Michel Tsimaratos

Differential Impact of Complement Mutations on Clinical Characteristics in Atypical Hemolytic Uremic Syndrome

Mutations in factor H (CFH), factor I (IF), and membrane cofactor protein (MCP) genes have been described as risk factors for atypical hemolytic uremic syndrome (aHUS). This study analyzed the impact of complement mutations on the outcome of 46 children with aHUS. A total of 52% of patients had mutations in one or two of known susceptibility factors (22, 13, and 15% of patients with CFH, IF, or MCP mutations, respectively; 2% with CFH+IF mutations). Age <3 mo at onset seems to be characteristic of CFH and IF mutation-associated aHUS. The most severe prognosis was in the CFH mutation group, 60% of whom reached ESRD or died within <1 yr. Only 30% of CFH mutations were localized in SCR20. MCP mutation-associated HUS has a relapsing course, but none of the children reached ESRD at 1 yr. Half of patients with IF mutation had a rapid evolution to ESRD, and half recovered. Plasmatherapy seemed to have a beneficial effect in one third of patients from all groups except for the MCP mutation group. Only eight (33%) of 24 kidney transplantations that were performed in 15 patients were successful. Graft failures were due to early graft thrombosis (50%) or HUS recurrence. In conclusion, outcome of HUS in patients with CFH mutation is catastrophic, and posttransplantation outcome is poor in all groups except for the MCP mutation group. New therapies are urgently needed, and further research should elucidate the unexplained HUS group.

Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome

We sought to ascertain the long-term outcome and genotype-phenotype correlations available for primary hyperoxaluria type 1 in a large retrospective cohort study. We examined the clinical history of 155 patients (129 families primarily from Western Europe, North Africa, or the Middle East) as well as the enzymatic or genetic diagnosis. The median age at first symptom was 4 years, and at diagnosis 7.7 years, at which time 43% had reached end-stage renal disease. Presentations included: (1) early nephrocalcinosis and infantile renal failure, (2) recurrent urolithiasis and progressive renal failure diagnosed during childhood, (3) late onset with occasional stone passage diagnosed in adulthood, (4) diagnosis occurring on post-transplantation recurrence, and (5) family screening. The cumulative patient survival was 95, 86, and 74% at ages 10, 30, and 50 years, respectively, with the cumulative renal survival of 81, 59, 41, and 10% at ages 10, 20, 30, and 50 years, respectively; 72 patients had undergone a total of 97 transplantations. Among the 136 patients with DNA analysis, the most common mutation was p.Gly170Arg (allelic frequency 21.5%), with a median age at end-stage renal disease of 47 years for homozygotes, 35 years for heterozygotes, and 21 years for other mutations. Our results underscore the severe prognosis of primary hyperoxaluria type 1 and the necessity for early diagnosis and treatment, as well as confirm a better prognosis of the p.Gly170Arg mutation.

Population Pharmacokinetics and Pharmacogenetics of Mycophenolic Acid Following Administration of Mycophenolate Mofetil in De Novo Pediatric Renal‐Transplant Patients

The objective was to develop a population pharmacokinetic‐pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal‐transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal‐transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8–A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2‐compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor influencing central volume of distribution and concomitant immunosuppressive medication and identified body weight and UGT2B7 802C>T genotype as individual factors influencing apparent oral clearance (CL/F) of MMF. CL/F in cyclosporine‐MMF‐treated patients was 33% higher than in tacrolimus‐MMF‐treated patients. The CL/F was significantly lower in patients with UGT2B7 802 C/C genotype compared with patients with UGT2B7 802 C/T and 802T/T genotypes, and this effect was independent of concomitant immunosuppressive medication or body weight. The population pharmacokinetic‐pharmacogenetic model of mycophenolic acid was validated. Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal‐transplant patients.

Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome.

Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.

Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1

Primary hyperoxaluria type 1 results from alanine:glyoxylate aminotransferase deficiency. Due to genotype/phenotype heterogeneity in this autosomal recessive disorder, the renal outcome is difficult to predict in these patients and the long-term impact of conservative management in children is unknown. We report here a multicenter retrospective study on the renal outcome in 27 affected children whose biological diagnosis was based on either decreased enzyme activity or identification of mutations in the patient or his siblings. The median age at first symptoms was 2.4 years while that at initiation of conservative treatment was 4.1 years; 6 children were diagnosed upon family screening. The median follow-up was 8.7 years. At diagnosis, 15 patients had an estimated glomerular filtration rate (eGFR) below 90, and 7 children already had stage 2-3 chronic kidney disease. The median baseline eGFR was 74, which rose to 114 with management in the 22 patients who did not require renal replacement therapy. Overall, 20 patients had a stable eGFR, however, 7 exhibited a decline in eGFR of over 20 during the study period. In a Cox regression model, the only variable significantly associated with deterioration of renal function was therapeutic delay with a relative risk of 1.7 per year. Our study strongly suggests that early and aggressive conservative management may preserve renal function of compliant children with this disorder, thereby avoiding dialysis and postponing transplantation.

Crescentic glomerulonephritis in hyper IgD syndrome.

Abstract The hyperimmunoglobulinemia D syndrome (HIDS) is a well-defined entity resembling familial Mediterranean fever. HIDS is a systemic inflammatory disease associated with stimulation of T-cell-mediated immunity. These patients are at low risk for amyloidosis and are not known to develop nephropathy. We report a boy of Mediterranean ancestry who exhibited typical HIDS and end-stage renal failure. Kidney biopsy revealed pauci-immune crescentic glomerulonephritis (cGN). We hypothesized that the glomerular involvement was secondary to the cytokine network activation observed in HIDS. Thus, cGN should be considered as part of the syndrome, and kidney biopsy should be performed early in the course of the renal disease in patients with HIDS.

CKD and Its Risk Factors among Patients with Cystinuria

BACKGROUND AND OBJECTIVES Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients. RESULTS Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3-72.1) years and median diagnosis delay was 1.3 (0-45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8-70.7). Among the 314 patients aged ≥16 years, using the last available plasma creatinine, 22.5% had an eGFR≥90 ml/min per 1.73 m(2) (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60-89, 45-59, 30-44, 15-29, and <15, respectively. Among these 314 patients, 28.6% had high BP. In multivariate analysis, CKD was associated with age (odds ratio, 1.05 [95% confidence interval, 1.03 to 1.07]; P<0.001), hypertension (3.30 [1.54 to 7.10]; P=0.002), and severe damage of renal parenchyma defined as a past history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size <10 cm in patients aged ≥16 years (4.39 [2.00 to 9.62]; P<0.001), whereas hypertension was associated with age (1.06 [1.04 to 1.08]; P<0.001), male sex (2.3 [1.3 to 4.1]; P=0.003), and an eGFR<60 ml/min per 1.73 m(2) (2.7 [1.5 to 5.1]; P=0.001). CONCLUSIONS CKD and high BP occur frequently in patients with cystinuria and should be routinely screened.

Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.

Crescentic glomerulonephritis is part of hyperimmunoglobulinemia D syndrome

Sirs, The syndrome associating fever and hyperimmunoglobulinemia D (HIDS, MIM#260920) is characterized by periodic febrile attacks occurring every 4–8 weeks with an intense inflammatory reaction accompanied by lymphadenopathies, abdominal pain, diarrhea, joint pain, hepatosplenomegaly, and cutaneous signs [1]. Mutations in the gene encoding the enzyme mevalonate kinase (MVK, MIM+251170) are responsible for this syndrome [2]. MVK deficit is known and causes the developmental disease called mevalonic aciduria (MVA) [3]. MVA is caused by homozygosity or compound heterozygosity for disease-causing mutations in the MK gene localized to chromosome 12q24. The gene is subject to autosomal recessive inheritance. MVA is biochemically characterized by the accumulation of mevalonic acid and mevalonolactone. The diagnosis of MVA should be suspected in patients with mild dysmorphic features, psychomotor retardation, failure to thrive, hepatosplenomegaly and recurrent febrile episodes. HIDS is clinically characterized by recurrent fever episodes associated with lymphadenopathy, arthralgia, gastrointestinal problems and skin rashes. HIDS/MVA can currently be confirmed by pathologically low activity of mevalonate kinase [4]. Thus, HIDS and MVK should be considered as the two sides of the same coin [5]. The phenotype variability cannot be explained by genotypic differences [6]. Although renal involvement in HIDS has been reported in a patient who experienced renal failure due to rapidly progressive pauciimmune crescentic glomerulonephritis (cGN), renal involvement is not part of the clinical synopsis in widely used databases such as OMIM and Orphanet [7]. Here we describe a case that could add a clinical feature in HIDS/MVA. Two years after the onset of renal replacement therapy, a patient previously described with renal failure due to cGN received a cadaveric donor renal transplant [7]. Quadruple sequential immunosuppressive treatment (ATGL, steroids, Ciclosporin A, Azathioprine) allowed good renal function. The attacks tapered during the transplantation period as long as high dose steroids were continued. After 30 months of follow-up, serum creatinine was 76 μmol/l, and there was no hematuria but a slight proteinuria (200 mg/24 hours). Two heterozygous mutations in the gene encoding the enzyme mevalonate kinase were determined in this patient (L264F and I268T). Forty months after transplantation, immunosuppressive treatment was adapted to improve stature growth, and steroids were progressively stopped. Febrile attacks recurred. Four months after steroid withdrawal, one febrile attack was associated with renal failure (serum creatinine 344 μmol/L). A rejection episode was suspected, but graft biopsy (20 glomeruli) showed recurrence of cGN while there was no argument for cellular or antibody-mediated acute rejection. Diffuse cGN was observed on the graft biopsy. Fibrocellular crescents were present in 50% of all glomeruli, and some of them were adherent to the collapsed capillary tufts. Glomerular capillary walls were wrinkled. No amyloid deposits were detected. As the first time, ANCA was negative. Immunostaining (with IgA, IgG, IgM, IgD, C1q, Pediatr Nephrol (2006) 21:1917–1918 DOI 10.1007/s00467-006-0209-0

Patient and transplant outcome in infants starting renal replacement therapy before 2 years of age

Background Despite major technical improvements in the care of children requiring renal replacement therapy (RRT) before 2 years of age, the management of those patients remains challenging and transplantation is generally delayed until the child weighs 10 kg or is 2 years old. In this national cohort study, we studied patient and graft survival in children starting RRT before 2 years of age to help clinicians and parents when deciding on RRT initiation and transplantation management. Methods All children starting RRT before 24 months of age between 1992 and 2012 in France were included through the national Renal Epidemiology and Information Network (REIN) registry. The primary endpoints were patient survival on dialysis and 10-year graft survival. Results A total of 224 patients were included {62% boys, median age 10.5 months [interquartile range (IQR) 5.8-15.6]}. The 10-year survival rate was 84% (IQR 77-89). Suffering from extrarenal comorbidities was the only factor significantly associated with both an increased risk of death on dialysis [hazard ratio 5.9 (95% confidence interval 1.8-19.3)] and a decreased probability of being transplanted. During follow-up, 174 renal transplantations were performed in 171 patients [median age at first transplantation 30.2 (IQR 21.8-40.7) months]. The 10-year graft survival was 74% (IQR 67-81). Factors associated with graft loss in multivariate analysis were the time spent on dialysis before transplantation, donor/recipient height ratio with an increased risk for both small and tall donors and presenting two human leucocyte antigen-antigen D-related mismatches. Conclusions This study confirms the good outcome of children starting RRT before 2 years of age. The main question remains when and how to transplant those children. Our study provides data on the optimal morphological and immunological matching in order to help clinicians in their decisions.