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Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.

Background: While patients with frequently relapsing nephrotic syndrome (FRNS) are initially treated with long-term alternate-day prednisolone, relapses and adverse effects are common. In an open-label randomized controlled trial, we compared the efficacy of therapy with low-dose daily to standard alternate-day prednisolone in reducing relapse rates over 12-month follow-up., Methods: Consecutive patients, aged 2-18 years, with FRNS were included. Following therapy of relapse, prednisolone was tapered to 0.75 mg/kg on alternate days. Stratifying for steroid dependence, patients were randomly assigned to prednisolone at 0.2-0.3 mg/kg daily or 0.5-0.7 mg/kg alternate day for 12 months. Relapses were treated with daily prednisolone, followed by return to intervention. Primary outcome was the incidence of relapses. Proportion with therapy failure (≥ 2 relapses in any 6 months or significant steroid toxicity) and sustained remission, cumulative prednisolone intake and adverse events were evaluated., Results: Patients receiving daily prednisolone (n = 30) showed significantly fewer relapses than those on alternate-day therapy (n = 31) (0.55 relapses/person-year versus 1.94 relapses/person-year; incidence rate ratio 0.28; 95% CI 0.15, 0.52). Daily therapy was associated with higher rates of sustained remission at 6 months (73.3 versus 48.4%) and 1 year (60 versus 31.6%; log rank p = 0.013), lower rates of treatment failure at 6 months (3.3 versus 32.8%) and 1 year (6.7 versus 57.4%; p < 0.0001), and lower prednisolone use (0.27 ± 0.07 versus 0.39 ± 0.19 mg/kg/day; p = 0.003). Three and two patients need to receive the study intervention to enable sustained remission and prevent treatment failure, respectively., Conclusions: In patients with FRNS, daily administration of low-dose prednisolone is more effective than standard-dose alternate day therapy in lowering relapse rates, sustaining remission, and enabling steroid sparing.

Both levamisole and mycophenolate mofetil (MMF) prevent relapses in patients with frequently relapsing nephrotic syndrome; however, their efficacy has not been compared prospectively. This single-center, randomized, open-label trial enrolled 149 children ages 6-18 years with frequently relapsing or steroid-dependent nephrotic syndrome. Participants were randomized in a 1:1 ratio to receive therapy with MMF (750-1000 mg/m 2 daily) or levamisole (2-2.5 mg/kg on alternate days) for 1 year; prednisolone was discontinued by 2-3 months. In intention-to-treat analyses, the frequency of relapse was similar between participants treated with MMF and levamisole (mean difference -0.29 relapses/patient-year; 95% confidence interval -0.65, 0.08). Relapse rates declined to almost one-third of baseline for both treatment groups. Therapy with MMF was not superior to levamisole in terms of the proportions of participants with sustained remission (40.8% vs. 34.2%), frequent relapses (14.5% vs. 16.4%), or treatment failure, a composite outcome of frequent relapses, steroid resistance, or significant steroid toxicity (15.8% vs. 20.6%). These outcomes were also similar in time to event analyses. Changes in anthropometry and blood pressure were similar between the groups, and the rates of adverse effects were low in both groups. Flow cytometry in 32 participants demonstrated similar proportions of B cells and CD4+, CD8+, T helper (Th)1, Th2, Th17, and T regulatory (Treg) cells during follow-up. Therapy with MMF was not superior to levamisole in the frequency of relapses, likelihood of sustained remission or corticosteroid sparing in children with frequently relapsing or steroid-dependent nephrotic syndrome. Registration CTRI/2012/02/002394., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Studies of nephrotic syndrome show that substitution of calcineurin inhibitors by mycophenolate mofetil (MMF) enables sustained remission and corticosteroid sparing and avoids therapy associated adverse effects. However, controlled studies in patients with steroid resistance are lacking. Here we examined the effect of switching from therapy with tacrolimus to MMF on disease course in an open-label, one-to-one randomized, controlled trial on children (one to 18 years old), recently diagnosed with steroid-resistant nephrotic syndrome, at a referral center in India. Following six months of therapy with tacrolimus, patients with complete or partial remission were randomly assigned such that 29 received MMF while 31 received tacrolimus along with tapering prednisolone on alternate days for 12 months. On intention-to-treat analyses, the proportion of patients with a favorable outcome (sustained remission, infrequent relapses) at one year was significantly lower (44.8%) in the MMF group than in the tacrolimus group (90.3%). The incidence of relapses was significantly higher for patients treated with MMF than tacrolimus (mean difference: 1.05 relapses per person-year). While there was no difference in the proportion of patients with sustained remission, the risk of recurrence of steroid resistance was significantly higher for patients receiving MMF compared to tacrolimus (mean difference: 20.7%). Compared to tacrolimus, patients receiving MMF had a significantly (71%) lower likelihood of a favorable outcome and significantly increased risk of treatment failure (frequent relapses, steroid resistance). Thus, replacing tacrolimus with MMF after six months of tacrolimus therapy for steroid-resistant nephrotic syndrome in children is associated with significant risk of frequent relapses or recurrence of resistance. These findings have implications for guiding the duration of therapy with tacrolimus for steroid-resistant nephrotic syndrome., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Desensitization with IVIG + rituximab combined with alemtuzumab induction gives HLA-sensitized patients an opportunity for successful kidney transplantation. However, it may be associated with a high risk for viral infections due to combined T cell and B cell depletion., Methods: Anti-cytomegalovirus (CMV) activity was assessed in 280 pretransplant and posttransplant blood samples from 33 desensitized patients who received alemtuzumab induction. CMV-specific CD8+ (CMV-Tc), CD4+ (CMV-Th) T cell activity, and natural killer (NK) cell number were measured by flow cytometry. Anti-CMV IgG was measured by enzyme-linked immunosorbent assay, and CMV DNA by polymerase chain reaction., Results: All 30 CMV sero (+) patients were (+) for CMV-Tc and/or Th predesensitization, while 3 sero (-) patients showed no CMV-T cell activity. CMV-Tc and/or Th became (-) in 50% to 70% of these sero (+) patients at 1 month post-alemtuzumab. However, 75% showed CMV-T cell (+) by 2 months and 95% did so by 3 months post-alemtuzumab. More than 50% of pretranslpant NK cell levels were detected post-alemtuzumab. Anti-CMV IgG levels did not decrease posttransplant in sero (+) patients. Four patients developed CMV viremia with clearance by 1.2 months, which correlated with an increase or appearance of CMV-T cells, even in the sero (-) patient., Conclusions: CMV-T cell activity, anti-CMV IgG, and NK cell-mediated antibody-dependent cell cytotoxicity were present in aleumtuzumab-treated CMV sero (+) patients. One sero (-) patient developed CMV-T cell responses post-CMV viremia. These results suggest that the IVIG + rituximab desensitization combined with alemtuzmab induction with triple immunosuppression maintenance does not result in prolonged suppression of anti-CMV immunity or increased risk for CMV infection.

Background: Desensitization with intravenous immunoglobulin and rituximab (I+R) significantly improves transplant rates in highly sensitized patients, but antibody-mediated rejection (ABMR) remains a concern., Patients and Methods: Between July 2006 and December 2012, 226 highly sensitized patients received transplants after desensitization. Most received alemtuzumab induction and standard immunosuppression. Two groups were examined: ABMR (n = 181) and ABMR (n = 45, 20%). Risk factors for ABMR, pathology, and outcomes were assessed., Results: Significant risks for ABMR included previous transplants and pregnancies as sensitizing events, donor-specific antibody (DSA) relative intensity scores greater than 17, presence of both class I and II DSAs at transplant and time on waitlist. The ABMR showed a significant benefit for graft survival and glomerular filtration rate at 5 years (P < 0.0001). Banff pathology characteristics for ABMR patients with or without graft loss did not differ. C4d versus C4d ABMR did not predict graft loss (P = 0.086). Thrombotic microangiopathy (TMA) significantly predicted graft failure (P = 0.045). The ABMR episodes were treated with I+R (n = 25), or, in more severe ABMR, plasma exchange (PLEX)+I+R (n = 20). Graft survival for patients treated with I+R was superior (P = 0.028). Increased mortality was seen in ABMR patients experiencing graft loss after ABMR treatment (P = 0.004). The PLEX + Eculizumab improved graft survival for TMA patients (P = 0.036)., Conclusion: Patients desensitized with I+R who remain ABMR have long-term graft and patient survival. The ABMR patients have significantly reduced graft survival and glomerular filtration rate at 5 years, especially TMA. Severe ABMR episodes benefit from treatment with PLEX + Eculizumab. The DSA-relative intensity scores at transplant was a strong predictor of ABMR. Donor-specific antibody avoidance and reduction strategies before transplantation are critical to avoiding ABMR and improving long-term outcomes.

Calcineurin inhibitors (CNIs) are effective immunosuppressive agents for the successful treatment of childhood steroid-resistant nephrotic syndrome (SRNS). Because these patients require long-term treatment, the identification of early markers of CNI-induced nephrotoxicity (CNIN) is imperative. The monitoring of CNI trough levels, serum creatinine, and glomerular filtration rate is not an accurate marker of CNIN. The present study has been undertaken to identify early markers of CNIN in SRNS patients. Twenty-four pediatric SRNS patients were included with paired renal biopsies, before initiation (time zero biopsy) and at least 1 year after CNI therapy (protocol renal biopsy) with standard dosage. Semiquantitative morphologic grading of the histologic features was done for assessing CNIN. Immunohistochemical markers for oxidative stress (nitrotyrosine [NT]), fibrogenic cytokine (transforming growth factor β1 [TGF-β1]), and endothelial injury (endothelial nitric oxide synthase [eNOS]) were evaluated. In addition, ultrastructural study was done to assess mitochondrial injury in endothelial and tubular epithelial cells. The protocol renal biopsies in comparison with time zero biopsies showed significant increase in glomerulosclerosis, juxtaglomerular apparatus hyperplasia, tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and smooth muscle vacuolization (P < .05 - P < .001). Significantly higher immunoexpression of eNOS (91.6%), NT (71%), and TGF-β1 (87.5%) was noted in posttreatment biopsies. Mean mitochondrial injury grade among post-CNI cases in endothelial cells and proximal tubular cells was 2.28 and 1.4, whereas in pre-CNI, it was 0.28 and 0.27, respectively. We propose that immunohistochemical overexpression of NT, eNOS, and TGF-β1 is an early marker of CNIN. Endothelial and proximal tubular mitochondrial injury may play an important role in the pathogenesis of CNIN., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Atypical hemolytic uremic syndrome associated with autoantibodies to complement factor H is an important cause of acute kidney injury; most patients require dialysis and are at risk of progressive renal failure., Case Characteristics: 7 patients with gastrointestinal symptoms, acute kidney injury, thrombotic microangiopathy and elevated levels of anti-complement factor H antibodies., Intervention: Prompt initiation of plasma exchanges and immunosuppression., Outcome: Remission of hematological and kidney functions., Message: Prompt and specific management of antibody associated hemolytic uremic syndrome is associated with favorable outcome.

Antibodies to complement factor H are an uncommon cause of hemolytic uremic syndrome (HUS). Information on clinical features and outcomes in children is limited. In order to explore this we studied a multicenter cohort of 138 Indian children with anti-complement factor H antibody associated HUS, constituting 56% of patients with HUS. Antibody titers were high (mean 7054 AU/ml) and correlated inversely with levels of complement C3, but not complement factor H. Homozygous deletion of the CFHR1 gene was found in 60 of 68 patients. Therapies included dialysis in 119 children, 105 receiving plasma exchanges and 26 intravenous immunoglobulin. Induction immunosuppression consisted of 87 children receiving prednisolone with or without intravenous cyclophosphamide or rituximab. Antibody titers fell significantly following plasma exchanges and increased during relapses. Adverse outcome (stage 4-5 CKD or death) was seen in 36 at 3 months and 41 by last follow up, with relapse in 14 of 122 available children. Significant independent risk factors for adverse outcome were an antibody titer over 8000 AU/ml, low C3 and delay in plasma exchange. Combined plasma exchanges and induction immunosuppression resulted in significantly improved renal survival: one adverse outcome prevented for every 2.6 patients treated. Maintenance immunosuppressive therapy, of prednisolone with either mycophenolate mofetil or azathioprine, significantly reduced the risk of relapses. Thus, prompt use of immunosuppressive agents and plasma exchanges are useful for improving outcomes in pediatric patients with anti-complement factor H-associated HUS.

There are limited data on the relative efficacy and safety of calcineurin inhibitors and alkylating agents for idiopathic steroid-resistant nephrotic syndrome in children. To clarify this, we compared tacrolimus and intravenous cyclophosphamide therapy in a multicenter, randomized, controlled trial of 131 consecutive pediatric patients with minimal change disease, focal segmental glomerulosclerosis, or mesangioproliferative glomerulonephritis, stratified for initial or late steroid resistance. Patients were randomized to receive tacrolimus for 12 months or 6-monthly infusions of intravenous cyclophosphamide with both arms receiving equal amounts of alternate-day prednisolone. The primary outcome of complete or partial remission at 6 months, based on spot urine protein to creatinine ratios, was significantly higher in children receiving tacrolimus compared to cyclophosphamide (hazard ratio 2.64). Complete remission was significantly higher with tacrolimus (52.4%) than with cyclophosphamide (14.8%). The secondary outcome of sustained remission or steroid-sensitive relapse of nephrotic syndrome at 12 months was significantly higher with tacrolimus than cyclophosphamide. Treatment withdrawal was higher with cyclophosphamide, chiefly due to systemic infections. Compared to cyclophosphamide, 3 patients required treatment with tacrolimus to achieve 1 additional remission. Thus, tacrolimus and prednisolone are effective, safe, and preferable to cyclophosphamide as the initial therapy for patients with steroid-resistant nephrotic syndrome.

Although therapy with intravenous (IV) rituximab and tacrolimus reduces the relapse rate in steroid-dependent nephrotic syndrome (SDNS), studies on comparative efficacy are lacking. We retrospectively reviewed the records of patients with difficult-to-treat SDNS who had previously received levamisole, cyclophosphamide and/or mycophenolate mofetil, then treated with either rituximab or tacrolimus and followed for 12 months. Between January 2009 and April 2010, ten patients received two to three doses of IV rituximab (375 mg/m(2)/week) and 13 received tacrolimus (0.1-0.2 mg/kg/day) for 12 months; none had previously received either agent. Patients received tapering doses of alternate-day prednisolone; other immunosuppressive agents were discontinued. The mean age of the patients at treatment initiation with rituximab and tacrolimus was 12.2 ± 2.3 and 12.3 ± 3.0 years, respectively. The respective pre-treatment relapse rates (3.1 ± 1.1 and 3.5 ± 1.6 relapses per year) and cumulative prednisolone dose (137.2 ± 69.4 and 140.5 ± 59.0 mg/kg/year) were similar. Therapy resulted in a decline in relapse rate in both groups (P < 0.001). The number of relapses in the rituximab and tacrolimus groups was similar at 6 months (0.3 ± 0.5 vs. 0.3 ± 0.6 episodes, respectively), 12 months (0.8 ± 1.0 vs. 0.9 ± 1.1 episodes) and last follow-up (1.2 ± 1.0 vs. 1.5 ± 1.3 episodes). There were no differences in relapse-free survival at 6, 12 and 18 months. Therapy resulted in a significant decline in the cumulative prednisolone dose (67.2% in the rituximab group and 43.6% in the tacrolimus group) and a reduced body mass index. These findings suggest that in our patients with difficult-to-treat SDNS, treatment with two to three doses of rituximab was as effective as 12 months of therapy with tacrolimus in terms of steroid sparing and reduction in the relapse rate.

Frasier syndrome is characterized by progressive glomerulopathy that is unresponsive to corticosteroids, male pseudohermaphroditism, and an increased risk of genitourinary tumors. Of 21 girls with steroid-resistant nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS) who were screened for mutations in the WT1 gene, two showed Frasier syndrome. Both patients had donor splice-site mutations in intron 9 of the WT1 gene and a male karyotype (46, XY). Long-term therapy with cyclosporine resulted in partial remission in both cases. One patient showed foci of gonadoblastoma in the excised dysgenetic gonads. This report highlights the need for screening for mutations in the WT1 gene in girls with steroid-resistant FSGS. Patients with Frasier syndrome might benefit from early gonadectomy.

Background: Hemolytic uremic syndrome (HUS) is a leading cause of acute kidney injury in children. Although international guidelines emphasize comprehensive evaluation and treatment with eculizumab, access to diagnostic and therapeutic facilities is limited in most developing countries. The burden of Shiga toxin-associated HUS in India is unclear; school-going children show high prevalence of anti-factor H (FH) antibodies. The aim of the consensus meeting was to formulate guidelines for the diagnosis and management of HUS in children, specific to the needs of the country. Methods: Four workgroups performed literature review and graded research studies addressing (i) investigations, biopsy, genetics, and differential diagnosis; (ii) Shiga toxin, pneumococcal, and infection-associated HUS; (iii) atypical HUS; and (iv) complement blockade. Consensus statements developed by the workgroups were discussed during a consensus meeting in March 2017. Results: An algorithm for classification and evaluation was developed. The management of Shiga toxin-associated HUS is supportive; prompt plasma exchanges (PEX) is the chief therapy in patients with atypical HUS. Experts recommend that patients with anti-FH-associated HUS be managed with a combination of PEX and immunosuppressive medications. Indications for eculizumab include incomplete remission with plasma therapy, life-threatening features, complications of PEX or vascular access, inherited defects in complement regulation, and recurrence of HUS in allografts. Priorities for capacity building in regional and national laboratories are highlighted. Conclusions: Limited diagnostic capabilities and lack of access to eculizumab prevent the implementation of international guidelines for HUS in most developing countries. We propose practice guidelines for India, which will perhaps be applicable to other developing countries. [ABSTRACT FROM AUTHOR]

Background: Anti-complement factor H (anti-CFH) antibody-associated hemolytic uremic syndrome (HUS) is an important cause of acute kidney injury in Indian children. While management comprises plasma exchange and immunosuppression, information on the impact on serial antibody titers and outcomes is limited. Methods: This retrospective study included 45 patients with anti-CFH-associated HUS who were followed for ≥12 months. Following the initial plasma exchange sessions, patients received prednisolone and either intravenous (IV) cyclophosphamide ( n = 31) or IV rituximab ( n = 14), followed by maintenance immunosuppression. Results: The median anti-CFH antibody titers fell from 3,215.5 [interquartile range (IQR) 1,977.9-8,453.9 to 414.6 (IQR 251.6-1,368.2) AU/ml with plasma exchange therapy ( P < 0.0001), and the decline was similar with three, five, or seven plasma exchange sessions ( P = 0.08). Serial anti-CFH titers were similar in patients receiving IV cyclophosphamide- and rituximab-based regimens during the 12-month follow-up ( P = 0.63). Renal outcomes and relapse frequencies at the 15.4-month follow-up were comparable. Seven patients relapsed 6.5 (IQR 2.2-12.3) months from treatment onset. Patients with relapse had higher antibody titers during remission ( P = 0.017). Titers of ≥1,300 AU/ml at 6 months predicted subsequent relapses. Conclusions: Our patients with anti-CFH antibody-associated HUS showed a significant fall in antibody titers following daily plasma exchange sessions. Therapy with cyclophosphamide- or rituximab-based regimens was associated with similar outcomes and a comparable decline in antibody titers. [ABSTRACT FROM AUTHOR]

Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. The best outcomes are seen in patients with steroid-dependent nephrotic syndrome who have failed to respond to multiple therapies. By contrast, the benefits of rituximab therapy are limited in patients with steroid-resistant nephrotic syndrome, particularly those with focal segmental glomerulosclerosis (FSGS). Therapy with plasma exchange and one or two doses of rituximab has shown success in patients with recurrent FSGS. Young patients and those with normal serum albumin at recurrence of nephrotic syndrome are most likely to respond to rituximab therapy. A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A2 receptor autoantibodies, which are implicated in the pathogenesis of this disorder. Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events. However, the available evidence of efficacy of rituximab therapy is derived chiefly from small case series and requires confirmation in prospective, randomized, controlled studies that define the indications for use and predictors of response to this therapy. [ABSTRACT FROM AUTHOR]

C1q nephropathy is a rare idiopathic glomerulopathy characterized by mesangial deposition of immunoglobulin and complement with C1q dominance or co-dominance, and the absence of clinical and laboratory evidence of systemic lupus erythematosus. Its clinical course is unpredictable and the response to corticosteroid or cytotoxic treatment is variable. Here, we report two cases of C1q nephropathy, one in a child and one in an adult, both presenting with impaired renal function and massive proteinuria. Both patients failed to respond to immunosuppressive medications; however, rituximab, an anti-CD20 antibody, was effective in preserving renal function in one patient and eliminating the need for hemodialysis in the other. In one patient, histologic regression of abnormalities was documented over 3 years post-treatment. Both patients have remained off other immunosuppressive medication for a prolonged period with stable renal function. These cases are, to our knowledge, the first reported successful treatment of C1q nephropathy with rituximab. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Successful treatment of DEAP-HUS with eculizumab" by D. Noone and colleagues in a 2013 issue.