67) and NPHP19 (DCDC2) [13]. In the NEPHREG registry, all patients with NPHP3 and with TMEM67 had hepatic involvement: hepatosplenomegaly and raised liver enzymes in 100% of patients with NPHP3, cholestasis in 50%, thrombocytopenia in 50%, ascites in 25% and pruritus in 50%; oesophageal varices in 17% of patients with TMEM67; hepatic fibrosis was rare with NPHP1 (hepatic involvement in 8%) [22]. The synonymous NPHP3 variant described by Olinger caused NPH with congenital hepatic fibrosis in several families [67], and the analysis of patients with WDR19 associated hepatobiliary involvement, which includes Caroli disease, mainly with genotypes without truncating variants [60, 70].

The recommendations for Joubert syndrome describe chronically raised transaminases and gamma-glutamyltransferase and portal hypertension in at least 2% of patients in the University of Washington cohort (13 patients: 4 with splenomegaly, 2 with varices, 6 with portosystemic shunt and 3 with liver transplantation) and in 13% of the National Institutes of Health (NIH) cohort, where 41% had raised enzymes [26]. Congenital hepatic fibrosis does not compromise the synthetic function of the liver [26]. Acoustic radiation force impulse (ARFI) elastography in 50 patients with ciliopathies (2 months to 66 years) found normal stiffness in 27, intermediate fibrosis in 11 and F4 fibrosis in 12, with complete concordance with histology in the 10 biopsied patients; fibrosis was associated with PKHD1, TMEM67 and TULP3, and stiffness was normal in patients with NPHP1, NPHP4 and WDR19 [73].

3.8. Central nervous system and oculomotor apraxia

Neurological involvement covers developmental delay, seizures, ataxia and vermis hypoplasia; when the molar tooth sign is present on magnetic resonance imaging (MRI), the diagnosis is Joubert syndrome [1, 22]. Cogan congenital oculomotor apraxia is associated with the NPHP1 deletion and has been described with NPHP4 [22, 42]; in the NEPHREG registry it was present in 10% of patients with NPHP1 and in 50% of patients with TMEM67 [22]. CEP83 is associated with intellectual disability [49], and XPNPEP3 with signs of mitochondrial disease, including neurological manifestations and deafness [1, 29].

3.9. Skeleton, laterality, heart and other organs

Skeletal anomalies (short stature, narrow thorax, brachydactyly and polydactyly, postaxial being the most frequent in the ciliopathies) are associated with IFT172, TTC21B, WDR19 and, provisionally, MAPKBP1 [1, 27]. In the NEPHREG registry, the four patients with IFT140 had skeletal anomalies (cone-shaped epiphyses in 3, asphyxiating thoracic hypoplasia in 2) and retinal dystrophy, compatible with Mainzer-Saldino syndrome, with CKD in all and ESKD in 2 (at 7 and 10 years) [22, 71]. Situs inversus and congenital heart defects are associated with the inversin compartment genes (INVS, NPHP3, NEK8, ANKS6) and with ZNF423 and TTC21B [1]. Pancreatic anomalies (cystic enlargement or fibrosis, depending on variant type) are associated with NEK8 and WDR19 [1]. SDCCAG8 is associated with obesity and hypogenitalism (cryptorchidism and micropenis; hypoplasia of the labia minora), ADAMTS9 with deafness, short stature and developmental delay, and DCDC2 with deafness [1]. Recurrent respiratory or ear infections were recorded in 8 of 152 children, with no conclusion regarding a motile cilia defect [22].

3.10. Nephronophthisis in the syndromic ciliopathies

NPH is part of several syndromic ciliopathies. In Joubert syndrome, kidney disease, including NPH, occurs in 23–35% of patients, on a continuum between NPH and cystic dysplasia, with ESKD at a mean of 13 years in juvenile forms; in the COACH subtype, NPH occurs in 21–33% [1]. The recommendations for Joubert syndrome report fibrocystic kidney disease in 25–30% and ESKD in 5.1% (30/586) in the University of Washington cohort and in 13% (13/97) in the NIH cohort; kidney failure appears to be the main cause of death after the first year of life [26]. In Bardet-Biedl syndrome, in a British cohort, CKD was present in 31% of children and 42% of adults and ESKD with dialysis or transplantation in 6% and 8%, respectively; in most children with CKD stages 4–5, kidney disease was diagnosed in the first year and almost all by 5 years [1, 74]. In Jeune asphyxiating thoracic dystrophy, respiratory failure is the main cause of perinatal and infant mortality, and the prevalence of kidney disease is unknown [1]. Meckel-Gruber syndrome, lethal in the prenatal or perinatal period, combines cystic kidney disease, occipital encephalocele, hepatic anomalies and polydactyly [1].

3.11. Natural history and treated disease

The progression data from the König cohorts reflect patients treated according to the paediatric nephrology practice of each centre, not untreated natural history, but because there is no disease-modifying treatment, age at ESKD approximates the spontaneous course of kidney function [17, 22]. Hildebrandt's German series of 1997 found a median age at ESKD of 13.1 years, practically the same as in recent cohorts [17, 38]. What treatment changes is the morbidity of CKD (anaemia, growth, bone disease) and survival after ESKD, which depends on dialysis and transplantation. In adulthood, the absence of a diagnosis leads to misclassifications that can result in inappropriate treatments, such as corticosteroid therapy in a Japanese case treated as chronic tubulointerstitial nephritis before the diagnosis of SLS [18, 75].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

Prenatal and neonatal period. Oligohydramnios with enlarged hyperechogenic kidneys, particularly with situs inversus, congenital heart disease, polydactyly or central nervous system malformation, suggests infantile NPH or a syndromic ciliopathy; the Oxford Desk Reference lists as clues in pregnancy and the perinatal period neonatal death and stillbirth, hyperechogenic kidneys, occipital encephalocele, ventriculomegaly or Dandy-Walker variant, polydactyly and short limbs and ribs [1, 3]. In the newborn and infant, severe HTN with enlarged cystic kidneys and neonatal tachypnoea are signs of infantile NPH [1, 22].

School age. The combination of polyuria, polydipsia and secondary enuresis in a child with urine without active sediment, anaemia and growth deceleration is the typical picture of juvenile NPH [1, 18]. Iron-resistant anaemia disproportionate to kidney function has been proposed as an early sign, although in the NEPHREG registry only 14 patients had it with an eGFR above 45 ml/min/1.73 m² [22]. CKD discovered on tests performed for another reason, with small or normal-sized hyperechogenic kidneys, is the other common mode of presentation [22].

Adolescence and adulthood. NPH should be part of the differential diagnosis of any CKD without an evident cause before 50 years, of "non-specific" chronic interstitial nephritis with inactive sediment and low-grade proteinuria, of CKD with severe HTN and vascular lesions in a young adult with persistently abnormal liver tests, and of CKD associated with blindness or retinopathy [18, 23, 24, 65]. The absence of polyuria does not exclude the diagnosis in adults [23].

Ophthalmological context. In the presence of early-onset retinal dystrophy (LCA or RP), the Oxford Desk Reference recommends asking about kidney disease, measuring blood pressure and requesting a renal ultrasound [76]. Patients with CEP290- or IQCB1-related retinopathy need nephrological surveillance even without initial kidney disease, because NPH may appear years later [20].

Family context. A sibling with CKD or ESKD in childhood or adolescence, parental consanguinity and male infertility in the family strengthen the suspicion; the absence of a family history does not exclude the diagnosis, because 82% of the children in the NEPHREG registry were sporadic cases [1, 3, 22]. Evaluation of a sibling as a potential living donor may reveal disease not yet recognised [23].

4.2. Extrarenal warning signs

Ciliopathy-directed examination, according to the Oxford Desk Reference, looks for growth abnormalities, lingual cysts, encephalocele, an abdomen enlarged by cystic kidneys, a bell-shaped thorax, polydactyly (postaxial in Bardet-Biedl, Meckel-Gruber, Jeune and Joubert syndromes; preaxial in the oral-facial-digital syndromes), abnormalities of eye movements and visual fields, photophobia, colobomas and retinal pigmentation, small genitalia, acanthosis nigricans, HTN and situs inversus [3]. Nystagmus and visual loss in the first months, night blindness and visual field restriction point to SLS; hepatosplenomegaly, raised liver enzymes and thrombocytopenia point to hepatic fibrosis; hypotonia, ataxia, episodic apnoea or tachypnoea and oculomotor apraxia point to Joubert syndrome [3, 22].

4.3. Urgent signs

Patients with NPH have obligatory salt and water losses through polyuria, so gastroenteritis, perioperative fasting or other intercurrent illness can cause dehydration, hypovolaemic hyponatraemia and acute worsening of kidney function; GeneReviews highlights the correction of fluid and electrolyte imbalances, particularly during intercurrent illness [1, 26]. In the clinical case in section 10, an adult with SLS without follow-up was admitted with hypovolaemic hyponatraemia with nausea and vomiting [64]. In advanced stages, fluid overload, hyperkalaemia, metabolic acidosis and uraemic symptoms require immediate assessment [1, 26]. In infantile NPH, severe HTN may be the initial manifestation [1]. In patients with hepatic fibrosis and portal hypertension, gastrointestinal bleeding requires urgent assessment with endoscopy [26].

4.4. Newborn screening

There is no newborn screening for NPH, and the sources consulted do not describe population screening programmes. In practice, early diagnosis depends on clinical recognition, prenatal ultrasound in the infantile forms and cascade testing of the siblings of an identified patient [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no consensus diagnostic criteria published by scientific societies for NPH or for SLS; a search for specific consensus statements and guidelines from 2015 to 2026 found none, and the applicable recommendations come from general guidelines on genetic testing in CKD and on CKD [24, 77]. GeneReviews establishes the diagnosis by identifying biallelic pathogenic variants in an NPHP gene in a patient with suggestive findings, and states that kidney biopsy is not necessary [1]. For registry purposes, NEPHREG defined clinical NPH by the presence of at least two of four criteria: a course with polyuria or polydipsia, CKD, suggestive ultrasound or biopsy, and a pedigree compatible with autosomal recessive inheritance; SLS was defined as NPH with RP [22]. For Snoek and colleagues, isolated NPH is difficult to recognise clinically and genetic testing is the only method that diagnoses it with certainty [18]; Petzold and colleagues conclude that NPH is defined more rigorously by its molecular basis than by its clinical presentation [61].

5.2. Initial clinical and laboratory assessment

GeneReviews proposes a three-step strategy before molecular testing: medical history (onset and course of the kidney disease, environmental factors, extrarenal manifestations, exclusion of other causes of CKD), physical examination aimed at features of a syndromic ciliopathy or of another syndromic cause of CKD, and a three-generation family history [1]. Initial tests include serum creatinine, eGFR, cystatin C when indicated, electrolytes, full blood count, calcium, phosphate, parathyroid hormone (PTH) and alkaline phosphatase, urine for proteinuria and liver function (transaminases, albumin, bilirubin and prothrombin time) [1]. eGFR is calculated with the 2012 Schwartz equation in children and CKD-EPI 2009 in adults, or by combining creatinine and cystatin C, which is more accurate when muscle mass is low [26]; KDIGO (Kidney Disease: Improving Global Outcomes) prefers enzymatic creatinine in children and allows an eGFR below 90 ml/min/1.73 m² after 2 years of age to be flagged as "low" [77]. Urine has an inactive sediment, low-grade or absent proteinuria until advanced stages, and low specific gravity or osmolality [1, 22]. In Joubert syndrome, a urine osmolality below 600 mOsm/kg predicted CKD in more than 75% of 93 patients, according to the 2020 recommendations [26].

5.3. Imaging

In the juvenile form, ultrasound shows small to normal-sized kidneys, with increased echogenicity, loss of corticomedullary differentiation and, in about half of patients and late in the course, cysts at the corticomedullary junction [1]. In the NEPHREG registry, 78% (119/152) had hyperechogenic kidneys with loss of corticomedullary differentiation, but only 51% (73/144) had cysts; in patients with NPHP1, cysts appeared at 12.3±3.9 years, whereas with NPHP3 and CEP290 they appeared early (at 0, 7 and 8 years and at 0, 1, 3 and 7 years, respectively) [22]. The absence of cysts in the early stages does not exclude NPH, and loss of corticomedullary differentiation also occurs in ADTKD and in HNF1B-associated disease [61]. In a 64-year-old Japanese man with rapidly progressive kidney failure and enlarged kidneys without cysts on computed tomography (CT) and MRI, MRI performed 5 years after the start of haemodialysis showed multiple medullary cysts that simultaneous CT did not reveal; this patient's molecular diagnosis remained incomplete, with a single heterozygous NPHP1 variant [78]. The authors concluded that MRI is superior to CT for late medullary cysts [78]. In the infantile form, the kidneys are moderately enlarged and cystic, with cortical hyperechogenicity [1]. Renal hyperechogenicity in childhood is sensitive but non-specific: among 79 consanguineous or multiplex families with hyperechogenic kidneys and suspected NPH-RC, exome sequencing found a monogenic cause in 50 (63%), of which 32 were in NPH-RC genes and the rest in tubulopathies (8), Alport syndrome (4), autosomal recessive polycystic kidney disease (ARPKD) (2), CAKUT (3) and autoimmune polyendocrinopathy (1) [79].

5.4. Histology

Kidney biopsy is not necessary when a genetic diagnosis is obtained, and at an advanced stage it shows only fibrosis and atrophy, which are of little informative value [1, 61]. The characteristic findings of the juvenile form are diffuse interstitial fibrosis, tubular atrophy, thickening and disruption of tubular basement membranes and occasional corticomedullary cysts [1, 61]. In the Japanese series of adults with histological suspicion of NPH, tubular cysts and the other classic findings did not distinguish patients with and without a genetic diagnosis; thick duplication of the tubular basement membrane (more than 10 µm), with α-smooth muscle actin-positive myofibroblasts within it, was significantly more frequent in genetic NPH and is the most specific histological finding of adult NPH [72].

5.5. Genetic tests: choice and order

The European recommendation of the ERA (European Renal Association) and ERKNet on genetic testing in CKD indicates targeted panels, or exome with a virtual panel, in diseases with locus heterogeneity, and comparative genomic hybridisation (CGH) or SNP microarrays, or MLPA, when large CNVs are suspected, with NPH (NPHP1) as an explicit example [24]. In cystic kidney disease manifesting prenatally or in early childhood, genetic testing is recommended as a first-line diagnostic procedure, with a comprehensive approach (extended panel or exome) from the outset and with a strategy that detects CNVs [24]. In CKD of unknown cause, which represents up to a third of adult-onset CKD, diagnostic yield ranges from 12% to 56% depending on the cohort, and genetic testing is recommended in severe or end-stage CKD with onset before 50 years without an evident non-genetic cause; the recommended turnaround time is 8–12 weeks, or 2 weeks for urgent indications such as prenatal or neonatal diagnosis [24]. The 2024 KDIGO guideline includes genetic diagnosis in the investigation of the cause of CKD and lists as situations in which testing is most informative early onset, syndromic or multisystem features, consanguinity, the possibility of targeted treatment and CKD of unknown cause in which biopsy would no longer be informative [77].

GeneReviews recommends a multigene inherited kidney disease or ciliopathy panel that includes the NPHP genes, because it maximises the likelihood of finding the cause and limits VUS and non-explanatory findings; it notes that the genes included and sensitivity vary between laboratories and that comprehensive genomic tests (exome and genome) do not require a gene hypothesis [1]. At a German centre, applying panels or exome with CNV and MUC1 analysis to 256 patients with suspected inherited kidney disease gave a diagnosis in 38.7%, with a yield of 72.0% in cystic diseases; family history, extrarenal manifestations and HTN were predictors of diagnosis [80].

Petzold and colleagues proposed a stepwise approach based on the Necker cohort: first, a curated panel or exome with a virtual panel of nephropathy and ciliopathy genes; then, in undiagnosed patients, particularly those with unexplained extrarenal features or atypical presentation (proteinuria, haematuria, late CKD), considering multisystem diseases and moving on to genome sequencing, with long-read sequencing for structural variants, CNVs and variable number tandem repeats (VNTR) [61]. In the same cohort, exome sequencing in 42 index cases without a diagnosis after a ciliopathy panel found pathogenic or likely pathogenic variants in 11 (26%), but in only 5 (12%) did they explain the kidney disease: LAMB2 (Pierson syndrome), COQ8B (primary coenzyme Q10 deficiency), COL4A3 (Alport), MUC1 (ADTKD, VNTR insertion detected by VNtyper and confirmed by SNaPshot) and AGXT (primary hyperoxaluria in an infant with ESKD at 4 months, hyperechogenic kidneys and retinal dystrophy); in 6 the exome explained only the extrarenal phenotype, and 74% remained without a diagnosis [61].

5.6. Limitations of the tests

Copy number variation. Detection of the common NPHP1 deletion, responsible for about 25% of all NPH, requires targeted deletion/duplication analysis (MLPA) or a genomic test such as an SNP array; a panel or exome without reliable CNV calling misses most cases with NPHP1 [1, 24]. ERA/ERKNet stresses that detection of large CNVs from panel or exome data is difficult and that CNV algorithms are not run automatically in all laboratories, with the NPHP1 and HNF1B deletions as examples [24]. In the Korean SLS series, 8 of 17 patients (47%) had large deletions, and genome sequencing was essential to detect the NPHP1 and IQCB1 deletions that escaped the panel and the exome [21].

False homozygosity and uniparental disomy. An apparently homozygous variant may correspond to hemizygosity due to deletion of one or more exons on the other allele, which sequencing does not detect, or to uniparental isodisomy; parental segregation clarifies the situation [1]. The most frequent form of this pitfall is the combination of a point variant in NPHP1 with deletion of the gene on the other allele [23, 36].

Deep intronic, synonymous and complex structural variants. Exome sequencing does not detect deep intronic variants, small CNVs, complex deletion-insertions, repeat expansions or mobile element insertions [61]. The Dutch patient with SLS described by de Bruijn and colleagues had, in 2012 and 2017, exome and short-read genome sequencing with only one heterozygous IQCB1 variant; optical genome mapping revealed a 6.2 kb insertion in intron 6, long-read sequencing identified a LINE-1/ERV1 mobile element in trans with the known variant, and long-read RNA-seq demonstrated a 276 bp pseudoexon with a premature stop codon and exon 6 skipping [63]. Synonymous variants are usually discarded by pathogenicity filters, but a synonymous NPHP3 variant explained disease in six families, which justifies re-evaluating rare synonymous variants in candidate genes [67]. The 1 bp insertion in the MUC1 VNTR, a cause of ADTKD and a phenocopy of late NPH, is not detectable by conventional exome sequencing [24, 61].

Mosaicism and de novo variants. When the variant is found in only one parent, with paternity and maternity confirmed, the other may have arisen de novo in the proband or correspond to parental post-zygotic mosaicism [1]. Saunier and colleagues described a de novo null NPHP1 variant in a patient hemizygous for the deletion [37].

Simple heterozygosity. Finding a single pathogenic variant in a recessive gene does not confirm the diagnosis. In the Necker cohort, 3 patients had only heterozygosity in recessive genes (NPHP1, WDR34, ORC6) [61], and in the iGeneTRAiN study the heterozygous NPHP1 deletion was more frequent among transplant recipients than among controls (36 versus 10; p<0.001), suggesting compound heterozygosity not detected by the array [18].

Overall yield. Even with panel, CNV analysis and exome, 26–40% of families remain without a molecular diagnosis in the large cohorts, and a negative result does not exclude NPH [1, 17, 61].

5.7. Functional tests and biomarkers under investigation

Immunofluorescence of nasal epithelial cells obtained by brushing, confirmed by Western blot, showed absence of nephrocystin-1 and nephrocystin-4 in all patients with causal variants in NPHP1, including a patient with the homozygous missense variant c.1027G>A on NM_000272.5 (c.859G>A on MANE), previously classified as a VUS; in two undiagnosed individuals, abnormal staining guided targeted genetic testing to the diagnosis [56]. This method is a research test, useful for reclassifying VUS in NPHP1 and NPHP4, and is not validated as a routine clinical test [56]. Urinary Dickkopf-3 (DKK3), a tubular protein associated with fibrosis, was measured in 357 samples from 247 individuals in the NEOCYST registry: the median DKK3/creatinine ratio was 11 pg/mg in controls and 1219 pg/mg in NPH, the highest among the ciliopathies studied; values above 4700 pg/mg were associated with a median annual eGFR loss of 5.04%, compared with a gain of 0.35% below the threshold, independently of diagnosis and eGFR (p=0.0029) [81]. DKK3 does not distinguish between ciliopathies and is a research marker of severity and short-term decline, without clinical validation [81].

5.8. Report content and variant interpretation

The report should state the gene, the reference transcript with version (preferably MANE Select), the HGVS description at DNA and protein level, zygosity, the phase of the variants when known and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP); for the NPHP1 deletion, it should state the method (MLPA, array or CNV calling from sequencing data) and the coordinates with the reference genome version [24, 62]. The difference in numbering between transcripts is a concrete source of error: the NPHP1 variant c.1027G>A p.(Gly343Arg) in the literature corresponds to this notation on NM_000272.5, but on the MANE transcript NM_001128178.3 it corresponds to c.859G>A p.(Gly287Arg), and the notation "NM_001128178.3:c.1027G>A" published in a 2022 letter fails validation [23, 31]. VUS should not be used for clinical decisions, according to ERA/ERKNet, which refers to the ACMG criteria [24]; segregation in the parents, variant phase, functional research tests and periodic reanalysis of the data allow them to be reclassified [1, 56].

5.9. Practical algorithm

The following table summarises the diagnostic sequence based on the recommendations and cohorts cited.

5.10. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible when both of the family's pathogenic variants have been identified [1]. In infantile NPH, suspicion may arise on ultrasound with oligohydramnios and enlarged hyperechogenic kidneys; in this situation, ERA/ERKNet recommends an urgent laboratory turnaround, of about 2 weeks [1, 24]. Prenatal testing for the juvenile forms, with postnatal expression, raises questions of perspective between professionals and families that GeneReviews recommends discussing during counselling [1].

6. Differential Diagnosis

6.1. Comparative table

Tubulointerstitial diseases, cystic diseases and conditions with urinary concentrating defect and growth restriction, such as nephrogenic diabetes insipidus and other tubulopathies, can mimic NPH [1]. The table brings together the monogenic differential diagnoses listed by GeneReviews, the phenocopies found in the exome cohorts and the syndromic ciliopathies with NPH.

6.2. Main differential diagnosis in children

In a child with polyuria, nephrogenic diabetes insipidus and the other tubulopathies are distinguished by onset from birth, their own electrolyte abnormalities and initially normal kidney function; in NPH, polyuria generally appears after 4–6 years and accompanies a fall in eGFR [1, 22]. ARPKD is distinguished by enlarged kidneys on neonatal ultrasound and by congenital hepatic fibrosis; infantile NPH may have enlarged cystic kidneys and, with NPHP3, hepatic fibrosis, so comprehensive genetic testing is the means of distinction [1, 24]. ERA/ERKNet clinically distinguishes NPH from polycystic kidney disease by small or normal-sized kidneys with tubulointerstitial cysts [24]. In exome sequencing of 79 families with renal hyperechogenicity in childhood, 18 of the 50 diagnoses were non-ciliary monogenic kidney diseases [79].

6.3. Main differential diagnosis in adults

In adults, ADTKD is the closest alternative diagnosis: ERA/ERKNet describes it as the "autosomal dominant equivalent of NPH", with typically later ESKD, and ADTKD-MUC1 overlaps mainly with isolated late-onset NPH, with small or normal-sized kidneys, occasional cysts, inactive sediment and slow CKD [24, 61]. Vertical transmission points to ADTKD; affected siblings with healthy parents and consanguinity point to NPH [1, 33]. NPH due to TTC21B or WDR19 can mimic severe hypertensive nephrosclerosis and thrombotic microangiopathy; the authors of the Paris series recommend suspecting it in CKD with severe HTN and vascular lesions in young adults with persistently abnormal liver tests and prescribing exome sequencing without excessive restrictions [65]. Significant proteinuria (more than 0.5 g/day) occurs in NPH, particularly with TTC21B p.(Pro209Leu), and may mimic minimal change disease or focal segmental glomerulosclerosis [61, 66]. Chronic interstitial nephritis attributed to drugs, as in the Belgian case attributed to lithium, and nephrosclerosis attributed to hypertensive disease of pregnancy, as in the Japanese SLS case described by Hirai, are other documented misclassifications [23, 83].

6.4. Phenocopies and dual diagnosis

The coexistence of "ciliopathic" extrarenal features, such as retinal dystrophy, hepatic fibrosis or polydactyly, with non-specific CKD does not necessarily imply a ciliopathy: in the Necker cohort, an infant with ESKD at 4 months, hyperechogenic kidneys and retinal dystrophy had primary hyperoxaluria due to AGXT, and six patients had a second genetic disease that explained only the extrarenal phenotype (APTX, TUBB3, DHX38, IQCE, CRX, RPGR) [61]. In the NEPHREG registry, 8 patients with a clinical diagnosis of NPH were reclassified after genetic testing (BBS7 in 2, BBS4, PKHD1, MKS1, AHI1, POC1B and UMOD) [22]. The therapeutic consequences of these alternative diagnoses are concrete: coenzyme Q10 supplementation in COQ8B deficiency, lumasiran or trials and combined liver-kidney transplantation in AGXT hyperoxaluria, consideration of tolvaptan in PKD1 disease, avoidance of unnecessary corticosteroid therapy in LAMB2 disease and cascade screening with ophthalmological and audiological assessment in Alport syndrome [61].

6.5. Boundaries with the syndromic ciliopathies

The distinction between SLS and Joubert syndrome rests on brain MRI: SLS does not have the molar tooth sign; the Oxford Desk Reference historically groups SLS among the cerebello-oculo-renal syndromes, but the current definition separates them [1, 52]. The distinction between SLS and Bardet-Biedl syndrome rests on obesity, polydactyly and intellectual disability, which in Bardet-Biedl syndrome appear at around 3–5 years, and on the type of nephropathy, which in Bardet-Biedl syndrome includes abnormal calyces (95% in a series from Smith), diverticula or communicating cysts (62%) and fetal lobulations (95%) [82]. SDCCAG8 and CEP290 cross this boundary, with SLS and Bardet-Biedl phenotypes [1]. In the differential diagnosis of Mainzer-Saldino syndrome, Jeune thoracic dystrophy manifests in the first year, with short ribs and without ocular or brain abnormalities, and Sensenbrenner dysplasia is distinguished by dolichocephaly due to sagittal craniosynostosis and by ectodermal signs of the hair, teeth and nails [71].

7. Treatments and Risk Management Strategies

7.1. Principles and sources of the recommendations

There is no cure or approved targeted therapy for NPH. Treatment aims to slow the progression of CKD and treat its complications: correction of fluid and electrolyte imbalances, particularly during intercurrent illness; treatment of anaemia, HTN, proteinuria and CKD mineral and bone disorder; growth hormone in children with severe growth restriction who meet the criteria; dialysis or kidney transplantation in ESKD; and vaccination according to international and regional recommendations [1]. GeneReviews notes that the preferred therapy may differ between adults and children and refers to the KDIGO guidelines of 2013 (CKD), 2017 (mineral and bone disorder, which includes the growth hormone criteria) and 2012 (acute kidney injury) [1]. The 2024 KDIGO guideline replaces the 2013 guideline for CKD and includes paediatric recommendations [77]. There is no NPH-specific guideline issued by ERKNet, IPNA or any other society; the recommendations applicable by extension are the ERA/ERKNet recommendation on genetic testing (2022), KDIGO 2024, the European Society for Paediatric Nephrology (ESPN) recommendations on growth hormone (2019) and the international care recommendations for Joubert syndrome (2020), which address the kidney and liver in ciliopathies with neurological involvement [24, 26, 77, 84]. The 2026 IPNA systematic review summarises the situation: there are no causal therapies and clinical trials remain absent [19].

7.2. Water and sodium balance

In the polyuric phase, patients with NPH have obligatory water and sodium losses. The 2020 recommendations for Joubert syndrome indicate prevention of dehydration in the early phase and of fluid overload in the late phase [26]. The ESPN recommendations state that children with CKD, hyponatraemia and polyuria should receive free water and sodium supplementation to avoid chronic intravascular depletion and allow growth [84]. KDIGO 2024 recommends, in children with CKD, that advice on sodium intake follow the recommended daily intake for age only when blood pressure is above the 90th centile [77]; routine sodium restriction may be inappropriate in salt-wasting NPH, and the decision should be based on each patient's serum sodium, volume status and blood pressure [26, 84]. During intercurrent illness, correction of fluid and electrolyte imbalances is the first goal of treatment [1].

7.3. Blood pressure and proteinuria

KDIGO 2024 suggests, in children with CKD, lowering the 24-hour mean arterial pressure measured by ambulatory blood pressure monitoring (ABPM) to the 50th centile or less for age, sex and height (recommendation 2C), with annual ABPM and standardised office measurement every 3–6 months; without ABPM, the auscultatory systolic pressure target is the 50th–75th centile, unless there is symptomatic hypotension [77]. In adults, it suggests a systolic pressure below 120 mmHg if tolerated (2B) [77]. KDIGO recommends an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) in CKD without diabetes with A3 albuminuria (1B) and suggests it with A2 albuminuria (2C), at the maximum tolerated approved dose, with monitoring of blood pressure, creatinine and potassium 2–4 weeks after initiation and continuation unless creatinine rises by more than 30% within 4 weeks; it advises against combining an ACEi, an ARB and a direct renin inhibitor (1B) [77].

The application of these recommendations to NPH has limits. Albuminuria is usually absent until advanced stages, and the nephroprotective benefit of ACE inhibitors in paediatrics has been demonstrated mainly in glomerulopathies and CAKUT, not in cystic disease [17]. In the cohort of 116 patients with NPHP1, ACEi treatment was associated with earlier ESKD (hazard ratio, HR, 2.80; 95% confidence interval, CI, 1.13–6.91) and an annual GFR loss of 7.2±0.4 versus 5.2±0.6 ml/min/1.73 m² without ACEi, but in the multivariate model only HTN remained significant (7.0±0.5 versus 4.6±0.4 ml/min/1.73 m²/year; p<0.01); the authors consider the results exploratory and acknowledge confounding by indication, because HTN appears close to ESKD [17]. Before KRT, the 62 hypertensive patients with NPHP1 were untreated (14), on monotherapy (32), dual therapy (8) or triple therapy (8), with calcium channel blockers in 23, beta-blockers in 18, ACE inhibitors in 27 and other drugs in 4 [17]. The divergence between the general KDIGO recommendation and the observational NPH data is resolved by indication: an ACEi or ARB is indicated when there is albuminuria or HTN that justifies it, and not as empirical nephroprotection in NPH without albuminuria. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recommended by KDIGO in adults with CKD, have no data in NPH or in children [77].

7.4. Anaemia

Anaemia is frequent in NPH and may appear before advanced CKD, sometimes more severe than predicted by kidney function [22, 26]. The US labels of the erythropoiesis-stimulating agents (ESAs) define the paediatric treatment of anaemia of CKD. Epoetin alfa (Epogen®, USA) is started in paediatric patients with CKD only when haemoglobin (Hb) is below 10 g/dl, with a starting dose of 50 U/kg three times a week intravenously (IV) or subcutaneously (SC) from 1 month of age, the intravenous route being preferred in haemodialysis; the dose is reduced or interrupted if haemoglobin approaches or exceeds 12 g/dl [85]. Darbepoetin alfa (Aranesp®, USA) is started in patients under 18 years at 0.45 µg/kg once weekly subcutaneously or intravenously, or, in non-dialysed patients, 0.75 µg/kg every 2 weeks, with the same initiation and reduction rules and with a conversion table from epoetin alfa [86]. For both, haemoglobin is monitored at least weekly until stable and then monthly; the dose is not increased more than once every 4 weeks, is reduced by at least 25% if haemoglobin rises by more than 1 g/dl in 2 weeks and is increased by 25% if it does not rise by more than 1 g/dl in 4 weeks; iron is supplemented when ferritin is below 100 µg/l or transferrin saturation below 20% [85, 86]. The labels' initiation threshold of 10 g/dl also applies to the early anaemia of NPH, which has no distinct indication. The European summaries of product characteristics (SmPCs) of the ESAs and national access in Portugal and Brazil were not consulted for this article.

7.5. Growth and growth hormone

Growth delay is frequent (34% of patients with NPHP1 in the 2022 cohort) and was independently associated with earlier ESKD (HR 3.52; 95% CI 1.67–7.41) [17]. About 40% of children with ESKD have a final height below the 3rd centile [84]. Before considering growth hormone (somatropin), the ESPN recommendations require correction of metabolic factors: free water and sodium supplementation in polyuric children with hyponatraemia, correction of metabolic acidosis to a serum bicarbonate of at least 22 mEq/l (sodium bicarbonate, or dialysis solutions with bicarbonate or lactate) and nutritional optimisation [84]. KDIGO 2024 advises against protein restriction in children with CKD and recommends protein and energy targets at the upper limit of normal in stages G2–G5 [77].

ESPN recommends considering somatropin in children with CKD stages 3–5 or on dialysis, older than 6 months, with height below the 3rd centile and growth velocity below the 25th centile persisting after correction of the other factors, and with growth potential (grade B, moderate evidence); it may be considered with height between the 3rd and 10th centiles and velocity persistently below the 25th centile (grade D) [84]. The pros and cons should be discussed particularly in syndromic kidney diseases, because patients with syndromes (Bardet-Biedl, Schimke, Galloway-Mowat) were excluded from trials and efficacy and safety in them were not assessed; fundoscopy before initiation excludes papilloedema [84]. The recommended dose is 0.045–0.05 mg/kg/day by subcutaneous injection in the evening (about 28–30 IU/m²/week, the doses of the randomised trials), with reference products or biosimilars and self-administration from 8–10 years if there is training and adherence [84]. Visits take place every 3–6 months, with height, growth velocity, puberty, bone age, kidney function, thyrotropin (TSH) and free triiodothyronine (T3), glucose, calcium, phosphorus, bicarbonate and PTH; response is adequate if velocity in the first year increases by more than 2 cm/year above baseline, and lack of response for at least 6 months requires review of adherence (insulin-like growth factor 1, IGF-1), weight-based dose and nutrition and consideration of discontinuation [84]. Contraindications are severe secondary hyperparathyroidism (intact PTH above 500 pg/ml or more than 9 times the upper limit, because of the risk of slipped capital femoral epiphysis), severe diabetic retinopathy, active malignancy, hypersensitivity (for example to m-cresol) and acute critical illness; it is discontinued at epiphyseal closure, at kidney transplantation, with PTH persistently above 500 pg/ml (it may be resumed), intracranial hypertension, slipped capital femoral epiphysis, lack of response with optimal control, accelerated bone maturation or unexplained fall in eGFR, and discontinuation is considered on reaching the genetic target centile [84].

Labels diverge between jurisdictions. In the USA, Nutropin AQ® (somatropin) is indicated for growth failure associated with CKD up to kidney transplantation, with a weekly dose of up to 0.35 mg/kg divided into daily subcutaneous injections; on haemodialysis, the injection is given at night before bedtime or at least 3–4 hours after the session, on continuous cycling peritoneal dialysis in the morning after finishing and on continuous ambulatory peritoneal dialysis in the evening at the overnight exchange [87]. The US label warns of an increased risk of intracranial hypertension in patients with CKD (fundoscopy before and periodically), recommends hip radiography before initiation in patients with renal osteodystrophy and monitoring for limping or hip or knee pain, and states that the product should not be used with a functioning allograft [87]. Genotropin®, Norditropin® and Omnitrope® do not carry the CKD indication in the current US labels [87]. In the European Union, Omnitrope® (centrally authorised biosimilar) has a paediatric indication in growth disturbance associated with chronic renal insufficiency at a dose of 0.045–0.050 mg/kg/day (1.4 mg/m²/day), with higher doses possibly needed if velocity is low and a dose correction after 6 months; the SmPC requires kidney function below 50% of normal before initiation, observation of growth for 1 year before initiation, established and maintained conservative treatment (acidosis, hyperparathyroidism, nutritional status) and discontinuation at kidney transplantation, and records the absence of final height data with this product in CKD [88]. Other somatropin products with this indication in the EU are nationally authorised and were not reviewed one by one.

7.6. Acidosis, mineral and bone disorder and other complications of CKD

KDIGO 2024 suggests considering pharmacological treatment, with or without dietary intervention, to prevent clinically relevant acidosis (for example, bicarbonate below 18 mmol/l in adults), without exceeding the upper limit of normal [77]; in children who are candidates for growth hormone, ESPN sets the target at least 22 mEq/l [84]. Treatment of CKD mineral and bone disorder (calcium, phosphate, PTH, alkaline phosphatase) follows the 2017 KDIGO guideline cited by GeneReviews, whose doses were not reviewed for this article [1]. The recommendations for Joubert syndrome include bone densitometry according to findings and attention to malnutrition and growth [26], and KDIGO 2024 recommends screening for malnutrition twice a year with a validated instrument in children with CKD G4–G5 or with poor growth [77]. In the clinical case in section 10, conservative treatment included sevelamer 800 mg three times a day, sodium bicarbonate 500 mg twice a day, allopurinol 300 mg/day, epoetin alfa 4000 IU subcutaneously per week and amlodipine 5 mg/day; these are doses from an adult case report, not label recommendations [64].

7.7. Kidney replacement therapy and transplantation

Kidney transplantation is the preferred treatment of ESKD, because NPH does not recur in the graft [1]. KDIGO 2024 considers pre-emptive transplantation, from a living or deceased donor, the treatment of choice in children with progressive and irreversible CKD, generally with an eGFR between 5 and 15 ml/min/1.73 m²; in children, insufficient growth refractory to optimised nutrition, growth hormone and medical treatment is an additional indication for starting KRT; in adults, pre-emptive transplantation and dialysis access are planned with a GFR below 15–20 ml/min/1.73 m² or a risk of KRT above 40% at 2 years [77]. Early diagnosis, including in siblings, allows a pre-emptive transplant to be prepared [1].

Transplant outcome data come from registries and single-centre series. In the North American NAPRTCS registry (North American Pediatric Renal Trials and Collaborative Studies), 2006 report, NPH was the primary diagnosis in 2.8% of paediatric kidney transplants; overall graft survival was significantly better in NPH than in the other patients, with significance only in living-donor recipients, creatinine clearance was better at all time points up to 5 years, and rates of thrombosis, acute and chronic rejection and causes of graft loss were similar [89]. In a Turkish centre with 180 paediatric transplant recipients, 17 (9.4%) had juvenile NPH, aged 12.6±4.3 years with follow-up of 79.5±41.9 months; 70.6% received a kidney from a living related donor and 23.5% were transplanted pre-emptively; acute rejection was 17.6% versus 34% in the other diagnoses (p<0.05), and GFR at 1 and 5 years was similar (96.7 versus 97.6 and 84.7 versus 86.7 ml/min/1.73 m²) [90]. In the Korean SLS series, two patients with NPHP4 lost their grafts, which shows that post-transplant prognosis can vary [21]. The literature cited by GeneReviews for non-recurrence is a conference abstract that could not be located in bibliographic databases, so the statement rests mainly on the tubular and genetic nature of the disease and on the registries above [1, 89].

A living related donor requires prior genetic testing when the familial variants are known: only relatives without biallelic variants proceed with evaluation, and heterozygosity does not, as a rule, exclude donation [1]. In an adult with a diagnosis of NPH, donation by an at-risk sibling without testing is contraindicated [18]. Gillion's Belgian family shows the concrete risk: the brother evaluated as a donor had CKD and the same NPHP1 variants [23]. In Matsuo's Japanese case, the 46-year-old father was the donor and the graft maintained normal function 12 years later (creatinine 0.94 mg/dl at 31 years of age), which illustrates that the recessive disease does not contraindicate donation by a heterozygous parent [75].

7.8. Extrarenal manifestations

Eye. No approved therapy prevents the retinal degeneration associated with NPHP1, NPHP4, IQCB1, SDCCAG8, WDR19 or TRAF3IP1. Care relies on supportive interventions for visual impairment; ophthalmological assessment includes acuity, visual fields, OCT and ERG, and strabismus, amblyopia and refractive errors are treated according to usual ophthalmological practice [21, 26]. The trials targeting the CEP290 intronic variant (sepofarsen, EDIT-101) are summarised in section 7.12.

Liver. In patients with hepatic fibrosis, the recommendations for Joubert syndrome indicate monitoring of platelets (downward trend) and spleen size, urgent assessment with endoscopy in the event of gastrointestinal bleeding and treatment of varices by sclerotherapy, band ligation, shunt or, rarely, liver transplantation; vaccination against hepatitis A and B is recommended in all children, liver biopsy is generally not indicated and, in the absence of other factors, there is no increased risk with hepatotoxic drugs [26]. When ESKD and advanced liver disease coexist, the decision between isolated kidney transplantation and combined transplantation is individual; the sources consulted do not provide outcome data for combined transplantation in NPH.

Skeleton and malformations. Treatment of the skeletal anomalies and craniosynostosis of the ciliary dysplasias (Mainzer-Saldino, Sensenbrenner, Jeune) is supportive, with kidney transplantation if needed [71].

Central nervous system. The developmental delay, oculomotor apraxia and respiratory dysfunction of Joubert syndrome have their own treatment.

7.9. Agents and circumstances to avoid

GeneReviews recommends avoiding nephrotoxins, such as non-steroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides, and managing patients with an eGFR below 60 ml/min/1.73 m² who undergo examinations with intravascular iodinated contrast according to the KDIGO acute kidney injury guideline [1]. The recommendations for Joubert syndrome are less restrictive regarding NSAIDs: avoid aminoglycosides when possible and use NSAIDs with caution, acknowledging that the risk has not been systematically assessed [26]. KDIGO 2024 recommends monitoring eGFR, electrolytes and the levels of nephrotoxic drugs or those with a narrow therapeutic window, limiting over-the-counter medicines and herbal products and adjusting doses to GFR [77]. Dehydration, prolonged fasting and sodium restriction not justified by blood pressure are risk circumstances in the polyuric phase [26, 84]. The prednisolone given in a Japanese SLS case, treated as chronic tubulointerstitial nephritis before the diagnosis, illustrates the risk of unnecessary treatments when a genetic diagnosis is lacking [18, 75].

7.10. Regulatory status

There is no medicine approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) with an indication for NPH or for SLS, and the EMA orphan designations report, consulted in October 2026, contains no designation with "nephronophthisis", "Senior-Løken", "Joubert" or "ciliopathy" in the condition text [91]. The drugs used are those for CKD, with the general label indications.

Access to these medicines in Portugal (INFARMED) and Brazil (ANVISA and CONITEC) was not reported in the sources consulted.

7.11. Clinical trials

There is no registered clinical trial of pharmacological intervention for NPH. A search of ClinicalTrials.gov in October 2026, with the terms "nephronophthisis", "Senior-Loken", "NPHP1" and "nephronophthisis-related ciliopathies", found only observational, sample collection, registry and digital therapy studies [92]. Stokman and colleagues had already noted, in April 2021, the absence of trials for NPH, explained by heterogeneity, small samples, the short therapeutic window, the paediatric population, the cost of orphan development and the lack of animal models that reproduce the juvenile form; if detected early, juvenile NPH would have a therapeutic window of a few years before KRT [25]. The IPNA systematic review (90 studies included) found clinical outcomes in all, surrogate parameters in 85% and patient-reported outcomes in only 41%, with 20 studies reporting more than one core outcome of the SONG Kids initiative (Standardized Outcomes in Nephrology – Children and adolescents), no validated instrument for NPH and a single prospective study [19].

The somatropin trials did not include patients identified as having NPH, nor patients with ciliary syndromes, so efficacy in syndromic NPH is extrapolated [84]. The gain in growth velocity is a surrogate outcome, and final height with somatropin in CKD is not documented for Omnitrope® [88]. The ophthalmological CEP290 trials include a single variant, assess only the retina and do not measure renal outcomes [92]; durable visual improvement after a single sepofarsen injection was described in a case report [94]. No indirect comparison between these studies is valid, and the absence of registered trials does not prove that no studies exist outside the public registries [92].

7.12. Therapies in preclinical research

All NPH-targeted approaches are at the preclinical stage. The table summarises them with the model and level of evidence.

The European TheRaCil consortium (Therapeutics for Renal Ciliopathies), funded by the Horizon Europe programme (grant agreement no. 101080717) and coordinated by the Institut Imagine, brings together 16 partners, including the Ciliopathy Alliance, NEOCYST and ERKNet; its objectives are to merge European ciliopathy databases, identify aberrant pathways, develop small molecules and ASOs and build patient-derived models; it is also developing patient-reported outcome measures for future trials [19, 97].

7.13. Developments in the last 6–12 months

Between October 2025 and October 2026 there were no regulatory approvals or human trial results for NPH. The relevant publications and announcements, with their level of evidence, were as follows. The exome study of the Necker cohort, published online on 4 December 2025, showed that exome sequencing after a negative panel explains the kidney disease in only 12% of cases and proposed a stepwise algorithm with genome and long-read sequencing (cohort study) [61]. The IPNA systematic review on outcomes (2026) documented the absence of trials and of validated instruments [19]. A 2026 systematic review showed extrarenal manifestations in 73.7% of patients with MAPKBP1 [27], and another analysis of 94 patients with WDR19 described genotype-phenotype correlations [70]. A 2025 Chinese series described the moderate to severe proteinuria associated with TTC21B [66], and a 2026 Japanese report documented the late appearance of medullary cysts visible on MRI and not on CT [78]. A 2026 German study confirmed the 72.0% yield of genetic testing in cystic kidney diseases [80]. In March 2026 a correction to the article on the mobile element insertion in IQCB1 was published [63]. In May 2026, Kidney Research UK announced funding for preclinical research on stop codon read-through induction, stating that there are no medicines that slow or reverse NPH [99]. The phase 3 HYPERION trial of sepofarsen, started in June 2025, is still recruiting [92]. The British RaDaR registry, with more than 37,000 participants, was described as a natural history and trial recruitment platform [93]. A 2026 review summarised the classification, clinical features and molecular mechanisms of NPH, including gene therapy and targeted molecular therapy strategies [55].

7.14. Special populations: pregnancy, perioperative care and transition

Pregnancy and lactation. The sources consulted contain no specific data on pregnancy in women with NPH, with or without transplantation. KDIGO 2024 recommends reviewing the teratogenicity of the drugs in use and providing regular contraceptive counselling to people with CKD and reproductive potential [77]. Hirai's case shows that NPH can be confused with nephrosclerosis due to hypertensive disease of pregnancy: a 31-year-old Japanese woman with RP had multiple corticomedullary cysts, atrophic tubules with segmental thickening of the tubular basement membrane and a homozygous NPHP1 deletion [83]. Reproductive risks and prenatal diagnosis options are in section 8.

Perioperative care and procedures. The main risk in the polyuric phase is dehydration during fasting, so the prevention of dehydration and electrolyte correction recommended for intercurrent illness apply to the perioperative period; nephrotoxins and iodinated contrast are managed according to section 7.9 [1, 26]. The sources consulted do not describe anaesthetic protocols specific to isolated NPH. Patients with Joubert syndrome are considered at high anaesthetic risk because of anomalies of the brainstem, central respiratory control, airway hypotonia and swallowing, with apnoea as a frequent complication, and should be assessed by anaesthesiology in advance [26].

Transition to adult care. KDIGO 2024 recommends preparing adolescents and families for transfer from 11–14 years, with readiness checklists and part of each visit without the parents [77]. In juvenile NPH, transition coincides with the period of greatest risk of ESKD (75% of patients with NPHP1 on KRT at 16.5 years) and frequently with transplantation, so it should be planned together with the transplant team and, in patients with SLS, ophthalmology [17].

7.15. Guideline recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Inheritance pattern and recurrence risks

NPH-RC is typically autosomal recessive [1]. The parents of a patient are presumed to be heterozygous, and GeneReviews recommends testing both after molecular diagnosis in the proband, to confirm heterozygosity and allow a reliable assessment of recurrence risk [1]. Heterozygotes are asymptomatic and are not at risk of developing the disease [1]. When both parents are heterozygous, each sibling of the patient has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being neither affected nor a carrier [1]. The children of a patient are obligate carriers, unless the other parent is also affected or a carrier [1]. The siblings of each of the patient's parents have a 50% chance of being carriers [1]. In consanguineous unions the risk that the partner of a carrier is also a carrier increases, and Snoek and colleagues highlight family planning in such unions as one of the implications of diagnosis in adults [18].

8.2. Particular genetic situations

Apparent homozygosity for a variant may reflect hemizygosity due to deletion of one or more exons on the other allele or uniparental isodisomy, and a variant found in only one parent, with paternity and maternity confirmed, may have arisen de novo in the proband or correspond to parental post-zygotic mosaicism [1]. These situations alter the recurrence risk and should be clarified before reproductive counselling. The dominant inheritance rarely described in Joubert syndrome (SLC30A7, SUFU, ZNF423) and the X-linked inheritance of OFD1 are exceptions that apply only when the molecular diagnosis demonstrates them [1]. Isolated heterozygosity for the NPHP1 deletion is relatively frequent in the population (it was found in 10 of the 3311 control donors in the iGeneTRAiN study), so testing the partner of a carrier should include CNV analysis [18].

8.3. Cascade testing and predictive testing in minors

GeneReviews considers it appropriate to evaluate the older and younger siblings of a patient, to identify as early as possible those who need supportive treatment and surveillance; diagnosis at an early stage allows a pre-emptive transplant to be prepared [1]. When the familial variants are known, targeted predictive testing may be offered to minors at 25% risk, in the context of formal genetic counselling, discussing beforehand the consequences (including socioeconomic changes and the need for long-term follow-up of those with a positive result) and the capabilities and limits of the test [1]. If the family does not opt for predictive testing, parents should watch for polydipsia, polyuria and the other signs of the disease, and annual measurement of blood pressure and urine protein/creatinine ratio and annual or biennial assessment of kidney and liver function should be offered [1]. When the familial variants are not known, GeneReviews proposes, based on the authors' experience and without support in the literature, the same attention to polyuria and polydipsia and annual measurement of blood pressure and protein/creatinine ratio when these are not part of child health visits [1].

8.4. Living related donor

Any relative who is a potential kidney donor for a patient with autosomal recessive NPH should undergo targeted molecular testing when the familial variants are known; only those without biallelic variants proceed with evaluation, and heterozygosity does not, as a rule, exclude donation [1]. ERA/ERKNet stresses counselling on living related donor transplantation for all patients with a genetic diagnosis [24]. Evaluation of the 31-year-old Belgian brother as a potential donor revealed CKD with the same NPHP1 variants as his transplanted brother [23]. In Matsuo's case, the presumed heterozygous father was the donor, with a functioning graft 12 years later [75].

8.5. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis and preimplantation genetic testing are possible when both familial pathogenic variants have been identified [1, 24]. GeneReviews notes that perspectives on prenatal diagnosis may differ between professionals and families, particularly when testing is intended for termination of pregnancy rather than early diagnosis, and ERA/ERKNet refers decisions to regional rules [1, 24]. In infantile NPH, ultrasound may show oligohydramnios and enlarged hyperechogenic kidneys; genetic testing with an urgent turnaround, of about 2 weeks, is the European recommendation for prenatal indications [1, 24].

8.6. Content of counselling

ERA/ERKNet considers genetic counselling recommended in the renal ciliopathies, because of variable expressivity, extrarenal manifestations and the options for prenatal and preimplantation diagnosis, and states that all patients with a genetic diagnosis should receive it, particularly regarding reproduction and living related donation [24]. Counselling should address the variability of age at ESKD, even within the family, the possibility of late extrarenal manifestations (particularly retinal, which may be subclinical with NPHP1), the implications of misclassification of adult relatives with CKD and the meaning of VUS, which should not be used for clinical decisions [1, 18, 24, 68].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and incidence: what each number measures

There is no validated population estimate of the prevalence of NPH outside Finland. The Finnish national survey by Ala-Mello and colleagues identified 59 patients over a 20-year period and calculated an incidence of 1:61,800 live births; the set included 17 patients from 4 families with a dominant pattern, who would now be classified as ADTKD, and 37 from 28 families with a recessive pattern [16]. Orphanet records, based on the same study, a birth prevalence of 1.25/100,000 (class 1–9/100,000), and the difference between the two values is not explained in the sources consulted; point prevalence in Europe is recorded as unknown [14]. Finland is a founder population, and the figure should not be generalised [16]. Other estimates are indirect attributions: König and colleagues cite an incidence of 1/1,000,000 to 1/50,000 depending on ethnicity and variant [17], and Snoek and colleagues cite 0.1–0.2 per 10,000 live births [18]. For SLS, Orphanet records a prevalence class of 1–9/1,000,000, supported by a reference that is a case report, not a population measurement [15, 83].

ESKD fractions provide another measure. NPH is described as the most frequent genetic cause of kidney failure in children [12] and as responsible for up to 10% of paediatric ESKD [17]; Snoek and colleagues cite about 15% of paediatric ESKD of genetic cause [18], and the TheRaCil consortium states that NPH and ARPKD together account for about 15% of paediatric CKD [97]. In the 2006 North American NAPRTCS registry, NPH was the primary diagnosis in 2.8% of paediatric kidney transplants, and in a paediatric centre with prevalent NPHP1 it reached 24% of transplant recipients [89]; in a Turkish centre it was 9.4% (17/180) [90]. In 1993 Antignac attributed 15% of French paediatric ESKD to NPH [34]. In adults with ESKD in the North American and European transplant cohorts, the homozygous NPHP1 deletion explained 0.5% of cases, 0.9% between 18 and 50 years and 2.1% between 18 and 29 years [18]. These values measure fractions of populations on KRT or transplanted, with their own referral biases, and cannot be converted into population prevalences.

9.2. United States and Europe

American data come mainly from the NAPRTCS registry and from the DeKAF Genomics, Gen03 and GoCAR transplant cohorts, which contributed most of the 5606 patients in iGeneTRAiN; 25 of the 26 patients with the homozygous NPHP1 deletion were of European ancestry and 1 of African ancestry, in the USA [18, 89]. In Europe, the main cohorts are the French cohort of the Institut Imagine and the Necker Hospital (samples from 1995 to 2019, 834 samples from 694 families), the German, Austrian and Dutch cohort of the NEPHREG registry and NEOCYST (Network for Early Onset Cystic Kidney Disease), Stokman's Dutch cohort of 40 patients and the British cohort of the RaDaR registry [17, 22, 61, 93, 101]. In the 2022 European cohort, which brought together the NEOCYST registry (105 patients), an ERKNet survey (60) and the literature (218), the most represented genes were NPHP1 (116), NPHP3 (101), NPHP11/TMEM67 (85) and NPHP4 (81) [17]. In Halbritter's worldwide cohort, the most frequent genes by sequencing were NPHP1 (23 patients, without testing for the deletion), NPHP4 (22), CEP290 (20), NPHP3 (17) and IQCB1 (16) [12, 60].

9.3. Populations with a founder effect or particular distribution

Finland is the only population with a national incidence estimate [16]. The TTC21B variant p.(Pro209Leu) is found in almost all North African and European patients with NPHP12, and in France it explained 6 of the 7 adults with nephroangiophthisis [65, 66]; among Asian patients with TTC21B variants, heterozygous p.(Cys518Arg) occurred in 72.7%, which the authors interpret as a population effect [66]. The IQCB1 variant c.1522_1523dup was found in the homozygous state or in trans in 5 patients from 3 unrelated Korean families (29.4% of the series), and the authors propose a Korean founder effect, without haplotype study, and targeted screening for this variant and for the NPHP1 deletion in Korean patients with a compatible phenotype [21]. In the same series, NPHP1 explained 35.3% of SLS, compared with 17.4–21% in international series, and there was no case due to CEP290, which accounted for 42.7% of 1301 families with SLS in a compilation cited by the authors [21]. In the Chinese ophthalmology-based series, CEP290 explained 61.4% of patients [20]. NPHP3 was originally described in a Venezuelan pedigree with late ESKD, and a consanguineous Filipino family with two missense NPHP4 variants had ESKD at a median of 36.2 years [17]. The original XPNPEP3 series involved two consanguineous families [29, 57]. The historical series of Chinese and Egyptian children with NPHP1 cited by König had median ages at ESKD of 12.9 and 7.9 years, respectively [17].

9.4. Portugal and Brazil

The only specific Portuguese data found come from the national inherited retinal dystrophy registry IRD-PT: among 1369 patients from 1125 families with genetic testing, 9 patients from 7 families had SLS (ORPHA:3156), all with a genetic diagnosis; "nephronophthisis" was recorded as a syndromic diagnosis in 2 patients, and the gene counts in the solved cohort, which cover all phenotypes and not only SLS, were 7 patients with CEP290, 2 with NPHP1, 2 with NPHP4, 1 with IQCB1 and 1 with TRAF3IP1 [102]. No data on renal NPH in Portugal, nor Brazilian data, were found in the sources consulted; absence from these sources does not demonstrate the absence of published data.

9.5. Special populations

Children with infantile NPH need KRT in the first years of life [1, 17]. Adults with late-onset NPH are the group at greatest risk of non-diagnosis: 88% of iGeneTRAiN patients had another diagnosis recorded, and in the Japanese series no patient over 50 years at biopsy had a variant, suggesting that test yield decreases with age [18, 72].

9.6. Reference networks and patient associations

The relevant European reference network is ERKNet (European Rare Kidney Disease Reference Network; https://www.erknet.org/) [1], with the addition, for SLS, of ERN-EYE (European Reference Network for rare eye diseases; https://www.ern-eye.eu/). NEOCYST (https://www.neocyst.de/) maintains the NEPHREG and NEOCYST registries in Germany, and TheRaCil (https://theracil.eu/) coordinates European therapeutic research [17, 97]. The British RaDaR registry includes more than 37,000 participants from more than 100 centres [93]. The reference centres cited by GeneReviews include the Radboudumc Center of Expertise for Rare Kidney Diseases and the UMC Utrecht Center for Hereditary and Congenital Kidney and Urinary Tract Disorders, in the Netherlands [1]. Patient associations include the Ciliopathy Alliance (United Kingdom, a TheRaCil partner), the NephHope Foundation (https://nephhope.org/), founded by the parents of a transplanted child, which funds research in NPH and SLS, the Joubert Syndrome & Related Disorders Foundation (https://www.jsrdf.org/), Retina International (https://www.retina-international.org/), EURORDIS (https://www.eurordis.org/), Kidney Research UK (https://www.kidneyresearchuk.org/) and, in the USA and Canada, the American Kidney Fund, the National Kidney Foundation, NephCure Kidney International and the Kidney Foundation of Canada [1, 3, 97]. In Portugal there is APIR, the Portuguese Association of Renal Insufficiency Patients (Associação Portuguesa de Insuficientes Renais; https://www.apir.org.pt/), with a general scope, and the national IRD-PT registry for retinal dystrophies [102]. No Brazilian association specific to NPH was identified in the sources consulted.

10. Illustrative Clinical Case

10.1. Senior-Løken syndrome due to a homozygous IQCB1 deletion diagnosed in adulthood

Demirtas and Bek published in 2025 the case of a Turkish man born in 2000, the son of consanguineous parents, with five unaffected siblings and no family history of kidney disease [64]. He had rotatory nystagmus from birth, wore glasses from 2 years of age and had visual loss at 8 years, with a diagnosis of RP in 2008 based on bone-spicule pigmentation in the fundus. At 18 years (2018) polyuria and polydipsia appeared, and CKD was suspected. In January 2020, at 20 years, he was referred to nephrology for tiredness, myalgia, polyuria, HTN and abnormal kidney function: he drank 5 l/day and had a urine output of 3.5 l/day; haemoglobin was 11.03 g/dl, urea 56.65 mg/dl, creatinine 2.59 mg/dl, sodium 140 mmol/l, potassium 3.8 mmol/l, albumin 4.26 g/dl, corrected calcium 9.19 mg/dl, phosphorus 3.58 mg/dl, intact PTH 226 pg/ml, urine protein/creatinine ratio 770.15 mg/g and eGFR 34.14 ml/min/1.73 m²; he was 180 cm tall, weighed 72 kg and had a blood pressure of 110/80 mmHg at the visit [64].

Dilated fundus examination showed pale waxy optic discs, diffuse irregularity of the retinal pigment epithelium and bilateral bone-spicule pigmentation, and ocular electrophysiology was compatible with RP (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC12664155/figure/Fig1/) [64]. Ultrasound in January 2020 showed normal-sized kidneys, regular contours and grade 1–2 parenchymal echogenicity; CT in August 2020 showed a subcentimetre haemorrhagic cyst in the middle third of the right kidney and several cysts of about 1 cm in the lower pole of the left kidney (Figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC12664155/figure/Fig2/) [64]. The kidney biopsy of February 2020 included 11 glomeruli, 2 with global sclerosis and the rest with focal mesangial proliferation, focal tubular atrophy, basement membrane thickening, hyaline casts, interstitial mononuclear infiltrate, prominent fibrosis and vascular myointimal thickening; immunofluorescence was negative, and the changes were classified as predominantly tubulointerstitial [64].

The patient was treated conservatively with sodium restriction, sevelamer carbonate 800 mg three times a day, sodium bicarbonate 500 mg twice a day, allopurinol 300 mg/day, epoetin alfa 4000 IU subcutaneously once a week and amlodipine 5 mg/day [64]. At 2 months, urea was 60 mg/dl, creatinine 2.74 mg/dl and uric acid 8.49 mg/dl. He stopped attending appointments and, in August 2021, was admitted with hypovolaemic hyponatraemia with nausea and vomiting. Because NPH was suspected, he underwent exome sequencing in December 2021, which revealed a homozygous deletion of the whole IQCB1/NPHP5 gene and confirmed SLS. In January 2023, at 23 years, urea was 202 mg/dl, creatinine 6.11 mg/dl and eGFR 11.8 ml/min/1.73 m², and he started peritoneal dialysis; at the last published check, creatinine was 12.9 mg/dl and eGFR 4.72 ml/min/1.73 m² [64].

10.2. Clinical reading of the case

The case brings together the elements that this article describes as typical of IQCB1: retinopathy from birth preceding kidney disease by more than a decade, nephropathy silent until CKD stage 3b, normal-sized kidneys with cysts only on CT and non-specific tubulointerstitial histology [1, 22]. The authors interpret retinal degeneration as present in almost all patients with IQCB1 and the phenotype as limited to the retina and kidney, and place the case among the rare adult diagnoses of SLS due to IQCB1, such as that of a 22-year-old Filipino man on haemodialysis and that of the Dutch patient with a mobile element insertion [63, 64]. The case illustrates three practical points. First, a patient with RP since childhood should have had early and serial renal assessment, as recommended by the Oxford Desk Reference and the SLS series [20, 21, 76]. Second, deletion of the whole gene requires that exome sequencing include CNV analysis, or that the laboratory use MLPA or an array [21, 24]. Third, the admission with hypovolaemic hyponatraemia shows the risk of obligatory water and sodium loss in NPH [1]. Two management decisions in the report differ from the recommendations applicable to NPH: routine sodium restriction, which ESPN and the recommendations for Joubert syndrome do not advise in the polyuric phase with salt wasting [26, 84], and the absence of any mention of preparation for pre-emptive transplantation, which KDIGO considers the treatment of choice [77]. The doses described are those of a case report, not of a label.

10.3. Complementary case: late diagnosis after transplantation

Matsuo and colleagues described a Japanese woman with nocturia and polyuria from 12 years of age, treated with oral iron, and creatinine of 3 mg/dl at 15 years [75]. Biopsy at 16 years showed global sclerosis in 6 of 13 glomeruli, 3 atubular glomeruli, severe interstitial fibrosis and irregular tubular atrophy and dilatation, and she was initially treated for chronic tubulointerstitial nephritis with prednisolone; a paternal cousin had died of kidney failure at 22 years. At 18 years, creatinine was 5.14 mg/dl, eGFR 10.4 ml/min/1.73 m², urine output 2200 ml/24 h, without proteinuria, and urinary β2-microglobulin 12.794 µg/ml (normal up to 0.289); CT showed atrophic kidneys. She received a kidney from her 46-year-old father at 19 years, after 3 haemodialysis sessions, with prolonged-release tacrolimus 4 mg/day and mycophenolate mofetil 1000 mg/day, and protocol biopsies showed no rejection. At 23 years, a visual field defect led to the diagnosis of RP sine pigmento, with night blindness retrospectively present since early adolescence, visual acuity of 1.2 in both eyes and an ellipsoid zone preserved only at the posterior pole, and to the clinical diagnosis of SLS; the authors do not report genetic confirmation. At 31 years, 12 years after transplantation, creatinine was 0.94 mg/dl, and the retina had been stable for 8 years [75]. The case illustrates late diagnosis in the absence of genetic testing and donation by a parent in a recessive disease.

11. Prognosis and Long-Term Follow-Up

11.1. Renal survival by gene

The European cohort of König and colleagues (2022) brought together 383 patients with a genetic diagnosis from the NEOCYST registry (enrolments from February 2010 to December 2020), an ERKNet survey and the literature up to March 2020, plus 44 patients without a genetic diagnosis; ESKD was defined as the start of KRT or an eGFR below 10 ml/min/1.73 m² by the FAS (Full Age Spectrum) equation [17]. The NPHP1 cohort included only patients from the registry and the survey, without cases from the literature, and the homozygous deletion was tested by polymerase chain reaction (PCR) or MLPA in 97 of the 165 patients tested [17].

The overall difference between genes was significant (p<0.0001), as was the difference between NPHP1 and NPHP4 (p<0.003), but not between NPHP4 and TMEM67 (p=0.539) [17]. The median of 13.5 years for NPHP1 is consistent with the median of 13.1 years (quartiles 11.3 and 17.3) in the 1997 German series and with the median of about 13 years that GeneReviews attributes to the juvenile form [1, 17, 38]. In the NEPHREG registry, 90 of the 152 children (58%) had reached ESKD; patients with NPHP1 without initial renal signs had CKD at 10.1±2.8 years and ESKD at 12.8±1.5 years, and among patients without NPHP1, 52% did not yet have ESKD and 31% maintained an eGFR above 90 ml/min/1.73 m² at last follow-up [22]. In the Necker cohort, the 19 patients with ESKD among the 42 studied by exome sequencing reached it at a median of 9 years (IQR 3–21) [61]. In the adult form, the median age at first KRT was 30 years, with a maximum of 61 years [18].

11.2. Progression factors

In the NPHP1 group of the 2022 cohort, growth delay (HR 3.52; 95% CI 1.67–7.41) and ACEi treatment (HR 2.80; 95% CI 1.13–6.91) were independent factors for earlier ESKD, and in the GFR loss model only HTN remained significant (7.0±0.5 versus 4.6±0.4 ml/min/1.73 m²/year; p<0.01) [17]. The authors consider these results exploratory, with possible confounding by indication, and they do not allow the conclusion that ACE inhibitors accelerate the disease [17]. Variant type modifies prognosis in NPHP3, NPHP4 and NPHP1, as described in section 2.7 [17]. Urinary DKK3 above 4700 pg/mg was associated with faster eGFR loss in the following year, but it is a research biomarker [81].

11.3. Prognosis after ESKD and extrarenal prognosis

Kidney transplantation has outcomes equal to or better than those of other causes of paediatric ESKD: in NAPRTCS, graft survival was better in recipients with NPH from living donors, and in a Turkish centre acute rejection was 17.6% versus 34% in the other diagnoses, with similar GFR at 5 years (84.7 ml/min/1.73 m²) [89, 90]. The kidney disease does not recur in the graft [1]. Long-term prognosis then depends on the extrarenal manifestations: progressive visual loss in SLS, which with NPHP4 and NPHP1 worsens with age and may become severe after 30 years [21, 68]; portal hypertension in patients with hepatic fibrosis [22, 26]; and neurological and respiratory complications in Joubert syndrome, in which kidney failure appears to be the main cause of death after the first year [26]. Matsuo's patient maintained a functioning graft and a stable retina at 31 years, 12 years after transplantation [75].

11.4. Surveillance

GeneReviews recommends surveillance at least annually in all patients, more frequently in advanced CKD, in patients at higher risk of progression and when therapeutic decisions are pending [1]. The initial assessment at diagnosis includes abdominal ultrasound (kidney size and parenchyma, situs inversus, liver, biliary tract, spleen and pancreas), blood pressure, growth and development, urine, kidney function, full blood count, mineral and bone disorder and liver function, and, depending on the gene and clinical features, brain MRI (molar tooth sign), echocardiography, ophthalmological examination (acuity, visual fields, retinal dystrophy), endocrine and metabolic assessment (sex and thyroid hormones, lipid profile, fasting glucose, glycated haemoglobin) and a genetics clinic visit [1]. The recommendations for Joubert syndrome indicate renal ultrasound at diagnosis and a second one in adolescence, noting that renal follow-up relies on history, examination and blood and urine tests because ultrasound does not reflect function [26]. The 2020 recommendations suggest more frequent monitoring of the retina and kidney in patients with CEP290 and of the liver in patients with TMEM67 [26].

12. Summary and Final Considerations

Nephronophthisis is an autosomal recessive chronic tubulointerstitial nephropathy caused by defects of the primary cilium, with more than 20 known genes and a recurrent NPHP1 deletion that explains about a quarter of cases [1, 39]. The infantile form presents in utero or in the first months with enlarged cystic kidneys and reaches ESKD in the first years; the juvenile form manifests at school age with polyuria, polydipsia, anaemia and growth delay, with ESKD at around 13 years; the adolescent and adult form reaches ESKD after 15 years, up to the seventh decade, and is frequently classified as CKD of unknown cause, chronic interstitial nephritis or nephrosclerosis [1, 17, 18]. Gene and variant type determine age at ESKD, with medians of 4 years for NPHP3, 13.5 years for NPHP1 and 16 years for NPHP4 in the 2022 European cohort [17].

The extrarenal manifestations define the related ciliopathies. Senior-Løken syndrome combines NPH with LCA or RP; IQCB1 and CEP290 produce severe retinopathy that precedes the nephropathy, NPHP1 and NPHP4 produce later or subclinical retinopathy, and assessment of the kidney and the eye should be simultaneous and independent [20, 21, 68]. Senior-Boichis syndrome combines NPH with congenital hepatic fibrosis, mainly with NPHP3 and TMEM67, and requires surveillance for portal hypertension [22, 26]. Joubert syndrome, isolated LCA and Meckel-Gruber syndrome share genes with NPH.

The diagnosis is molecular. The first-line test is an extended panel or an exome with a virtual panel, with mandatory CNV analysis or MLPA for the NPHP1 deletion; when it is negative and there are extrarenal features or an atypical presentation, the next steps are genome and long-read sequencing, which detect intronic deletions and mobile element insertions [24, 61, 63]. Even so, 26–40% of families remain without a diagnosis, and a negative result does not exclude the disease [17, 61].

There is no targeted therapy and no registered interventional trial for NPH. Treatment is that of CKD, adapted to the obligatory water and sodium loss of the polyuric phase, with correction of acidosis, treatment of anaemia, somatropin in children with growth delay who meet the criteria and kidney transplantation, preferably pre-emptive, without recurrence of the disease in the graft [1, 77, 84]. A living related donor requires prior genetic testing [1]. Targeted approaches (prostaglandin E2 receptor agonists, eupatilin, ASOs, stop codon read-through induction) are at the preclinical stage, and the European TheRaCil consortium is preparing the databases and outcomes for future trials [95–97, 99]. Genetic counselling follows the autosomal recessive model, with testing of the parents, cascade testing of siblings and prenatal or preimplantation diagnosis when both variants have been identified [1, 24].

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