Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant membranous nephropathy (MGN) was conducted. Although MGN remains the most common cause of adult-onset nephrotic syndrome, its management is still controversial. Cyclosporine has been shown to be effective in cases of progressive MGN, but it has not been used in controlled studies at an early stage of the disease. METHODS: We conducted a randomized trial in 51 biopsy-proven idiopathic MGN patients with nephrotic-range proteinuria comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 78 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy-five percent of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 43% (N = 9) of the cyclosporine remission group and 40% (N = 2) of the placebo group by week 52. The fraction of the total population in remission then remained almost unchanged and significant different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period. In the subsequent follow-up, renal insufficiency, defined as doubling of baseline creatinine, was seen in two patients in each group, but remained equal and stable in all of the other patients. CONCLUSION: This study suggests that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of MGN. Although a high relapse does occur, 39% of the treated patients remained in remission and were subnephrotic for at least one-year post-treatment, with no adverse effect on filtration function.

A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.

UNLABELLED: A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. BACKGROUND: A clinical trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) was conducted. Despite the fact that it is the most common primary glomerulonephritis to progress to renal failure, treatment trials have been very limited. METHODS: We conducted a randomized controlled trial in 49 cases of steroid-resistant FSGS comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 200 weeks, and the short- and long-term effects on renal function were assessed. RESULTS: Seventy percent of the treatment group versus 4% of the placebo group (P < 0. 001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 40% of the remitters by 52 weeks and 60% by week 78, but the remainder stayed in remission to the end of the observation period. Renal function was better preserved in the cyclosporine group. There was a decrease of 50% in baseline creatinine clearance in 25% of the treated group compared with 52% of controls (P < 0.05). This was a reduction in risk of 70% (95% CI, 9 to 93) independent of other baseline demographic and laboratory variables. CONCLUSIONS: These results suggest that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of FSGS. Although a high relapse rate does occur, a long-term decrease in proteinuria and preservation of filtration function were observed in a significant proportion of treated patients.

Hepatitis B virus vaccine: a randomized trial of a reduced dose regimen in hemodialysis patients.

To test the hypothesis that increasing the dose enhances response to hepatitis B virus vaccine in hemodialysis patients, we performed a randomized, double blind, controlled clinical trial. Twenty-four hemodialysis patients were randomly assigned to receive either three 20 mcg or the recommended three 40 mcg intramuscular injections over 6 months. In addition, 19 normal volunteers also received three 20 mcg doses of the vaccine. The presence of Anti-HBs was determined qualitatively and quantitatively. Non-uremic subjects seroconverted more frequently than did either of the dialysis patient groups. Doubling the individual doses of vaccine did not improve the response of the dialysis patients. We conclude that the response to the vaccine is not diminished when dialysis patients are given half the recommended dose of the vaccine and that the cost of vaccinating this high-risk population could be substantially reduced.

Roentgenographic manifestations of maxillomandibular renal osteodystrophy.

We examined 30 male chronic hemodialysis patients and 18 male controls without known bone or renal disease to determine the utility of maxillomandibular, non-dominant hand, shoulder and pelvis films in the evaluation of renal osteodystrophy. We used panoramic periapical radiographs to examine the maxilla and mandible and sensitive rapid processing films for the hand, shoulder and pelvis. Films were evaluated by experienced personnel without knowledge of the patients. There were significant differences between patients and controls in creatinine, urea nitrogen, total protein, albumin, alkaline phosphatase and phosphorus. Twenty-three patients had abnormal hand radiographs and 22 patients had abnormal jaw radiographs (p less than 0.05 vs. controls). Four patients had changes in the hands, but not in the jaw; 4 had opposite findings. Changes in the jaw tended to be more severe than in the hands in those with involvement of both. We concluded that dental and hand radiography are good screening techniques for evaluating bone disease. They may be useful in evaluating treatment for renal osteodystrophy.

Primary glomerulonephritis complicating diabetic nephropathy: report of seven cases and review of the literature.

Glomerulonephritis has been recognized as a rare complication of diabetes mellitus. The clinical, pathologic, and laboratory findings for 18 diabetic patients were reviewed. Eight of these patients (44 per cent) were found to have primary glomerulonephritis in addition to diabetic nephropathy. Although this series may not represent the true incidence of complicating glomerulonephritis in diabetes, it is probable that the incidence of this condition has been underestimated. An additional 26 previously reported cases are reviewed.

Are home hemodialysis aides cost-effective? Cost of home hemodialysis aides.

Payment for home hemodialysis aides has been proposed as a means of inducing shifts from center hemodialysis to less-expensive home hemodialysis. By using a simulation model, we computed the cost per life year of end-stage renal disease care when changes in the proportions of patients treated by center for home hemodialysis are brought about by paying for home hemodialysis aides. If all home hemodialysis patients receive payment for aides, total costs will increase unless there are sufficient shifts from center to home hemodialysis to offset the increased costs. The cost-effectiveness of home hemodialysis aides is critically dependent on who receives a paid aide, the salary of the aid, and the number of patients who move from center to home hemodialysis. Poorly formulated regulations may jeopardize the cost-effectiveness of home hemodialysis and increase the total cost of end-stage renal disease care.

Mezlocillin pharmacokinetics in renal impairment.

Mezlocillin kinetics was examined in 28 adult subjects with varying renal function. Mezlocillin 3 gm, was infused over 30 min. Mean peak plasma concentrations ranged from 204 to 253 mg/I. When the area under the curve (AUC) was plotted against creatinine clearance (CCr), the relationship found was expressed by the equation AUC = 656e(-0.01)(CCr). From this relationship a dosage nonogram was derived describing a power function with the following equaton: Dose fraction = 1.32--e(-0.01)(CCr). Therapeutic guidelines are suggested.

Cost-effective care of end-stage renal disease: a billion dollar question.

We examined the survival time and costs of therapy for patients with end-stage renal disease. A computer simulation model of the current system was constructed to estimate the cost-effectiveness of home and center hemodialysis and live related as well as cadaver donor renal transplantation. Analysis of the simulation showed that live related donor transplantation was the least costly and had the greatest survival time, while center hemodialysis had the poorest cost-effectiveness. By simulating changes to the present system of care, we found that shifts from center dialysis to either home dialysis or cadaver donor transplantation would save $7000 to $8000 per life year, or $284 million per year for the existing end-stage renal disease population. However, if legislative changes fail to produce real shifts from center hemodialysis, costs will increase. We conclude that the substantial costs for end-stage renal disease can be contained by shifting from the widespread use of center hemodialysis.

Diuretics, hepatic and thoracic duct lymph flows in the dog.

1. Simultaneous thoracic duct and hepatic lymph flows were measured in 29 mongrel dogs before and after the intravenous administration of mannitol, ethacrynic acid, frusemide and chlorothiazide in separate experiments. 2. Thoracic duct lymph flow increased significantly after each diuretic agent was administered. 3. Hepatic lymph flow increased only after ethacrynic acid and mannitol administration. Frusemide and chlorothiazide did not alter hepatic lymph flow. 4. These data show that increases in thoracic duct lymph flow after ethacrynic acid and mannitol arise partly from the liver, as well as from other organs.

Home health care: the dietitian's role.

Nutritional services are an important part of the home care program. Medicare, Medicaid, and other third-party mechanisms do not reimburse providers for such services, even though the cost for home care is lower than for institutional care. Recognizing the need for nutritional services, the Veterans Administration has included the dietitian as a member of the home care team. Skills and guidelines developed by The American Dietetic Association for home and ambulatory care were adapted and utilized in developing a dietetic home care procedure which helps to avoid institutional care and provides a better quality of life at home. Nutritional services should be an integral part of all home health care programs. Because most home care programs do not have funds for a dietitian's service, legislative and/or regulatory action is needed to provide reimbursement for nutritional home care services.

Protection from gentamicin nephrotoxicity by cephalothin and carbenicillin.

In rats, cephalothin exerts a protective effect upon the nephrotoxicity of gentamicin. To examine the possibility that this effect is also observed with carbenicillin, we gave the following (milligrams per kilogram) to rats daily for 14 days: gentamicin alone, 60; gentamicin plus cephalothin, 100, 500, or 1,000; gentamicin plus carbenicillin, 50, 100, 250, 500, or 1,000. A 500-mg/kg dose of cephalothin afforded significant partial protection from gentamicin nephrotoxicity, as did a 100-mg/kg dose of carbenicillin. Increasing doses of either drug failed to increase protection. The data suggest that in rats not only does carbenicillin afford some protection from gentamicin nephrotoxicity, but also that it does so at a lower dose than cephalothin. These findings may in part explain the divergent observations regarding the nephrotoxicity of cephalothin-gentamicin combination therapy in rats and humans.

Comparative nephrotoxicity of aminoglycoside antibiotics in rats.

Netilmicin, gentamicin, tobramycin, amikacin, kanamycin, streptomycin, and sisomicin were given daily for 15 days to groups of rats at three dosage levels corresponding to 10, 15, or 25 times the dose recommended for humans on a weight basis. Decreased urinary osmolality and increased urinary excretion of protein and beta-N-acetyl hexosaminidase were dose-related features of nephrotoxicity. Decreased tubular resorption of glucose and phosphate were observed with the most toxic regimens after extensive renal damage had occurred. All aminoglycosides accumulated in renal tissue; however, the concentration of drug in the renal cortex at the time the rats were killed was not useful for the prediction of renal impairment. Streptomycin and netilmicin exhibited a flat dose-reponse curve with respect to histological damage, as compared with the curves for the other drugs. Results of studies of creatinine clearance and examination of renal tissue suggested the following order of increasing toxicity of the treatment regimens: (1) 0.9% NaCl and uninjected controls; (2) streptomycin; (3) netilmicin; (4) tobramycin; (5) sisomicin, amikacin, and kanamycin; and (6) gentamicin.

Pharmacokinetics of netilmicin in patients with renal impairment and in patients on dialysis.

The pharmacokinetics of netilmicin were examined in 25 adult subjects, 7 normal subjects, and 18 patients with renal impairment. Five were dialysis patients who were studied on and off dialysis. Netilmicin, 2 mg/kg, was infused intravenously over 1 h. The peak serum concentration ranged from 9 to 11 mug/ml. The mean biological half-life of netilmicin for subjects with a creatinine clearance (Ccr) > 70 ml/min was 2.7 h, for those with Ccr > 25 < 70 ml/min it was 10 h, for those with Ccr > 4 < 25 ml/min it was 32 h, and for those who were anephric it was 42 h. Ccr was correlated positively with the elimination constant and the drug's serum clearance. It was negatively correlated with the drug's volume of distribution. The dialyzer clearance of netilmicin was positively correlated with plasma flow rate and was similar to values previously reported for gentamicin. Netilmicin behaves in a fashion similar to other aminoglycosides. Therapeutic guidelines are suggested.

Failure of plasma exchange and immunosuppression to improve renal function in Goodpasture's syndrome.

A young woman with anti-glomerular basement membrane (GBM) antibody mediated rapidly progressive glomerulonephritis and pulmonary hemorrhage was treated with immunosuppression and intensive plasma exchange. She did not have end stage renal failure when therapy was initiated. Despite a dramatic reduction in circulating anti-GBM antibody, renal function progressively decreased. The role of plasma exchange in the therapy of anti-GBM antibody mediated disease remains unclear.

Prevailing patterns and predictor variables in patients with acute tubular necrosis.

The courses of 276 acute tubular necrosis patients referred for dialysis were reviewed in search for prognostic indicators. Sixty-three percent survived. Of 28 possible predictor variables, a posttoxic cause and nonoliguria were favorable, whereas myocardial infarction and peritonitis affected survival unfavorably. Total pareneral nutrition influenced survival favorably only in those with multiple complications or peritonitis. No single variable or combination predicted a lethal outcome. Since survivors were frequently restored to complete health, we advocate an aggressive therapeutic approach even in the face of multiple complications.

Calcitriol in dialysis patients.

We conducted a 7-month randomized, single, double, single-blind comparison of calcitriol (1,25(OH)2D3) with vitamin D3 in 22 hemodialysis patients to study the effects on the biochemical abnormalities associated with osteodystrophy. Calcitriol was given for 3 mo. All patients had initial prestudy calcium values less than or equal to 9.5 mg/100 ml, and phosphate values less than or equal to 4.5 mg/100 ml. Data were analyzed using the Normalized Trend Index (NTI). Calcitriol induced a rise in calcium (8.7 to 10.25 mg/100 ml) (p less than 0.001) and a fall in alkaline phosphatase (p less than 0.005), while D3 had no appreciable effect. The mean dose of calcitriol during treatment was 0.579 microgram/day while that for D3 was 706 IU/day. The effect on serum phosphate concentration was variable. Hypercalcemia as high as 13.2 mg/100 ml occurred in 2 of 13 patients on 1,25(OH)2D3, but in every instance promptly returned to normal with dose reduction. No other adverse effects were noted with therapy. We conclude that calcitriol reverses the biochemical abnormalities of osteodystrophy. Since its effects are rapidly reversed with discontinuation, the drug is probably safe as well as effective.

Nephrotoxicity of netilmicin in combination with non-aminoglycoside antibiotics.

To assess the possibility that non-aminoglycoside antibiotics may adversely affect the nephrotoxicity of the new semisynthetic aminoglycoside netilmicin, we gave ampicillin, carbenicillin, methicillin, cefamandole, and clindamycin, either singly or in combination with netilmicin, at two dose concentrations in rats. Results were compared as to the effect of netilmicin given singly and to saline-injected and noninjected controls. Antibiotic combinations resulted in no greater nephrotoxicity than did netilmicin alone. Netilmicin concentrations in renal tissue were high, and these levels were not consistently affected by the other drugs. The data suggest that in rats the nephrotoxicity of netilmicin is not affected adversely by the presence of non-aminoglycoside antibiotics.