Robert G. Luke

Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent

PURPOSE Physicians increasingly prescribe cyclosporine as an immunosuppressive agent for both organ-transplant and non-organ-transplant recipients. Investigators have reported a high incidence of drug-induced hypertension even when clinical nephrotoxicity was not present. We wanted to determine the reason. PATIENTS AND METHODS A comparison was made of hypertension in 15 cyclosporine-treated transplant recipients with that in a similar group of 15 azathioprine-treated transplant recipients. RESULTS Hypertension in the cyclosporine group responded differently from that seen in the azathioprine group and from previously described forms of post-transplantation hypertension. Hypertensive cyclosporine-treated patients show a sodium acquisitive renal state that responds to sodium restriction. Unlike rat models, which suggest cyclosporine-induced stimulation of the renin-angiotensin system, or previous forms of post-transplant hypertension in humans, plasma renin levels were not elevated and blood pressure did not respond to a test dose of captopril. CONCLUSION Hypertension in cyclosporine-treated patients is an iatrogenic form of hypertension that may be associated with an early, subtle, renal defect in sodium excretion, a genesis of hypertension that is consistent with Guytons view of essential hypertension.

Inhibition of Angiotensin-Converting Enzyme in Renal-Transplant Recipients with Hypertension

HYPERTENSION has a high prevalence among recipients of renal allografts.1 , 2 Such post-transplantation hypertension may contribute3 , 4 to the high mortality from atherosclerotic vascular disease ...

Surgical therapy for persistent hypertension after renal transplantation.

SUMMARY The presence of the original diseased native kidneys in renal allograft recipients is associated with an increased prevalence of persisting post-transplant hypertension. In 9 of 10 such transplant patients bilateral nephrectomy of these native kidneys, performed at least 1 year after successful transplantation of a renal allograft, resulted in improved blood pressure control. Although these 10 patients had higher peripheral plasma renin activity (PRA) than normotensive patients (5.9 ± 1.3 ng/ml/hr versus 1.5 ± 0.3 mg/ml/hr), selective renal vein renin measurements did not consistently demonstrate higher renin concentrations from the native kidneys. Removal of the original kidneys was beneficial even in some patients who had stenosis of the allograft artery demonstrated by arteriography.

Race, Socioeconomic Status, and the Development of End-Stage Renal Disease

The reasons for the increased annual incidence of end-stage renal disease (ESRD) in blacks compared with whites are unclear, but may include lack of access to treatment of the causative disease, which likely relates closely to socioeconomic status (SES). End-stage renal disease rates for diabetic glomerulosclerosis, hypertensive nephrosclerosis, and glomerulonephritis were determined in the 9,390 black and white New York State residents who began treatment within the Medicare program between 1982 and 1988. The relationship between the incidence of ESRD, age, and SES, as measured by the race-specific median family income in the patients zip code, was estimated using a series of logistic-regression models for 12 populations: three causes of renal failure by two races by two sexes. For whites, incidence rates of diabetic glomerulosclerosis and hypertensive nephrosclerosis were significantly negatively associated with declining SES for the 45 to 65 year and 25 to 55 year age groups, respectively. In contrast, there was no relationship between the incidence of these diseases and SES in blacks. For glomerulonephritis, effects of SES were minor for both races. Better access to treatment of diabetes and hypertension might well decrease the annual incidence of ESRD due to diabetic glomerulosclerosis and hypertensive nephrosclerosis in whites. If the SES measures used for blacks are adequate, predisposition to progressive renal damage in response to renal injury or environmental factors other than SES are stronger risk factors for ESRD than SES.

Parenteral essential amino acids in acute renal failure.

Parenteral 1.75 per cent L-essential amino acids in 47 per cent dextrose (Group I 11 patients) or 47 per cent dextrose (Group II, 9 patients) were administered to patients with severe acute renal failure in a single blind-controlled study. Survival rates (55 per cent in Group I and 56 per cent in Group II) and duration of renal failure were similar in the two groups. Rate of daily rise in blood urea nitrogen was significantly reduced during intravenous nutrition in Group I but not in Group II. Serious complications of intravenous nutrition did not occur. Since improved nitrogen metabolism is demonstrated, further trials of essential amino acid therapy in acute renal failure are indicated.

Effect of Chloride on Renin and Blood Pressure Responses to Sodium Chloride

Both the inhibition of renin release by sodium chloride and salt-sensitive hypertension have been attributed to sodium. We evaluated the contribution of chloride to these responses to sodium chloride. In the Sprague-Dawley rat, acute and chronic administration of sodium salts other than sodium chloride failed to suppress plasma renin activity, whereas renin was inhibited by both sodium chloride and by selective chloride (without sodium) loading. Plasma renin activity was stimulated by selective chloride depletion. Similarly, in humans, plasma renin activity was suppressed by sodium chloride but not by sodium bicarbonate infusion. In a preliminary study in the Dahl salt-sensitive rat, in contrast to sodium chloride loading, sodium bicarbonate loading failed to produce hypertension. Thus, both the renin and possibly the blood pressure responses to sodium chloride are dependent on chloride.

Effect of Acute and Chronic Calcium Administration on Plasma Renin

To evaluate the effect of Ca(++) on renin release, plasma renin activity (PRA) was measured after acute and chronic Ca(++) administration. 1% CaCl(2) was infused into one renal artery of 10 anesthetized dogs (0.3 mg/kg/min). The excreted fraction of filtered calcium (EF(ca++)) and EF(Na+) from the infused kidney were elevated (P < 0.04) during three successive 15-min infusion periods. Serum calcium concentration was significantly elevated (P < 0.001). Creatinine clearance, systemic arterial pressure, and renal blood flow did not change (P > 0.10). Compared to control (45 ng/ml/h+/-5.2 SE), renal venous PRA was suppressed (P < 0.0001) after infusion of Ca(++) for 15, 30, and 45 min (20 ng/ml/h+/-4.6, 16 ng/ml/h+/-4.0, and 13 ng/ml/h+/-2.7, respectively). 15 and 30-min after infusion, PRA did not differ from control (P > 0.20). Chronic Ca(++) loading was achieved in Sprague-Dawley rats by replacing drinking water with 1% CaCl(2) for 17 days. At sacrifice, serum Ca(++), Na(+), and K(+) of controls (n = 12) did not differ (P > 0.60) from Ca(++)-loaded rats (n = 12). Ca(++) excretion (467 mueq/24 h+/-51) was elevated (P < 0.001) compared to controls (85 mueq/24 h+/-12). PRA (8.6 ng/ml/h+/-1.4) and renal renin content of Ca(++)-loaded rats did not differ from controls (P > 0.80). However, after 8 days of sodium deprivation, both PRA and renal renin content of calcium-loaded animals were significantly lower than the respective values in pair-fed controls (P < 0.005). During the period of sodium deprivation, calcium-drinking animals were in greater negative sodium balance than controls (P < 0.005). The data are consistent with the hypothesis that acute and chronic calcium administration inhibit renin secretion.

Renal effects of amphotericin B lipid complex

A study was conducted to compare the renal effects of amphotericin B lipid complex (ABLC), a lipid formulation of the widely used antifungal medication, with conventional amphotericin B (AmB) in the treatment of serious fungal infections, including invasive candidiasis, cryptococcal meningitis, and aspergillosis. The clinical experience of ABLC includes two types of open-label studies: randomized comparative (ABLC 5 mg/kg/d compared with AmB 0.6 to 1 mg/kg) and emergency use. In the comparative studies, changes in serum creatinine were evaluated three ways: doubling of the baseline value, an increase from < or = 1.5 mg/dL at baseline to > or = 1.5 mg/dL, and an increase from < or = 1.5 mg/dL at baseline to > or = 2.0 mg/dL. More patients in the AmB group reached these end points than in the ABLC group (P < or = 0.007), and the time needed to reach each of these end points was significantly shorter for the AmB group (P < or = 0.02). Increased serum creatinine was reported as an adverse event more frequently by patients receiving AmB than by patients receiving ABLC. In the emergency use study, a steady and statistically significant decrease in serum creatinine was observed among patients who started ABLC treatment with serum creatinine greater than 2.5 mg/dL due to prior AmB treatment. ABLC offers the physician a valuable, less-nephrotoxic alternative to AmB for the treatment of patients with severe, invasive fungal infections.

It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis

Maintenance of metabolic alkalosis generated by chloride depletion is often attributed to volume contraction. In balance and clearance studies in rats and humans, we showed that chloride repletion in the face of persisting alkali loading, volume contraction, and potassium and sodium depletion completely corrects alkalosis by a renal mechanism. Nephron segment studies strongly suggest the corrective response is orchestrated in the collecting duct, which has several transporters integral to acid-base regulation, the most important of which is pendrin, a luminal Cl/HCO(3)(-) exchanger. Chloride depletion alkalosis should replace the notion of contraction alkalosis.

Changing patterns of end-stage renal disease due to hypertension

We analyzed the records of all residents of Jefferson County, Alabama, accepted for renal replacement therapy between 1982 and 1987 and compared them with those accepted between 1974 and 1978 to determine any changes in the distribution and frequency of end-stage renal disease (ESRD) due to hypertension (H-ESRD). H-ESRD increased from 6.4 to 9.6 per 100,000 in blacks and from 0.36 to 0.62 per 100,000 in whites. Smoothed age- and race-specific yearly H-ESRD rates decreased in blacks under age 50. Peak incidence of H-ESRD shifted from age 40 to 49 in 1974 through 1978 to age 50 to 59 in 1982 through 1987 (P less than 0.0001). Blacks were referred for care with significantly higher blood pressure levels and serum creatinine concentrations than whites, and had more severe retinal vascular disease. Factors significantly associated with a shorter time from referral to renal replacement therapy were black race, female gender, blood urea nitrogen and serum creatinine concentrations, carbohydrate intolerance, and the use of alpha-agonist and/or angiotensin-converting enzyme (ACE) inhibitor. We conclude that racial distribution and risk for H-ESRD have not changed. Peak rates of H-ESRD have been delayed nearly a decade, suggesting a possible effect of better awareness and treatment of hypertension.