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.

Treatment of glomerulonephritis in the elderly.

With the increasing use of renal biopsy in the elderly, glomerulonephritis is now known to be a common finding. Whereas membranous glomerulonephritis and minimal change disease are common in younger and older adults, primary amyloidosis and crescentic glomerulonephritis are more common in the elderly. Other glomerulonephritides such as focal segmental glomerulosclerosis or IgA nephropathy are very uncommon in the elderly. Because of the serious consequences of the nephrotic syndrome and acute and chronic renal failure in the elderly, aggressive treatment with immunosuppression should not be withheld. Caution should always be taken because of the presumed greater morbidity and mortality from such treatment in the elderly.

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.

Polyclonal immunoglobulin G deposition disease: a unique entity.

We report a unique case of tubular polyclonal immunoglobulin G (IgG) deposition disease (PIDD) superimposed on diabetic nephropathy in an 84-year-old man presenting with subacute renal failure and proteinuria. The deposits were located exclusively between the tubular epithelial cells and the tubular basement membranes (TBMs) and stained intensely with antisera to IgG heavy chain and both kappa and lambda light chains. Electron microscopy revealed large predominantly extracellular electron-dense deposits with a distinctive curvilinear substructure. The associated light microscopic findings of tubular simplification with features of acute tubular necrosis implicate this tubulopathy as the cause of the acute renal failure. This appears to represent a unique entity that does not fit into any previously described category of renal tubular immune complex or immunoglobulin deposition disease.

Cyclosporine treatment of lupus membranous nephropathy.

Few studies describe the treatment of membranous nephropathy associated with systemic lupus erythematosus. Although cyclosporine-A has been used to treat patients with the nephrotic syndrome and also with systemic lupus, only a few of these patients have had lupus membranous nephropathy. In this pilot study, we assessed the safety and efficacy of cyclosporine in ten nephrotic patients with either pure membranous lupus nephropathy (seven patients) or membranous lupus nephropathy with superimposed mild proliferative lesions (three patients). Cyclosporine (4-6 mg/kg/day) alone (2 patients), or in conjunction with low dose corticosteroids (8 patients) was given for a period of up to 43 months. Six patients achieved a nadir proteinuria of less than 1 gram daily, two patients decreased urinary protein excretion to 1-2 grams daily, and the remaining two patients continued to excrete over 2 grams of protein daily. All patients experienced symptomatic improvement of their nephrotic syndrome and serum creatinine was not significantly increased at the end of the study period. Three patients with superimposed mild proliferative lesions experienced renal and systemic lupus flares while on treatment requiring additional immunosuppressive therapy. Side-effects were minor except for transient rises in serum creatinine in one patient and a case of drug-related hepatitis possibly caused by cyclosporine. Repeat renal biopsies in five patients revealed a decrease in the lupus activity index and a rise in the chronicity index. There was an increase in the stage of the membranous nephropathy on these repeat biopsies, but a reduction in the number of fresh deposits.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous "pulse" cyclophosphamide therapy of crescentic glomerulonephritis.

Pulse steroids and monthly intravenous cyclophosphamide with a rapid steroid taper were used to treat seven patients with crescentic glomerulonephritis. Despite major impairment of renal function, all patients had a marked improvement in GFR by six months and improvement in proteinuria occurred in six of the seven patients. Two patients were able to discontinue dialysis. The doses of steroids and cyclophosphamide used were less than in comparable studies and side-effects of therapy were minimal. Repeat renal biopsies at over one year demonstrated marked glomerulosclerosis despite relatively stable renal function. Histologic analysis of total glomerular involvement indices on serial biopsies suggested no recruitment of new glomeruli into the crescenteric process once treatment had been initiated. Thus, intravenous pulse cyclophosphamide with pulse steroid therapy appears to be a safe and effective initial therapy for some patients with RPGN. Significant glomerulosclerosis on repeat biopsies suggests that glomerulosclerosis may be predetermined by the initial degree of irreversible glomerular damage and that the long-term course of the disease remains guarded.

Acute deterioration of renal function associated with enteric hyperoxaluria.

Enteric hyperoxaluria due to malabsorption syndromes has been well documented to cause renal calculi and chronic tubulointerstitial renal damage. Rarely, in the setting of intestinal bypass operations for morbid obesity, enteric hyperoxaluria has produced acute renal failure. We report two patients who suffered acute deterioration of renal function associated with increased intestinal absorption and renal excretion of oxalate associated with steatorrhea. One patient had a large portion of his small bowel resected many years prior to the onset of the renal failure and the second patient had chronic pancreatitis causing steatorrhea. Both patients had renal biopsy documentation of the acute nature of the tubular damage produced by oxalate deposition. The mechanisms of their deterioration of renal function may relate to sudden increases in steatorrhea in association with episodes of volume depletion. Enteric hyperoxaluria may be an easily overlooked and potentially preventable etiology of acute renal dysfunction.

The hyperlipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, oncotic pressure, and viscosity.

Although hyperlipidemia is a common feature of the nephrotic syndrome, the distribution of cholesterol among the plasma lipoproteins and the mechanism of the enhanced hepatic synthesis of lipoprotein lipids are not well understood. We studied the distribution of cholesterol among the plasma lipoproteins, as well as the relation between total cholesterol and plasma albumin concentration, oncotic pressure, and viscosity in 20 consecutive adult patients with uncomplicated nephrotic syndrome. The total plasma cholesterol (mean +/- S.D., 302 +/- 100 mg per deciliter [7.8 +/- 2.6 mmol per liter]) and low-density-lipoprotein cholesterol concentrations (215 +/- 89 mg per deciliter [5.6 +/- 2.3 mmol per liter]) were elevated in most patients, but the high-density-lipoprotein cholesterol level was normal or low (46 +/- 18 mg per deciliter [1.2 +/- 0.5 mmol per liter]) in 95 per cent of the patients. Thus, many hypercholesterolemic patients with unremitting nephrotic syndrome may be at increased risk for atherosclerotic heart disease. A significant inverse correlation was found between the total plasma cholesterol concentration and both the plasma albumin concentration (r = -0.528) and the plasma oncotic pressure (r = -0.674), but not the plasma viscosity (r = +0.319). Enhanced hepatic synthesis of lipoprotein lipids may be stimulated by a decreased plasma albumin concentration or oncotic pressure but does not appear to be due to changes in plasma viscosity.

Potassium and renal failure.

Hyperkalemia caused by decreased renal K+ secretion may be seen in patients with mild, moderate, or severe ARF or CRF. Decreased K+ secretion by the distal tubule may be due primarily to a decrease in tubular fluid flow rate, as in ARF, or it may be due to diminished circulating aldosterone concentrations, as in patients with hyporeninemic hypoaldosteronism. Patients with CRF adapt to K+ loads by increasing K+ excretion per nephron as well as by transferring K+ more rapidly into cells. However, an increased K+ load may still produce hyperkalemia in the CRF patient because of limitations in the adaptive responses. Hyperkalemia may present a true medical emergency in the patient with renal failure. Although the serum K+concentration can usually be controlled by the administration of calcium, glucose and insulin, sodium bicarbonate, diuretics, and/or the use of K+ exchange resins, dialysis may be necessary. Hyperkalemia complicating acute or chronic renal failure is an important, common problem requiring the use of peritoneal dialysis or hemodialysis.