Lupus Nephritis in Indian Children: Flares and Refractory Illness

Objective: To evaluate the incidence of flares and treatment resistance in children with lupusnephritis and their association with renal outcomes. Methods: We retrospectively reviewedthe case records of 34 children treated for lupus nephritis (Class II-IV) at a single center.Patients were followed for a minimum of five years to evaluate treatment response, onset offlares, and renal survival. Regression analyses were performed to identify the factorsassociated with treatment refractoriness, incidence of flares and renal survival. Results: Theincidence of flares was 0.16 episodes/person/year. Eight patients (23.5%) were refractory totreatment. The five-year renal survival was 79%. Multiple episodes of flares (P=0.028) andtherapy refractoriness (P=0.003) were associated with poor renal survival. Conclusions:Prevention and aggressive management of renal flares is expected to prevent progression toend stage renal disease in lupus nephritis.

Phenotype of Dent Disease in a Cohort of Indian Children.

Objective: To describe the clinical and genotypic features of Dent disease in children diagnosed at our center over a period of 10 years. Design: Case series. Setting: Pediatric Nephrology Clinic at a referral center in Northern India. Methods: The medical records of patients with Dent disease diagnosed and followed up at this hospital from June 2005 to April 2015 were reviewed. The diagnosis of Dent disease was based on presence of all three of the following: (i) low molecular weight proteinuria, (ii) hypercalciuria and (iii) one of the following: nephrolithiasis, hematuria, hypophosphatemia or renal insufficiency, with or without mutation in CLCN5 or OCRL1 genes. Results: The phenotype in 18 patients diagnosed with Dent disease during this period was characterized by early age at onset (median 1.8 y), and polyuria, polydipsia, salt craving, hypophosphatemic rickets and night blindness. Rickets was associated with severe deformities, fractures or loss of ambulation in six patients. Nephrocalcinosis was present in three patients, while none had nephrolithiasis. Generalized aminoaciduria was seen in 13 patients, two had glucosuria alone, and one had features of Fanconi syndrome. Over a median follow up of 2.7 years, one patient developed renal failure. Genetic testing (n=15) revealed 5 missense mutations and 3 nonsense mutations in CLCN5 in 13 patients. Five of these variations (p.Met504Lys, p.Trp58Cys, p.Leu729X, p.Glu527Gln and p.Gly57Arg) have not been reported outside the Indian subcontinent. Conclusion: Our findings suggest a severe phenotype in a cohort of Indian patients with Dent disease.

Plasma Exchanges and Immunosuppression for Anti-complement Factor H Associated Hemolytic Uremic Syndrome.

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.

Cystatin C-based Glomerular Filtration Rate Estimating Equations in Early Chronic Kidney Disease.

Objective: To Compare performance of combined creatinine and cystatin C-based equation with equations based on either cystatin C or creatinine alone, in early chronic kidney disease. Design: Diagnostic accuracy study. Setting: Tertiary-care hospital. Patients: One hundred children with chronic kidney disease who underwent 99mTc diethylenetriamine pentaacetic acid (DTPA) glomerular filtration rate measurement. Methods: Estimating equations for glomerular filtration rate (GFR) based on serum cystatin C alone and in combination with serum creatinine were generated using regression analyses. These equations and the creatinine-based equation [0.42 x height/creatinine] were validated in 42 children with glomerular filteration rate between 60 and 90 mL/min/1.73 m2. Bias, precision and accuracy of estimating equations using DTPA glomerular filteration rate as gold standard. Results: Cystatin C-based equation (GFR=96.9 - 30.4 x cystatin) overestimated while the combined cystatin C-and creatininebased equation [GFR=11.45 x (height/creatinine) 0.356 x (1/ cystatin) 0.188] underestimated the measured GFR. Cystatin Cbased equation had less bias (1.9 vs. 12.4 ml/min/1.73 m2), and higher precision (13.1 vs. 25.6 mL/min/1.73 m2) and accuracy (92.1% vs. 75.7%) than creatinine-based equation. The combined cystatin C and creatinine equation had bias (-1.4 mL/ min/1.73 m2) precision (15.2 mL/min/1.73 m2) and accuracy (91.2%) similar to cystatin C-based equation. Conclusions: Cystatin C-based equation has a better performance in estimating glomerular filtration rate than creatinine-based equation in children with early chronic kidney disease. Addition of creatinine equation does not improve the performance of the cystatin C-based equation.

Effect of Enalapril on Glomerular Filtration Rate and Proteinuria in Children with Chronic Kidney Disease: A Randomized Controlled Trial.

Objective: To evaluate the efficacy of enalapril treatment on decline in glomerular filtration rate and reduction in proteinuria in children with chronic kidney disease (CKD). Design: Open-label, randomized controlled trial. Setting: Pediatric nephrology clinic at a tertiary-care referral hospital. Intervention: Children with GFR between 15-60 mL/min/1.73 m2 were randomized to receive either enalapril at 0.4 mg/kg /day or no enalapril for 1 year. Outcome measures: Change in GFR using 99mTc-DTPA and urine protein to creatinine ratio. Secondary outcomes included occurrence of composite outcome (30% decline in GFR or end stage renal disease) and systolic and diastolic blood pressure SDS during the study period. Results: 41 children were randomized into two groups; 20 received enalapril while 21 did not receive enalapril. During 1 year, GFR decline was not different in the two groups (regression coefficient (r) 0.40, 95% CI -4.29 to 5.09, P=0.86). The mean proteinuria reduction was 65% in the enalapril group, significantly higher than control group. The difference was significant even after adjustment for blood pressure was 198.5 (CI 97.5, 299.3; P<0.001). 3 (17.6%) patients in enalapril and 7 (36.8%) in nonenalapril group attained the composite outcome. Conclusions: Enalapril is effective in reducing proteinuria in children with CKD and might be renoprotective in proteinuric CKD.

Etiology and Outcome of Crescentic Glomerulonephritis.

Objective: To determine the etiology, course and predictors of outcome in children with crescentic glomerulonephritis (GN). Study design: Retrospective, descriptive study. Setting: Pediatric Nephrology Clinic at a referral center in Northern India. Methods: Clinic records of patients aged <18 year with crescentic GN diagnosed from 2001-2010 and followed at least 12-months were reviewed. Crescentic GN, defined as crescents in ≥50% glomeruli, was classified based on immunofluorescence findings and serology. Risk factors for renal loss (chronic kidney disease stage 4-5) were determined. Results: Of 36 patients, (median age 10 yr) 17 had immune complex GN and 19 had pauci-immune crescentic GN. The etiologies of the former were lupus nephritis (n=4), postinfectious GN (3), and IgA nephropathy, Henoch Schonlein purpura and membranoproliferative GN type II (2 each). Three patients with pauci-immune GN showed antineutrophil cytoplasmic antibodies (ANCA). Rapidly progressive GN was present in 33 patients, and required dialysis in 12. At median 34 (19-72) months, 2 patients with immune complex GN and 8 with pauci-immune GN showed renal loss. Renal survival was 94.1% at 3 yr, and 75.3% at 8 yr in immune complex GN; in pauci-immune GN survival was 63.2% and 54.1%, respectively (P=0.054). Risk factors for renal loss were oliguria at presentation (hazards ratio, HR 10.50; P=0.037) and need for dialysis (HR 6.33; P=0.024); there was inverse association with proportion of normal glomeruli (HR 0.91; P=0.042). Conclusions: Pauci-immune GN constitutes one-half of patients with crescentic GN at this center. Patients with pauci-immune GN, chiefly ANCA negative, show higher risk of disease progression. Renal loss is related to severity of initial presentation and extent of glomerular involvement.

Disease Course in Steroid Sensitive Nephrotic Syndrome.

Objective: To review the disease course in patients with steroid sensitive nephrotic syndrome (SSNS) and the factors that determine outcome Design: Retrospective, analytical Setting: Pediatric Nephrology Clinic at referral center in North India Participants/patients: All patients with SSNS evaluated between 1990 and 2005 Intervention: None Main outcome measures: Disease 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. Results: Records of 2603 patients (74.8% boys) were reviewed. The mean age at onset of illness and at evaluation was 49.7±34.6 R E S E A R C H P A P E R INDIAN PEDIATRICS 881 VOLUME 49__NOVEMBER 16, 2012 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. Conclusions: A 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.

Incidence of Acute Kidney Injury in Hospitalized Children.

Objective: To determine the incidence and outcome of acute kidney injury (AKI) in hospitalized patients. Design: Prospective, observational. Setting: Tertiary care center in North India. Participants/patients: Inpatients, 1 month to 18-yr-old. Intervention: None. Main Outcome Measures: Incidence of AKI based on the serum creatinine criteria proposed by the AKI Network. Results: During 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). Conclusions: AKI is common in critically ill children, especially younger patients with septicemia and shock, and results in increased hospital stay and high mortality.

Primary hyperoxaluria type 1 with a novel mutation.

Primary hyperoxaluria type 1 [PH1] is an autosomal recessive disorder caused by a deficiency of alanine-glyoxylate aminotransferase AGT, which is encoded by the AGXT gene. We report an Indian family with two affected siblings having a novel mutation in the AGXT gene inherited from the parents. The index case progressed to end stage renal disease at 5 months of age. His 4 month old sibling is presently under follow up with preserved renal function.

Pyelonephritis presenting with severe acute renal failure.

We describe an unusual case of an 8-yr-old child presenting with low grade fever and acute renal failure. Investigations showed blood urea 246 mg/dl, serum creatinine 6.4 mg/dl, microscopic hematuria and 2+ proteinuria. Renal biopsy was done in view of rapidly worsening kidney function and showed dense lymphoplasmacytic infiltrate and neutrophils with focal areas of interstitial necrosis, confirming acute pyelonephritis. Ultrasonography and MRI demonstrated multiple renal abscesses. He was managed with antimicrobial therapy and hemodialysis.

Beneficial effects of rituximab therapy for systemic lupus erythematosus.

We report an 11-yr-old girl with systemic lupus erythematosus (SLE) with recurrent flares of skin and systemic manifestations, which were poorly controlled with conventional therapy. Treatment with rituximab, a monoclonal antibody against CD20, was associated with remission of symptoms and a steroid sparing effect that persisted for more than 9 months. Therapy with rituximab appears promising in subjects with SLE.

Long-term outcome in children with primary distal renal tubular acidosis.

OBJECTIVE: To evaluate complications in adequately treated children with distal renal tubular acidosis (RTA) and to identify factors influencing their development. DESIGN: Records of patients with primary distal RTA followed for 2 or more years at this hospital were reviewed. Case records were examined for age at onset of symptoms and at initiation of treatment, treatment details, follow-up and complications. Height, weight and growth velocity were expressed as standard deviation score (SDS) during different periods of follow-up. Regression analysis was performed to evaluate factors influencing increase in height and weight SDS. P value of less than 0.05 was considered significant. RESULTS: Of 18 patients (eleven boys), the diagnosis was established at the median (range) age of 6 yr (1.5-13 yr). These patients were followed up for a median (range) period of 4 yr (2-18.5 yr). Short stature (height SDS <-2) was noted in all patients at the time of diagnosis with median (range) height SDS of -5.2(-7.5 - -0.4). All patients had failure to thrive with median (range) weight SDS of -3(-5.7 - -1.5). Height SDS increased by median (range) of 2 (1.2-5.5) to become -2.7(-4.8 - -1.1) at last follow-up. Weight SDS increased by median (range) of 0.9 (-0.6 - 2.8) to become -2.4 (-4 - -0.5). Median (range) growth velocity SDS decreased from 3 (1-16) during first year of treatment to 1(-0.3 - 7) at four years with an increase in mean height SDS by 1.3 during the first two years of treatment. Height SDS at last follow-up was not influenced by the age at initiation of treatment, follow-up duration, initial height SDS or severity of acidosis at diagnosis. Increase in height SDS correlated negatively with base excess and height SDS at diagnosis, and positively with follow-up duration on univariate analyses. Initial height SDS was the only factor that influenced increase in height SDS on multivariate analyses. Increase in weight SDS was negatively correlated with base excess and initial weight SDS with significant association with initial weight SDS, on multivariate analyses. All patients had rickets at the time of diagnosis with pathological fractures in four. Rickets resolved without treatment with vitamin D in seventeen patients after a median (range) period of 4 mo (1-12 mo). Eight patients (44.4%) had nephrocalcinosis at diagnosis. Twenty-four hour urine calcium excretion was higher in those with nephrocalcinosis (p = 0.01). Creatinine clearance remained normal in all except one who progressed to renal failure. CONCLUSION: There is a need for early diagnosis, appropriate treatment and regular follow-up of patients with distal RTA for improving outcome.

Non-azotemic refractory rickets in Indian children.

In order to examine the etiology of refractory rickets, we evaluated the case records of patients presenting between 1990 and 2002. Subjects with impaired renal functions were excluded. Of 131 patients, 25.9 % each had hypophosphatemic rickets and distal renal tubular acidosis (RTA), 19.6 %vitamin D dependent rickets (VDDR), 11.3 % proximal RTA, 9.1 % liver disease and 6.1 % malabsorption. A significant proportion of patients with VDDR and proximal RTA showed deformities in the first year of life, whereas those with distal RTA and hypophosphatemic rickets presented later. Patients with hypophosphatemic rickets had predominant involvement of lower limbs; hypercalciuria was found in 4. Distal RTA was associated with marked rickets and normal levels of alkaline phosphatase. Hypophosphatemia and low tubular reabsorption of phosphate, though characteristic of hypophosphatemic rickets, was also seen in patients with VDDR (19.2%) and distal RTA (17.6 %). Our findings suggest that application and interpretation of appropriate investigations are useful in determining the cause of non-azotemic refractory rickets allowing initiation of specific therapy.

Diagnóstico y tratamiento de las infecciones del tracto urinario / Management of urinary tract infection

Urinary tract infections cause sifnificant morbidity in children and should be treated promptly and appropriately. Several urinary screening tests are available but urine culture is necessary for accurate diagnosis of UTI. Significant proportions of children with UTI have underlying urinary tract anomaly such as VUR. Hence all children should have some investigations that should be tailored bassed on "high-risk" approach. Antibiotic prophylaxis is the preferred treatment of VUR and indications of surgery are limited. Parents of children with VUR should be told to maintain high index of suspicion for subsequent UTI. Recent studies have questioned the role of UTI and VUR in renal scarring and the utility of aggressive imaging following UTI. Well designed studies are needed to asses the benefits of imaging protocols and the role of antibiotic prophylaxis in prevention of UTI and treatment of VUR. Probiotics for prevention of UTI and development of noninvasive genetic screening test for VUR are promising areas for future research.

Las infecciones del tracto urinario (ITU) son causa importante de morbilidad en niños y se deben tratar con rapidez y apropiadamente. Existen distintas pruebas en la orina para la pesquisa pero el urocultivo es necesario para el diagnóstico preciso de la ITU. Una proporción significativa de niños con ITU presentan una alteración subyacente del tracto urinario como el reflujo vesicoureteral (RVU). Los niños con ITU deben ser estudiados sobre la base de un enfoque de "alto riesgo". Un porcentaje importante de pacientes presenta recurrencias. La estrategia que se utiliza con mayor frecuencia para evitar ITU es la administración profiláctica de antibióticos en dosis bajas. Se necesitan estudios bien diseñados para evaluar los beneficios de los protocolos de estudios por imágenes y el papel que desempañan los antibióticos profilácticos en la prevención de ITU y el tratamiento del RVU. Los probióticos para evitar la ITU y el desarrollo de pruebas genéticas no invasivas para la pesquisa de RVU son arreas promisorias para futuras investigaciones.

Renal tubular dysgenesis.

A neonate with acute renal failure due to renal tubular dysgenesis is described. The diagnosis was confirmed on renal histology, characterized by short and poorly developed proximal renal tubules.

Short term efficacy of intravenous dexamethasone and methylprednisolone therapy in steroid resistant nephrotic syndrome.

OBJECTIVE: To compare the short term efficacy of intravenous pulses of methylprednisolone and dexamethasone in treatment of steroid resistant nephrotic syndrome in children. METHOD: We prospectively treated 81 children with idiopathic steroid resistant nephrotic syndrome with six alternate-day pulses of intravenous dexamethasone (5 mg/kg) or methylprednisolone (30 mg/kg). Fifty-nine patients received dexamethasone and 22 were treated with methylprednisolone. Two patients in dexamethasone and one in methylprednisolone group developed serious infection during administration of alternate-day pulses and could not complete the therapy. RESULTS: The median age at treatment was 38 (36-74.7) months. Of patients who completed therapy, 20 (35.1 percent) (95 PERCNT CI 22.9-48.9) and 7 (33.1 percent) (95 percent CI 14.6-56.9) patients in dexamethasone and methylprednisolone group, respectively achieved complete remission. Following alternate day pu1ses the median urinary albumin to creatinine ratio decreased from 9.2 to 1.5 (P less tha 0.005) in dexamethasone group and from 12.1 to 0.7 (P less than 0.005) in methylprednisolone group. The median reduction in urinary albumin to creatinine ratio was 54.1 PERCNT (95 percent CI 32.7- 83.9) and 63.2 percent (95 percent CI 23.5- 100) in dexamethasone and methylprednisolone group respectively. The chief side effects of therapy were transient hypertension or worsening of preexisting hypertension, which occurred in 31 (54.4 percent) patients in dexamethasone group and 10 (47.6 percent) in the methylprednisolone group. The hypertension was satisfactorily controlled on antihypertensive drugs. One or more side effects were observed in 66.7 percent (95 percent CI 52.9-78.6) children receiving dexamethasone therapy and 61.9percent (95 percent CI 38.4-81.9) receiving methylprednisolone, which was comparable. CONCLUSIONS: We conclude that intravenous dexamethasone is as effective as methylprednisolone in inducing remission in patients with steroid resistant nephrotic syndrome.

Pseudohypoparathyroidism presenting with bony deformities resembling rickets.

Pseudohypoparathyroidism (PHP), characterized by hypocalcemia, hyperphosphatemia and elevated parathormone level, may rarely be associated with bony deformities resembling rickets. The authors report two siblings with clinical and radiological features suggestive of rickets unresponsive to treatment with vitamin D. Low serum calcium, elevated serum phosphate, normal renal functions, raised tubular maximum of phosphate and high serum parathormone were suggestive of PHP. Treatment with 1-hydroxyvitamin D and calcium carbonate led to decrease in bone pain, increase in height and weight and resolution of radiological features. PHP should be suspected in patients with bony deformities, hypocalcemia, elevated blood phosphate levels and normal renal functions.

Chronic renal failure in children.

OBJECTIVE: To determine the etiology of chronic renal failure amongst children attending the Pediatric Nephrology services at a tertiary care center. SUBJECT: We reviewed the records of 305 children, diagnosed to have chronic renal failure (CRF) over a 7-year period. CRF was defined as glomerular filtration rate (GFR) below 50-mL/1.73 m2/min persisting for more than 3 months. RESULTS: The mean age at onset and presentation of CRF in these patients was 5.9 and 8 years respectively. Ninety-six children were below 5 years of age. Mean (SD) levels of blood urea and creatinine at presentation were 150 and 4.6 mg/dL respectively. The median GFR at presentation was 18.5 mL/min/1.73 m(2) while 25.3 patients were already in end stage renal failure indicating that these patients were referred late. The mean (SD) hemoglobin at presentation was 7.6 (2.6) g/dL. The mean height and weight SD scores were 2.9 and 2.4 respectively. Obstructive uropathy was the commonest cause of CRF present in 97 children. Other causes included chronic glomerulonephritis in 84, reflux nephropathy in 51, hereditary nephritis in 20, renal dysplasia in 15 and hemolytic uremic syndrome in 5 children. The mean (SD) duration of follow-up was 11(15) months. Peritoneal or hemodialysis was performed in 63 patients. Fifteen patients underwent a live-related renal transplantation. The rest opted out of dialysis program and were conservatively managed due to financial constraints. CONCLUSIONS: The commonest causes of CRF were obstructive and reflux nephropathy. A significant proportion of patients presented late; had severe CRF and were malnourished and stunted. Majority of these were managed conservatively due to lack of financial resources.

Management of urinary tract infections.

Urinary tract infection (UTI) is common in childhood. It may result in long-term complications due to renal scaring. Younger children are at higher risk of renal scarring. The diagnosis of UTI is based on urine culture. The bacterial count for diagnosis of UTI depends on the method of urine collection. Urinalysis is useful for making a presumptive diagnosis of UTI and allows initiation of empirical treatment in high-risk patients, after urine culture has been obtained. The treatment of UTI is guided by the severity of illness and age of the patient. Following a UTI, investigation should be performed to identify an underlying urinary tract anomaly. Recurrence of UTI occurs in 30-50% children. Important predisposing factors include VUR, urinary tract obstruction, voiding dysfunction and constipation. Vesicoureteric reflux (VUR) is seen in 30-50% children with UTI. The cornerstone of management of VUR is long-term antibiotic prophylaxis, which has been found to be as effective as surgical reimplantation.