Ashima Gulati

Efficacy and Safety of Treatment with Rituximab for Difficult Steroid-Resistant and -Dependent Nephrotic Syndrome: Multicentric Report

BACKGROUND AND OBJECTIVES The treatment of idiopathic nephrotic syndrome is often complicated by a refractory and relapsing course, with risk of drug toxicity and progressive renal failure. We report the efficacy and safety of rituximab in patients with steroid-resistant (SRNS) and steroid-dependent nephrotic syndrome (SDNS) refractory to standard therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cohort study in academic, tertiary care centers in India and the United States. Patients with SRNS or SDNS, not responding to medications or showing calcineurin inhibitor toxicity, treated with two to four doses of intravenous rituximab, and followed ≥12 months were included. Remission was termed as complete, partial, or no response. RESULTS Thirty-three patients with SRNS (24 initial, 9 late resistance) and 24 with SDNS, with mean ages of 12.7 ± 9.1 and 11.7 ± 2.9 years, respectively, were included. Six months after rituximab therapy, 9 (27.2%) patients with SRNS showed complete remission, 7 (21.2%) had partial remission, and 17 (51.5%) had no response. At 21.5 ± 11.5 months, remission was sustained in 15 (complete: 7, partial: 8) patients. Of 24 patients with SDNS, remission was sustained in 20 (83.3%) at 12 months and in 17 (71%) at follow-up of 16.8 ± 5.9 months. The mean difference in relapses before and 12 months after treatment with rituximab was 3.9 episodes/patient per year. CONCLUSIONS Therapy with rituximab was safe and effective in inducing and maintaining remission in a significant proportion of patients with difficult SRNS and SDNS.

Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children

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.

Overall Neutralization of Complement Factor H by Autoantibodies in the Acute Phase of the Autoimmune Form of Atypical Hemolytic Uremic Syndrome

Complement is a major innate immune surveillance system. One of its most important regulators is the plasma protein factor H (FH). FH inactivation by mutations or by autoantibodies is associated with a thrombotic microangiopathy disease, atypical hemolytic uremic syndrome. In this study, we report the characterization of blood samples from 19 anti-FH Ab-positive atypical hemolytic uremic syndrome patients collected at the acute phase of the disease. Analyses of the functional consequences and epitope mapping, using both fluid phase and solid phase approaches, were performed. The anti-FH Abs perturbed FH-mediated cell protection (100%), inhibited FH interaction with C3 (46%), and caused C3 consumption (47%). The Abs were directed against multiple FH epitopes located at the N and C termini. In all tested patients, high titers of FH-containing circulating immune complexes were detected. The circulating immune complex titers correlated with the disease stage better than did the Ab titers. Our results show that anti-FH autoantibodies induce neutralization of FH at acute phase of the disease, leading to an overall impairment of several functions of FH, extending the role of autoantibodies beyond the impairment of the direct cell surface protection.

Peripheral Gangrene in Children With Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe clinical manifestation, frequent recurrence, and poor long-term prognosis. It is usually caused by abnormalities in complement regulation. We report 2 cases of children affected by a catastrophic extrarenal complication. A 4-year-old Indian girl developed gangrene of the finger tips 2 days after initial presentation of aHUS. Factor H autoantibodies were identified. Renal function continued to decline despite daily plasma exchanges, and she was started on peritoneal dialysis 5 days after admission. The distal tips of the left hand remained gangrenous with a line of demarcation. Three weeks later, she did not return for follow-up and died at home because of dialysis-related complications. An Arabic girl developed end-stage renal disease due to aHUS in the fourth month after birth. A de novo activating C3 mutation was found. At age 9 months, she suddenly developed ischemic changes in fingers of both hands and several toes. The lesions progressed, and several finger tips became gangrenous despite intense plasma exchange therapy. The decision was made to administer complement blocking therapy with the C5 antibody eculizumab. All nonnecrotic digits rapidly regained perfusion. The 3 already gangrenous fingers healed with loss of the end phalanges. During maintenance, eculizumab aHUS activity subsided completely and some late recovery of renal function was observed. aHUS may present by thrombotic macroangiopathy of small peripheral arteries. Eculizumab appears effective in preserving tissue viability if administered before gangrene occurs and should be considered as first-line rescue therapy in such cases.

Large vessel vasculitis

Takayasu arteritis is a chronic granulomatous disease of the aorta and its major branches that usually affects women during the second and third decades of life, but it has been reported in young children. This review details the clinical, pathological and radiological features, differential diagnoses and management of the condition, focusing chiefly on the disease in children. The recent definition of Takayasu arteritis is discussed. The condition should be considered in patients with unexplained arterial hypertension or unexplained inflammatory syndromes without signs of localization. Since the disease may be life-threatening and progressive, early recognition is necessary to initiate appropriate therapy. Patients with persistent ischaemic symptoms including hypertension might benefit from revascularization procedures.

Daily Corticosteroids Reduce Infection-associated Relapses in Frequently Relapsing Nephrotic Syndrome: A Randomized Controlled Trial

BACKGROUND AND OBJECTIVES Relapses of nephrotic syndrome often follow minor infections, commonly of the upper respiratory tract. Daily administration of maintenance prednisolone during intercurrent infections was examined to determine whether the treatment reduces relapse rates in children with frequently relapsing nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a randomized controlled trial (nonblind, parallel group, tertiary-care hospital), 100 patients with idiopathic, frequently relapsing nephrotic syndrome eligible for therapy with prolonged low-dose, alternate-day prednisolone with or without levamisole were randomized to either receive their usual dose of alternate-day prednisolone daily for 7 days during intercurrent infections (intervention group) or continue alternate-day prednisolone (controls). Primary outcome was assessed by comparing the rates of infection-associated relapses at 12-month follow-up. Secondary outcomes were the frequency of infections and the cumulative amount of prednisolone received in both groups. RESULTS Patients in the intervention group showed significantly lower infection-associated (rate difference, 0.7 episodes/patient per year; 95% confidence intervals [CI] 0.3, 1.1) and lower total relapse rates (0.9 episodes/patient per year, 95% CI 0.4, 1.4) without increase in steroid toxicity. Poisson regression, adjusted for occurrence of infections, showed that daily administration of prednisolone during infections independently resulted in 59% reduction in frequency of relapses (rate ratio, 0.41; 95% CI 0.3, 0.6). For every six patients receiving this intervention, one showed a reduction of relapse frequency to less than three per year. CONCLUSIONS Daily administration of maintenance doses of prednisolone, during intercurrent infections, significantly reduces relapse rates and the proportion of children with frequently relapsing nephrotic syndrome.

Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome

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.

Efficacy and safety of rituximab in children with difficult-to-treat nephrotic syndrome

BACKGROUND Rituximab has emerged as an important medication for patients with steroid-dependent or steroid-resistant nephrotic syndrome. PATIENTS We report the efficacy and safety of therapy with intravenous rituximab, administered once weekly for 2-4 doses, in 193 patients (mean age 10.9, range 2.2-18.7 years) with difficult-to-treat steroid dependence (n = 101), calcineurin inhibitor (CNI)-dependent steroid resistance (n = 34) and CNI-resistant nephrotic syndrome (n = 58) managed at this center during 2006-13. OUTCOMES Therapy in patients with steroid dependence and CNI-dependent steroid resistance led to significantly reduced relapse rates (respective mean difference 2.7 relapses/year and 2.2 relapses/year, corresponding to a decrease in relapses by 81.8 and 71.0%; both P < 0.0001). This resulted in a significant reduction in steroid requirement (mean difference 104.5 and 113.6 mg/kg/year, respectively; both P < 0.0001) and a trend to improved standard deviation scores for height (P = 0.069) and body mass index (P = 0.029). Remission was longer in patients with steroid dependence compared with CNI-dependent steroid resistance (median 16 versus 10 months; P < 0.0001). Prior response to cyclophosphamide predicted a lower risk of relapse in the former (hazard ratio, HR 0.56; P = 0.045); patients with initial resistance and CNI-dependent steroid resistance had increased risk of relapse (HR 2.66; P = 0.042). B-cell recovery, noted in 62.5% patients at 6 months, was not related to occurrence of relapse; redosing (n = 42 patients) was safe and effective. Response to therapy was unsatisfactory in patients with steroid- and CNI-resistant nephrotic syndrome, with remission in 29.3%. Focal segmental glomerulosclerosis was associated with higher odds of non-response (odds ratio 11.1; P = 0.028) and lack of response was associated with progressive chronic kidney disease (HR 9.97; P = 0.035). Therapy with rituximab was safe; adverse effects or infections were noted in 19 (9.8%) patients. CONCLUSIONS Therapy with rituximab is effective and safe in reducing relapse rates and need for immunosuppressive medications in patients with steroid-dependent and CNI-dependent steroid-resistant nephrotic syndrome.

Incidence of acute kidney injury in hospitalized children

ObjectiveTo determine the incidence and outcome of acute kidney injury (AKI) in hospitalized patients.DesignProspective, observational.SettingTertiary care center in North India.Participants/patientsInpatients, 1 month to 18-yr-old.InterventionNone.Main Outcome MeasuresIncidence of AKI based on the serum creatinine criteria proposed by the AKI Network.ResultsDuring February to September 2008, thirty nine of 108 (36.1%) critically ill patients and 34 of 378 (9.0%) patients who were not critically ill developed AKI (P <0.001); the respective incidence densities were 45.1 and 11.7 cases/1000 patient days, respectively. The maximal stage of AKI was stage 1 in 48 (65.8%) patients, stage 2 in 13 (17.8%) and stage 3 in 12 (16.4%) patients; 11 (15.1%) required dialysis. Patients with AKI had a significantly longer duration of hospital stay (9 days vs 7 days, P<0.02) and higher mortality (37% vs 8.7%; hazard ratio, HR 2.73; 95% CI 1.64, 4.54). Independent risk factors for AKI were young age (HR 0.89; 95% CI 0.83, 0.95), shock (HR 2.65; 95% CI 1.32, 5.31), sepsis (HR 3.64; 95% CI 2.20, 6.01), and need for mechanical ventilation (2.18; 95% CI 1.12, 4.26). Compared to patients without AKI, the mortality was higher for AKI stage 2 (HR 5.18; 95% CI 2.59, 10.38) and stage 3 (HR 4.34; 95% CI 2.06, 9.16). Shock was an independent risk factor for mortality (HR 10.7; 95% CI 4.96, 22.98).ConclusionsAKI is common in critically ill children, especially younger patients with septicemia and shock, and results in increased hospital stay and high mortality.

Frasier syndrome: early gonadoblastoma and cyclosporine responsiveness

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.