Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis

NPH comprises a clinically and genetically heterogeneous group of autosomal recessive tubulointerstitial cystic kidney disorders representing the most frequent monogenic cause of ESKD in children and adolescents.Stokman M.F. Saunier S. Benmerah A. Renal ciliopathies: sorting out therapeutic approaches for nephronophthisis.,Harambat J. van Stralen K.J. Kim J.J. Tizard E.J. Epidemiology of chronic kidney disease in children. Incidence ranges from 1 per 1,000,000 to 1 per 50,000 depending on ethnicity and underlying disease-causing variant.

König J, Ermisch-Omran B, Omran H. Nephronophthisis and autosomal dominant interstitial kidney disease (ADIKD). Pediatric Kidney Disease. In: Geary, D., Schaefer, F. (eds) Pediatric Kidney Disease. Springer; 2021:369-388.

,Nephronophthise und assoziierte Ziliopathien. Variants in 25 genes have been identified to be associated with NPH, still leaving about 40% of patients genetically unsolved.Nephronophthise und assoziierte Ziliopathien.Nephronophthisis: a review of genotype-phenotype correlation.Stokman M. Lilien M. Knoers N. Adamiok-Ostrowska A. Piekiełko-Witkowska A. Ciliary genes in renal cystic diseases. A large homozygous deletion on chromosome 2q12-q13 including the entire NPHP1 gene is the most frequent disease-causing variant accounting for 20% to 40% of all cases. Variants in the other known NPHP genes makeup for 3% or less each.Nephronophthisis: a review of genotype-phenotype correlation.,Konrad M. Saunier S. Heidet L. et al.Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis.Halbritter J. Porath J.D. Diaz K.A. et al.Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.Konig J. Kranz B. Konig S. et al.Phenotypic spectrum of children with nephronophthisis and related ciliopathies. Three clinical subtypes have been established based on age at onset of ESKD as follows: Infantile, juvenile, and adolescent NPH.Nephronophthisis and related syndromes.,Salomon R. Saunier S. Niaudet P. The so called “classical juvenile NPH” is the most common entity associated with ESKD at a median age of 13 years.Hildebrandt F. Strahm B. Nothwang H.G. et al.Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie. Conversely, in infantile NPH, ESKD is reached before the age of 5 years (mean age 8 months) whereas in adolescent forms kidney function is usually preserved until adulthood (mean age 19 years).Nephronophthisis and related syndromes.,Gagnadoux M.F. Bacri J.L. Broyer M. Habib R. Infantile chronic tubulo-interstitial nephritis with cortical microcysts: variant of nephronophthisis or new disease entity?.,Omran H. Fernandez C. Jung M. et al.Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. Variants in NPHP2 and NPHP3 rather predispose for infantile NPH, whereas other genes are linked to late onset forms (e.g., NPHP4).Nephronophthisis: a review of genotype-phenotype correlation.,Educational paper: ciliopathies. Nevertheless, the more widespread use of modern sequencing techniques in combination with clinical information gained from large-scale databases opened up new perspectives to define more precisely the age spectrum for the onset of ESKD associated with distinct gene variants. This particularly applies to the homozygous NPHP1 deletion.Snoek R. van Setten J. Keating B.J. et al.NPHP1 (Nephrocystin-1) gene deletions cause adult-onset ESRD.,Fujimaru T. Kawanishi K. Mori T. et al.Genetic background and clinicopathologic features of adult-onset nephronophthisis. Similarly, distinctive NPHP3 variants have been reported to cause late onset NPH in contrast to the majority of patients displaying an infantile disease course.Olbrich H. Fliegauf M. Hoefele J. et al.Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis.Sun L. Tong H. Wang H. et al.High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients.Molinari E. Decker E. Mabillard H. et al.Human urine-derived renal epithelial cells provide insights into kidney-specific alternate splicing variants.

Herein, we analyzed differences in gene-related kidney survival based on large patient cohorts of >80 each. Furthermore, we assessed potential prognostic factors for the NPHP1 cohort, representing the clinically most relevant group. This is one of the largest studies addressing kidney survival for NPH in genetically characterized individuals.

DiscussionSince the identification of a large homozygous 290 kb deletion covering the entire NPHP1 gene in the 1990s,Adamiok-Ostrowska A. Piekiełko-Witkowska A. Ciliary genes in renal cystic diseases. tremendous progress has been made in the molecular understanding of NPH and related ciliopathies.Stokman M.F. Saunier S. Benmerah A. Renal ciliopathies: sorting out therapeutic approaches for nephronophthisis.,Santoni M. Piva F. Cimadamore A. et al.Exploring the spectrum of kidney ciliopathies.Gherman A. Davis E.E. Katsanis N. The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia.Arnaiz O. Malinowska A. Klotz C. et al.Cildb: a KnowledgeBase for centrosomes and cilia.Braun D.A. Hildebrandt F. Hildebrandt F. ,  However, the focus of most scientific efforts has been on the discovery of the genetic background and molecular pathways.Nephronophthisis: a review of genotype-phenotype correlation.,Adamiok-Ostrowska A. Piekiełko-Witkowska A. Ciliary genes in renal cystic diseases.,Halbritter J. Porath J.D. Diaz K.A. et al.Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.,Chaki M. Hoefele J. Allen S.J. et al.Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. Consequently, a lack of clear-cut genotype-phenotype correlations and prognostic factors is preventing reliable prognosis of kidney survival, and individual counseling. Herein, we present one of the largest studies addressing kidney survival in genetically characterized NPH cohorts.In 1997, Hildebrandt et al.Hildebrandt F. Strahm B. Nothwang H.G. et al.Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie. established creatinine based, age–dependent quartiles for the NPHP1-related progression of chronic kidney failure. The survey was based on a large number of 308 serial serum creatinine values originating from 19 individuals only. The present study covered a significantly higher number of patients including 97 individuals with a homozygous NPHP1 deletion. Still, results were consistent with those of the historical study. Median age at ESKD was 13.5 years versus 13.1 years in the historical cohort and 12.9 years in a recent survey of 20 Chinese children.Hildebrandt F. Strahm B. Nothwang H.G. et al.Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie.,Tang X. Liu C. Liu X. et al.Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy. Quartiles of 25% and 75% reaching ESKD were similar to 10.5 years and 16.5 years compared with 11.3 years and 17.3 years.Hildebrandt F. Strahm B. Nothwang H.G. et al.Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie. In a series of 20 Egyptian children with NPHP1 variants including 5 with a homozygous deletion, Soliman et al.Soliman N.A. Hildebrandt F. Otto E.A. et al.Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: a single center experience. reported a significantly earlier onset of ESKD (7.9 years). Surprisingly, in that survey, children without NPHP1 deletion showed a worse kidney outcome compared with those with a homozygous deletion whereas in our study it was the other way around (P = 0.03). Eight NPHP1 patients (5 with a homozygous deletion) retained residual kidney function beyond the age of 20 years. This is in line with previous case reports and the recent awareness of NPHP1 variants being responsible for a remarkable number of adult-onset ESKD.Salomon R. Saunier S. Niaudet P. ,Hildebrandt F. Strahm B. Nothwang H.G. et al.Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie.,Educational paper: ciliopathies.Snoek R. van Setten J. Keating B.J. et al.NPHP1 (Nephrocystin-1) gene deletions cause adult-onset ESRD.Fujimaru T. Kawanishi K. Mori T. et al.Genetic background and clinicopathologic features of adult-onset nephronophthisis.Biallelic variants in NPHP3 were originally described in a Venezuelan pedigree presenting with late onset ESKD.Omran H. Fernandez C. Jung M. et al.Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree.,Olbrich H. Fliegauf M. Hoefele J. et al.Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis. Recent reports identified NPHP3 variants as one of the most relevant genetic causes for infantile NPH.Halbritter J. Porath J.D. Diaz K.A. et al.Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.,Sun L. Tong H. Wang H. et al.High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients.,Bergmann C. Fliegauf M. Brüchle N.O. et al.Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia.,Tory K. Rousset-Rouvière C. Gubler M.C. et al.Mutations of NPHP2 and NPHP3 in infantile nephronophthisis. In a worldwide cohort of 1056 patients displaying a NPH phenotype, 17 were identified with either a homozygous or compound heterozygous variant in NPHP3, of whom 9 presented an onset of ESKD before the age of 2 and only 3 individuals reached ESKD beyond 5 years of age.Halbritter J. Porath J.D. Diaz K.A. et al.Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Similarly, ESKD in our NPHP3 cohort (n = 15) occurred at a median age of 3.3 years. No association between the NPHP3 genotype and the age at ESKD has been revealed so far.Omran H. Fernandez C. Jung M. et al.Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree.,Chaki M. Hoefele J. Allen S.J. et al.Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. In this study, we found a significant association between the time of ESKD and variant type. Individuals carrying 2 missense variants presented a significantly better kidney survival compared with those with at least 1 truncating variant. However, it needs to be mentioned that 24 of 27 patients with 2 missense variants belonged to the same Venezuelan pedigree.Olbrich H. Fliegauf M. Hoefele J. et al.Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis.For NPHP4, there was significant phenotypic overlap with the NPHP1 cohort, particularly when presenting as isolated kidney disease and reaching ESKD in the early teens. However, the overall kidney survival was much better as compared with other NPHP groups. Even the ‘trunc/trunc’ scenario was characterized by juvenile NPH mimicking the situation of most NPHP1 patients. Comparable survival rates were observed among large international NPH cohorts comprising 45 patients with NPHP4 variants.Chaki M. Hoefele J. Allen S.J. et al.Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies.,Stokman M.F. van der Zwaag B. van de Kar N. et al.Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy. In contrast, Halbritter et al.Halbritter J. Porath J.D. Diaz K.A. et al.Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. described 22 NPHP4 patients with 19 experiencing rather early ESKD (mean 12.5 years). None of the studies revealed a correlation between variant type and the onset of ESKD. We observed an earlier onset of ESKD in individuals with 2 truncating NPHP4 alleles. Supporting this observation, a case series on a consanguineous Filipino family carrying 2 NPHP4 missense variants reported a consistently late onset kidney failure (median age 36.2 years).Mistry K. Ireland J.H. Ng R.C. et al.Novel mutations in NPHP4 in a consanguineous family with histological findings of focal segmental glomerulosclerosis.NPHP11/TMEM67 related kidney survival was characterized by an overall lower percentage of ESKD accounting for 35% of NEOCYST patients and 45% when including published cases. This is in line with a large genotype-phenotype study including 22 individuals with Joubert syndrome caused by biallelic NPHP11/TMEM67 variants, of whom only 50% showed kidney involvement.Fleming L.R. Doherty D.A. Parisi M.A. et al.Prospective evaluation of kidney disease in Joubert syndrome. Though the overall onset of ESKD in our cohort was 11.9 years, 2 groups could be distinguished, namely those with severe and early kidney involvement, and those with mild or no obvious kidney phenotype. This reflects the wide phenotypic spectrum covered by NPHP11/TMEM67 variants comprising isolated liver disease, Joubert syndrome with and without kidney involvement, COACH syndrome, RHYNS syndrome, and lethal Meckel-Gruber syndrome.Brancati F. Camerota L. Colao E. et al.Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.Vogel I. Ott P. Lildballe D. et al.Isolated congenital hepatic fibrosis associated with TMEM67 mutations: report of a new genotype-phenotype relationship.Otto E.A. Tory K. Attanasio M. et al.Hypomorphic mutations in meckelin (MKS3/TMEM67) cause nephronophthisis with liver fibrosis (NPHP11).Smith U.M. Consugar M. Tee L.J. et al.The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Previous genotype-phenotype correlation studies identified the association of variant and phenotypic severity, observing mostly truncating variants or missense variants clustering within exons 8 to 15 to be causative for lethal Meckel-Gruber syndrome phenotypes.Iannicelli M. Brancati F. Mougou-Zerelli S. et al.Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. Nevertheless, this did not apply to kidney survival in the current study population. The presence of disease-causing variants in exons 8 to 15 was not associated with age at ESKD. In patients with such variants in 1 allele, onset of ESKD was 11.8 years (n = 19) compared with 11.3 years in patients without a disease-causing variant in exons 8 to 15 (n = 18). Biallelic exon 8 to 15 variants (n = 4) were associated with ESKD at a median age of 9.2 years (n = 3) (Supplementary Table S5). This observation underpins the idea of the organ-specific impact of distinct genotypes, which is an important point to keep in mind for the clinical management of affected patients.So far, neither molecular markers nor clinical factors associated with kidney prognosis have been unraveled for NPH. In this study, applying an in-depth phenotyping registry-based approach, we were able to identify 2 independent factors associated with an earlier onset of ESKD in NPHP1 patients, namely growth retardation and ACEI treatment. Whereas growth retardation was observed in 34% consistent with previous data (11%–40%),Stokman M.F. van der Zwaag B. van de Kar N. et al.Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy.,Cantani A. Bamonte G. Ceccoli D. et al.Familial juvenile nephronophthisis. A review and differential diagnosis. information on the effects of ACEI treatment in the setting of NPH is extremely sparse. The association of ACEIs with a negative effect on kidney survival observed in our study appeared peculiar at first glance considering the nephroprotective benefits of ACEI treatment in the setting of chronic kidney disease.Hou F.F. Zhang X. Zhang G.H. et al.Efficacy and safety of benazepril for advanced chronic renal insufficiency.,Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. However, a detailed look at the original pediatric data reveals that these benefits were mainly limited to glomerulopathies and congenital anomalies of the kidney and urinary

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