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Background: Survival after pediatric liver transplantation has increased dramatically over the years, revealing extra-hepatic complications including impaired kidney function. We conducted a large single-center retrospective study to evaluate kidney outcomes after pediatric liver transplantation., Methods: From electronic charts of 121 children who underwent liver transplantation during 2007-2020, we collected pre- and post-transplant data. We investigated the presence of post-transplant permanent kidney injury, including proteinuria, hypertension, and decreased estimated glomerular filtration rate (eGFR). We excluded children who died, underwent liver-kidney transplantation, or had less than 1 year of follow-up., Results: During a median follow-up of 5.1 (interquartile range 2.9-7.3) years, eGFR decreased, mostly in the first year post-transplant. In addition, 41% of the children presented with acute kidney injury. At their last follow-up, 35% showed permanent kidney injury (hypertension 13%, proteinuria 36%, and eGFR < 90 mL/min per 1.73 m 2 7%). Kidney ultrasounds were abnormal for 44% of the children at the last visit, compared to 11% before transplant (p < 0.001). In multivariate analysis, abnormal kidney ultrasound before transplant (odds ratio = 4.53, 95% CI 1.1-18.7) and liver disease with potential risk of primary kidney involvement (odds ratio = 4.77, 95% CI 1.58-14.4) were predictors for hypertension or decreased eGFR at the last follow-up., Conclusions: The high prevalence of kidney injury after pediatric liver transplantation and the pretransplant predictors for kidney injury highlight the importance of a thorough kidney pretransplant evaluation and follow-up., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Solid organ transplantation has evolved in recent decades, resulting in a rise in patient and graft survival. Frequent hospitalizations affect graft function, patients' health, and quality of life. This study characterizes the frequency and causes of post-transplant hospitalizations among pediatric recipients., Methods: This is a retrospective observational study evaluating pediatric kidney transplant recipients (KTR) and liver transplant recipients (LTR) aged 0-21 years, followed at a tertiary pediatric center in Israel from 2012 to 2017. Data were collected starting at 60 days post-transplantation. Diagnoses of admissions were based on clinical, laboratory, and radiographic findings., Results: Forty-nine KTR experienced 199 all-cause re-hospitalizations (median number of re-hospitalizations per patient - 3 (IQR [interquartile range] 1-5.5), while 351 re-hospitalizations were recorded in 56 LTR (median - 5 [IQR 2-8.8]). Median follow-up time was 2.2 years for KTR (IQR 1-3.9) and 3 years for LTR (IQR 2.1-4.1). The most common cause for hospitalization for both cohorts was infection (50.8% and 62%, respectively). Gram-negative bacteria were the most common pathogens identified in KTR, while viral pathogens were more common in LTR (51% and 57% of pathogen-identified cases, respectively)., Conclusions: This is the largest study to describe rehospitalizations for pediatric solid organ recipients. The hospital admission rate was higher in LTR in comparison to KTR. Infections were the most common cause of hospitalization throughout the whole study period in both populations. Frequent hospitalizations impose a heavy burden on patients and their families; better understanding of hospitalization causes may help to minimize their frequency., (© 2023 Wiley Periodicals LLC.)

Background: Differences in serologic response to COVID-19 infection or vaccination were reported in adult kidney transplant recipients (KTR) compared to non-immunocompromised patients. This study aims to compare the serologic response of naturally infected or vaccinated pediatric KTR to that of controls., Methods: Thirty-eight KTR and 42 healthy children were included; aged ≤18 years, with a previously confirmed COVID-19 infection or post COVID-19 vaccination. Serological response was measured by anti-spike protein IgG antibody titers. Response post third vaccine was additionally assessed in KTR., Results: Fourteen children in each group had previously confirmed infection. KTR were significantly older and developed a 2-fold higher antibody titer post-infection compared to controls [median (interquartile range [IQR]) age: 14.9 (7.8, 17.5) vs. 6.3 (4.5, 11.5) years, p = 0.02; median (IQR) titer: 1695 (982, 3520) vs. 716 (368, 976) AU/mL, p = 0.03]. Twenty-four KTR and 28 controls were vaccinated. Antibody titer was lower in KTR than in controls [median (IQR): 803 (206, 1744) vs. 8023 (3032, 30,052) AU/mL, p < 0.001]. Fourteen KTR received third vaccine. Antibody titer post booster in KTR reached similar levels to those of controls post two doses [median (IQR) 5923 (2295, 12,278) vs. 8023 (3034, 30,052) AU/mL, p = 0.37] and to KTR post natural infection [5282 AU/mL (2583, 13,257) p = 0.8]., Conclusion: Serologic response to COVID-19 infection was significantly higher in KTR than in controls. Antibody level in KTR was higher in response to infection vs. vaccination, contrary to reports in the general population. Response to vaccination in KTR reached levels comparable to controls only after third vaccine., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Blood pressure (BP) monitoring following pediatric kidney transplantation is essential for optimizing graft perfusion. Differences between invasive BP and noninvasive BP (NIBP) measurements are sometimes considerable. We aimed to assess agreement between invasive BP and NIBP in pediatric patients after kidney transplantation and compare with measurements obtained by systolic Doppler with manual sphygmomanometer as a reference technique., Methods: A prospective, observational cohort study, of children aged 18 years or younger, admitted immediately following kidney transplantation to the pediatric intensive care unit of a tertiary, university-affiliated medical center, between May 2019 and June 2021., Results: Eighty-two paired simultaneous measurements of invasive BP, NIBP, and Doppler BP in 18 patients were compared. Patients were significantly hypertensive, with mean systolic NIBP above the 95th percentile (96 ± 6%). Systolic invasive BP measurements were significantly higher than NIBP (149 ± 20 vs. 136 ± 15 mmHg, p < 0.001). Substantial differences (≥ 20 mmHg) were found in 23% (95% CI 15-34%). Similar disagreement was found between systolic invasive and Doppler BP (150 ± 23 and 137 ± 17 mmHg, respectively, p < 0.001). In contrast, systolic NIBP was in good agreement with Doppler BP (135 ± 17 and 138 ± 18, respectively, p = 0.27). A moderate to strong correlation was found between higher systolic invasive BP and the difference to systolic Doppler BP (Spearman's ρ = 0.63, p < 0.001)., Conclusions: In children immediately following kidney transplantation, clinically significant disagreement was found between invasive and noninvasive BP measurements. Invasive BP values were significantly higher than those obtained by Doppler. Better agreement was found between NIBP and Doppler. These issues should be considered when interpreting BP measurements in this sensitive patient population. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Rationale & Objective: Prednisone protocols for children with idiopathic nephrotic syndrome (INS) are generally similar in dose and duration, despite wide variations in time to response. We assessed the feasibility of a novel clinical treatment protocol characterized by a shorter duration and lower cumulative dose for children with early clinical response., Study Design: Nonrandomized pilot clinical trial., Setting & Participants: The study population included 59 children with newly diagnosed INS treated between 2014 and 2019 who responded to treatment within 8 days., Intervention: The intervention group (n = 27) was treated with a response-adjusted protocol during which responders received an 8-week course of tapering doses of prednisone. The usual care group (n =32) was treated with the standard protocol (prednisone, 60 mg/m 2 /24 hours for 6 weeks, followed by 40 mg/m 2 /48 hours for 4 weeks, followed by a slow taper for a total of 24 weeks)., Outcome: Consent rate, cumulative prednisone dose, the development of frequently relapsing or steroid-dependent nephrotic syndrome (FRNS or SDNS, respectively), relapses per year, treatment with steroid-sparing therapies, and adverse effects of steroid therapy over 3 years of follow-up observation., Results: The consent rate was 88%. The mean cumulative steroid dose for the initial treatment was 70 mg/kg and 141 mg/kg (P < 0.001) in the intervention and usual care groups, respectively. None of the patients in the intervention group relapsed while on faster steroid taper down. The occurrence of FRNS and SDNS in the intervention group was not statistically different than in the usual care group, hazard ratios were 0.80 (95% CI, 0.37-1.73) and 0.61 (95% CI, 0.30-1.27), respectively. The proportions of relapse-free patients were similar (P = 0.5), and adverse steroid events did not differ between the groups., Limitations: Lack of randomization and small sample size., Conclusions: These findings demonstrate the feasibility of a shortened duration of steroid dosing for INS when patients demonstrate an initial clinical response to treatment. A larger study is needed to characterize the relative efficacy and toxicity of this novel treatment regimen., Funding: This study received no funding., Trial Registration: Registered at ClinicalTrials.gov with study number NCTO2649413., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Genetic kidney diseases contribute a significant portion of kidney diseases in children and young adults. Nephrogenetics is a rapidly evolving subspecialty; however, in the clinical setting, increased use of genetic testing poses implementation challenges. Consequently, we established a national nephrogenetics clinic to apply a multidisciplinary model., Methods: Patients were referred from different pediatric or adult nephrology units across the country if their primary nephrologist suspected an undiagnosed genetic kidney disease. We determined the diagnostic rate and observed the effect of diagnosis on medical care. We also discuss the requirements of a nephrogenetics clinic in terms of logistics, recommended indications for referral, and building a multidisciplinary team., Results: Over 24 months, genetic evaluation was completed for a total of 74 unrelated probands, with an age range of 10 days to 72 years. The most common phenotypes included congenital anomalies of the kidneys and urinary tract, nephrotic syndrome or unexplained proteinuria, nephrocalcinosis/nephrolithiasis, tubulopathies, and unexplained kidney failure. Over 80% of patients were referred due to clinical suspicion of an undetermined underlying genetic diagnosis. A molecular diagnosis was reached in 42/74 probands, yielding a diagnostic rate of 57%. Of these, over 71% of diagnoses were made via next generation sequencing (gene panel or exome sequencing)., Conclusions: We identified a substantial fraction of genetic kidney etiologies among previously undiagnosed individuals which influenced subsequent clinical management. Our results support that nephrogenetics, a rapidly evolving field, may benefit from well-defined multidisciplinary co-management administered by a designated team of nephrologist, geneticist, and bioinformatician. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Aims: Traditional methods that use clinical parameters to determine dry weight in hemodialysis patients are inaccurate. This study aimed to compare clinical assessment of fluid status to sonographic parameters of fluid status in pediatric patients undergoing chronic hemodialysis., Methods: In a prospective observational study, pediatric patients maintained on chronic hemodialysis (ages 2.3-20 years) were evaluated clinically and sonographically before and after dialysis at 6 consecutive sessions. Sonographic parameters examined were number of lung B-lines as a measure of extravascular volume and inferior vena cava (IVC)/aorta ratio as a measure of intravascular volume. Clinical assessment of fluid status was compared to sonographic assessment., Results: Twelve patients were evaluated during 72 dialysis sessions. Sonographic parameters were significantly lower post-dialysis than pre-dialysis (B-lines number 4.5 ± 5 vs. 7.69 ± 7.46, p < 0.0001; IVC/aorta ratio 0.9 ± 0.2 vs. 1.1 ± 0.2, p < 0.0001, respectively). Ultrafiltration volume correlated with change in B-lines number during dialysis (r = 0.39, p < 0.01). Percent of blood volume drop correlated with post-dialysis IVC/aorta ratio (r = 0.48, p < 0.001). A higher percent of symptomatic episodes occurred with post-dialysis IVC/aorta ratio <0.8 versus ≥0.8 (39.1 vs. 15.2%, p = 0.036). Four patients were hypertensive, a clinical parameter implying fluid overload, in only one sonographic evaluation indicated fluid overload. Eight patients were clinically determined to be euvolemic, in three of them sonographic evaluation discovered covert fluids., Conclusion: Bedside ultrasound is a single modality that can be used to assess both extravascular and intravascular fluid status. It may contribute to clinical decisions differentiating fluid-related versus fluid-unrelated hypertension and identifying patients with covert fluids., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

We describe the clinical and laboratory manifestations and outcomes of 25 pediatric solid organ transplant recipients who tested positive for severe acute respiratory coronavirus-2. Twenty-one (84%) developed a mild disease; 22 of 23 (96%) had a positive serologic response. Two patients (8%), both kidney transplant recipients with additional comorbidities, developed a severe disease. The findings emphasize the need for close monitoring of this population., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Hypercalcemia with low parathyroid hormone (PTH) level, hypercalciuria, nephrocalcinosis, or nephrolithiasis, was recently reported as caused by mutations in CYP24A1 and SLC34A genes. These encode for vitamin D-24A-hydroxylase and for the renal phosphate transporters NaPiIIa and NaPiIIc, respectively. We aimed to describe the clinical course of these monogenic disorders in patients with and without found mutations during long-term follow-up. Methods: Ten patients with hypercalcemia, hypercalciuria, elevated 1,25-(OH) 2 D levels and suppressed PTH were followed in our center during 1998-2019. Relevant laboratory and imaging data and results of genetic evaluation were retrieved from medical files. Results: The median age at presentation was 9.5 months (range 1 month-11 years), six were males, and the median follow-up time was 3.8 (1.1-14) years. Mutations in CYP24A1 and SLC34A3 were identified in three and one patients, respectively. Five patients presented with nephrocalcinosis, three with nephrolithiasis, and two had normal renal ultrasound. High blood calcium and 1,25-(OH) 2 D levels at presentation decreased during follow-up [11.1 ± 1 vs. 9.9 ± 0.5 mg/dl ( p = 0.012), and 307 ± 130 vs. 209 ± 65 pmol/l ( p = 0.03), respectively]; this paralleled an increase in suppressed PTH levels (5.8 ± 0.9 vs. 11.8 ± 7.3 pg/ml, p = 0.2). Substantial improvements in hypercalciuria and renal sonography findings were not observed. Two patients had impaired renal function (eGFR 84-88 ml/min/1/73 m 2 ) at the last follow up. Interventions included appropriate diet, citrate supplementation, and thiazides. Conclusion: Despite improvement in hypercalcemia and 1,25-(OH) 2 D levels, not all the patients showed improvements in hypercalciuria and nephrocalcinosis. Deterioration of renal function was also observed. Long-term follow up and intervention to prevent nephrocalcinosis and nephrolithiasis are recommended in these children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gurevich, Levi, Borovitz, Alfandary, Ganon, Dinour and Davidovits.)

Background: Initial reports in adult kidney transplant recipients (KTR) indicate low immunogenicity after 2 doses of the BNT162b2 COVID-19 mRNA vaccine. We describe the immunogenicity of this vaccine compared to the serologic response in naturally infected COVID-19 positive adolescent and young adult KTR., Methods: For this prospective observational study, the study group included 38 KTR who received 2 doses of the tested vaccine, and the control group included 14 KTR who had a previous polymerase chain reaction-confirmed COVID-19 infection., Results: The mean age was 18 ± 3 y. Positive serologic responses were observed in 63% and 100% of the study and control groups, respectively (P = 0.01). Antibody titers were almost 30-fold higher in the control than the study group (median [interquartile range (IQR)]: 2782 [1908-11 000] versus 100.3 [4.7-1744] AU/mL, P < 0.001), despite the longer time from the COVID-19 infection to serologic testing compared to time from vaccination (median [IQR]: 157.5 [60-216] versus 37 [20.5-53] d, P = 0.011). Among vaccinated patients, higher proportions of those seronegative than seropositive were previously treated with rituximab (50% versus 8%, P = 0.01). Time from the second vaccine dose to serologic testing was longer in seropositive than seronegative patients (median [IQR]: 24.5 [15-40] versus 46 [27-56] d, P = 0.05). No patient developed symptomatic COVID-19 disease postvaccination., Conclusions: The BNT162b2 COVID-19 mRNA vaccine yielded higher positive antibody response in adolescent and young adult KTR than previously reported for adult KTR. Antibody titers after vaccination were significantly lower than following COVID-19 infection. Longer time may be required to mount appropriate humoral immunity to vaccination in KTR., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We investigated the risk of kidney injury among adolescents with and without a congenital single functioning kidney (SFK)., Methods: This retrospective study is based on a medical evaluation database of 17-year-old Israeli conscripts, born during 1989-1999. Those with congenital SFK diagnosis, verified by a pediatric nephrologist's review of the original military medical committee classifications, were compared to the rest of the cohort. Kidney injury (KI) was defined as proteinuria, high blood pressure (BP), or estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m 2 prior to army recruitment. Risk factors for KI were examined using logistic regression., Results: Of 979,630 screened candidates, 353 were diagnosed with SFK. The yearly incidence of SFK gradually increased in the first years of the study, reaching a plateau in 1995 (5.5 ± 1.2/10,000 births/year). The male to female ratio was 2.7:1. Concomitant genital malformations were documented in 5.5% of those with SFK. KI was more prevalent in the SFK than the control group (42.2% vs. 23.5%, p < 0.001). All three components of KI were more common in the SFK than the control group: high BP (31.7% vs. 23.1%, p < 0.001), proteinuria (18.2% vs. 0.4%, p < 0.001), and eGFR <90 ml/min/1.73m 2 (12.0% vs 0.1%, p < 0.001). Multivariate analysis of the SFK group revealed associations of higher mean BMI, male sex, and smaller ultrasonographic kidney length with KI., Conclusions: This large population-based study documents a significant risk for KI among adolescents with SFK. Obesity represents a major modifiable risk factor for KI, implicating the need for closer follow-up in this group during childhood., (© 2021. IPNA.)

Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with prednisone 2 mg/kg/day or 60 mg/m 2 /day. Retrospective data support the use of lower doses. We designed a prospective randomized pilot study to investigate the efficacy of different doses in achieving remission of steroid sensitive nephrotic syndrome relapse. The cohort included 30 children with relapsed steroid sensitive nephrotic syndrome, mean age 6.3 ± 3 years and mean disease duration 2.2 ± 1.8 years. The children were randomized to receive 2, 1.5, or 1 mg/kg/day prednisone. The corresponding times to response, defined as the first of 3 consecutive days without proteinuria, were 7.2 ± 1.4, 10.2 ± 5.1, and 9 ± 3.3 days; the difference between the 1.5 and 2 mg/kg/day groups was statistically significant. One patient each in the 1 mg/kg/day and the 1.5 mg/kg/day groups failed to respond and were switched to 2 mg/kg/day, leading to a response after 3 and 10 days, respectively. Mean cumulative prednisone doses in the 3 groups were 45.5 ± 3.4, 42.7 ± 25.9, and 24.9 ± 7.4 mg/kg, respectively (P < 0.05).Conclusion: In the present study, treatment of childhood steroid sensitive nephrotic syndrome relapse with prednisone 1-1.5 mg/kg/day led to a significantly lower cumulative dose than the standard dose. Treatment with a lower dose may be equally safe and effective to the standard dose.What is Known:• Relapses of steroid-sensitive nephrotic syndrome are traditionally treated with standard-dose steroids.• Treatment with corticosteroids may have significant adverse effects mainly with long-term use.What is New:• Treatment of steroid sensitive nephrotic syndrome relapse with 1-1.5 mg/kg/day prednisone may lead to a significantly lower cumulative dose.• Treatment with a lower steroid dose may be as effective as the standard dose in achieving remission of steroid sensitive nephrotic syndrome relapse.

Background: Hemolytic uremic syndrome (HUS) is a significant cause for complicated acute kidney injury. In Western countries, >90% of HUS are Shiga toxin Escherichia coli (STEC) associated., Methods: This is a retrospective review of all Israeli children diagnosed with HUS in 4 major medical centers in Israel during 1999-2016. Patients were categorized into 4 HUS etiological groups according to international guidelines: I, inherited or acquired damage to the complement cascade ("atypical HUS" [aHUS]); II, infection associated ("typical" HUS - STEC associated, Pneumococcus); III, coexisting disease; IV: other and unknown causes., Results: Seventy-five children with HUS were identified; the mean annual incidence was 1.5 ± 0.7 cases/106 per year. Distribution according to etiological groups was: I: 24.0%; II: 14.7%; III: 9.3%; IV: 52.0%. Group I comprised high proportions of Arabs (55.6%), children of consanguineous parents (61.0%), and hypertension. Group II included a high proportion of children with diarrhea on presentation and central nervous system involvement. Only 5 (6.6%) had proven STEC-HUS. Group IV was similar in most characteristics to group II. Logistic regression analysis revealed 3 independent factors associated with the diagnosis of aHUS: consanguinity, lack of diarrhea, and lack of leukocytosis at presentation. Receiver operating analysis curve showed an area under the curve of 0.9 (95% CI 0.82-0.98)., Conclusions: HUS incidence is lower in Israel than in most countries, especially because STEC-HUS is very rare. aHUS is the largest defined etiological group; some distinctive characteristics were identified that could facilitate its diagnosis. The current classification system leaves a high rate of "unknown cause" HUS., (© 2020 S. Karger AG, Basel.)

Purpose: Epidemiological studies demonstrate an association of increased body mass index and risk of kidney stone formation in adults. We conducted a population based pediatric study to examine the epidemiology of nephrolithiasis in Israeli children during a 30-year period, and to determine body mass index distribution during the same period., Materials and Methods: We accessed data from the compulsory medical evaluations of 17-year-old military service candidates in Israel before their enlistment during 1980 to 2013. Candidates for the army with a history of stone disease were compared to those without such a history., Results: Of 1,908,893 candidates 1,691 reported a history of nephrolithiasis, yielding an average prevalence rate of 88.6 per 100,000. During 1980 to 1995 the average reported prevalence of nephrolithiasis was 69 cases per 100,000. From 1995 onward the reported prevalence increased by an average of 6% yearly, reaching 120 per 100,000 during 2010 to 2012. This increased prevalence was observed for males and females but was more prominent among males. Mean ± SD body mass index of stone formers was higher than that of controls (22.7 ± 3.5 vs 22.1 ± 3.9 kg/m 2 , p <0.001). The trend of increasing body mass index among male candidates during 1995 to 2012 parallels the trend of increasing nephrolithiasis during these years. The odds ratio for nephrolithiasis in candidates with body mass index 30 or greater kg/m 2 was 1.7 (range 1.4 to 2.1) compared to candidates with a body mass index of 18.5 to 24.9 kg/m 2 ., Conclusions: This large, population based study documents an increasing prevalence of nephrolithiasis in children. The possible association of this finding with the increase in body mass index during the same period warrants further investigation., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Bartter and Gitelman syndromes are typical normotensive salt losing hypokalaemic tubulopathies. Their pathogenesis was gradually deciphered in the past 5 decades, first by typical salt balance studies and histopathology, followed by genetic characterization and discovery of the affected different ion channels. Although the different genotypic subtypes were originally thought to show a similar phenotype, important clinical and biochemical differences can now be found. New findings on the regulation of these channels, as well as the recent discovery of newly affected genes, merit an update on this topic., Recent Findings: Na-K-2CL cotransporter and NaCl cotransporter, the two main luminal channels in the thick ascending limb and distal convoluted tubule were found to be regulated by Ste 20-related proline alanine-rich kinase and oxidative stress response kinase. Knockout mice to these channels express a Bartter-like phenotype. MAGE-D2 is new gene found to cause severe polyhydramnios and transient postnatal Bartter-like syndrome. Variants in the different channels causing Bartter syndromes/Gitelman syndromes may also confer susceptibility for hypertension or protect against it., Summary: It remains to be determined if polymorphism or epigenetic changes in these genes and proteins may affect salt handling, explaining, apart from Bartter syndromes and Gitelman syndromes, also hypertension or stroke tendency, or both.

Background: Idiopathic membranoproliferative glomerulonephritis (MPGN) is a rare disease, accounting for 3-5% of all cases of primary nephritic syndrome. We report an uncommon case of familial MPGN type I associated with a new mutation in the complement factor H gene (CFH)., Methods: Clinical data were collected on three siblings with known factor H deficiency who presented with MPGN. All underwent immunological and genetic assays. Their parents and ten healthy adults served as controls for the DNA analysis., Results: All three children presented with recurrent episodes of hematuria and proteinuria, the youngest starting at age 5 months. One child currently has nephrotic syndrome and end-stage renal disease. All of the children were found to be homozygous for a C.262C > A (p.Pro88Thr) mutation in exon 3 of CFH that is associated with a quantitative/functional deficiency of factor H. The parents of the three siblings were found to be heterozygous for the mutation. None of the controls carried this mutation., Conclusions: Different mutations in CFH may be responsible for different glomerular diseases, including MPGN type I. A modifier gene or an environmental trigger may contribute to this phenotype-genotype discrepancy. Understanding the role of the alternative complement pathway in this disease would allow us to offer these patients more targeted therapy, including a clinical trial of eculizumab.