The pathophysiology of the leading cause of pediatric acute nephritis, acute postinfectious GN, including mechanisms of the pathognomonic transient complement activation, remains uncertain. It shares ...clinicopathologic features with C3 glomerulopathy, a complement-mediated glomerulopathy that, unlike acute postinfectious GN, has a poor prognosis.
This retrospective study investigated mechanisms of complement activation in 34 children with acute postinfectious GN and low C3 level at onset. We screened a panel of anticomplement protein autoantibodies, carried out related functional characterization, and compared results with those of 60 children from the National French Registry who had C3 glomerulopathy and persistent hypocomplementemia.
All children with acute postinfectious GN had activation of the alternative pathway of the complement system. At onset, autoantibodies targeting factor B (a component of the alternative pathway C3 convertase) were found in a significantly higher proportion of children with the disorder versus children with hypocomplementemic C3 glomerulopathy (31 of 34 91% versus 4 of 28 14%, respectively). In acute postinfectious GN, anti-factor B autoantibodies were transient and correlated with plasma C3 and soluble C5b-9 levels. We demonstrated that anti-factor B antibodies enhance alternative pathway convertase activity
, confirming their pathogenic effect. We also identified crucial antibody binding sites on factor B, including one correlated to disease severity.
These findings elucidate the pathophysiologic mechanisms underlying acute postinfectious GN by identifying anti-factor B autoantibodies as contributing factors in alternative complement pathway activation. At onset of a nephritic syndrome with low C3 level, screening for anti-factor B antibodies might help guide indications for kidney biopsy to avoid misdiagnosed chronic glomerulopathy, such as C3 glomerulopathy, and to help determine therapy.
Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (
), which encodes the ClC-Kb chloride ...channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with
mutations. Functional analyses were performed in
oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed
decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes.
Abstract
Background
Recommendations for management of Finnish-type congenital nephrotic syndrome (CNS) followed by many teams include daily albumin infusions, early bilateral nephrectomy, dialysis ...and transplantation. We aimed to assess the treatment and outcome of patients with CNS in France.
Methods
We conducted a nationwide retrospective study on 55 consecutive children born between 2000 and 2014 treated for non-infectious CNS.
Results
The estimated cumulative incidence of CNS was 0.5/100 000 live births. The underlying defect was biallelic mutations in NPHS1 (36/55, 65%), NPHS2 (5/55, 7%), PLCE1 (1/55, 2%), heterozygous mutation in WT1 (4/55, 7%) and not identified in nine children (16%). Fifty-three patients (96%) received daily albumin infusions from diagnosis (median age 14 days), which were spaced and withdrawn in 10 patients. Twenty children (35%) were managed as outpatients. Thirty-nine patients reached end-stage kidney disease (ESKD) at a median age of 11 months. The overall renal survival was 64% and 45% at 1 and 2 years of age, respectively. Thirteen children died during the study period including four at diagnosis, two of nosocomial catheter-related septic shock, six on dialysis and one after transplantation. The remaining 13 patients were alive with normal renal function at last follow-up median 32 months (range 9–52). Renal and patient survivals were longer in patients with NPHS1 mutations than in other patients. The invasive infection rate was 2.41/patient/year.
Conclusions
Our study shows: (i) a survival free from ESKD in two-thirds of patients at 1 year and in one-half at 2 years and (ii) a significant reduction or even a discontinuation of albumin infusions allowing ambulatory care in a subset of patients. These results highlight the need for new therapeutic guidelines for CNS patients.
Observations of a large Dent disease cohort Blanchard, Anne; Curis, Emmanuel; Guyon-Roger, Tiphaine ...
Kidney international,
August 2016, 2016-08-00, 20160801, Letnik:
90, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Dent disease classically combines low-molecular-weight proteinuria, hypercalciuria with nephrocalcinosis, and renal failure. Nephrotic range proteinuria, normal calciuria, and hypokalemia have been ...rarely reported. It is unknown whether the changes in phenotype observed over time are explained by a decrease in glomerular filtration rate (GFR) or whether there is any phenotype-genotype relationship. To answer this we retrospectively analyzed data from 109 male patients with CLCN5 mutations (Dent-1) and 9 patients with mutation of the OCRL gene (Dent-2). In Dent-1 disease, the estimated GFR decreased with age, by 1.0 to 1.6 ml/min per 1.73 m2/yr in the absence and presence of nephrocalcinosis, respectively, with no significant difference. Median values of low-molecular-weight proteinuria were in the nephrotic range and remained at the same level even in late renal disease. End-stage renal disease occurred in 12 patients, at a median age of 40 years. Hypercalciuria decreased with glomerular filtration and was absent in 40% of the patients under 30 and 85% of those over the age of 30. Hypophosphatemia did not resolve with age and calcitriol concentrations were in the upper normal range. Kalemia decreased with age, with half of the patients over the age of 18 presenting with hypokalemia. Thus, no phenotype/genotype correlation was observed in this cohort of patients with Dent disease.
Socioeconomic status is an important determinant of health. Its impact on kidney transplantation outcome has been studied among adults but data in children are scarce, especially in Europe. Here, we ...investigate the association between the level of social deprivation (determined by the continuous score European Deprivation Index) and graft failure risk in pediatric kidney transplant recipients. All patients listed under 18 years of age who received a first kidney transplant between 2002 and 2014 in France were included. Of 1050 kidney transplant recipients (males 59%, median age at transplantation 13.2 years, preemptive transplantation 23%), 211 graft failures occurred within a median followup of 5.9 years. Thirty-seven percent of these patients belong to the most deprived quintile, suggesting that deprivation is more frequent in pediatric patients with end-stage kidney disease (ESKD) than in the general population. Five- and ten-year graft survival were 85% and 69%, respectively, in the most deprived quintile vs. 90% and 83%, respectively, in the least deprived quintile. At any time after transplantation, patients in the most deprived quintile had almost a two-fold higher hazard of graft failure compared with the least deprived quintile, after adjustment for age at renal replacement therapy, duration of dialysis, primary kidney disease, and rural/urban living environment (hazard ratio 1.99; 95% confidence interval 1.20-3.28). The hazard of graft failure did not differ significantly between girls and boys. Thus, our findings suggest a lower socioeconomic status is independently associated with poor graft outcome in pediatric kidney transplantation.
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Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been ...reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.
Background
Co-occurrence of polycystic kidney disease and hyperinsulinemic hypoglycemia has been reported in children in a few families associated with a variant in the promotor of the
PMM2
gene, at ...position -167 upstream of the coding sequence.
PMM2
encodes phosphomannomutase 2, a key enzyme in N-glycosylation. While biallelic coding
PMM2
mutations are involved in congenital disorder of glycosylation CDG1A, that particular variant in the promoter of the gene, either in the homozygous state or associated with a mutation in the coding exons of the gene, is thought to restrict the N-glycosylation defect to the kidney and the pancreas.
Methods
Targeted exome sequencing of a panel of genes involved in monogenic kidney diseases.
Results
We identified a
PMM2
variant at position -167 associated with a pathogenic
PMM2
variant in the coding exons in 3 families, comprising 6 cases affected with a cystic kidney disease. The spectrum of phenotypes was very broad, from extremely enlarged fetal cystic kidneys in the context of a COACH-like syndrome, to isolated cystic kidney disease with small kidneys, slowly progressing toward kidney failure in adulthood. Hypoglycemia was reported only in one case.
Conclusion
These data show that the
PMM2
promotor variation,
in trans
of a
PMM2
coding mutation, is associated with a wide spectrum of kidney phenotypes, and is not always associated with extra-renal symptoms. When present, extra-renal defects may include COACH-like syndrome. These data prompt screening of
PMM2
in unresolved cases of fetal hyperechogenic/cystic kidneys as well as in cystic kidney disease in children and adults.
Graphical Abstract
In contrast to shigatoxin-associated
(STEC) causing hemolytic uremic syndrome, STEC-unrelated infections associated with thrombotic microangiopathy are less characterized.
Our retrospective study in ...a four-hospital institution of 530 consecutive patients with adjudicated thrombotic microangiopathies during the 2009-2016 period studied STEC-unrelated infections' epidemiology and major outcomes (death, acute dialysis, and major cardiovascular events).
STEC-unrelated infection was present in 145 of 530 (27%) patients, thrombotic microangiopathies without infection were present in 350 of 530 (66%) patients, and STEC causing hemolytic and uremic syndrome was present in 35 of 530 (7%) patients. They (versus thrombotic microangiopathy without infection) were associated with age >60 years (36% versus 18%), men (53% versus 27%), altered consciousness (32% versus 11%), mean BP <65 mm Hg (21% versus 4%), lower hemoglobin and platelet count, and AKI (72% versus 49%). They were associated with more than one pathogen in 36 of 145 (25%) patients (either isolated 14% or combined 86% to other causes of thrombotic microangiopathy); however, no significant clinical or biologic differences were noted between the two groups. They were more frequently due to bacteria (enterobacteria 41%,
11%, and
3%) than viruses (Epstein-Barr 20%, cytomegalovirus 18%, influenza 3%, hepatitis C 1%, HIV 1%, and rotavirus 1%). STEC-unrelated infections were independent risk factors for in-hospital death (odds ratio, 2.22; 95% confidence interval, 1.18 to 4.29), major cardiovascular event (odds ratio, 3.43; 95% confidence interval, 1.82 to 6.69), and acute dialysis (odds ratio, 3.48; 95% confidence interval, 1.78 to 7.03). Bacteria (versus other pathogens), and among bacteria, enterobacteria, presence of more than one bacteria, and
without shigatoxin were risk factors for acute dialysis.
Infections are frequent thrombotic microangiopathy triggers or causes, and they are mostly unrelated to STEC. Infections convey a higher risk of death and major complications. The most frequent pathogens were enterobacteria,
, Epstein-Barr virus, and cytomegalovirus.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_09_07_CJN17511120.mp3.
The impact of blood pressure on neurological symptoms and risk of end-stage kidney disease (ESKD) is unknown in primary and secondary thrombotic microangiopathies (TMAs).
We measured baseline ...systolic (SBP) and diastolic (DBP) BP in consecutive 563 patients with adjudicated primary and secondary TMAs, and assessed its association with the risk of ESKD.
Normal BP, grade 1, 2 and 3 hypertension were present in 243 (43.1%), 132 (23.4%), 101 (17.9%) and 88 (15.6%), respectively. Significant BP differences were noted in relation to the cause of TMA: highest BP values were found in patients with atypical hemolytic-uremic syndrome (aHUS), pregnancy, transplantation and auto-immune-related TMAs. Normal BP or grade 1 hypertension was found in 17/18 (94.4%) patients with thrombotic thrombocytopenic patients (only 1/18 (5.6%) had a SBP value>150 mmHg). In contrast, BP values could not differentiate isolated "essential" malignant hypertension (MH) from MH associated with aHUS (isolated MH (n=15): BP (median (IQR)): 220 (182-249)/132 (101-150) mmHg; MH with aHUS (n=5): BP: 223 (196-245)/131 (111-144) mmHg). The risk of vigilance disturbances (6.9%, 15.0%, 25.0%, respectively), epileptic seizures (1.5%, 4.0%, 12.5%, respectively) and posterior reversible encephalopathy syndrome (0.76%, 2.97%, 6.82%, respectively) increased with increasing baseline BP values from grade 1 to grade 3 hypertension. ESKD occurred in 35/563 (6.2%) patients (1.23%, 2.27%, 11.9% and 19.3% of patients with normal BP, grade 1, 2 and 3 hypertension, respectively). As compared to patients with normal BP (<120/139 mmHg), grade 1, grade 2 and grade 3 hypertension were associated with a greater risk of ESKD in univariate (OR: 1.91 0.83-4.40, 13.2 3.56-48.9 and 34.8 9.31-130, respectively) and multivariate (OR: 0.89 0.30-2.69, 7.00 1.57-31.3 and 19.7 4.53-85.2, respectively) analyses. The association between BP and the risk of ESRD was unchanged after adjustment on eculizumab use (OR: 3.46 1.41-8.49, 17.7 4.44-70.0 and 70.6 8.61-579, respectively). Patients with MH, regardless of its cause, had a greater risk of ESKD (OR: 26.4 10.0-69.8 vs other patients).
Baseline BP differs in primary and secondary TMAs. High BP reduces the neurological tolerance of TMAs and is a powerful independent risk factor of ESKD, even after adjustment on TMA's cause.
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.
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.
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.
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.
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