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The number of patients with hypertension-associated end-stage renal failure (ESRF) continues to increase despite improved antihypertensive management and early detection programs. Variation for the development of renal complications in hypertension may reflect independent genetic susceptibility to ESRF. The genetically hypertensive fawn-hooded rat is characterized by the early presence of systolic hypertension, glomerular hypertension, progressive proteinuria (UPV), and focal glomerulosclerosis (FGS), resulting in premature death as a result of renal failure. In the present study, the genetic basis of hypertension-associated ESRF in an F2 intercross consisting of 337 animals, in which systolic BP, UPV, albuminuria, and FGS, were studied at 8 wk after a unilateral nephrectomy performed at 5 to 6 wk of age. A total genome scan, consisting of 418 markers, was used to identify regions that contribute to the pathogenesis of UPV and FGS. Linkage analysis revealed five loci involved in the development of renal impairment. Of these five, two (Rf-1, Rf-2) had been identified previously. There seems to be strong interactive effects between the various loci and their impact on UPV and the other parameters of renal impairment, as well as an interaction with BP. In particular, Rf-1 seems to play a major role in determining the severity of the disease. This study is the first to report the interaction of more than two loci to produce progressive renal failure, suggesting that the genetic dissection of renal failure in humans will require understanding of how multiple genes interact with each other and BP to produce ESRF.

Background: Fawn-hooded hypertensive (FHH) rats carry several genes which determine the susceptibility to develop renal damage, while renal damage resistant August x Copenhagen Irish (ACI) rats do not. Kidneys from heterozygous (FHH x ACI) F(1) rats, appear to be largely, but not completely, protected after blood pressure elevation with N(omega)-nitro-L-arginine methyl ester (L-NAME). We examined the role of an increased haemodynamic burden on the development of renal damage combining unilateral nephrectomy (UNx)- and L-NAME-induced hypertension in F(1) and ACI rats. Additionally, we investigated whether a general toxic effect of L-NAME, independent from a blood pressure elevation, caused renal damage in F(1) rats in animals simultaneously treated with L-NAME and the ACE inhibitor lisinopril., Methods: Surgery was performed and L-NAME treatment (50 or 150 mg/l) was started at the age of 15 weeks. Systolic blood pressure (SBP) and urinary albumin excretion (UaV) were measured at 6 and 12 weeks post-UNx, followed by autopsy to determine the incidence of focal glomerulosclerosis (FGS). Using lisinopril (LIS) and L-NAME, another group of rats was evaluated at 12, 18, and 24 weeks after start of treatment., Results: At similar L-NAME intake, F, rats developed more severe hypertension and more UaV than ACI rats. The increase in UaV per mmHg increase in SBP was fivefold higher in F(1) compared with ACI rats. In F(1) rats, the increase in UaV per percentage incidence increase in FGS was three times higher. In LIS treated F(1) rats, no significant UaV or FGS was measured at low blood pressure levels, indicating that renal damage in hypertensive F(1) rats is not a direct effect of L-NAME, but the result of the high blood pressure or another action of the renin-angiotensin system., Conclusion: We conclude that heterozygosity for the genes influencing the development of renal damage in the FHH strain increases the susceptibility of the kidney to develop damage after UNx combined with systemic hypertension.

Previous studies of glomerular permselectivity have indicated that both size selectivity and charge selectivity changes play a role in the pathogenesis of proteinuria. In this study, we measured Ficoll sieving coefficients, hemodynamic parameters, and urinary protein excretion rates in the FHH strain of fawn-hooded rats. These animals spontaneously develop systemic and glomerular hypertension, proteinuria, and focal and segmental glomerulosclerosis at a relatively young age. Three groups of FHH rats were studied: two-kidney controls (2K), untreated uninephrectomized rats (CON-NX), and uninephrectomized rats treated with the angiotensin I converting enzyme inhibitor enalapril (ENA-NX). CON-NX rats had higher glomerular transcapillary pressures (delta P) and higher urinary excretion rates of both total protein (UpV) and albumin (UaV) than did 2K rats, whereas treatment with enalapril prevented both glomerular hypertension and the increased proteinuria. Ficoll sieving coefficients were significantly higher in both groups of NX rats compared with 2K rats only for Stokes-Einstein radii (rs) > or = 46 A. Fits of sieving data to pore models showed a small increase in the number of large, nonselective pores in NX, which was not prevented by enalapril treatment. Total clearances of Ficoll with rs = 36 A (the size of albumin) in CON-NX and ENA-NX groups were unchanged compared with 2K animals. In contrast, UaV in CON-NX rats was more than six times that of 2K and ENA-NX rats. Across groups, UpV, UaV, and the ratio (UaV)/(UpV) all correlated strongly with delta P.(ABSTRACT TRUNCATED AT 250 WORDS)

Fawn-hooded (FH) rats with congenital proteinuria and systemic and glomerular hypertension are very susceptible to renal damage at a young age. In this study, the effects of unilateral nephrectomy (UNX) on the function and structure of the remaining kidney in the FHH substrain were assessed. A long-term study was performed to determine the changes in systemic blood pressure, renal function, and proteinuria during the development of chronic renal failure in UNX-FHH and two-kidney (2K) FHH rats. Renal micropuncture and morphologic studies were performed at 4 wk after surgery. The long-term study showed that, after UNX, systolic blood pressure did not differ significantly (from that of 2K-FHH rats. After UNX, there was compensatory hyperfiltration, at about 70% of the 2K level, that could be maintained for 12 wk only. The subsequent fall in GFR was preceded by severe proteinuria. The mean survival time of UNX-FHH rats was only 35 wk. Micropuncture studies showed that the high mean glomerular capillary pressure of 2K-FHH rats was further elevated after UNX. The glomerular capillary ultrafiltration coefficient did not differ significantly between UNX-FHH and 2K-FHH rats. The weight of the remaining kidney and the mean glomerular tuft volume in UNX-FHH were, on average, 36 and 31% greater than in 2K rats. The results indicate that the FHH rat is extremely vulnerable to the adverse renal effects of UNX.(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerular filtration rate (GFR) and urinary protein excretion (UpV) were studied in male rats with a uninephrectomy at 3 (UNX-3) or 15 weeks of age (UNX-15) and fed a low (12%, LP), normal (24%, NP) or high (36%, HP) protein diet. Measurements were made every 12 weeks throughout the entire life-span. The UNX rats were compared with sham-operated (2K) rats of the same age and on the same diets. At 12 weeks after surgery, the GFR of UNX rats, corrected for differences in body weight, age and protein intake (GFRcor), ranged between 73% and 77% of that of 2K rats. On the HP and NP diet, UpV was higher in UNX-3 than in UNX-15 rats. On the LP diet, UpV was equally low in both groups. Long-term follow-up indicated that the GFR of UNX rats on the HP diet started to decline first, followed by those on an NP diet, while those on an LP diet had the longest period of stable GFR. For UNX rats, the time to reach a GFRcor of 50% was used as an indicator of the length of renal survival. Analysis of variance of the renal survival times indicated a highly significant interaction between the protein diet and age at the time of UNX. On the HP diet, UNX-3 rats have a shorter renal survival time than UNX-15, while on the LP diet UNX-3 rats have a longer renal survival time. This indicates that the long-term outcome of UNX at young age depends on the protein intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Removal of one kidney during childhood differs from removal of a kidney from an adult as the child's future depends on an adequate function of the remaining kidney during a longer period of time. We assessed the long-term effect of unilateral nephrectomy in childhood on renal function, protein excretion, and blood pressure. Data were obtained from 111 subjects undergoing uninephrectomy for unilateral renal disease before the age of 16 years who had no evidence of renal abnormalities in the contralateral kidney at the time of surgery. At investigation the patients were 18 to 56 years of age with an interval of up to 52 years after uninephrectomy. On average, renal function was well maintained at approximately 75% of the reported normal two-kidney value. Blood pressure in men was higher than in women. Stratification for age showed no statistically significant differences between those undergoing uninephrectomy before or after the age of 4.5 years. Stratification for post-uninephrectomy interval revealed renal function to be lower and blood pressure, urinary albumin excretion, and protein excretion to be higher in those with an interval of more than 25 years. In men over 30 years of age, linear regression analysis indicated a decrease in glomerular filtration rate, effective renal plasma flow, and creatinine clearance, and an increase in blood pressure and albumin excretion with time. Controlled longitudinal studies are needed to detect true changes and to ascertain whether such changes are different from the age-related changes seen in individuals with two kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in renal function were followed lifelong in male rats with only 1 kidney either intact or damaged by ureteral obstruction or ischemia. After surgery the rats were given a low (12%) or a high (36%) protein diet. After a period with a stable glomerular filtration rate, which was longer on the low protein diet, there was a linear decline in rats with an intact single kidney. The rate of decline was highest on the high protein diet, resulting in a shorter survival time. A decrease in urine osmolality and an increase in protein excretion preceded the decrease in filtration rate, while it was followed by an increase in blood pressure. The glomerular filtration rate of the rats with a single damaged kidney initially recovered to 75 to 80% of that of rats with an intact single kidney on the same diet. There was a linear decrease in the glomerular filtration rate, with the highest rate of decrease on the high protein diet. The mean survival time was less than that of rats with a single intact kidney. Proteinuria preceded the decrease in filtration rate, while hypertension was observed later. We conclude that in rats with a solitary kidney renal failure eventually develops. A low protein diet postpones and attenuates this development but it does not prevent it.

The early interactive nephrotoxicity of cyclosporine was studied in rats immediately after either unilateral nephrectomy or a combination of temporary renal ischemia and contralateral nephrectomy. Cyclosporine was administered intramuscularly (IM) for 4 weeks. In comparison to vehicle-treated animals, the rats receiving cyclosporine showed neither the compensatory increase in glomerular filtration rate after unilateral nephrectomy nor the recovery of function after renal ischemia. It is concluded that cyclosporine interferes with the normal compensatory response resulting from an acute loss of renal function. This could be due to an interaction with renal hemodynamics or hormonal factors mediating the compensatory renal response.

Changes in glomerular filtration rate (GFR) and urinary protein excretion were determined during a lifelong follow-up period in male WAG/Rij rats, unilaterally nephrectomized (NX) just after weaning, and compared with changes in control rats with both kidneys intact (2K). After surgery, the animals were given either a low-protein (LP; 12%), normal-protein (NP; 24%) or high-protein (HP; 36%) diet. The GFR of 2K-rats was highest with the HP diet and lowest with the LP diet. With all three diets, the GFR of 2K rats remained stable for about 2 years. The mean survival time of 2K rats was not affected by the dietary protein intake and amounted to about 120 weeks. Initially, the GFR of NX rats was highest with the HP and lowest with the LP diet. The GFR remained stable for a period of 36 weeks with the HP diet, 48 weeks with the NP diet, and 72 weeks with the LP diet. Subsequently, the GFR fell linearly in the great majority of cases with all three diets. The highest rate of decline was found in NX rats given the HP diet. As a result, from week 72, the GFR of the NX rats on the LP diet was significantly higher than that of NX rats on either the NP or the HP diet. With all three diets the mean survival time of NX rats was less than that of 2K rats on the same diet. The mean survival time of NX rats on the HP diet was also less than that of NX rats on the LP or NP diet. Proteinuria preceded the fall in GFR in NX rats. The proteinuria was most severe in NX rats on the HP diet, but only moderate with the LP diet. We conclude that, in a rat strain not very prone to develop renal lesions, the GFR of a solitary kidney eventually declines. An LP diet postpones but does not prevent the decline.