Karen M. Gaudio

Steroid-Responsive Nephrotic Syndrome of Childhood: A Long-Term Study of Clinical Course, Histopathology, Efficacy of Cyclophosphamide Therapy, and Effects on Growth

The long-term clinical course of 60 children with steroid-responsive nephrotic syndrome, observed for a minimum of 10 years from onset, was studied (mean 14.5 +/- 0.5 years). Four children had only a single episode, seven children experienced only one to three relapses early in their course, and the remaining 49 patients (82%) experienced frequently relapsing steroid-dependent disease. Nearly half of these (47%) continued to relapse into their late teens and early twenties. All 20 children treated with cyclophosphamide because of steroid-induced side effects developed complete remissions of the nephrotic syndrome. These were sustained in 70% for 9.1 +/- 0.6 years, with a reduction of disease severity in the remaining 30%. In contrast, only 48% of patients treated with prednisone alone were in remission at last follow-up (P = .06). Ten of the children treated with cyclophosphamide had the minimal change lesion prior to therapy; 90% of these had permanent remissions. Only 50% of the six children with focal glomerulosclerosis and four children with mesangial proliferation have had permanent remissions. None of the patients developed renal insufficiency. Children treated with prednisone alone were -0.93 +/- 0.3 SD below the mean for height at last follow-up. Cyclophosphamide treatment was associated with an increase in height SD scores from -0.84 +/- 0.4 to -0.28 +/- 0.3. Children with severe growth impairment demonstrated dramatic catch-up growth when treated with cyclophosphamide with SD scores increasing from -2.29 +/- 0.8 to -0.43 +/- 0.6 (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effect of thyroxin in the treatment of ischemic acute renal failure.

To evaluate the effect of thyroxin (T4) on recovery from ischemic acute renal failure, rats were treated with T4 (10 or 20 μg/100 g body wt.) or normal saline (NS) either immediately prior to, immediately after or 24 h after 45 min of renal ischemia. Animals given T4 prior to ischemia had no significant increase in Inulin clearance (Cin) (377±40 μl/min per 100 g body wt.) as compared with saline-treated ischemic controls (306±54). In contrast, animals treated immediately after ischemia with either dose of T4 demonstrated significantly better kidney function (Cin 515±59 μl/min per 100 g body wt., Uosm 842±88 mosmol/kg, FENa 0.52%±0.12% and Cin 543±71, Uosm 939±103, FENa 0.48±0.12, for 10 and 20 μg/100 g body wt., respectively). Moreover, the improvement in renal function was sustained and Cin was significantly better at day 3 (748±70) and day 7 (990±75) compared with saline controls (560±30 and 732±45, respectively). Animals which received T4 24 h after ischemia showed significantly higher Cin when compared with ischemic controls. To assess the impact of T4 on recovery of renal ATP,31P-NMR was used. T4-treated rats demonstrated 90%±5% recovery of renal ATP by 120 min of reflow, whereas NS animals had only 64%±1%. In addition, cellular morphology was better preserved in T4 animals. These data indicate that animals treated postischemically with T4 showed accelerated and sustained recovery from acute renal failure. This beneficial effect appears to be related to cellular mechanisms which are essential for the restoration of sublethally injured cells.

Effect of treatment with cyclosporine versus azathioprine on incidence and severity of cytomegalovirus infection posttransplantation.

The incidence and severity of cytomegalovirus (CMV) infection were evaluated in 24 renal transplant patients treated with steriods and cyclosporine and compared with 40 patients treated with steroids and azathioprine: 58% of patients receiving azathioprine and 33% of patients receiving cyclosporine required additional therapy with antithymocyte globulin (ATG) to treat steroid-resistant rejections. CMV antibody titers and cultures of urine and saliva were determined monthly for 4–6 months following transplant in all patients. Both the frequency of CMV infection (occurring in 58% of patients on steroids and cyclosporine and in 48% of patients on steroids and azathioprine) and its severity (21% of cyclosporine-treated patients and 22% of azathioprine-treated patients with symptoms) were similar in both groups. Use of ATG was associated with an increased incidence of CMV disease, especially for patients in the azathioprine group. Both the incidence of CMV disease, and the number of patients with symptoms in the azathioprine group were significantly lower when patients who had received ATG were excluded from analysis. When results were analyzed in just the cadaveric recipients in each group, the incidence and severity of CMV infection tended to be higher in azathioprine-treated patients compared with those maintained on cyclosporine. This could have been explained by the more frequent use of ATG in 84% of azathioprine maintained patients compared with 35% of cyclosporine

Role of heat stress response in the tolerance of immature renal tubules to anoxia

The stress response was studied in suspensions of tubules from immature (IT) and mature (MT) rats after noninjury, heat, oxygen, and anoxia. Under all conditions, IT exhibited more exuberant activation of heat shock transcription factor (HSF) than MT. Characterization of activated HSF in immature cortex revealed HSF1. Also, 2 h after each condition, heat shock protein-72 (HSP-72) mRNA was twofold in IT. As the metabolic response to 45 min of anoxia, 20-min reoxygenation was assessed by measuring O2 consumption (O2C). Basal O2C was manipulated with ouabain, nystatin, and carbonylcyanide p-chloromethyoxyphenylhydrazone (CCCP). Basal O2C in IT were one-half the value of MT. After anoxia, basal O2C was reduced by a greater degree in MT. Ouabain reduced O2C to half the basal value in both noninjured and anoxic groups. Basal O2C was significantly stimulated by nystatin but not to the same level following anoxia in MT and IT. Basal O2C was also stimulated by CCCP, but after anoxia, CCCP O2C was significantly less in MT with no decrease in IT, suggesting mitochondria are better preserved in IT. Also, O2C devoted to nontransport activity was better maintained in IT.The stress response was studied in suspensions of tubules from immature (IT) and mature (MT) rats after noninjury, heat, oxygen, and anoxia. Under all conditions, IT exhibited more exuberant activation of heat shock transcription factor (HSF) than MT. Characterization of activated HSF in immature cortex revealed HSF1. Also, 2 h after each condition, heat shock protein-72 (HSP-72) mRNA was twofold in IT. As the metabolic response to 45 min of anoxia, 20-min reoxygenation was assessed by measuring O2 consumption (O2C). Basal O2C was manipulated with ouabain, nystatin, and carbonylcyanide p-chloromethyoxyphenylhydrazone (CCCP). Basal O2C in IT were one-half the value of MT. After anoxia, basal O2C was reduced by a greater degree in MT. Ouabain reduced O2C to half the basal value in both noninjured and anoxic groups. Basal O2C was significantly stimulated by nystatin but not to the same level following anoxia in MT and IT. Basal O2C was also stimulated by CCCP, but after anoxia, CCCP O2C was significantly less in MT with no decrease in IT, suggesting mitochondria are better preserved in IT. Also, O2C devoted to nontransport activity was better maintained in IT.

Pathogenesis and Treatment of Acute Renal Failure

This article reviews the current understanding of the pathophysiologic sequence of events that culminate in an acute renal insult. The use of urinary indices to differentiate the physiologic causes of oliguria, namely, diminished intravascular volume or renal perfusion, from an established acute renal failure, is discussed for children and adolescents, as well as for neonates. Treatment modalities for the support of children with acute renal failure are described in detail.

Progression of Orthostatic Proteinuria to Focal and Segmental Glomeruloscierosis

Focal glomerulosclerosis, with the nephrotic syndrome and progressive renal insufficiency, developed in a 15-year-old boy who presented initially 1 year earlier with orthostatic proteinuria. Although generally considered to be a benign disorder, this case suggests that on rare occasions, serious glomerular diseases may develop in patients with orthostatic proteinuria or that significant glomerular disease may occasionally present with postural proteinuria.

Serum hemolytic factor D values in children with steroid-responsive idiopathic nephrotic syndrome

Serum hemolytic factor D activity, an important component of the ACP, was measured in patients with SR-INS. The mean serum factor D hemolytic activity of patients with SR-INS in relapse was significantly reduced compared to the mean of the control group. Twenty-one of 27 SR-INS patients in relapse (78%) had reduced serum factor D activity. In contrast, the mean serum factor D hemolytic activity of SR-INS patients in remission was not significantly different from that in the control group. Factor D hemolytic activity was also reduced in other types of renal disease with the nephrotic syndrome. Serum factor D values were highly correlated with the serum albumin concentration. Although hemolytic factor D activity could not be detected in the urine, the low molecular weight and the significant correlation with serum albumin concentration suggest that urinary loss is responsible for the low serum levels of factor D. Deficient serum values of factor D may contribute to the increased susceptibility of SR-INS patients in relapse to bacterial infections with organisms which activate the ACP.

Glycolysis Is Not Responsible for the Tolerance of Immature Renal Tubules to Anoxia

We have previously shown that the immature tubule is tolerant of prolonged anoxia. In addition, cellular ATP is maintained at 2-fold higher levels during anoxia in the immature tubules compared with the mature tubules. The purpose of this study was: 1) to determine whether anaerobic glycolysis contributes to the tolerance to anoxia and preservation of cellular ATP in immature tubules and 2) to evaluate whether the tolerance demonstrated by immature tubules is dependent on preservation of cellular ATP. Suspensions of proximal tubules from immature (8-10 d) and mature (8-10 wk) rats were subjected to 15 and 45 min of anoxia in a standard buffer and in buffers designed to inhibit glycolysis. Lactate dehydrogenase release was used to assess plasma membrane damage, ATP levels were determined as an index of cellular energy and total lactate production was measured to evaluate glycolytic activity. After 45 min of anoxia, total lactate production was less in immature tubules (101 ± 48 μg of lactate/mg of DNA) compared with mature tubules (148 ± 36 μg of lactate/mg of DNA). After inhibition of glycolytic metabolism, ATP decreased to similar levels in both immature and mature tubules. However, immature tubules remained resistant to anoxic damage(lactate dehydrogenase: mature tubules 38 ± 4%, immature tubules 29± 1.0%). Therefore, enhanced glycolytic activity does not play a dominant role in the tolerance of the developing kidney to anoxia, and this tolerance is not primarily dependent on preservation of cellular ATP.

Immature renal tubules are resistant to prolonged anoxia

ABSTRACT: Very few data are available regarding the decreased susceptibility of the developing kidney to anoxia. Therefore, the purpose of this study was to develop an experimental system that would allow comparison of an anoxic insult in immature and mature proximal tubule segments and to investigate the hypothesis that the developing kidney is resistant to anoxia as compared with the mature kidney. Suspensions of proximal tubules from immature (age 8–10 d) and mature (8–10 wk) rats were obtained. The purity of the tubule suspension from the immature rats was documented by villin staining. A common buffer solution was developed to compare results from the immature and mature tubules. To study the response of the tubules to anoxia, we subjected the tubule suspension from both the immature and mature rats to 15, 30, 45, and 60 min of anoxia. Lactate dehydrogenase release was measured to assess plasma membrane damage, and ATP levels were determined as an index of cellular energy. After a short anoxic insult (15 or 30 min), the percentage of lactate dehydrogenase release was not significantly different from mature tubules. After prolonged anoxia (45 and 60 min) lactate dehydrogenase release continued to increase, whereas membrane integrity stabilized in the immature tubules. ATP levels decreased in both immature and mature tubules after anoxia, but the decline of ATP was greater in the mature tubules, with a plateau at 20% of basal ATP levels as compared with 40% in the immature tubules. Therefore, the developing kidney is resistant to prolonged anoxia.

Immature tubules are tolerant of oxygen deprivation

The tolerance of immature tissues to injury has been noted over the past several decades. Traditional teaching relates this tolerance to energy derived from anaerobic glycolysis. This mini-review describes investigations of the hypothesis that the immature kidney is less susceptible to oxygen deprivation than the mature kidney. Utilizing proximal tubule suspensions from immature and mature rats, studies assessing ATP levels as an index of cellular energy and lactate dehydrogenase (LDH) release as a determinant of plasma membrane damage demonstrate the developing kidney is resistant to prolonged anoxia. ATP is maintained at twofold higher levels during anoxia in the immature tubule compared with the mature tubule. The contribution of anaerobic glycolysis to the tolerance of the immature renal tubules is investigated by two inhibitors of the glycolytic pathway, L-glucose and iodoacetate. Following 70% – 90% inhibition of glycolysis, ATP is decreased to similar levels in immature and mature tubules. However, immature tubules remain resistant to anoxic damage with no significant change in LDH release. Therefore, enhanced glycolytic activity does not play a dominant role in the tolerance of the developing kidney to anoxia, and this tolerance is not primarily dependent on preservation of cellular ATP.