Georges Deschênes

Phenotype–genotype correlation in antenatal and neonatal variants of Bartter syndrome

BACKGROUNDnAnte/neonatal Bartter syndrome (BS) is a hereditary salt-losing tubulopathy due to mutations in genes encoding proteins involved in NaCl reabsorption in the thick ascending limb of Henles loop. Our aim was to study the frequency, clinical characteristics and outcome of each genetic subtype.nnnMETHODSnCharts of 42 children with mutations in KCNJ1 (n = 19), SLC12A1 (n = 13) CLCNKB (n = 6) or BSND (n = 4) were retrospectively analysed. The median follow-up was 8.3 [0.4-18.0] years.nnnRESULTSnWe describe 24 new mutations: 10 in KCNJ1, 11 in SLC12A1 and 3 in CLCNKB. The onset of polyhydramnios, birth term, height and weight were similar for all groups; three patients had no history of polyhydramnios or premature birth and had CLCNKB mutations according to a less severe renal sodium wasting. Contrasting with these data, patients with CLCNKB had the lowest potassium (P = 0.006 versus KCNJ1 and P = 0.034 versus SLC12A1) and chloride plasma concentrations (P = 0.039 versus KCNJ1 and P = 0.024 versus SLC12A1) and the highest bicarbonataemia (P = 0.026 versus KCNJ1 and P = 0.014 versus SLC12A1). Deafness at diagnosis was constant in patients with BSND mutations; transient neonatal hyperkalaemia was present in two-thirds of the children with KCNJ1 mutations. Nephrocalcinosis was constant in KCNJ1 and SLC12A1 but not in BSND and CLCNKB patients. In most cases, water/electrolyte supplementation + indomethacin led to catch-up growth. Three patients developed chronic renal failure: one with KCNJ1 mutations during the second decade of age and two with CLCNKB and BSND mutations and without nephrocalcinosis during the first year of life.nnnCONCLUSIONSnWe confirmed in a large cohort of ante/ neonatal BS that deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. Chronic renal failure is a rare event, associated in this cohort with three genotypes and not always associated with nephrocalcinosis.

Rituximab efficiency in children with steroid-dependent nephrotic syndrome

Although most patients with idiopathic nephrotic syndrome (NS) respond to steroid treatment, development of steroid dependency may require a long-term multidrug therapy including steroid and calcineurin inhibitor. Rituximab was shown to allow a reduction of the doses of steroid and immunosuppressive drugs in those patients. In the present series, 22 patients with steroid-sensitive, but steroid-dependent nephrotic syndrome were treated with rituximab. Rituximab reduced B cell count down to an undetectable level in all patients. A second treatment was necessary in 18 patients in order to maintain B cell depletion for up to 18xa0months. B cell depletion lasted 4.9 to 26xa0months (mean 17.2xa0months). At last follow-up, 9 patients were in remission without oral steroid or calcineurin inhibitor, although B cell count had recovered for 2.9 to 17xa0months (mean 9.5xa0months). A remission under ongoing B cell depletion was observed in 10 other patients in the absence of oral steroid or calcineurin inhibitor. Rituximab failed in 2 patients and 1 refused any additional treatment, despite B cell recovery and relapse. Toxicity of rituximab was limited to reversible cytokine shock in 2 patients and reversible neutropenia in 1 patient. No severe infection was observed.

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming’s procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200xa0mg/m2/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3xa0months, 25% at 6xa0months]. Twenty-four children (median age 6.0xa0years, 2.8–14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6xa0months (estimated probability 17.6%, 95% credibility interval: 5.4–35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6xa0months, median (Q1–Q3) prednisone maintenance dose decreased from 25 (10–44) to 9 (7.5–11.2) mg/m2 e.o.d (pu2009<u20090.001) and cumulative dose from 459 (382–689) to 264 (196–306) mg/m2/month (pu2009<u20090.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.

Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation

The development of membranoproliferative glomerulonephritis (MPGN) is associated with uncontrolled activation of the complement alternative pathway. This dysregulation is related either to C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase, or to homozygous loss-of-function mutation of the complement regulatory protein factor H. Heterozygous mutations in the genes coding for factor H, or for the other alternative pathway inhibitory proteins factor I and membrane cofactor protein, have recently been identified in a small number of patients with MPGN with exclusive C3 deposits. We report three hypocomplementemic children with dense deposit disease (nu2009=u20091) or immune-complex-mediated MPGN type I (nu2009=u20092), associated with both C3NeF activity and heterozygous mutation of factor H or factor I. These observations highlight the possible combination of genetic and acquired defect in complement control in various subtypes of MPGN, a finding that may influence the treatment strategy in some patients.

Cyclophosphamide in steroid-dependent nephrotic syndrome.

In order to determine the long-term effects of cyclophosphamide (CPO) and to identify parameters associated with sustained remission, we retrospectively studied the data from 90 patients with steroid-dependent nephrotic syndrome (SDNS) who received a single course of oral cyclophosphamide (2xa0mg/kg/day for 10 to 12xa0weeks). The median follow-up period after CPO was 5.5xa0years (interquartile range 3.2–8.5). Sustained remission reached the cumulative rate of 57% at 1xa0year, 42% at 2xa0years, and 31% at 5xa0years. For the patients who relapsed, the median threshold dose of prednisone between CPO initiation and first relapse has significantly decreased (22.1xa0mg/kg/day versus 4.9xa0mg/kg/day, pu2009<u20090.001). No further immunosuppressive agent was required in 60% of all patients. Young age at CPO initiation was associated with a lower rate of sustained remission (pu2009<u20090.001). Age at diagnosis of nephrotic syndrome, gender, cumulative dose of CPO (in mg/kg), and level of steroid dependence at CPO initiation did not influence the outcome. The incidence of side effects was low. These findings suggest that despite the wide use of new immunosuppressive agents, a short course of CPO remains an effective second-line therapy in SDNS patients. Optimal efficiency was observed in children over 7.5xa0years.

Ocular involvement in hemolytic uremic syndrome due to factor H deficiency—are there therapeutic consequences?

Factorxa0H deficiency is responsible for thrombotic microangiopathy (TMA) via uncontrolled activation of the alternative pathway of the complement system. Ocular TMA has never been reported in patients with factorxa0H abnormalities. A male patient with congenital homozygote factorxa0H deficiency reached end-stage renal disease at the age of 10xa0years. Hemodialysis was uneventful for 3xa0years, when, suddenly, unilateral ocular pain and blurred vision occurred while he had febrile pharyngitis. Ophthalmologic examination found vitreous bleeding, elevated ocular pressure, choroidal hemorrhage (ultrasound biomicroscopy) and retinal ischemia (fluorescein angiography). C-reactive protein concentration was increased, while haptoglobin levels remained normal. We suspected that TMA due to factorxa0H deficiency was responsible for the ocular manifestations and immediately initiated daily plasma exchanges (PEs) with fresh frozen plasma (FFP) for 10xa0days followed by three sessions per week. Factorxa0H serum level increased from 6% to 82%, and C3 level normalized. Progressively, ocular pain decreased, and visual acuity and ophthalmologic findings showed improvement. When there is permanent activation of the alternative pathway in patients with end-stage renal disease (ESRD), the search for secondary targets might be of interest. In nephrectomized patients, no biological parameter can predict isolated ocular TMA. Early ophthalmologic investigation and substitution of factorxa0H via FFP may avoid irreversible damage.

Association of migraine‐like headaches with Schimke immuno‐osseous dysplasia

Schimke immuno‐osseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia, nephropathy, and T‐cell deficiency. SIOD is caused by mutations in the putative chromatin remodeling protein SMARCAL1. We report an 8‐year‐old boy with SIOD and recurrent, severe, refractory migraine‐like headaches. Through a retrospective questionnaire‐based study, we found that refractory and severely disabling migraine‐like headaches occur in nearly half of SIOD patients. We have also found that the vasodilator minoxidil provided symptomatic relief for one patient. We hypothesize that these headaches may arise from an intrinsic vascular, neuroimmune, or neurovascular defect resulting from loss of SMARCAL1 function.

Non-atheromatous arterial stenoses in atypical haemolytic uraemic syndrome associated with complement dysregulation

BACKGROUNDnA child, who presented atypical haemolytic uraemic syndrome (aHUS) at the age of 1 month, developed cerebral ischaemic events at the age of 10 years.nnnRESULTSnStenoses of both carotid arteries, left subclavian and vertebral arteries, several intracranial, right humeral, several coronary, and all pulmonary arteries were demonstrated. At the age of 13 years, left subclavian and right cervical carotid arteries were occluded. Right carotid recanalization induced intracranial dissection and death. The child had a Lys350Asp factor B mutation.nnnCONCLUSIONnArterial steno-occlusive lesions appear as potential complications of dysregulated complement activation in aHUS. Endovascular treatment should be considered cautiously in this setting.

Inhibition of K+ secretion in the distal nephron in nephrotic syndrome: possible role of albuminuria

Non‐technical summaryu2002 Plasma potassium concentration is a major determinant of muscle contractility and nerve conduction. The maintenance of plasma potassium concentration depends on the ability of kidneys to daily secrete in the urine the exact quantity of potassium ingested in the food. We show that in nephrotic syndrome, a common disease featuring abnormal urinary protein excretion and sodium retention, the membrane protein called ROMK channel responsible for kidney potassium secretion is inhibited. Thus, nephrotic rats are unable to excrete a dietary load of potassium and develop hyperkalaemia. Based on these findings, we would recommend not only a low sodium diet but also a controlled potassium diet for patients with nephrotic syndrome.

Prevalence of Hypertension in Children with Early-Stage ADPKD

BACKGROUND AND OBJECTIVESnAutosomal dominant polycystic kidney disease is the most common inheritable kidney disease, frequently thought to become symptomatic in adulthood. However, patients with autosomal dominant polycystic kidney disease may develop signs or symptoms during childhood, in particular hypertension. Although ambulatory BP monitoring is the preferred method to diagnose hypertension in pediatrics, data in children with autosomal dominant polycystic kidney disease are limited.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnOur retrospective multicenter study was conducted to collect ambulatory BP monitoring recordings from patients with autosomal dominant polycystic kidney disease age <18 years old. Basic anthropometric parameters as well as data on kidney function, BP treatment, and kidney ultrasound were also collected.nnnRESULTSnData from 310 children with autosomal dominant polycystic kidney disease with a mean age of 11.5±4.1 years old were collected at 22 European centers. At the time when ambulatory BP monitoring was performed, 95% of children had normal kidney function. Reference data for ambulatory BP monitoring were available for 292 patients. The prevalence rates of children with hypertension and/or those who were treated with antihypertensive drugs were 31%, 42%, and 35% during daytime, nighttime, or the entire 24-hour cycle, respectively. In addition, 52% of participants lacked a physiologic nocturnal BP dipping, and 18% had isolated nocturnal hypertension. Logistic regression analysis showed a significant association between a categorical cyst score that was calculated on the basis of the number of cysts >1 cm per kidney and daytime hypertension (odds ratio, 1.70; 95% confidence interval, 1.21 to 2.4; P=0.002), nighttime hypertension (odds ratio, 1.31; 95% confidence interval, 1.05 to 1.63; P=0.02), or 24-hour hypertension (odds ratio, 1.39; 95% confidence interval, 1.08 to 1.81; P=0.01). Kidney length, expressed as SD score, was also significantly associated with nighttime hypertension (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.42; P=0.10).nnnCONCLUSIONSnThese data indicate high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages.