The mechanism of the diuretic braking phenomenon was studied in nine male hypertensive patients by assessing the diurnal pattern of renal sodium (Na) excretion during furosemide therapy, and the response to a test dose of furosemide (10 to 15 mg hr-1 i.v.) infused alone and with chlorothiazide (500 mg bolus i.v.). Patients were studied after one month of twice-daily administration of: placebo (P): chlorothiazide 500 mg (C); furosemide 40 mg (F); furosemide with spironolactone (100 mg b.i.d.) for the last 36 hours (F + S; N = 6). During F therapy, furosemide-induced natriuresis was followed by six hour periods of decreased UNaV. Diuretic therapy with F or C for one month reduced BP, but did not alter body weight, plasma volume (PV), glomerular filtration rate or PAH clearance. After P, the test infusion of furosemide increased fractional Na excretion (FENa) by +10.5 +/- 0.7%; this increment was reduced after therapy with F (+8.9 +/- 0.7%; P less than 0.05), C (+8.5 +/- 1.0%; P less than 0.01), or F + S (+8.9 +/- 0.9%; P less than 0.05). Renal furosemide excretion was greater (P less than 0.05) after F and C treatments (133 +/- 10 micrograms.min-1 and 130 +/- 13 micrograms.min-1, respectively) compared with P (94 +/- 9 micrograms.min-1). After P, a test dose of chlorothiazide given during furosemide infusion increased FENa further (+7.5 +/- 1.2%); this increment was greater after therapy with F (+10.1 +/- 1.4%; P less than 0.01) and F + S (+11.3 +/- 0.8%; P less than 0.05) but not after C (+6.3 +/- 1.5%; P greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of < 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140±6 vs. 122±5 ml/min, P < 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy. (J. Clin. Invest. 1991. 88:524-530.) Key words: hyperfiltration * barrier size-selectivity * transmembrane protein shunting. heteroporous membrane models Introduction Considerable evidence in experimental animals and some indirect evidence in humans suggests that the development ofinsu-

Abstract. Collapsing focal segmental glomerulosclerosis (FSGS) is a distinct clinicopathologic entity seen most commonly in young African American patients who present with renal insufficiency and nephrotic syndrome. The only epidemiologic factor previously linked to collapsing FSGS is HIV infection. Here clinicopathologic findings are reported for a distinctive population of seven patients, who were older, Caucasian, and HIV negative and developed collapsing FSGS during active treatment of malignancy (multiple myeloma in six patients and metastatic breast carcinoma in one). Although oncologic treatment regimens included vincristine for four patients, doxorubicin for five patients, cisplatin for two patients, and total-body irradiation for one patient, the only agent common to all patients was pamidronate (Aredia). All patients had normal renal function before the administration of pamidronate. Patients began therapy with pamidronate at or below the recommended dose of 90 mg, intravenously, monthly, which was increased to 180 mg monthly in two patients and 360 mg monthly in three patients. Patients received pamidronate for 15 to 48 mo before presentation with renal insufficiency (mean serum creatinine, 3.6 mg/dl) and full nephrotic syndrome (mean 24-h urinary protein excretion, 12.4 g/d). Pamidronate, which is a member of the class of bisphosphonates, is widely used in the treatment of hypercalcemia of malignancy and osteolytic metastases. At the recommended dose of 90 mg, intravenously, monthly, renal toxicity is infrequent; however, higher doses have produced nephrotoxicity in animal models. The temporal association between pamidronate therapy and the development of renal insufficiency, the use of escalating doses that exceed recommended levels, and the distinctive pattern of glomerular and tubular injury strongly suggest a mechanism of drug-associated podocyte and tubular toxicity. These data provide the first association of collapsing FSGS with toxicity to a therapeutic agent.

Furosemide increases sodium (Na+) and potassium (K+) excretion but if dietary salt is provided, a compensatory reduction in Na+ and K+ excretion follows which restores neutral balances within 18 to 24 hours. This compensation is not interrupted by blockade of the renin-angiotensin-aldosterone system (RAA) alone with captopril. Since plasma norepinephrine concentration increases after furosemide and alpha 1 adrenoreceptors can mediate enhanced Na+ reabsorption, we administered prazosin (2 mg 6 hr-1) to six normal volunteers consuming a daily intake of 270 mmol of Na+ and 75 mmol of K+, and added captopril (25 mg 6 hr-1) for an additional day to block the RAA system concurrently. Furosemide (40 mg day-1) was given for the last four days. Prazosin given alone before the diuretic reduced (P less than 0.05) BP and plasma angiotensin II (AII) concentration and increased body weight and heart rate. However, when given with furosemide, neither prazosin nor prazosin with captopril modified the short-term natriuretic or kaliuretic responses to furosemide, or the ensuing compensatory reductions in Na+ and K+ excretion. Accordingly, cumulative balances for Na+ and K+ remained neutral over four days of diuretic administration. Neither drug altered the renal responsiveness to the diuretic which was assessed from the relationship between renal Na+ and K+ excretion and diuretic elimination. Although the BP was maintained when furosemide was given alone, when given with prazosin and captopril, the mean BP fell by 13 +/- 5 mm Hg (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)