Aaron L. Friedman

Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration.

Changes in proteinuria have been suggested as a surrogate outcome for kidney disease progression to facilitate the conduct of clinical trials. This report summarizes a workshop sponsored by the National Kidney Foundation and US Food and Drug Administration (FDA) with the following goals: (1) to evaluate the strengths and limitations of criteria for assessment of proteinuria as a potential surrogate end point for clinical trials in chronic kidney disease (CKD), (2) to explore the strengths and limitations of available data for proteinuria as a potential surrogate end point, and (3) to delineate what more needs to be done to evaluate proteinuria as a potential surrogate end point. We review the importance of proteinuria in CKD, including the conceptual model for CKD, measurement of proteinuria and albuminuria, and epidemiological characteristics of albuminuria in the United States. We discuss surrogate end points in clinical trials of drug therapy, including criteria for drug approval, the definition of a surrogate end point, and criteria for evaluation of surrogacy based on biological plausibility, epidemiological characteristics, and clinical trials. Next, the report summarizes data for proteinuria as a potential surrogate outcome in 3 broad clinical areas: early diabetic kidney disease, nephrotic syndrome, and diseases with mild to moderate proteinuria. We conclude with a synthesis of data and recommendations for further research. At the present time, there appears to be sufficient evidence to recommend changes in proteinuria as a surrogate for kidney disease progression in only selected circumstances. Further research is needed to define additional contexts in which changes in proteinuria can be expected to predict treatment effect. We recommend collaboration among many groups, including academia, industry, the FDA, and the National Institutes of Health, to share data from past and future studies.

Clinical trial of focal segmental glomerulosclerosis in children and young adults

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Circulating suPAR in Two Cohorts of Primary FSGS

Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.

Prospective trial of warfarin and dipyridamole in patients with membranoproliferative glomerulonephritis

A prospective trial of warfarin and dipyridamole was performed in patients with membranoproliferative glomerulonephritis. Eighteen completed either a control or treatment year, and 13 completed both a control and treatment year. To obviate the bias of excluding control patients who had renal failure after one year, both an unpaired and a paired analysis were performed. The unpaired analysis compared 10 patients followed for an initial control year with eight patients receiving treatment first. Renal function remained stable over the year in the treated group, but worsened in the control group. Slopes of regression lines for reciprocal serum creatinine values were significantly different between groups (p less than 0.025). Urine protein excretion also decreased in the treated group. Four of 10 control patients had a two-fold increase in serum creatinine levels, but no treatment patient did. In the paired crossover analysis, significant differences in renal function were detected between control and treatment years in six patients whose renal function significantly changed over one of the years. In every instance, there was better preservation of renal function in the treatment year. Urinary protein also decreased significantly over the treatment year compared with the control year. Bleeding was the most frequent complication. These data suggest that warfarin and dipyridamole have a beneficial effect on renal function in membranoproliferative glomerulonephritis.

Fluid therapy for children: Facts, fashions and questions

Fluid therapy restores circulation by expanding extracellular fluid. However, a dispute has arisen regarding the nature of intravenous therapy for acutely ill children following the development of acute hyponatraemia from overuse of hypotonic saline. The foundation on which correct maintenance fluid therapy is built is examined and the difference between maintenance fluid therapy and restoration or replenishment fluid therapy for reduction in extracellular fluid volume is delineated. Changing practices and the basic physiology of extracellular fluid are discussed. Some propose changing the definition of “maintenance therapy” and recommend isotonic saline be used as maintenance and restoration therapy in undefined amounts leading to excess intravenous sodium chloride intake. Intravenous fluid therapy for children with volume depletion should first restore extracellular volume with measured infusions of isotonic saline followed by defined, appropriate maintenance therapy to replace physiological losses according to principles established 50 years ago.

Oxidative stress in juvenile essential hypertension.

Objective Oxidative stress, an antioxidant/pro-oxidant imbalance, in patients with juvenile essential hypertension was measured via several biochemical parameters. As the blood pressure is associated with the body mass index (BMI), results were compared with those on BMI-matched controls. Design and setting A prospective observational study at a university teaching hospital. Patients Children and adolescents with essential hypertension (mean ± standard deviation: age 14.4 ± 3.1 years, BMI 25.0 ± 6.9 kg/m2, n = 52) before any treatment, and controls with a similar BMI distribution (age 14.3 ± 4.3 years, BMI 24.4 ± 6.6 kg/m2, n = 48). Methods Measurements were made of the plasma levels of (1) nitrites + nitrates, an indirect measure of available nitric oxide; (2) lipid peroxidation end-products, as malondialdehydes and free thiols; and (3) the redox status of the red blood cell glutathione, as a new oxidative stress parameter. Results There were decreased plasma levels of nitrates and increased levels of lipid peroxidation end-products in the hypertensive patients, resulting in a consistent increase in the plasma lipid peroxidation/nitric oxide ratio as compared with the controls with the same BMI (P < 0.01). This ratio additionally correlated directly with both the systolic and diastolic blood pressures for the overall patient population (P < 0.001). A significant glutathione depletion in the red blood cells resulted in an elevated ratio of oxidized/reduced forms with a reduced in vitro antioxidant protective capacity in the hypertensive patients versus the BMI-matched controls (P < 0.001). Conclusions The presence of systemic oxidative stress was proven in hypertensive children and adolescents, irrespective of their BMI.

Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial

Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone.

A prospective double-blind study of growth failure in children with chronic renal insufficiency and the effectiveness of treatment with calcitriol versus dihydrotachysterol

Because controlled trials in adults have shown accelerated deterioration of renal function in a small number of patients receiving calcitriol for renal osteodystrophy, we initiated a prospective, randomized, double-blind study of the use of calcitriol versus dihydrotachysterol in children with chronic renal insufficiency. We studied children aged 1½ through 10 years, with a calculated glomerular filtration rate between 20 and 75 ml/min per 1.73 m 2 , and with elevated serum parathyroid hormone concentrations. Ninety-four patients completed a mean of 8.0 months of control observations and were randomly assigned to a treatment period; 82 completed the treatment period of at least 6 months while receiving a calcitriol dosage (mean±SD) of 17.1±5.9 ng/kg per day or a dihydrotachysterol dosage of 13.8±3.3 μg/kg per day. With treatment the height z scores for both calcitriol- and dihydrotachysterol-treated groups showed no differences between the two groups. In relation to cumulative dose, there was a significant decrease in glomerular filtration rate for both calcitriol and dihydrotachysterol; for calcitriol the rate of decline was significantly steeper ( p =0.0026). The treatment groups did not differ significantly with respect to the incidence of hypercalcemia (serum calcium concentration >2.7 mmol/L (>11 mg/dl)). We conclude that careful follow-up of renal function is mandatory during the use of either calcitriol or dihydrotachysterol because both agents were associated with significant declines in renal function. There was no significant difference between calcitriol and dihydrotachysterol in promoting linear growth or causing hypercalcemia in children with chronic renal insufficiency. Dihydrotachysterol, the less costly agent, can be used with equal efficacy.

Extracellular fluid restoration in dehydration: a critique of rapid versus slow.

Abstract We compared current recommendations for treatment of severe dehydration by World Health Organization physicians and by the American Academy of Pediatrics Committee on Pediatric Gastroenterology with those in general textbooks of pediatrics, written mostly by pediatric nephrologists. The former recommend rapid (1- to 2-h) and generous intravenous restoration of extracellular fluid (ECF) volume followed by oral rehydration therapy (ORT) to replace potassium, current maintenance, and diarrheal losses – the rapid rehydration regimen. Oral feedings usually are resumed in 8–24 h. General textbooks of pediatrics usually recommend giving 20 ml/kg saline ”to restore circulation,” followed by the deficit therapy regimen to correct serum electrolyte abnormalities and replace remaining deficits of water, sodium, chloride, and potassium over 1–2 days. Mortality for hospitalized patients with dehydration treated with rapid rehydration was <3 per 1,000; no recent results are reported for patients treated by deficit therapy. The rapid rehydration regimen improves patient well being and restores perfusion, so that oral feedings are readily tolerated and renal function corrects serum electrolyte abnormalities in 6 h. Amounts of saline given correspond to amounts given for treating various forms of shock. Deficit therapy regimens provide less ECF restoration and are slower at restoring perfusion; tolerance for oral feedings is delayed. Two hundred pediatric nephrologists were surveyed, asking how they would treat a patient with severe dehydration and a patient with 40% burns. Only 30 of 200 responded; 29 used a deficit therapy regimen, with 20–40 ml/kg ECF replacement, while a majority rapidly and generously restored ECF volume in burn shock. We recommend that fluid therapy chapters should stop teaching deficit therapy for treating severe dehydration and instead teach the rapid rehydration regimen.

Effects of prolonged growth hormone administration in rats with chronic renal insufficiency

ABSTRACT: Recombinant hGH (rhGH) augments short-term linear growth in experimental animals and children with chronic renal failure. Significant augmentation of final height, however, requires prolonged growth hormone therapy during years of growth. The effects of prolonged rhGH treatment on linear growth, progression of renal dysfunction, and longevity in the setting of renal insufficiency are unknown. We examined at 9, 15, and 25 wk growth in length and weight, glomerular filtration rate measured by inulin and creatinine clearance, food efficiency (g ingested/weight gained), and survival in treated (U-GH) and untreated (U) 75% nephrectomized uremic rats and in treated (S-GH) and untreated (S) sham-operated rats. We also measured kidney weight to body weight ratios at the time the rats were killed. Treatment was rhGH 1.0 mg s.c. three times a week during wks 4–12 of life. Length of U-GII rats was greater than that of U rats (p < 0.05) at 15 and 25 wk (but not at 9 wk) and equal to that of S rats throughout the study. Length of S-GH rats exceeded that of S rats. At 9 wk, weight was diminished in both U and U-GH rats (p < 0.05) versus S and S-GH rats.; by 15 wk, U-GH rat weight was equal to S rat weight. Glomerular filtration rate measured by creatinine was markedly reduced in U and U-GH rats and did not increase in response to prolonged rhGH in either U-GH or S-GH rats. Diminished food efficiency of U rats versus S rats (p < 0.05) was not improved significantly by rhGH. Mortality from chronic renal failure was eight of 19 (42%) in U-GH rats compared with four of 13 (31%) in U rats. Both mean glomerular area and sclerotic index were increased in U-GH rats versus U rats (p < 0.05). The growth-promoting effect of rhGH was observed late (rather than early) in the growth period. Prolonged rhGH treatment did result in U-GH rats attaining length and weight comparable to S rats, ameliorating the growth failure due to uremia. Glomerular filtration rate was not adversely affected by prolonged rhGH treatment, and there appeared to be significant renal growth with growth hormone administration as measured by kidney weight/body weight ratio. Survival data, however, suggest that the growth-stimulating effect of rhGH in uremic animals may be accompanied by a trend toward reduced longevity, and histologic evaluation revealed increased glomerular hypertrophy and glomerulosclerosis in both normal and uremic rats treated with rhGH.