Angiotensin-converting enzyme and endothelial constitutive nitric oxide synthase polymorphisms in Turkish renal transplant population and possible influence on renal artery atherosclerosis and graft survival.

BACKGROUND: Renal transplant recipients are prone to accelerated atherosclerosis secondary to immunosuppressants, which may decrease graft survival. We sought to analyze the effects on renal graft survival of atherosclerotic degeneration in the renal artery and the influence of angiotensin-converting enzyme (ACE) endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphisms. METHODS AND PATIENTS: Thirty three renal transplant recipients (25 men) of mean age 28.4 +/- 9.6 years, received organs from 11 living related donors and were followed for at least 36 months. Genotyping was performed for the insertion/deletion ACE (I/D), angiotensin (AGT) (M-->T, 235), angiotensine 1 receptor (A-->C, 1166), angiotensin 2-receptor (A-->G, 1223), and ecNOS (b-->a, intron4) gene polymorphisms. Renal artery biopsies were performed during transplantation surgery to analyze the presence of atherosclerosis. RESULTS: Pathological examination indicated that 18 donor specimens and nine recipient specimens had atherosclerotic degeneration. Survival analysis (36 months) indicated that graft survival rates of recipients who had atherosclerosis in the renal artery and who received an organ from donors with an atherosclerotic renal artery were shorter than in their counterparts (P = .02, P = .04, respectively). Comparison of genetic variations of recipients revealed that CC/TC variation of AGT was higher in patients with atherosclerosis (81% vs 53%, P = .03). There was no significant difference between groups in means of other gene polymorphisms. CONCLUSION: Renin-angiotensin system gene polymorphism analysis of patients in renal transplantation waiting list may provide information about allograft survival and posttransplant atherosclerotic degeneration at graft vasculature of young transplant recipients.

Mast cell chymase in the ischemic kidney of severe unilateral renovascular hypertension.

Chymase degrades angiotensin I (AI) to form angiotensin II (AII), probably constituting a bypass of the renin-angiotensin cascade. Chymase activity increases in some vascular diseases. In the kidney, an increase in chymase activity was reported in an animal model of ischemic kidney of renovascular hypertension (RVH); however, no such evidence has been provided in humans. We treated a 64-year-old patient with severe unilateral RVH and atherosclerosis, for whom removal of the ischemic kidney was the only option. Using immunohistochemical staining, we investigated chymase activity in the removed kidney and associated artery and vein. An increase in chymase activity, together with mast cells infiltrating the interstitium, was observed where interstitial fibrosis was seen. In the renal artery, where severe atherosclerosis was seen, and also in the vein, mast cell infiltration in the adventitia was accompanied by chymase. The captopril test showed an increase in serum aldosterone level, with a concomitant increase in plasma renin activity and decrease in blood pressure. Because the decrease in blood pressure implies a decrease in circulatory AII levels, it is plausible that in this patient, chymase had a role in AII formation in the adrenal gland to stimulate aldosterone secretion. Thus, by means of captopril, AI levels increased, and chymase may have produced AII in loci tissues, which, in turn, stimulated aldosterone secretion. This is the first report of an increase in chymase activity in the interstitium of an ischemic kidney and renal artery and vein in a patient with RVH and atherosclerosis.

Epithelial COX-2 expression is not regulated by nitric oxide in rodent renal cortex.

In the adult rodent kidney cortex, cyclooxygenase-2 (COX-2), NO synthase (NOS1), and renin synthesis change in parallel on alterations in distal tubular NaCl concentration, and their products in part may mutually determine synthesis and activity of these enzymes. Epithelial NO synthesis has been postulated to exert a stimulatory role on COX-2 expression. Changes in COX-2 and NOS1 may be assessed histochemically by determining changes in the number of positive cells. In rat, macula densa and adjacent cells may co-express COX-2 and NOS1, whereas cell groups of the upstream thick ascending limb (cTAL) express COX-2 alone. We have tested whether the stimulation of COX-2 expression by short- and long-term unilateral renal artery stenosis, low salt, and furosemide treatment depends on co-expression of NOS1. These conditions produced significant respective increases (40% to 351%, P<0.05) in the number of COX-2 immunoreactive cells, regardless of whether NOS1 was present or not, suggesting that co-expression of NOS1 is not necessary to produce these changes. Under high-salt conditions, analogous though inverse changes were recorded (-62% to -73%, P<0.05). In mice with genetic deletion of NOS1, low- and high-salt diets caused similar changes of COX-2 immunoreactivity (106% and -52%, P<0.05) than those seen in wild-type mice (43% and -78%, P<0.05). We conclude that alterations of distal tubular NaCl concentration and presumably NaCl transport induce changes in epithelial COX-2 expression that does not depend on presence of co-expressed NOS1. It therefore seems unlikely that NO is part of a signal transduction chain between tubular chloride sensing and the modulating effects of prostaglandins in tubulo-vascular information transfer.

Determination of urinary N-acetyl-beta-glucosaminidase in patients with hypertension and renal artery stenosis.

The purpose of the study was to measure the urinary excretion of N-acetyl-beta-glucosaminidase (U-NAG) in patients suspected of having renovascular hypertension and to compare the enzyme excretion before and after active intervention with operation or percutaneous transluminal renal angioplasty (PTRA). Eighty-one patients with severe, therapy-resistant hypertension were examined with regard to renal artery stenosis (RAS). At least one significant renal artery stenosis was found in 61 patients, whilst the remaining 20 patients were classified as having essential hypertension. Enzyme levels were found to be significantly higher in RAS patients as compared with patients with severe hypertension lacking significant renal artery stenosis, 0.66 (0.41-0.91, median value, 1st and 3rd quartiles) versus 0.35 (0.27-0.54); P < 0.01. Both groups of patients had significantly higher U-NAG values than a healthy reference population (0.2, 0.13-0.27; P < 0.01). Forty of the RAS patients were randomized to surgery or PTRA and followed prospectively for 2 years. After either renal vascular surgery or PTRA a significant rise in U-NAG excretion was observed 7-10 days after treatment. Urinary NAG excretion remained elevated during long-term follow-up. It is suggested that U-NAG should be determined in patients with therapy-resistant hypertension with suspicion of renal artery stenosis.

Coexistence of hyperplasia of renomedullary interstitial cells and juxtaglomerular cells after acute occlusion of renal artery.

A left renal artery aneurysm was found in a 45-year-old normotensive man. In an attempt to evade the possible occurrence of aneurysmal rupture, aneurysmectomy in addition to left renal biopsy (first surgery) was performed. This vascular operation led to a virtually complete renal artery stenosis concomitant with the development of hypertension. The renin-angiotensin-aldosterone system and levels of plasma prostaglandins were also increased following this failed surgery. Reconstruction of the affected renal artery was technically so difficult that left nephrectomy was carried out (second surgery). Renal specimens obtained at the first surgery revealed no histological abnormalities. Discriminating histological findings of the kidney obtained at the second surgery were remarkable; hyperplasia of the juxtaglomerular cells producing renin and hyperplasia of the renomedullary interstitial cells which had pecularities similar to cells known to secrete renal prostaglandins. High levels of the renin-angiotensin-aldosterone system and plasma prostaglandins after the first surgery were reduced following the second surgery. It is suggested that acute constriction of the renal artery led to a hyperplastic change of the juxtaglomerular cells and the renomedullary interstitial cells and stimulated an inappropriate release of renin and renal prostaglandins.

Observations on the use and limitations of renal vein renins in hypertensive patients.

From our consecutive series of renal vein renin studies in 170 patients with kidney disorders and hypertension, we present those cured by surgical correction of a unilateral renal artery stenosis during the period 1973--75. The renin secretion patterns of these patients range between no demonstrable abnormality, even with a stimulating procedure using dihydralazine 7.5 i.v., and massive renin secretion already during basal conditions. Thus, the renin secretion may not be increased even after stimulation in some patients with durable unilateral renovascular hypertension. This fact may be explained by the rise of the systemic blood pressure, eventually maintained by sodium and water retention and accompanied by adaptive changes in the contralateral kidney. The perfusion pressure is thereby kept normal in the affected kidney, eliminating a stimulus for renin secretion. It is likely that many cases of renovascular hypertension pass through an early stage where no involvement of the renin-angiotensin system may be discovered. Of course, these patients will also benefit from surgery. The conclusion is that renin studies for diagnostic purposes should be performed when patients are on treatment and kept normotensive for some time, and that an additional challenge of the perfusion pressure, i.e., by use of dihydralazine, intravenously should be performed.