Abraham P. Provoost

Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat.

Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.

Renal Function up to 50 Years After Unilateral Nephrectomy in Childhood

Removal of one kidney during childhood differs from removal of a kidney from an adult as the childs 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)

Altered renal hemodynamics and impaired myogenic responses in the fawn-hooded rat.

The present study examined whether an abnormality in the myogenic response of renal arterioles that impairs autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC) contributes to the development of renal damage in fawn-hooded hypertensive (FHH) rats. Autoregulation of whole kidney, cortical, and medullary blood flow and PGC were compared in young (12 wk old) FHH and fawn-hooded low blood pressure (FHL) rats in volume-replete and volume-expanded conditions. Baseline RBF, cortical and medullary blood flow, and PGC were significantly greater in FHH than in FHL rats. Autoregulation of renal and cortical blood flow was significantly impaired in FHH rats compared with results obtained in FHL rats. Myogenically mediated autoregulation of PGC was significantly greater in FHL than in FHH rats. PGC rose from 46 +/- 1 to 71 +/- 2 mmHg in response to an increase in renal perfusion pressure from 100 to 150 mmHg in FHH rats, whereas it only increased from 39 +/- 2 to 53 +/- 1 mmHg in FHL rats. Isolated perfused renal interlobular arteries from FHL rats constricted by 10% in response to elevations in transmural pressure from 70 to 120 mmHg. In contrast, the diameter of vessels from FHH rats increased by 15%. These results indicate that the myogenic response of small renal arteries is altered in FHH rats, and this contributes to an impaired autoregulation of renal blood flow and elevations in PGC in this strain.The present study examined whether an abnormality in the myogenic response of renal arterioles that impairs autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC) contributes to the development of renal damage in fawn-hooded hypertensive (FHH) rats. Autoregulation of whole kidney, cortical, and medullary blood flow and PGC were compared in young (12 wk old) FHH and fawn-hooded low blood pressure (FHL) rats in volume-replete and volume-expanded conditions. Baseline RBF, cortical and medullary blood flow, and PGCwere significantly greater in FHH than in FHL rats. Autoregulation of renal and cortical blood flow was significantly impaired in FHH rats compared with results obtained in FHL rats. Myogenically mediated autoregulation of PGC was significantly greater in FHL than in FHH rats. PGC rose from 46 ± 1 to 71 ± 2 mmHg in response to an increase in renal perfusion pressure from 100 to 150 mmHg in FHH rats, whereas it only increased from 39 ± 2 to 53 ± 1 mmHg in FHL rats. Isolated perfused renal interlobular arteries from FHL rats constricted by 10% in response to elevations in transmural pressure from 70 to 120 mmHg. In contrast, the diameter of vessels from FHH rats increased by 15%. These results indicate that the myogenic response of small renal arteries is altered in FHH rats, and this contributes to an impaired autoregulation of renal blood flow and elevations in PGC in this strain.

A Frequent Pathway to Glomerulosclerosis: Deterioration of Tuft Architecture – Podocyte Damage – Segmental Sclerosis

Lesions in glomerular architecture include mesangial expansion, capillary ballooning, capillary unfolding and microaneurysm formation. Such lesions appear to develop in response to mechanical overextension. A frequent pathway to segmental glomerulosclerosis starts from capillary ballooning and unfolding. Podocytes supporting those deranged capillaries are exposed to increased mechanical stress. This may lead to podocyte injury terminating in detachments from the GBM. Naked GBM areas at peripheral capillary loops allow the attachment of parietal cells to the GBM, i.e. the formation of a tuft adhesion to Bowmans capsule. An adhesion has a strong tendency to progress to segmental sclerosis.

Impaired autoregulation of renal blood flow in the fawn-hooded rat

The responses to changes in renal perfusion pressure (RPP) were compared in 12-wk-old fawn-hooded hypertensive (FHH), fawn-hooded low blood pressure (FHL), and August Copenhagen Irish (ACI) rats to determine whether autoregulation of renal blood flow (RBF) is altered in the FHH rat. Mean arterial pressure was significantly higher in conscious, chronically instrumented FHH rats than in FHL rats (121 +/- 4 vs. 109 +/- 6 mmHg). Baseline arterial pressures measured in ketamine-Inactin-anesthetized rats averaged 147 +/- 2 mmHg (n = 9) in FHH, 132 +/- 2 mmHg (n = 10) in FHL, and 123 +/- 4 mmHg (n = 9) in ACI rats. Baseline RBF was significantly higher in FHH than in FHL and ACI rats and averaged 9.6 +/- 0.7, 7.4 +/- 0.5, and 7.8 +/- 0.9 ml. min-1. g kidney wt-1, respectively. RBF was autoregulated in ACI and FHL but not in FHH rats. Autoregulatory indexes in the range of RPPs from 100 to 150 mmHg averaged 0.96 +/- 0.12 in FHH vs. 0.42 +/- 0.04 in FHL and 0.30 +/- 0.02 in ACI rats. Glomerular filtration rate was 20-30% higher in FHH than in FHL and ACI rats. Elevations in RPP from 100 to 150 mmHg increased urinary protein excretion in FHH rats from 27 +/- 2 to 87 +/- 3 microg/min, whereas it was not significantly altered in FHL or ACI rats. The percentage of glomeruli exhibiting histological evidence of injury was not significantly different in the three strains of rats. These results indicate that autoregulation of RBF is impaired in FHH rats before the development of glomerulosclerosis and suggest that an abnormality in the control of renal vascular resistance may contribute to the development of proteinuria and renal failure in this strain of rats.

Rf-2 gene modulates proteinuria and albuminuria independently of changes in glomerular permeability in the fawn-hooded hypertensive rat

We report that Rab38 , a gene within the Rf-2 locus appears to influence the development of proteinuria (UPV) and albuminuria (UAV) in fawn-hooded hypertensive rats (FHH). Using congenic animals, we narrowed the region to eight genes; however, only one gene had a sequence variant. Rab38 has a

Nephrotoxicity of Aminoglycosides in Young and Adult Rats

ABSTRACT: The nephrotoxicity of gentamicin and amikacin was evaluated comparatively in young and adult rats. The aminoglycosides were administered once daily for 14 days, gentamicin in a dose of either 20 or 60 mg/kg, and amikacin in a dose of either 60 or 180 mg/kg. Renal function was measured during and after treatment. In adult rats there was a dose dependent fall in the glomerular filtration rate which was preceded by histopathological changes in the proximal tubules. The nephrotoxicity of gentamicin was more severe than that of amikacin. The nephrotoxicity of either aminoglycoside was less severe in young rats than in adult rats. In the proximal tubules there were less histopathological changes in young rats than in the adult rats. The mechanism underlying this difference in nephrotoxicity was investigated by measuring the renal accumulation of gentamicin and amikacin. The renal uptake after the first dose of either aminoglycoside was similar in young and adult rats. Expressed as a percentage of the injected amount, the uptake decreased as the aminoglycoside dosage increased. The uptake of gentamicin was somewhat greater than that of amikacin. In young rats, the aminoglycoside concentration in total kidney as well as in renal cortex, was significantly less than in adult rats. This difference was due to the larger wet kidney weight relative to body weight in the young rats. The lower renal aminoglycoside levels in the young rats provide an explanation for the difference observed in aminoglycoside nephrotoxicity when comparing young and adult rats.

Recoverability of renal function after relief of chronic partial upper urinary tract obstruction

obstruction [4]. The reason for the lack of correlation Introduction between the experimental data and the clinical situation is that the complete occlusion of the ureter by ligation Obstructive uropathy with resultant hydronephrosis is the eventual outcome of many urological disorders. obtained in animals is not comparable with the incomplete occlusions that are more likely to occur in clinical Apart from accidental ligation or ureteric calculus, obstruction in humans is nearly always chronic and types of hydronephrosis. partial. The accurate prediction of the recoverability of kidney function after the release of chronic partial Function of the contralateral kidney obstruction is of great clinical value to the urologist and nephrologist. If restoration or improvement of renal In the past, theories of renal counterbalance and renal function appears probable, surgical relief of obstruction atrophy of disuse have considerably aCected the treatmay be indicated, even though there has been a considerment options of prolonged unilateral ureteric obstrucable initial loss of function. In patients whose kidney tion. It was commonly believed that once hypertrophy function is irreversibly damaged by the underlying of the contralateral healthy kidney had fully developed obstructive process, it may be preferable to apply nonsurthe damaged kidney would not regain its function [5]. gical management or total removal of the disordered Hydronephrotic atrophy was considered complete in system by nephrectomy. The aim of the present paper is 6 months, while compensatory hypertrophy was conto discuss the diCerent factors that may potentially aCect sidered complete in 4–6 weeks [5]. Animal as well as recoverability and to review the currently available tests human studies challenged this theory and now it is well that have been proposed to predict recovery of renal established that recovery of even a poorly functioning function upon relief of chronic partial obstruction. kidney is possible, despite compensatory hypertrophy of its partner. Nevertheless, the degree of recovery of the damaged kidney is influenced by the functional status of Factors that may aVect recovery of renal the contralateral kidney. Prominent recovery occurs function under the stimulus of impaired function or removal of the opposite kidney [6–8]. Duration of obstruction Schirmer and Hendricks [9], studying metabolic The degree of recovery of renal function after the release aspects of unilateral hydronephrosis, reported that of unilateral ureteric obstruction correlates inversely oxygen consumption in the obstructed kidney fell to with the duration of the obstruction [1,2]. In dogs there 30% of that in the control after 2 weeks of complete was rarely any return of renal function with release of ureteric occlusion. If the obstruction was then released, unilateral complete ureteric obstruction after 40 days the oxygen consumption of the hydronephrotic tissue [3]. However, the situation in humans is largely recovered to 70% of control values. However, if the unknown. Function has been reported to return in contralateral ureter was subsequently obstructed, the clinical cases after more than 150 days of complete recovery of the previously hydronephrotic kidney was further enhanced to 87% of the control.

Renal Doppler Ultrasound in Children with Obstructive Uropathy: Effect of Intravenous Normal Saline Fluid Load and Furosemide

PURPOSE We studied the effect of hyperhydration with normal saline and furosemide on renal resistive index in children with obstructive uropathy. MATERIALS AND METHODS 99mTechnetium-mercaptoacetyltriglycine diuretic renography and Doppler ultrasound were done in 27 children (54 renal units) with unilateral or bilateral hydronephrosis. Doppler studies were performed at baseline, and after infusion of normal saline and administration of furosemide. Half-time drainage, considered the gold standard for the diagnosis of renal obstruction, was compared to resistive index. RESULTS There was a positive correlation between half-time and resistive index on both Doppler studies. With a resistive index of 0.70 as the critical value for predicting renal obstruction 82 versus 100% sensitivity (p < 0.006), 63 versus 94% specificity (p < 0.04) and 76 versus 98% overall accuracy (p < 0.0005) were obtained for Doppler studies at baseline and after induced diuresis, respectively. All children with false-positive results were younger than age 4 years. CONCLUSIONS Doppler ultrasonography after hyperhydration with normal saline and furosemide is an accurate method for diagnosing renal obstruction in children. It is more sensitive, specific and accurate than baseline Doppler studies.

Nephrotoxicity of Cis-Platin Comparing Young and Adult Rats

ABSTRACT. The effect of Cis-platin on the glomerular filtration rate and effective renal plasma flow was determined using a radioisotope clearance technique in young (3 wk old) and adult (more than 12 wk old) rats. Cis-platin was administered intravenously in dosages ranging from 2.5 to 10 mg/kg body weight, either as a single dose or fractionated over 5 consecutive days. Following either dose regimen, identical total doses of Cis-platin caused less severe nephrotoxicity in young rats than in adult ones. In adult rats fractionated dosage significantly reduced nephrotoxicity. This was not observed in young rats. The difference in nephrotoxicity between young and adult rats was due to the renal handling of Cis-platin. After a single dose of 5 and 7.5 mg/kg body weight, platinum concentrations were measured in urine and renal tissue. During the first 2 days after Cis-platin administration, up to 60% of the amount of platinum injected was excreted in the urine of both age groups. There was a marked difference, however, in renal platinum concentration between the two groups. In young rats renal platinum concentration was only 63 and 49% of that in adult rats after 5 and 7.5 mg/kg body weight, respectively. We believe that this is due to the comparatively larger renal mass in relation to body weight in the young animals. Relatively more renal tissue provides at least partial protection against nephrotoxic drugs in these young rats.