ACE inhibition has variable renal protective efficacy in the adriamycin model. Neither increasing the dose of the ACE inhibitor beyond the optimal level nor co-treatment with AII-A overcome the individual therapy resistance. Thus, in established adriamycin nephrosis, blockade of the renin-angiotensin system at two different levels offers no additional benefit over ACE inhibition alone, either on the group or individual level.

Renal function measurement by clearance methods relies on accurately timed urine collection. In small experimental animals, renal function measurement is usually performed under anesthesia and/or with the application of bladder catheters to ensure accurate urine collection. To avoid both anesthesia and the need for bladder catheters we developed a method to measure glomerular filtration rate (GFR) in spontaneously voiding conscious rats. GFR was measured as the urinary clearance of constantly infused 125I-iothalamate. To correct for incomplete bladder emptying urinary clearance of 125I-iothalamate was multiplied by the ratio of plasma and urinary clearance of simultaneously infused 131I-hippuran, a correction method that has been previously validated in humans. Reproducibility of the technique was evaluated by analysis of the results of four consecutive clearance periods during the day (intra-assay variation) in a group of 17 rats and of two consecutive clearance periods on two or three separate days in a group of 20 rats (inter-assay variation), all with normal renal function. Application of the correction method reduced the intra-assay coefficient of variation (mean +/- SD) from 37.4 +/- 14.3 to 5.4 +/- 2.3% (P < 0.05). The mean inter-assay coefficient of variation fell slightly from 23.4 +/- 10.3 to 11.0 +/- 7.2% (P < 0.10). In rats with moderately impaired renal function (N = 8) the intra-assay variation fell from 27.9 +/- 20.7 to 2.7 +/- 1.6% (P < 0.05). Our data show that this correction method is a useful technique to assess renal function in conscious, spontaneously voiding rats.

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A direct consequence of glomerular protein leakage is an increased exposure of proximal tubular cells to proteins. The aim of the present study was to examine whether chronic proteinuria affects the tubular handling of proteins and whether anti-proteinuric therapy by angiotensin-converting-enzyme (ACE) inhibition restores this tubular function. Renal uptake and catabolic rate of the low-molecular-weight protein (LMWP) myoglobin was determined in anaesthetized control and adriamycin-induced nephrotic rats by external counting after radiolabelling. Proteinuria correlated with the uptake as well as the catabolism of myoglobin. The higher the proteinuria, the lower was the renal uptake of myoglobin (r =0.72, P =0.002). Also, the catabolic rate of myoglobin (r =0.80, P =0.0002) was lower with increasing severity of proteinuria. During treatment with the ACE inhibitor lisinopril, proteinuria was lowered by 79+/-9% (mean+/-S.E.M.). Renal uptake and catabolic rate of the LMWP were not restored by ACE inhibition. The catabolic rate of myoglobin was even decreased further with 48+/-5% compared with pretreatment levels. In summary, adriamycin-induced proteinuria is associated with a lower uptake and a lower catabolic rate of LMWP in the proximal tubule. ACE inhibition lowers proteinuria, but does not restore the affected LMWP uptake and rate of catabolism. The rate of LMWP catabolism is even decreased further. In contrast, the urinary excretion of N -acetyl glucosaminidase, the tubular marker of toxicity, was effectively returned to normal levels during ACE inhibition. Taken together, the data suggest that proteinuria is toxic for the proximal tubular cells and that ACE inhibition protects the remaining functional tubular cells directly against destruction through decreasing hypercatabolism.

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