Stanley A. Mendoza

Treatment of steroid-resistant focal segmental glomerulosclerosis with pulse methylprednisolone and alkylating agents

In children, steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) is frequently a progressive condition resulting in end-stage renal disease. There have been no reports of effective treatment for this condition. For the past several years, the Pediatric Nephrology services at the University of California, San Diego and Stanford University Schools of Medicine have treated these patients with a protocol involving infusions of high doses of methylprednisolone, often in combination with oral alkylating agents. Twenty-three children have been treated in this manner with a follow-up of 46±5 months. Twelve of these children are in complete remission. Six have minimal to moderate proteinuria. Four children remain nephrotic. Each of these children has a normal glomerular filtration rate. One child developed chronic renal failure and subsequently died while on dialysis. These results appear significantly better than previous series of children with FSGS. A controlled, multi-center trial of this protocol has been proposed.

Hypertension in infants—a complication of umbilical arterial catheterization

Hypertension was observed in ten infants. Seven had thrombosis either of one renal artery or of both. The seven infants had previously had an indwelling catheter in the umbilical artery. One infant who had not had an indwelling umbilical arterial catheter had stenosis of a renal artery. No etiology for the hypertension was found in two infants, one of whom had had an umbilical arterial catheter. Response to antihypertensive medication was generally poor. Five of the infants died. We recommend prompt diagnostic evaluation in hypertensive infants. Nephrectomy should be considered, if the renal artery is occluded. Hypertension appears to be a life-threatening complication of umbilical arterial catheterization.

Serum IgE in patients with minimal-change nephrotic syndrome

Serum levels of IgE were studied in 53 children; 17 children had minimal-change nephrotic syndrome, 9 had probable MCNS, and 27 had other renal diseases. These studies showed higher levels of IgE in patients with MCNS and probable MCNS than in the renal control subjects or in the general population. Patients with MCNS who received therapy with cyclophosphamide had lower levels of IgE than those who did not.

Peritoneal dialysis for acute renal failure in children.

Fifty infants and children with acute renal failure were treated with acute peritoneal dialysis between 1987 and 1990. The patients were dialyzed using either a catheter introduced percutaneously over a guide-wire (n=40) or a Tenckhoff catheter (n=10). The cause of the acute renal failure was primary renal disease in 17 children, cardiac disease in 19, and trauma/sepsis in 14. Peritoneal dialysis succeeded in controlling metabolic abnormalities, improving fluid balance, and relieving the complications of uremia. The procedure had few major complications. Overall mortality was 50%, reflecting the serious nature of the underlying diseases. We conclude that acute peritoneal dialysis is a safe and effective treatment in most pediatric patients with acute renal failure. Our series of patients treated with acute peritoneal dialysis serves as a basis of comparison for the evaluation of new modalities of therapy in childhood acute renal failure.

Hyperkalemia, acidosis, and short stature associated with a defect in renal potassium excretion

A-9-year-old boy with growth failure, acidosis, and persistent hyperkalemia was evaluated. Glomerular filtration rate, serum aldosterone and cortisol values, and hematologic data were within normal ranges. There was no suggestion of hyperkalemic periodic paralysis. Urinary acidification was normal, but the bicarbonate threshold was low (21–22 mEqll). During treatment with a thiazide diuretic, serum potassium and bicarbonate concentrations became normal. When the diuretic was discontinued, hyperkalemia occurred at a normal serum bicarbonate concentration. It is assumed that this patient has a specific defect in renal excretion of potassium; this is the second report of a patient with this defect.

Steroid-resistant nephrotic focal segmental glomerulosclerosis : a treatable disease

Abstract. If not aggressively treated, oral steroid-resistant (SRst) nephrotic focal segmental glomerulosclerosis (FSGS) is likely to progress to end-stage renal failure. Three observations challenge the conclusion of the International Study of Kidney Diseases in Children (ISKDC) that SRst FSGS is unresponsive to further immunosuppression: (1) The ISKDC definitions of response and relapse, which fit the patterns in minimal change disease, precluded appropriate recognition of partial or gradual responses. (2) In two ISKDC studies, a small number of children with FSGS in one case, and the use of a year of alternate-day prednisone as a control in the other, may have obscured the effects of cyclophosphamide. (3) Recent studies of more aggressive therapies have provided strong evidence of benefit. High-dose methylprednisolone infusion therapy, with alternate-day prednisone alone or with alternate-day prednisone plus an alkylating agent (the M-P/triple therapy protocol) has achieved sustained, complete remissions with stable renal function in 66% of children with SRst FSGS, and near-complete resolution of proteinuria in another 9%. Cyclosporine (CsA) plus alternate-day prednisone has produced complete or near-complete remissions in 35% of similar cases. Whether or not controlled studies will confirm the apparently greater efficacy of the M-P/triple therapy protocol, the favorable outcomes with both the M-P and the CsA regimens support the conclusion that a conservative approach to SRst FSGS is no longer appropriate.

Rationale of the growth failure in children with renal diseases study

The Growth Failure in Children With Renal Diseases Study was organized to evaluate linear growth in children with chronic; moderate renal failure who are being treated with 1,25-dihydroxyvitamin D 3 or di.hydrotachysterol in a randomized, double-blind, controlled clinical trial. This study was also prompted in 1980 by the need to compare the results (efficacy and safety) of long-term 1,25-dihydroxyvitamin D3 therapy with those in a control group of children with chronic moderate renal failure, with particular attention given to the rate of progression of renal failure, to confirm or refute reports that this therapy may accelerate deterioration of renal function.

Chapter 5 Early Stimulation of Na+-H+Antiport, Na+-K+Pump Activity, and Ca2+Fluxes in Fibroblast Mitogenesis

Publisher Summary Understanding of the mechanisms of the action of proliferative stimuli requires the identification of the intracellular signals, which initiate or modulate the mitogenic response. Ion fluxes and redistributions may play an important role in mediating the action of mitogenic agents. In recent years, it has become apparent that changes in cation fluxes are among the earliest events observed in quiescent cells stimulation to divide. The pattern of changes—originally described in mouse Swiss 3T3 cells—can be described as Na + cycle composed of Na + influx through an amiloride-sensitive Na + –H + antiport system, which leads to the intracellular alkalinization and Na + efflux via the ouabain-sensitive Na + –K + pump. This results in active K + uptake and in the restoration of the electrochemical gradient of Na + across the plasma membrane. Because these changes have been demonstrated in a wide range of quiescent cell types stimulated to proliferate by a variety of growth-promoting factors, thus increased ionic fluxes represent one of the key events that take place when quiescent cells are stimulated to reinitiate DNA synthesis and cell division.

Ineffectiveness of Ascorbic Acid Therapy in Nephropathic Cystinosis

Because high concentrations of ascorbic acid (0.57 mM) lower the free (nonprotein) cystine content of cultured cystinotic skin fibroblasts by over 50 per cent, we did a double-blind clinical trial to establish whether this drug would benefit cystinotic children. Sixty-four patients were randomized into the study; 32 received ascorbic acid (200 mg per kilogram of body weight per day), and 32 placebo. The study was terminated after approximately two years because there was no indication that vitamin C was beneficial and accumulating evidence that it might be harmful. Of 11 patients who left the study because of death or the requirement for dialysis or renal transplantation, eight were receiving ascorbic acid. The estimated relative risk (treatment vs. control) of an adverse event was R = 2.7, with a 90 per cent confidence interval of (0.8, 11.5). The serum creatinine concentration increased 0.53 mg per deciliter per year in patients receiving vitamin C and 0.24 mg per deciliter per year in patients receiving placebo (P = 0.08).

Management of the difficult nephrotic patient

Most children with nephrotic syndrome do well, usually with multiple relapses and remissions. Some children require high doses of oral steroids to sustain a remission and develop significant steroid toxicity. These patients frequently can be managed with oral alkylating agents or with cyclosporine. A few nephrotic children to not respond to oral prednisone. The most common biopsy finding in steroid-resistant patients is focal segmental glomerulosclerosis. Many patients with this condition progress to chronic renal failure. Evidence suggests that the outcome is improved with either cyclosporine or with a protocol using pulse intravenous methylprednisolone and oral alkylating agents.