Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

BACKGROUND AND HYPOTHESIS: IgA vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Treatment recommendations are, due to a lack of evidence, based on expert opinion resulting in variation. The aim of this study was to describe clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy proven IgAVN to identify prognostic risk factors and signals of treatment efficacy. METHODS: Retrospective data were collected on 1148 children with biopsy proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analyzed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow up. RESULTS: The median follow up was 3.7 years (IQR 2-6.2). At last follow up, 29% of patients had an eGFR < 90 ml/min/1.73m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second line immunosuppressive regimen to be superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow up. CONCLUSION: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

Therapeutic Approach for Recurrent Focal Segmental Glomerulosclerosis in Pediatric Renal Transplant Recipients: A Single-Center Experience.

INTRODUCTION: Recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KTx) develops in 40% of patients, leading to graft loss in half of cases. Extracorporeal apheretic treatments, combined with immunosuppressive drugs, seem to be the most promising therapies, but at now limited reports are available, mainly in pediatric patients. OBJECTIVE: We aimed to assess the efficacy of immunoadsorption (IA) to treat recurrent FSGS in pediatric patients. METHODS: We report a case series of 4 pediatric patients (aged 4-12 years) followed at our institution for early recurrent FSGS after KTx. FSGS recurrence was treated with early and intensive apheretic treatments IA. RESULTS: After IA initiation, a partial remission (PR) of proteinuria at 24-month follow-up was achieved only in 1 patient. The others showed a mild reduction of nephrotic proteinuria, without PR, but gained a significant improvement in clinical signs of nephrotic syndrome (reduction of edema, increased serum albumin, and total protein levels). After a median follow-up of 38 (22-48) months, renal function was almost stable over time in all patients, except one who returned to hemodialysis after 22 months. No severe IA-related complications occurred. CONCLUSIONS: According to our clinical experience, IA revealed as a safe and effective therapy to treat patients with recurrent FSGS after KTx and it could maintain stable renal function in 75% of patients.

Peripheral nervous system manifestations of Shiga toxin-producing E. coli-induced haemolytic uremic syndrome in children.

BACKGROUND: The Neurological involvement is the most common extra-renal complication of Shiga toxin-producing E. coli-hemolytic uremic syndrome (HUS) or typical HUS. On brain magnetic resonance examination, main neurological signs encompass acute lesions of the basal ganglia and the white matter, which could usually regress after Eculizumab infusion. In contrast, peripheral nervous system (PNS) manifestations in typical HUS are very rare and, when occurring, they require a careful management of neurological sequelae and an intensive multidisciplinary neuro-rehabilitation program. CASE PRESENTATION: Here, we present two pediatric cases of severe and complicated typical HUS with PNS manifestations who required therapeutic treatment and an intensive multidisciplinary neuro-rehabilitation program. In both cases, PNS manifestations were followed by the recovery from typical HUS-related severe central neurological damage and manifested mainly with marked bilateral motor deficit and hyporeflexia/areflexia in the lower limbs. The peripheral polyneuropathy was treated with immunosuppressive therapy (methylprednisolone boluses, i.v. immunoglobulins, plasma exchange), followed by a prolonged intensive neuro-rehabilitation program. After 8 months of rehabilitation, both patients gained complete functional recovery. CONCLUSIONS: PNS manifestations during typical HUS are a rare event and potentially leading to severe disability. A timely clinical assessment is mandatory to set up a prompt therapeutic and rehabilitation program and to obtain a complete clinical and functional recovery.

From Uganda to Italy: a case of nephrotic syndrome secondary to Plasmodium infection, Quartan malarial nephropathy and kidney failure.

Gentile F, Martino M, Santangelo L, Giordano P, Torres DD, Carbone V, Di Palma AM, Rossini M, Gesualdo L, Giordano P, Giordano M. From Uganda to Italy: a case of nephrotic syndrome secondary to Plasmodium infection, Quartan malarial nephropathy and kidney failure. Turk J Pediatr 2019; 61: 776-779. Malaria (M), the first parasitic infection, is sometimes associated with nephrotic syndrome (NS) in tropical areas. Kidney involvement during quartan malaria is represented by immune-complex mediated glomerulonephritis (GN). Generally, NS develops several weeks after onset of quartan fever and its clinical course proceeds slowly to end-stage kidney disease (ESKD) even after eradication of the infection. We describe a case of Plasmodium malariaeassociated nephrotic syndrome and chronic proliferative glomerulopathy in a boy from Uganda. Renal biopsy revealed chronic proliferative GN with capillary wall thickening producing a double contour, segmental sclerosis and tubular atrophy. Blood Giemsa smear contained rare ring-form trophozoites and gametocytes of Plasmodium spp. This case highlights the importance of obtaining remote travel histories from immigrants presenting with nephrotic syndrome especially due to the current immigration crisis in Europe. Malaria has low prevalence or less known in our continent and requires more medical attention by European doctors.

A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement.

BACKGROUND: Thrombotic microangiopathy (TMA) is a clinical syndrome encompassing a large group of rare but severe disorders including thrombotic thrombocytopenic purpura (TTP) and both typical and atypical forms of hemolytic uremic syndrome (HUS). The key role of the complement system is well known in TTP and atypical HUS, but recent reports describe its involvement in the pathogenesis of HUS secondary to gastrointestinal infections due to Shiga toxin-producing Escherichia coli (STEC). METHODS: TMA mainly affects the kidney, but extra-renal complications are frequently described. The involvement of the central nervous system (CNS) represents often a life-threatening condition and it can result in serious long-term disability in HUS patients who overcome the acute phase of illness. In the present study, we retrospectively analyzed a pediatric cohort of a single tertiary pediatric hospital in Southern Italy, in which this complication occurred in 12/54 children (22% of cases), of whom five with severe neurological involvement had been successfully treated with eculizumab. RESULTS: The great clinical variability of brain injury in our cohort has led us to retrospectively build a "neurological score" useful to assess the clinical severity of neurologic involvement. Subjects with higher neurologic score due to the most severe CNS involvement resulted in the group of patients early treated with eculizumab, obtaining a good clinical response (four out five patients). In conclusion, the early treatment with eculizumab in children with severe neurological involvement during STEC-HUS was associated with complete regression of both acute kidney injury (AKI) and neurological lesions observed at magnetic resonance imaging (MRI). CONCLUSIONS: A "neurological score" may be a useful tool to drive the early treatment of CNS complications in STEC-HUS with eculizumab, although future perspective controlled studies are urgently needed to validate this therapeutic approach.

Indications and results of renal biopsy in children: a 36-year experience.

BACKGROUND: This study was conducted to investigate retrospectively the indications for renal biopsy (RB) in native kidneys and to analyze pathological findings in a single tertiary pediatric hospital in Southern Italy for the last 36 years. METHODS: All patients who underwent RB at our hospital from 1979 to 2014 were included. All renal tissue specimens were studied under light and immunofluorescent microscopy, while electron microscopy was performed only for specific clinical indications. RESULTS: The study group included 213 patients (female 43.2%) who underwent 225 percutaneous native kidney biopsies. Median age was 10.4 years (range 0.6-24 years). The most frequent indication for RB was nephrotic syndrome (44.4%), followed by proteinuria (27.6%), asymptomatic hematuria (17.3%) and acute kidney injury (9.8%). Gross hematuria appeared after biopsy in less than 5% of the patients, but none of them needed blood transfusion. Adequate renal tissue sample was obtained in 95.5% of the renal biopsies. Primary glomerulonephritis (GN) was the most common finding (61.4%), followed by secondary GN (21.4%), tubulointerstitial diseases (3.7%) and hereditary nephropathy (2.8%), while in 10.7% of the cases, normal renal tissues were found. According to histopathological diagnosis, the most common causes of primary GN were IgA nephropathy (20.9%), followed by minimal change disease (18.1%) and focal segmental glomerulosclerosis (11.6%). CONCLUSIONS: The epidemiology of glomerular disease in our single-center cohort is similar to that shown in other national and international reports. Moreover, our study shows that percutaneous ultrasound-guided RB is a safe, reliable and effective technique in children.

Desmopressin acetate in percutaneous ultrasound-guided kidney biopsy: a randomized controlled trial.

BACKGROUND: Bleeding complications occur in one-third of percutaneous kidney biopsies and increase costs of the hospital stay. The aim of the study was to evaluate the effect of prebiopsy administration of desmopressin acetate versus placebo in the incidence of postbiopsy bleeding complications. STUDY DESIGN: Double-blind randomized controlled clinical trial. SETTING & PARTICIPANTS: We enrolled all patients with serum creatinine level ≤1.5 mg/dL and/or estimated glomerular filtration rate ≥60 mL/min/1.73 m(2) and normal coagulation parameters undergoing ultrasound-guided biopsy of the native kidney in our unit from August 2008 to December 2009. INTERVENTION: We examined prebiopsy subcutaneous administration of desmopressin acetate, 0.3 µg/kg, compared with placebo. OUTCOMES & MEASUREMENTS: The primary outcome was incidence of bleeding complications. Secondary outcomes were hematoma size, postbiopsy hemoglobin level, coagulation parameters, glomerular filtration rate, blood pressure, and length of hospital stay. RESULTS: 162 adult patients (88 men and 74 women) were enrolled; 80 were allocated to desmopressin treatment, and 82, to the placebo group. Desmopressin compared with placebo significantly decreased the risk of postbiopsy bleeding (11 of 80 [13.7%] vs 25 of 82 [30.5%]; relative risk, 0.45; 95% CI, 0.24-0.85; P = 0.01), hematoma size (median, 208 [25th-75th percentile, 120-300] vs 380 [25th-75th percentile, 270-570] mm(2); P = 0.006] in the 36 patients who experienced bleeding, and mean hospital stay (4.9 ± 1.1 vs 5.9 ± 1.7 days; P = 0.004); postbiopsy hemoglobin levels were not affected significantly in either group. LIMITATION: Single-center design of the study. CONCLUSIONS: Prebiopsy desmopressin administration decreases the risk of bleeding and hematoma size in patients undergoing percutaneous kidney biopsy without a cost increase.

Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common cause of chronic renal failure among primary glomerulonephritis patients. The best treatment for IgAN remains poorly defined. We planned a long-term, prospective, open-label, multicentre, centrally randomized controlled trial to assess whether the combination of prednisone and ramipril was more effective than ramipril alone in patients with proteinuric IgAN. METHODS: Ninety-seven biopsy-proven IgAN patients with moderate histologic lesions, 24-h proteinuria > or =1.0 g and estimated glomerular filtration rate (eGFR) > or = 50 ml/min/ 1.73 m(2) were randomly allocated to receive a 6-month course of oral prednisone plus ramipril (combination therapy group) or ramipril alone (monotherapy group) for the total duration of follow-up. The primary outcome was the progression of renal disease defined as the combination of doubling of baseline serum creatinine or end-stage kidney disease (ESKD). The secondary outcomes were the rate of renal function decline defined as the eGFR slope over time, and the reduction of 24-h proteinuria. RESULTS: After a follow-up of up to 96 months, 13/49 (26.5%) patients in the monotherapy group reached the primary outcome compared with 2/48 (4.2%) in the combination therapy group. The Kaplan-Meier analysis showed a significantly higher probability of not reaching the combined outcome in the combination therapy group than in the monotherapy group (85.2% versus 52.1%; log-rank test P = 0.003). In the multivariate analysis, baseline serum creatinine and 24-h proteinuria were independent predictors of the risk of primary outcome; treatment with prednisone plus ramipril significantly reduced the risk of renal disease progression (hazard ratio 0.13; 95% confidence interval 0.03-0.61; P = 0.01). The mean rate of eGFR decline was higher in the monotherapy group than in the combination therapy group (-6.17 +/- 13.3 versus -0.56 +/- 7.62 ml/min/ 1.73 m(2)/year; P = 0.013). Moreover, the combined treatment reduced 24-h proteinuria more than ramipril alone during the first 2 years. CONCLUSIONS: Our results suggest that the combination of corticosteroids and ramipril may provide additional benefits compared with ramipril alone in preventing the progression of renal disease in proteinuric IgAN patients in the long-term follow-up.

Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood. Different prevalences among ethnic groups and familial aggregation, together with an increased familial risk, suggest important genetic influences on its pathogenesis. A locus for familial IgAN, called "IGAN1," on chromosome 6q22-23 has been described, without the identification of any responsible gene. The partners of the European IgAN Consortium organized a second genomewide scan in 22 new informative Italian multiplex families. A total of 186 subjects (59 affected and 127 unaffected) were genotyped and were included in a two-stage genomewide linkage analysis. The regions 4q26-31 and 17q12-22 exhibited the strongest evidence of linkage by nonparametric analysis (best P=.0025 and .0045, respectively). These localizations were also supported by multipoint parametric analysis, in which peak LOD scores of 1.83 ( alpha =0.50) and 2.56 ( alpha =0.65) were obtained using the affected-only dominant model, and by allowance for the presence of genetic heterogeneity. Our results provide further evidence for genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, with small or moderate effects in determining the pathological phenotype. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution to familial IgAN.

Role of interferon-gamma gene polymorphisms in susceptibility to IgA nephropathy: a family-based association study.

T helper (h) lymphocytes in pathogenic immune response at mucosal effector site play a key role in IgA nephropathy (IgAN). We evaluated the impact of some Th1/Th2/Th3/T(R)-type, and of monocyte/macrophage cytokines on IgAN susceptibility with a family-based association study including 53 patients, 45 complete trios, 4 incomplete trios and 36 discordant siblings. Cytokine gene polymorphisms with a potential regulatory role on their production were investigated using the family-based association test (FBAT): IFNgamma intron-1 CA repeat at position 1349-1373; IL-13 -1055C/T; TGFbeta +915G/C; IL-10 5'-proximal and distal microsatellites; TNFalpha -308G/A, -238G/A. The FBAT multi-allelic analysis showed an association between IFNgamma polymorphism and susceptibility to IgAN (P=0.03). The bi-allelic analysis evidenced that the 13-CA repeat allele was preferentially transmitted to the affected individuals (P=0.006; Bonferroni P-value=0.04). The direct sequencing of IFNgamma amplicons showed a strict association between the 13-CA repeat allele and the A variant of the +874T/A single nucleotide polymorphism (SNP rs2430561) directly adjacent to the 5' end of the microsatellite. The in vitro production of IFNgamma evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the +874A allele and a lower production of IFNgamma (P=0.028 Mann-Whitney test). This SNP affects IFNgamma production lying within a binding site for the transcription factor NF-kappaB. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFNgamma gene polymorphisms. This first family-based association study demonstrates that the +874A allele, strictly associated with IFNgamma 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.