Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort.

BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.

A small molecule chaperone rescues keratin-8 mediated trafficking of misfolded podocin to correct genetic Nephrotic Syndrome.

Podocin is a key membrane scaffolding protein of the kidney podocyte essential for intact glomerular filtration. Mutations in NPHS2, the podocin-encoding gene, represent the commonest form of inherited nephrotic syndrome (NS), with early, intractable kidney failure. The most frequent podocin gene mutation in European children is R138Q, causing retention of the misfolded protein in the endoplasmic reticulum. Here, we provide evidence that podocin R138Q (but not wild-type podocin) complexes with the intermediate filament protein keratin 8 (K8) thereby preventing its correct trafficking to the plasma membrane. We have also identified a small molecule (c407), a compound that corrects the Cystic Fibrosis Transmembrane Conductance Regulator protein defect, that interrupts this complex and rescues mutant protein mistrafficking. This results in both the correct localization of podocin at the plasma membrane and functional rescue in both human patient R138Q mutant podocyte cell lines, and in a mouse inducible knock-in model of the R138Q mutation. Importantly, complete rescue of proteinuria and histological changes was seen when c407 was administered both via osmotic minipumps or delivered orally prior to induction of disease or crucially via osmotic minipump two weeks after disease induction. Thus, our data constitute a therapeutic option for patients with NS bearing a podocin mutation, with implications for other misfolding protein disorders. Further studies are necessary to confirm our findings.

A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants.

While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.

Mendelian steroid resistant nephrotic syndrome in childhood: is it as common as reported?

BACKGROUND: Primary steroid resistant nephrotic syndrome (SRNS) is thought to have either genetic or immune-mediated aetiology. Knowing which children to screen for genetic causes can be difficult. Several studies have described the prevalence of genetic causes of primary SRNS to be between 30 and 40%, but these may reflect a selection bias for genetic testing in children with congenital, infantile, syndromic or familial NS and thus may overestimate the true prevalence in a routine clinical setting. METHODS: Retrospective electronic patient record analysis was undertaken of all children with non-syndromic SRNS and presentation beyond the first year of life, followed at our centre between 2005 and 2020. RESULTS: Of the 49 children who met the inclusion criteria, 5 (10%) had causative variants identified, predominantly in NPHS2. None responded to immunosuppression. Of the 44 (90%) who had no genetic cause identified, 33 (75%) had complete or partial remission after commencing second-line immunosuppression and 67% of these had eGFR > 90 ml/min/1.73 m2 at last clinical follow-up. Of the children who did not respond to immunosuppression, 64% progressed to kidney failure. CONCLUSIONS: In our cohort of children with non-syndromic primary SRNS and presentation beyond the first year of life, we report a prevalence of detectable causative genetic variants of 10%. Those with identified genetic cause were significantly (p = 0.003) less likely to respond to immunosuppression and more likely (p = 0.026) to progress to chronic kidney disease. Understanding the genetics along with response to immunosuppression informs management in this cohort of patients and variant interpretation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-term obesity prevalence and linear growth in children with idiopathic nephrotic syndrome: is normal growth and weight control possible with steroid-sparing drugs and low-dose steroids for relapses?

BACKGROUND: Long-term steroid treatment in children is known to cause obesity and negatively affect growth. The objective of this study was to determine the prevalence of obesity and overweight and analyze linear growth in children with nephrotic syndrome. METHODS: The study involved 265 children treated with glucocorticoids for nephrotic syndrome for a mean duration of 43 months (range: 6-167, IQR: 17, 63.3). Height, weight, and BMI SDS were recorded at each visit. Rate of change between the final and initial height, weight, and BMI was calculated (Δ score). The cumulative steroid dose (mg/kg/day) during follow-up was calculated. Relapses without significant edema were treated with low-dose steroids and steroid-sparing drugs were used in children with steroid dependency/frequent relapses. RESULTS: Mean first BMI SDS was + 1.40 ± 1.30 and final + 0.79 ± 1.30. At initial assessment, 41.4% of the patients were obese (BMI ≥ 95th percentile) and 19.5% were overweight (BMI 85th-95th percentile). At the last clinical visit, 24% were obese and 17% overweight. The children had lower BMI SDS at last clinical visit compared to initial assessment. Mean first height SDS of the cohort was - 0.11 ± 1.22 and final score 0.078 ± 1.14 (p < 0.0001). Almost 85% of patients were treated with steroid-sparing drugs. CONCLUSIONS: Our results indicate that children with nephrotic syndrome, despite a need for steroid treatment for active disease, can improve their obesity and overweight and also improve their linear growth from their first to last visit with us.

The effect of levamisole on kidney function in children with steroid-sensitive nephrotic syndrome.

BACKGROUND: Levamisole is frequently used as a steroid-sparing agent in children with steroid-sensitive nephrotic syndrome. Side effects, such as neutropenia, gastro-intestinal upset and skin rash, have been reported. We noted an increase in creatinine in some of our patients, but literature on the effect of levamisole on kidney function is lacking. METHODS: A retrospective cohort study was conducted, including patients 1-18 years of age, treated for steroid-sensitive nephrotic syndrome with levamisole at Great Ormond Street Hospital for Children between January 2010 and January 2020. Data was collected on clinical observations and serum creatinine values before, during and after treatment. eGFR was calculated using the Schwartz equation. RESULTS: In total, 75 children were included in the analysis. The median duration of treatment was 19 (IQR 12-27) months. The median estimated GFR was 134 (IQR 119-160), 101 (IQR 91-113) and 116 (IQR 106-153) ml/min/1.73 m2, respectively, before, during and after treatment with levamisole. The difference between eGFR before and after treatment compared with during treatment was statically significant (P < 0.0001). During the treatment period, the eGFR decrease was not progressive. The median levamisole dose was 2.5 (IQR 2.3-2.6) mg/kg on alternate days, and the dose was not correlated with the decrease in eGFR (r = 0.07, 95% CI - 0.22 to 0.35). CONCLUSION: Levamisole significantly decreases eGFR. However, this decrease is not progressive or irreversible and would not be an indication to discontinue the treatment.

Early relapse of atypical hemolytic uremic syndrome following ABO-incompatible living-related pediatric kidney re-transplant successfully treated with eculizumab.

BACKGROUND: A 3-year-old girl with clinical features of atypical HUS (complement Factor I mutation inherited from an asymptomatic mother and Factor H autoantibodies) was treated with plasma exchange, progressed to kidney failure (KF) aged 4 years, and received an en bloc kidney DCD transplant aged 8 years with primary graft non-function necessitating transplant nephrectomy at the time of transplantation. She subsequently underwent re-transplantation from her father. This is a retrospective study of electronic patient records and medical notes. CASE-DIAGNOSIS/TREATMENT: A 9-year-old girl received an ABO-incompatible (ABOi) living-related kidney transplant from her father with recipient and donor blood groups of O and A, respectively, with baseline recipient anti-A titers 1:128 reducing to 1:4 at the time of transplant with B lymphocyte depletion with rituximab and four sessions of immunoadsorption. Six hours post-transplant, she had recurrence of aHUS and received the first dose of eculizumab. She continues on monthly home eculizumab infusions with stable kidney allograft function and negative anti-A titers 7 years post-kidney transplantation. CONCLUSIONS: This is the first report of a pediatric high-risk ABOi living-related kidney transplantation in whom early relapse of aHUS was successfully treated with eculizumab with good long-term patient and allograft outcome.

Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome.

BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance. METHODS: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls. RESULTS: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10-43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10-17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6. CONCLUSIONS: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

Activation of podocyte Notch mediates early Wt1 glomerulopathy.

The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.

Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations.

X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years. Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common. The rarity of the disease and the large number of variants make it difficult to discern specific genotype-phenotype relationships. A new treatment, an anti-FGF23 antibody, that may affect the natural history of the disease is currently being investigated in clinical trials.

The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.

BACKGROUND: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly. METHODS AND RESULTS: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F. CONCLUSIONS: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

Integrin α3 mutations with kidney, lung, and skin disease.

Integrin α(3) is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment. We identified three patients with homozygous mutations in the integrin α(3) gene that were associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. The patients had a multiorgan disorder that included congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The renal and respiratory features predominated, and the lung involvement accounted for the lethal course of the disease. Although skin fragility was mild, it provided clues to the diagnosis.

The clinical spectrum of hemolytic uremic syndrome secondary to complement factor H autoantibodies.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is associated with significant mortality, progression to end-stage renal disease and recurrence post transplantation. The deficiency of CFHR plasma proteins and autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) has a more favorable outcome. Guidelines suggest plasma therapy be initiated within 24 hours of presentation of aHUS. Presentation of aHUS, particularly, DEAP-HUS is associated with a diarrheal prodrome in up to 53% of patients and initiation of appropriate therapies is frequently delayed. CASES: We report on 3 patients with DEAP-HUS, who presented with a diarrheal prodrome that delayed diagnosis and initiation of plasma therapy past the 24-hour window recommended. C3 was low in 2 cases at presentation. All patients had positive complement factor H (CFH) autoantibodies. Despite delay in initiating plasma therapy, all 3 cases remitted with restoration of normal renal function following initial presentation. One patient had a relapse but responded to further plasma exchange and immunosuppression. The remaining 2 patients were relapse-free without maintenance immunosuppression. CONCLUSION: Our cases highlight the complexity of diagnosing DEAP-HUS due to the common occurrence of diarrhea in the prodromal phase and the subsequent delay in initiating of plasma therapy. We therefore advocate a low threshold for testing CFH autoantibodies in ambiguous cases where there is no history of bloody diarrhea or Shiga-toxin exposure.

Successful treatment of DEAP-HUS with eculizumab.

BACKGROUND: Deficiency of complement factor H-related (CFHR) proteins and CFH autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) represents a unique subgroup of complement-mediated atypical HUS (aHUS). Autoantibodies to the C-terminus of CFH block CFH surface recognition and mimic mutations found in the genetic form of (CFH-mediated) aHUS. CFH autoantibodies are found in 10-15 % of aHUS patients and occur--so far unexplained--almost exclusively in the background of CFHR1 or CFHR3/CFHR1 deletions. METHODS: As a well-defined role for eculizumab in the treatment of complement-mediated aHUS is becoming established, its role in DEAP-HUS is less conspicuous, where a B-cell-depleting and immunosuppressive treatment strategy is being proposed in the literature. RESULTS: We here show eculizumab to be safe and effective in maintaining a disease-free state, without recurrence, in a previously plasma-therapy-dependent DEAP-HUS patient, and in another patient in whom, although showing a good clinical response to plasma therapy, the therapy was hampered by allergic reactions to fresh frozen plasma and contend there is a rationale for the use of eculizumab in concert with an immunosuppressive strategy in the treatment of DEAP-HUS. Considering the high rate of early relapse, the possible coexistence and contribution of both known and unknown complement-gene mutations, the probable pathogenic role of CFHR1 as a complement alternative pathway (CAP) regulator, the experimental nature of measuring and using anti-CFH autoantibodies to guide management, and until the positive reports of immunosuppression in addition to plasma therapy are confirmed in prospective studies, we feel that a complement-directed therapy should not be neglected in DEAP-HUS. Serial CFH autoantibody titer testing may become a valuable tool to monitor treatment response, and weaning patients off eculizumab may become an option once CFH autoantibody levels are depleted. CONCLUSIONS: A prospective study of eculizumab treatment in a larger cohort of DEAP-HUS patients is required to validate the applicability of our positive experience.

Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years.

BACKGROUND: Nephrotic syndrome (NS) presenting early in life is caused by heterogeneous glomerular diseases. We retrospectively evaluated whether histological diagnosis in children presenting with NS in the first year of life predicts remission or progression to end-stage kidney disease (ESKD). METHODS: This is a single centre retrospective review of all children diagnosed with NS before one year of age between 1990 and 2009. All subjects had a renal biopsy, which was independently blindly reviewed by a single renal pathologist for the purpose of this study. RESULTS: Forty-nine children (25 female) who presented at 0.1-11.6 (median 1.6) months were included with 31 presenting within the first three months of life. Histopathological review diagnostic categories were; 13 Mesangial proliferative glomerulopathy (MesGN), 12 Focal and segmental glomerulosclerosis (FSGS), 11 Finnish type changes, eight Diffuse Mesangial Sclerosis (DMS), three Minimal change disease (MCD) and one each of Dense Deposit Disease (DDD) and Membranous nephropathy. Two children died from haemorrhagic complications of the biopsy. Eight children achieved remission (four MesGN, one Finnish type changes, one FSGS, one MCD and one membranous) with patient and renal survival of 73 % and 43 %, respectively, at follow-up duration of 5-222 (median 73) months (with five lost to follow-up). All children with Finnish-type histopathological changes presented within five months of age. Due to the historical nature of the cohort, genetic testing was only available for 14 children, nine of whom had an identifiable genetic basis (seven NPHS1, one PLCE1 and one ITGA3) with none of these nine children achieving remission. All of them had presented within four months of age and required renal replacement therapy, and two died. CONCLUSIONS: Histopathological findings are varied in children presenting with NS early in life. Whilst groups of histological patterns of disease are associated with differing outcomes, accurate prediction of disease course in a specific case is difficult and more widespread genetic testing may improve the understanding of this group of diseases and their optimal management.

A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.

BACKGROUND: Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. METHODS: The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. RESULTS: The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. CONCLUSIONS: The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.

Notch promotes dynamin-dependent endocytosis of nephrin.

Notch signaling in podocytes causes proteinuria and glomerulosclerosis in humans and rodents, but the underlying mechanism remains unknown. Here, we analyzed morphologic, molecular, and cellular events before the onset of proteinuria in newborn transgenic mice that express activated Notch in podocytes. Immunohistochemistry revealed a loss of the slit diaphragm protein nephrin exclusively in podocytes expressing activated Notch. Podocyte-specific deletion of Rbpj, which is essential for canonical Notch signaling, prevented this loss of nephrin. Overexpression of activated Notch decreased cell surface nephrin and increased cytoplasmic nephrin in transfected HEK293T cells; pharmacologic inhibition of dynamin, but not depletion of cholesterol, blocked these effects on nephrin, suggesting that Notch promotes dynamin-dependent, raft-independent endocytosis of nephrin. Supporting an association between Notch signaling and nephrin trafficking, electron microscopy revealed shortened podocyte foot processes and fewer slit diaphragms among the transgenic mice compared with controls. These data suggest that Notch signaling induces endocytosis of nephrin, thereby triggering the onset of proteinuria.

Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment.

Inactivating mutations in phosphate-regulating endopeptidase (PHEX) cause X-linked hypophosphatemic rickets (XLHR) characterized by phosphaturia, hypophosphatemia, bony deformities, and growth retardation. We assessed the efficacy of combined calcitriol and orally administered phosphate (Pi) therapy on longitudinal growth in relation to age at treatment onset in a retrospective, single-center review of children with XLHR and documented PHEX mutations. Growth was compared in those who started treatment before (G1; N = 10; six boys) and after (G2; N = 13; five boys) 1 year old. Median height standard deviation score (HSDS) at treatment onset was normal in G1: 0.1 [interquartile range (IR) -1.3 to 0.4) and significantly (p = 0.004) lower in G2 (IR -2.1 (-2.8 to -1.4). Treatment duration was similar [G1 8.5 (4.0-15.2) vs G2 11.9 (6.2-14.3) years; p = 0.56], as were prescribed phosphate and calcitriol doses. Recent HSDS was significantly (p = 0.009) better in G1 [-0.7 (-1.5 to 0.3)] vs G2 [-2.0 (-2.3 to -1.0)]. No effects of gender or genotype on growth could be identified. Children with PHEX-associated XLHR benefit from early treatment and can achieve normal growth. Minimal catchup growth was seen in those who started treatment later. Our findings emphasize the importance of early diagnosis to allow treatment before growth has been compromised.