Treatment of Henoch-Schönlein Purpura glomerulonephritis in children with high-dose corticosteroids plus oral cyclophosphamide.

BACKGROUND: Henoch-Schönlein Purpura (HSP) is a common childhood vasculitis with manifestations in numerous organ systems, including glomerulonephritis. Patients with more severe HSP-associated glomerulonephritis may develop chronic renal failure. Currently, no widely accepted treatment protocols exist for patients with significant renal involvement. METHODS: We retrospectively reviewed the clinical courses of 12 children (mean age 9 years) with HSP glomerulonephritis treated with high-dose corticosteroids plus oral cyclophosphamide. All patients had nephrotic-range proteinuria, and all had significant histopathologic changes on biopsy, including crescentic nephritis in 10 patients. Treatment consisted of either intravenous pulse methylprednisolone or oral prednisone followed by oral cyclophosphamide (2 mg/kg/day) for 12 weeks, along with either daily or alternate-day oral prednisone. Prednisone was tapered following completion of cyclophsophamide. RESULTS: Serum albumin rose significantly after treatment from 2.8 +/- (SD) 0.5 to 3.7 +/- 0.4 g/dl (p < 0.001), and there was a concurrent reduction in proteinuria, as reflected by decreasing serial protein-to-creatinine ratios: from 6.3 +/- 4.4 to 0.8 +/- 0.8 (p = 0.002). Renal function remained normal in all patients. Hypertension developed during treatment in 10 patients, all but 1 of whom were normotensive at last follow-up, 35 +/- 17 months following biopsy. CONCLUSIONS: We conclude that treatment of children with HSP nephritis with high-dose corticosteroids plus oral cyclophosphamide is safe and, as in nephrotic syndrome, appears to significantly reduce proteinuria which is a known risk factor for the development of renal insufficiency in HSP. Further studies with larger numbers of patients should be conducted to confirm this finding.

Response to early measles-mumps-rubella vaccination in infants with chronic renal failure and/or receiving peritoneal dialysis.

Achieving immunity to childhood viral infections before renal transplantation is crucial. However, children with chronic renal failure (CRF) may respond poorly to vaccination, making it difficult to achieve immunity before transplantation, particularly if they will require transplantation at a young age. To address this problem, we developed a protocol of early measles-mumps-rubella (MMR) vaccination in infants with CRF. Nine infants received MMR vaccine at a mean age of 11.6 +/- 2.5 months. When vaccinated, 6 of the children (67%) were on peritoneal dialysis, and 3 (33%) had CRF [glomerular filtration rate (GFR) < 30 mL/min/1.73 m2]. Eight patients were later transplanted at a mean age of 16.8 +/- 4.8 months. Titers were measured before transplantation in all patients. Response to vaccination was excellent, with 89% developing immunity to measles, 88% developing immunity to mumps, 100% developing immunity to rubella, and 88% developing immunity to all three components of the vaccine. These response rates were equivalent to, or slightly better than, those previously reported by Schulman for older children (19 +/- 6 months) on dialysis: 80% for measles, 50% for mumps, 100% for rubella, and 30% for all three components. We conclude that early MMR vaccination induces immunity in most infants with CRF, even those on peritoneal dialysis. Response rates are similar to those previously reported in older children. This approach may help to facilitate transplantation in young infants by achieving immunity earlier than traditional vaccination schedules.

Renal tubular dysgenesis in twins.

In a fetal autopsy series, we have explored the occurrence of renal tubular dysgenesis in twins. Renal tubular dysgenesis was found exclusively among those monozygotic twins with evidence of twin transfusion syndrome, particularly in those donor twins with oligohydramnios and growth restriction. We infer that hypotension in the donor twin of the twin transfusion syndrome pair is responsible for the failure of proximal convoluted tubule differentiation, and the disturbance of renal function is manifested as oligohydramnios prenatally, and either oliguria or tubular dysfunction postnatally.

Neoral induction in pediatric renal transplantation.

Neoral was instituted in pediatric renal transplant patients with the hypothesis it would have more predictable kinetics than Sandimmun. However, significant questions have arisen concerning potential toxicity and dosing interval related to its rapid absorption with subsequent high initial peak. This is compounded by the fact that children appear to metabolize cyclosporine at a greater rate than adults. This combination of a rapid peak and rapid absorption may then result in lower trough levels at 12 h. We compared the trough cyclosporine levels of nine children who received Neoral with nine who received Sandimmun at the time of initial transplantation. More frequent dosing (every 8 h) was required in the Neoral population compared with the Sandimmun population for the 1st month in order to obtain comparable trough levels. Beyond the initial 4-6 weeks, trough levels were similar for Neoral and Sandimmun. Whereas 1-month creatinine levels and blood pressures were similar, the number of blood pressure medications was significantly higher in the Neoral group. At 5.5 +/- 1.1 months' followup, a single patient in the current Neoral group and in the retrospective Sandimmun group each experienced a single OKT3 allograft-treated rejection. We suggest that the area under the curve is different in Neoral than Sandimmun, and the initial dosing frequency may need to be adjusted accordingly.

Outcome of antineutrophil cytoplasmic autoantibodies-positive glomerulonephritis and vasculitis in children: a single-center experience.

Vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCA) can be accompanied by a focal and necrotizing glomerulonephritis that carries a high morbidity. As many as 60% of reported children with ANCA-associated glomerulonephritis progress to end-stage renal disease. Seven children (13.0+/-0.89 years, mean age +/- SEM) with both a focal and necrotizing glomerulonephritis and a positive ANCA titer are described. Presenting symptoms were constitutional (100%) and sinopulmonary (71%); additional renal features included microscopic hematuria (100%), proteinuria (71%), and renal insufficiency (71%). Acute therapy (0 to 2 weeks from diagnosis) included intravenous corticosteroids and intravenous cyclophosphamide for all patients. Induction therapy (2 weeks to 6 months from diagnosis) consisted of cyclophosphamide (100%) and daily corticosteroids (86%) for a minimum of 6 months. Maintenance therapy that followed 6 months of induction therapy consisted of alternate day steroids (100%) combined with either oral azathioprine (50%) or oral cyclophosphamide (50%). Long-term follow-up for 48+/-12 months in all seven patients revealed that only one (14%) patient had end-stage renal disease, whereas the remaining patients had microscopic hematuria (100%), proteinuria (50%), and renal insufficiency (33%). These findings suggest that early recognition and aggressive treatment of children with ANCA-associated glomerulonephritis and vasculitis may result in an improved renal outcome compared with previous reports.

Improvement of glycemic control by CAPD with intraperitoneal insulin in a child with IDDM and ESRD.

Use of intraperitoneal insulin in diabetic end-stage renal disease (ESRD) patients receiving continuous ambulatory peritoneal dialysis (CAPD) is known to result in improved glycemic control. This route of insulin administration, although standard in adult diabetic CAPD patients, has not previously been reported in children. A 12-year old boy with ESRD from renal dysplasia who also had insulin-dependent diabetes mellitus (IDDM) was treated with CAPD and intraperitoneal insulin prior to renal transplantation. Diabetes and renal dysplasia were both diagnosed at 11 weeks of age. When he reached end-stage he was initially started on hemodialysis via a central line but was switched to CAPD because of recurrent line sepsis. His IDDM had been poorly controlled up to that time. CAPD was performed using 4 exchanges per day of 1.5% dialysate with a fixed dose of insulin added to each bag and with adjustments made based on blood glucose. His glycemic control markedly improved, with a fall in his glycosylated hemoglobin from 13.6% to 6%. CAPD was continued for 7 months until a living-related renal transplant was performed. Two episodes of peritonitis occurred while the patient received CAPD (1 episode/3.5 patient-months). We conclude that the use of intraperitoneal insulin in children with IDDM and ESRD leads to improved glycemic control. The rate of peritonitis, however, may be increased in these children.

Beneficial effect of Sandoglobulin upon allograft survival in the pediatric renal transplant recipient.

The use of pooled immunoglobulin (IgG) has been shown to decrease panel reactive antibodies (PRA) in highly sensitized patients awaiting transplantation. IgG infusions have also been found effective for CMV prophylaxis. Analysis of 52 non-highly sensitized children (ages 1-18) who received kidney transplants from May 1991 through January 1995 was undertaken to determine if the immunoglobulin administered for CMV prophylaxis effected allograft survival. Comparison of the "Sando Pos" group (those who received Sandoglobulin for CMV prophylaxis) to the "Sando Neg" group demonstrates a significantly improved allograft survival at 1, 2, and 3 yr post-transplantation. Despite the Sando Pos group being younger [7.3 +/- 1.3 yr vs. 10.7 +/- 0.9 yr; (mean +/- SEM) p < 0.05] allograft survival was 95%, 95% and 88% in the Sando Pos group vs. 88%, 79% and 79% in the Sando Neg group at 1, 2 and 3 yr, respectively (p < 0.01 at all three time points). It is concluded that the potential mechanism of the immunosuppressive benefit of Sandoglobulin is speculative but presumed to be upon inhibition of anti-HLA class I antibodies. We conclude that Sandoglobulin may not only be useful for CMV prophylaxis but also as an adjunct to routine immunosuppression.

Recognition and management of angiotensin converting enzyme inhibitor fetopathy.

Angiotensin converting enzyme (ACE) inhibitors are extensively used for the treatment of hypertension, to decrease proteinuria, and to mitigate hyperfiltration. These drugs now have been shown to be fetotoxic causing profound fetal hypotension, renal tubular dysplasia, anuria-oligohydramnios, growth restriction, hypocalvaria, and death when used in the second and third trimesters of pregnancy. We recommend that ACE inhibitors not be used in pregnancy. However, if a child is born with ACE inhibitor fetopathy, aggressive therapy with dialysis to remove the inhibitor may mitigate the profound hypotensive effects. Therapy will depend on the specific ACE inhibitor, and care recommendations cannot be generalized for the entire class of drugs as their protein binding and volume of distribution differ substantially.

Continuous venovenous hemodiafiltration in infants and children.

Continuous venovenous hemodiafiltration (CVVHD) is not commonly used in pediatric intensive care units due to the lack of suitable equipment needed for this technique of renal replacement therapy (RRT). We have used an adapted hemodialysis machine that includes a blood pump controller, an air leak detector, and a venous pressure monitor over the past year in the pediatric intensive care unit. Blood lines available for hemodialysis were used for CVVHD, limiting the extracorporeal circuit volume to 38 mL, which allows for CVVHD capability in an infant as small as 4.5 kg without a blood-primed circuit. We have compared this experience to previous continuous arteriovenous hemodiafiltration (CAVHD) at our institution. The two groups (CVVHD and CAVHD) were similar in age, weight, blood pressure, and indication for RRT. There was significantly less number of hemofilters used, an improved number of hours per hemofilter, and a significantly less change of RRT modality due to ineffective dialysis (CVVHD 0% v CAVHD 32%) when using CVVHD. Furthermore, an average of 48% less heparin was used in the CVVHD population. We conclude that CVVHD can be safely and effectively carried out in infants and small children with less heparinization, no need for arterial access, and less risk of ineffective RRT.

Recurrent focal segmental glomerulosclerosis in pediatric renal transplant recipients: successful treatment with oral cyclophosphamide.

Focal segmental glomerulosclerosis (FSGS) is the most common glomerulopathy leading to end-stage renal disease in children and transplantation is complicated by recurrent disease in a significant percentage of children. Treatment of recurrent FSGS has included high-dose steroids, high-dose cyclosporine (CSA), plasmapheresis, and ACE inhibitors with mixed results. We have had a consistent approach using oral cyclophosphamide (CTX) to treat recurrent FSGS since 1982. Three patients with ESRD secondary to nephrotic syndrome had recurrent disease. Biopsies in all 3 were consistent with recurrent FSGS. Patients were begun on a 8-12 week course of 1-2 mg/kg/day of CTX and dosage was adjusted for WBC count. Azathioprine was with held during CTX. Patients' dosage at the end of 12 weeks ranged from 0.89-1.75 mg/kg/day. All patients tolerated CTX well. After 8-12 weeks of treatment, 2 patients with nephrotic syndrome normalized their serum albumin and had negative to trace protein on urinary dipstick. One patient with proteinuria decreased his protein excretion from 770 to 340 mg/m2/day. At follow-up at 8, 38, and 125 months post-transplant, these 3 patients have stable graft function and negative to trace protein on urinalysis. The patient followed for 125 months has had 2 additional relapses at 51 and 82 months post-transplant that were treated successfully with pulse intravenous steroids. Three pediatric patients with recurrent focal segmental glomerulosclerosis post-renal transplant were treated with oral CTX and had significant improvement in proteinuria and preservation of graft function. This suggests that oral CTX is a potentially effective and well-tolerated treatment for recurrent FSGS in children.

Renal sonography is not a reliable screening examination for vesicoureteral reflux.

A retrospective analysis of 493 infants and children was performed to determine the reliability of renal sonography for identifying vesicoureteral reflux. Sonography was done in all cases within 8 hours of a voiding cystourethrogram. Vesicoureteral reflux was documented in 272 of 986 kidneys on voiding cystourethrography and there were 201 refluxing kidneys with normal ultrasound (25 with grade I reflux, 119 with grade II, 50 with grade III, 6 with grade IV and 1 with grade V). In 71 of the refluxing kidneys the ultrasound was abnormal due to pelvicaliceal dilatation in 45, a duplication anomaly in 6 and renal fossae abnormality in 20. Of the kidneys with vesicoureteral reflux 74% were sonographically normal. Sonography was not sufficiently sensitive or specific for detecting vesicoureteral reflux, since 28% of the missed refluxing kidneys had grade III or higher reflux.

Angiotensin-converting enzyme inhibitor fetopathy.

Angiotensin-converting enzyme (ACE) inhibitors are widely used for controlling hypertension. Their use in women who are pregnant is not without risk to the fetus. We describe three infants exposed in utero to ACE inhibitors who had adverse outcomes. These cases, combined with other reports in the literature, suggest strongly that these drugs are fetotoxic. ACE inhibitor fetopathy is characterized by fetal hypotension, anuria-oligohydramnios, growth restriction, pulmonary hypoplasia, renal tubular dysplasia, and hypocalvaria. Although the true frequency of adverse fetal effects has yet to be determined, because of the debilitating and lethal nature of the fetal damage when it occurs, it is our recommendation that ACE inhibitors not be used in pregnancy, particularly in the second and third trimesters.

Pulmonary function variation in ventilator dependent critically ill infants on peritoneal dialysis.

Four ventilator dependent infants on PD for acute renal failure underwent pulmonary function (PFT) evaluation at varying times in the PD cycle. Mid dwell peak intraperitoneal pressure (IPP) correlated with a significant decrease in pulmonary compliance and increase in air way resistance. This further correlated with a decrease in PO2 and an increase in PCO2 on arterial blood gas analysis. Etiology of the PFT changes appear to correlate most closely with IPP yet other factors including pulmonary artery shunting as well as hypercapnea secondary to a 4.25% dialysate are being evaluated as additional causative factors.

"Dilatation" of the left renal vein on computed tomography in children: a normal variant.

Compression of the left renal vein (LRV) between the superior mesenteric artery and the aorta is thought to be a cause of hematuria, periureteral and gonadal varices, and varicocele ("Nutcracker phenomenon"). Previous investigators have suggested that this diagnosis can be made on computed tomography when the LRV ratio greater than or equal to 1.5 (the diameter of the LRV proximal to the aorto-mesenteric angle divided by the diameter of the LRV distal to the aorto-mesenteric angle). This study was designed to establish the normal range for the LRV ratio on CT in children. The LRV ratio was measured in thirty-nine consecutive children undergoing intravenously enhanced CT of the abdomen. None of the children had hematuria on urinalysis immediately before or after the CT. Children with any known abnormality involving the kidneys, adrenal glands, IVC, or renal or gonadal veins were excluded. The patients ranged in age from 3.4 to 18.5 years (mean = 10.6 years). LRV ratio ranged from 0.78 to 2.00 (mean = 1.46; S.D. = 0.312). Twenty of the 39 children (51.3%) had a LRV ratio greater than or equal to 1.50. The conclusion is that the normal range for the LRV ration is too wide for it to be useful in diagnosing LRV entrapment and that a LRV ratio greater than or equal to 1.5 on CT is normal in children.

Renal obstructive dysplasia: ultrasound diagnosis and therapeutic implications.

57 cases of renal obstructive dysplasia (defined as the abnormal development of nephronic and ductal structures due to in utero obstruction of the urinary tract) were evaluated in terms of sonographic findings, renal and other associated anomalies, and current status of the child. More than one-third of the cases had bilateral disease and although not uniformly fatal bilateral involvement was associated with significant morbidity and mortality. In 12 of the 33 cases with unilateral dysplasia there was an association with contralateral renal problems including uretero-pelvic junction obstruction, vesicoureteral reflux and aplasia. Almost one-half of the cases had congenital anomalies, these included VACTERL association, congenital heart disease, cranial abnormalities and gastrointestinal malformations. Fifteen stillborns and 12 of the patients with bilateral involvement and four with unilateral involvement have died. Four patients are on dialysis (two with bilateral involvement and two with unilateral renal obstructive dysplasia). Only one-quarter are otherwise normal. More serious problems are reported in this mixed age population of patients with obstructive renal dysplasia than has been identified in previous studies. Management decisions of the fetus and child must be based on this new age-expanded population.