Rajendra N. Srivastava

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.

Hemolytic uremic syndrome in children in northern India

We observed 73 patients with the hemolytic uremic syndrome (HUS) in 9 years (1980–1988), comprising 34% of patients with acute renal failure treated over the same period. There were 53 boys and 20 girls; 59% were below the age of 2 years and 33% between 2 and 5 years. Acute, usually severe dysentery, responding poorly to various antibiotics, was the prodromal illness in 80%, whereas 12% had watery diarrhea. Most patients had severe renal involvement with anuria in 56% and oliguria in 30%. A polymorphonuclear leukocytosis was present in 85% of cases, but had no correlation with the highest levels of blood urea. Coagulation abnormalities suggesting consumption coagulopathy were found in 24 of 30 cases. The results of stool culture showedShigella species in 7 cases and nontyphoidalSalmonella in 9.Escherichia coli were isolated in 11 cases, but were not further characterized. Renal biopsy showed total or patchy cortical necrosis in 20 of 50 cases. The patients were managed with supportive care, including transfusion of fresh blood or plasma and dialysis as required. The mortality was 60%, being chiefly related to the duration of renal failure and presence of renal cortical necrosis, whereas persistent dysentery and infections were complicating factors. The presence of convulsions and coagulation defects had no relation to the outcome. Our observations indicate that HUS in children in northern India is mostly related to dysentery, likely to be shigellosis, and is usually associated with severe renal damage and a high death rate.

Pulse corticosteroid therapy with methylprednisolone or dexamethasone

Intravenous pulse steroid therapy consists of administration of supraphysiological doses of glucocorticoids. It is useful in conditions where rapid immunosuppression and antiinflammatory effect is desired, as in systemic lupus erythematosus, pemphigus, renal transplantation, steroid resistant nephrotic syndrome and crescentic glomerulonephritis. This therapy may be associated with significant adverse reactions including hypertension, arrhythmias, hypokalemia, psychosis and infections. High dose steroid therapy should therefore be used in selected cases and under careful supervision. The drug most widely used for this treatment is methylprednisolone. However, in view of its easy availability and cost, dexamethasone has been often used in India for the above conditions. While there are no controlled studies comparing the two drugs, it appears that the two drugs may be similar in efficacy. Patients requiring high dose intravenous steroid therapy may be treated effectively with either methylprednisolone or dexamethasone.

Aetiology of nephrolithiasis in north Indian children

The aetiology of nephrolithiasis was investigated in 32 north Indian children (25 boys, 7 girls, mean age 7.9±3.3 years). An underlying disorder was detected in 16 (50%) patients and included idiopathic hypercalciuria (8 patients), hyperoxaluria (3 patients) and renal tubular acidosis, primary hyperparathyroidism and hyperuricosuria (1 patient each). Magnesium ammonium phosphate calculi were found in 2 patients with recurrent urinary tract infections, 1 of whom had a duplex pelvic collecting system. In 16 patients (50%) a cause for renal calculi was not identified. Our findings suggest that an underlying disorder is present in a large proportion of children with nephrolithiasis where appropriate treatment may be beneficial.

Crescentic glomerulonephritis in children: a review of 43 cases.

Forty-three children with crescentic glomerulonephritis (GN), having large crescents in more than 50% of the glomeruli, were observed during a period of 22 years. There were 17 boys and 26 girls between the ages of 3.5 and 14 years (mean 8.7 +/- 2.6). Thirty-one patients (72%) presented with acute nephritic features and increasing renal insufficiency (rapidly progressive GN) whereas 12 had an insidious onset with nephrotic syndrome, or rarely with nonspecific symptoms. Eleven patients had evidence of poststreptococcal GN and 6 an underlying systemic disorder. Renal biopsy showed large crescents in greater than 80% of the glomeruli in 38 cases (100% in 28) which were predominantly fibrocellular or fibrous in 80% of the patients. Nineteen patients (44%) were treated with prednisolone, cyclophosphamide and dipyridamole; in addition, 8 were also given anticoagulants. Six patients received pulse doses of corticosteroids. In 23 patients, there was inexorable progression of renal failure, 14 showed partial improvement but subsequently had varying degrees of renal insufficiency and in 6, there was recovery of renal function with normal levels of serum creatinine. Of the latter, 4 had received immunosuppressive anticoagulant therapy and 2 only supportive care. Of 11 patients with poststreptococcal crescentic GN, 7 progressed to end-stage renal disease and 2 developed chronic renal insufficiency. Our findings confirm the poor outcome of crescentic GN in children, irrespective of the underlying etiology. In a small proportion of cases, the disorder may have an insidious onset and a slowly progressive course, but an equally grave prognosis.

Late resistance to corticosteroids in nephrotic syndrome

Corticosteroid resistance appeared late in the course of relapsing nephrotic syndrome in 12 patients who previously had steroid-sensitive relapses for 0.8 to 13 years. In 11 patients, renal histology performed earlier in the course of the disease showed minimal change in eight, mesangial proliferative glomerulonephritis (MesPGN) in two, and focal segmental glomerulosclerosis (FSGS) in one. Renal biopsy in another patient and a repeat procedure in four of eight patients who initially showed minimal change was done after they had developed steroid resistance, and showed FSGS. Cyclophosphamide was given to 11 patients after they became steroid resistant, and induced remission in eight that continued for 1 to 2 years in two patients. The other six had relapses that were steroid sensitive, but three of them (two with FSGS and one with MesPGN) later became resistant to steroids as well as to cyclophosphamide. Of six patients with FSGS, four with initial or subsequent resistance to cyclophosphamide eventually developed renal insufficiency. The other two have remained in remission for 12 to 16 years; one of these did not receive cyclophosphamide. Our observations suggest that patients with late steroid resistance comprise a heterogeneous group; those with FSGS and resistance to cyclophosphamide therapy may have a poor outcome.

Long-term, low-dose prednisolone therapy in frequently relapsing nephrotic syndrome

The efficacy of daily administration of a small dose of prednisolone was examined in 21 patients with corticosteroid-responsive, frequently relapsing nephrotic syndrome (FRNS). After induction of remission of a third or subsequent relapse with a 6-week course of prednisolone (standard therapy with prednisolone, STP), this drug was continued in a single daily dose of 0.25 mg/kg body weight (low-dose prednisolone, LDP) for 18 months. Relapses occurring during this period were treated with STP, following which LDP therapy was resumed. The historical controls comprised 14 patients with FRNS in whom relapses were treated with STP and who were observed over a minimum period of 30 months. The two groups were comparable for age at the onset of nephrotic syndrome and sex. Twenty patients completed LDP therapy, during which 12 had no relapse, 6 had infrequent and 2 frequent relapses (1 patient became steroid dependent and was taken off LDP). Twelve patients were followed for 12–42 months after stoppage of LDP during this period 7 had no relapse, 4 had infrequent relapses and 1 showed steroid dependence. The number of relapses during LDP therapy (0.5/patient per year) was significantly less (P<0.001) than in the preceding 12 months (3.62/patient per year), and continued to remain low during the following 12 months (0.6/patient per year). Whereas the frequency of relapses in the LDP group was similar to that in the historical control group in the 1st year of comparison, it was significantly less during LDP therapy (0.5/patient per year versus 2.25/patient per year). No side effects were observed in patients on the LDP regimen, at the end of which the height percentiles improved in 6 patients and remained unchanged in 14. Our observations indicate that long-term therapy with a small daily dose of prednisolone can significantly reduce the number of relapses in patients with FRNS, and that the beneficial effect may continue even after its stoppage.

Neonatal renal failure due to obstructive candidal bezoars

Abstract. Acute renal failure (ARF) developed in a 7-week-old infant due to bilateral candidal bezoars (fungal balls) causing obstruction at the pelviureteric junction. The baby was born at term with an appropriate birthweight, and had been treated with broad-spectrum antibiotics for respiratory distress and septicemia during the 1st week of life. Recovery from ARF followed renal decompression with bilateral nephrostomy tube placement and parenteral administration of amphotericin B and 5-flucytosine.

Renal tubular acidosis preceding systemic lupus erythematosus.

A 10-year-old girl with distal renal tubular acidosis (RTA) for 4 years (adequately treated for 3 years) developed clinical features suggesting systemic lupus erythematosus (SLE) with supprotive laboratory evidence. Whe had heavy proteinuria and a decreased creatinine clearance (CCr). Renal biopsy showed diffuse proliferative and sclerosing glomerulonephritis with severe tubulointerstitial changes. Following treatment with corticosteroids and cyclophosphamide, she had a clinical remission, an increase inCcr and recovery from systemic acidosis. It is likely that distal RTA in this patient was a manifestation of SLE.

Disease course in steroid sensitive nephrotic syndrome

ObjectiveTo review the disease course in patients with steroid sensitive nephrotic syndrome (SSNS) and the factors that determine outcomeDesignRetrospective, analyticalSettingPediatric Nephrology Clinic at referral center in North IndiaParticipants/patientsAll patients with SSNS evaluated between 1990 and 2005InterventionNoneMain outcome measuresDisease course, in patients with at least 1-yr follow up, was categorized as none or infrequent relapses (IFR), frequent relapses or steroid dependence (FR), and late resistance. Details on complications and therapy with alternative agents were recorded.ResultsRecords of 2603 patients (74.8% boys) were reviewed. The mean age at onset of illness and at evaluation was 49.7±34.6 and 67.5±37.9 months respectively. The disease course at 1-yr (n=1071) was categorized as IFR in 37.4%, FR in 56.8% and late resistance in 5.9%. During follow up, 224 patients had 249 episodes of serious infections. Alternative medications for frequent relapses (n=501; 46.8%) were chiefly cyclophosphamide and levamisole. Compared to IFR, patients with FR were younger (54.9±36.0 vs. 43.3±31.4 months), fewer had received adequate (≥8 weeks) initial treatment (86.8% vs. 81.7%) and had shorter initial remission (7.5±8.6 vs. 3.1±4.8 months) (all P<0.001). At follow up of 56.0±42.6 months, 77.3% patients were in remission or had IFR, and 17.3% had FR.ConclusionsA high proportion of patients with SSNS show frequent relapses, risk factors for which were an early age at onset, inadequate initial therapy and an early relapse.