Ajay P. Sharma

Changing trends of histopathology in childhood nephrotic syndrome

This study was conducted to analyze the trend of histopathologic subtypes in idiopathic nephrotic syndrome (INS) in a homogenous racial group in India population. A prospective analysis of 400 consecutive children with INS was performed. Kidney biopsies were performed according to standard indications. Steroids were administered following the Arbeitsgeminschaft fur Padiatrische Nephrologie protocol. Cyclophosphamide was administered to children in the frequent-relapser, steroid-dependent, and steroid-nonresponder categories. Of the various histopathologic subtypes, focal segmental glomerulosclerosis (FSGS) was the most common (87 of 222 subtypes; 39.1%). Children who underwent biopsy between July 1992 and December 1996 (group B, n = 157) were compared with our initial published data of biopsies performed between January 1990 and June 1992 (group A, n = 65), with similar indications for biopsy in both groups. The incidence of FSGS was significantly greater in biopsies performed in the recent period (group B, 47% versus group A, 20%; P = 0.0002). The different clinical and biochemical parameters were also analyzed to differentiate FSGS from the other 2 subtypes. Hypertension (P = 0. 005), renal insufficiency at presentation (P = 0.001), and steroid resistance (P = 0.0006) were significantly greater in children with FSGS. On follow-up (mean, 5.4 years), children with FSGS were at a significantly greater risk for developing renal insufficiency (P = 0. 0001). We conclude there is a shift toward an increasing prevalence of FSGS over the years in the Indian population. This trend has immense therapeutic and prognostic significance.

Do current recommendations for kidney biopsy in nephrotic syndrome need modifications

Abstractu2002The current recommendations of kidney biopsy in childhood idiopathic nephrotic syndrome (CINS) were put forward to minimize unnecessary kidney biopsies in underlying minimal change disease (MCD). However, there remains a diversity of opinion about the criteria for biopsying children with idiopathic nephrotic syndrome. This study was conducted to prospectively study their usefulness in avoiding biopsies in MCD and to evaluate further modifications for minimizing biopsies in CINS. Of 400 consecutive CINS patients, 222 patients were subjected to kidney biopsy according to the current recommendations. The histopathology spectrum of these selectively biopsied children revealed focal segmental glomerulosclerosis (FSGS) in 39%, MCD in 34.2%, membranoproliferative glomerulonephritis (MPGN) in 16.2%, mesangioproliferative glomerulonephritis (MesPGN) in 7.6%, membranous nephropathy (MN) in 1.8%, and diffuse mesangial sclerosis (DMS) in 0.9%. We observed that despite the current recommendations and efforts to minimize biopsy, 34% of children had MCD on histopathology. Two or more clinical (hematuria and hypertension) or biochemical (renal insufficiency) parameters were present in all children with MPGN. Low C3 was present only in children with MPGN. All the steroid responders were found to have MCD, FSGS, or MesPGN on biopsy. Cyclophosphamide response correlated better with steroid responsiveness (P=0.02) than with histo- pathology (P=0.80) in MCD, FSGS, and MesPGN. Based on these observations, we suggest some modifications in current recommendations for kidney biopsy to minimize biopsying children with MCD. These are (1) biopsies in children (age 1–16 years) should be restricted (a) to a subgroup with two or more clinical and biochemical parameters and (b) in steroid non-responders, (2) the decision to administer cyclophosphamide should be based on steroid response pattern without requiring a prior routine biopsy.

Histopathological spectrum of childhood nephrotic syndrome in Indian children.

Nephrotic syndrome in children is a clinical manifestation of different histopathological subtypes. There is a paucity of recent large studies dealing with the histopathological spectrum from developing countries. A prospective study was performed from January 1990 to December 2000xa0at our center, involving 600 children (with age of onset up to 16xa0years) with idiopathic nephrotic syndrome (INS). The objectives were: (1) to study the histopathological distribution of different subtypes of INS and (2) to compare the clinical and biochemical parameters at the time of diagnosis of minimal change disease (MCD) with non-MCD subtypes. For the purpose of this study we analyzed only those children with INS who underwent biopsies. The study group included 290 children in which adequate biopsy reports were available. There were 213 males and 77 females. Mean age at onset of INS was 7.9+5.1xa0years. Facial edema was found in 286 (98.6%), microhematuria in 120 (41.3%), gross hematuria in 7 (2.5%), and hypertension in 77(26.8%) patients. All patients of the study group were seronegative for HBsAg and HIV. Focal and segmental glomerulosclerosis (FSGS) was the most common histopathological subtype, occurring in 110 of 290 children (38%). Other subtypes included MCD in 95 children (32%), membranoproliferative glomerulonephritis (MPGN) in 44 children (15%), mesangioproliferative glomerulonephritis in 33 children (11%), membranous glomerulonephritis in 5 children (2%), and diffuse mesangial sclerosis in 3 children (1%). In children under 8xa0years of age, MCD was the most common entity, whereas FSGS predominated in children with age at onset greater than 8xa0years. The age at onset of nephrotic syndrome was significantly higher in the non-MCD group than the MCD group. The incidence of hypertension, microhematuria, and gross hematuria was significantly lower in the MCD group. MCD remains the most common histopathological subtype in Indian children with INS and onset under 8xa0years of age. The incidence of MPGN continues to be high. MCD can be differentiated from non-MCD subtype by younger age at onset, absence of hypertension, and absence of microscopic hematuria.

ETIOLOGY, PROGNOSIS, AND OUTCOME OF POST-OPERATIVE ACUTE RENAL FAILURE

A Multivariate analysis was done in all patients who developed post operative ARF, during the period 1990–1995 to determine the etiological spectrum and to identify various variables affecting the outcome. Of 140 patients (110 operated at SGPGI and 30 operated outside) 116 underwent elective surgery. The different types of surgery leading to ARF were urosurgery (3.5%), open heart surgery (32.9%), gastrosurgery (16.4%), pancreatic surgery (9.3%), obstetrical surgery (3.6%) and others (2.8%). The incidence of ARF in SGPGI patients was highest in pancreatic surgery group (8.2%) followed by open heart surgery (3%). The different etiological factors responsible for ARF were perioperative hypotension (67.1%), sepsis (63.6%) and exposure to nephrotoxic drugs (29.3%). Sixty-four patients (45.7%) required dialysis. The overall mortality was 45% The mortality was highest in patients who underwent open heart surgery (89.1%) followed by pancreatic surgery (84.6%). The factors associated with high mortality, other than the type of surgery, were preoperative hypotension (p <0.05), oliguria (p <0.01), need for dialysis (p <0.05) and multiorgan failure (p <0.001). AM following emergency surgery had poor outcome, though not statistically significant. Perioperative sepsis (p <0.05) and preoperative use of aminoglycoside (p <0.05) were significantly higher in patients operated outside SGPGI. This was associated with higher incidence of ARF. Thus we conclude that presence of multiorgan failure, oligoanuria, preoperative hypotension and need far dialysis are poor prognostic markers in ARF following surgery.

Acute renal failure associated with liver disease in India : Etiology and outcome

Background/Aims and Method Acute renal failure (ARF) associated with liver disease is a commonly encountered clinical problem of varied etiology and high mortality. We have prospectively analyzed patients with liver disease and ARF to determine the etiology, clinical spectrum, prognosis and factors affecting the outcome. Results Other than hepatorenal syndrome patients, out of 221 cases, 66 developed ARF secondary to various liver disease like cirrhosis (n = 29, mortality 8, risk factors—older age p < 0.01, grade III/IV encephalopathy p < 0.05), fulminant hepatic failure (n = 25, mortality 15, risk factor—prolonged prothrombin time p < 0.01), and obstructive jaundice (n = 12, mortality 7, risk factor—sepsis p < 0.01). In these three groups the factors leading to ARF were volume depletion (24), gastrointestinal bleed (28), sepsis (34), drugs (27) [aminoglycosides (9) and NSAID (18)] along with hyperbilirubinemia. Various types of ARF with contemporaneous liver injury were malaria (n = 37, mortality 15, risk factors—higher bilirubin p < 0.001, higher creatinine p < 0.05, anuria p < 0.05 and dialysis dependency p < 0.05), sepsis (n = 36, mortality 22, risk factors—age p < 0.001, higher bilirubin p < 0.01, oliguria p < 0.05), hypovolemia with ischemic hepatic injury (n = 14, mortality 5, risk factors—higher creatinine p < 0.05 and SGPT p < 0.01), acute pancreatitis (n = 12, mortality 4, risk factors—higher bilirubin p < 0.001, higher SGPT p < 0.01, dialysis dependency p < 0.05), rifampicin toxicity (n = 10, no mortality), paroxysmal nocturnal hemoglobinuria (n = 3, no mortality), CuSO4 poisoning (n = 3 mortality 2), post abortal (n = 11, mortality 6, risk factors—higher creatinine p < 0.05 and SGPT p < 0.01), ARF following delivery including HELLP syndrome (n = 12, mortality 4, risk factors—higher bilirubin p < 0.01 and SGPT p < 0.01), and of uncertain etiology (n = 14 mortality 4). 133 patients (60.2%), required hemodialysis hemodialfiltration or peritoneal dialysis. Conclusion ARF associated with liver disease is having high mortality (42.5%). Avoidance of dehydration, hypotension, nephrotoxic drugs and sepsis, with promot dialytic support are necessary to reduce mortality and morbidity.

Cyclosporin A withdrawal in live related renal transplantation: long‐term results

Cyclosporin A (CsA) withdrawal after 1 yr of stable graft function has been shown to be beneficial in cadaveric renal transplantation. This strategy could be even more suitable for ‘immunologically advantaged’ grafts as in live related renal transplantation. We report the long‐term outcome of patients in a live related transplantation programme undergoing early (between 1989 and 1992) and late (1993 onwards) CsA withdrawal as compared with those on long‐term low dose CsA (1993 onwards). Two‐hundred and fifty‐two patients were divided into three groups based on the following immunosuppressive protocol: group ECyW (n=99), early CsA withdrawal (9 months after transplantation); group LCyW (n=44), late CsA withdrawal (median 16 months, range 13–22 months after transplantation); and group LDCy (n=109), long‐term low dose CsA. The median period of follow‐up was 66 months after transplantation (range 43–84 months). There was no difference in the actuarial 6‐yr patient or graft survival among the three groups. Acute rejection episodes were more frequent in ECyW (54.4%) than in LDCy (31.8%) and LCyW (23.8%) (p=0.001). The risk of developing late (≥9 months) acute rejection was highest in ECyW 32/99 (32.3%) as compared with LCyW 8/44 (18.4%; p=0.08) and LDCy 8/109 (7.3%; p=0.0001). Of the 32 ECyW patients who developed acute rejection episodes after CsA withdrawal, 13 (40.6%) lost their grafts either due to uncontrolled acute rejection or to chronic rejection. Chronic rejection was higher in ECyW (24%) than in LCyW (11%; p=0.04) and LDCy (17%; p=0.17). Antihypertensive requirement was highest in patients maintained on low dose CsA. Graft function, as measured by serum creatinine levels, was significantly better in LCyW (1.24±0.4 mg%) as compared with ECyW (1.49±0.5 mg%) and LDCy (1.48±0.6 mg%). Early CsA withdrawal after live related renal transplantation is associated with a significant risk of acute rejection and subsequent chronic rejection. Slow withdrawal after 1 yr is safe and more economical than the long‐term administration of low dose CsA.

Prognostic significance of distal renal tubular acidosis in posterior urethral valve

Abstractu2002The prognostic significance of distal renal tubular acidosis (DRTA) in the development of overt nephropathy (ON) in children with posterior urethral valves (PUV) is not clear. This condition was studied prospectively in 22 children with posterior urethral valve (PUV), with normal renal function. Prior to surgery, the children with ON had a higher incidence of bilateral reflux (P=0.006), but the difference was not significant for age at surgery (P=0.31), duration of voiding symptoms prior to surgery (P=0.30), presence of DRTA (P=0.35) and bladder abnormalities (P=0.27), with none of these factors being significant on logistic regression analysis. At the end of the follow-up, after surgery, age at surgery (P≤0.0001), duration of voiding symptoms prior to surgery (P≤0.0003), persistent DRTA (P=0.0001) and persistent bladder dysfunction (P=0.02) after surgery were significantly higher in children with ON. On univariate logistic regression analysis, age at surgery (P=0.009), duration of voiding symptoms prior to surgery (P=0.01), persistent DRTA (P=0.002) and persistent bladder abnormalities (P=0.03) after surgery were significant for ON after surgery, but on stepwise multivariate logistic regression analysis only persistent DRTA (P=0.002) turned out to be significant. We conclude that persistent DRTA after surgery can predict overt nephropathy in children with PUV after surgery.

Cyclosporine level: which single-point estimation of drug level is the best?

CYCLOSPORINE (CyA) has a narrow therapeutic window, with potential side effects and risk of rejection from underdosing. Area under the curve (AUC) of blood CyA concentration versus time is the best indicator of systemic drug exposure, but this is cumbersome and impractical for routine clinical use. Traditionally, trough blood levels (CO) have been used. Cyclosporine pharmacokinetics in Indian patients may not be identical to Western patients. Adequate study in this patient population is required to know which single-point drug level estimation is the best.