John A. Luetscher

Cyclosporine-Associated Chronic Nephropathy

We evaluated glomerular filtration in 17 recipients of heart transplants who were treated for 12 months or longer with cyclosporine (cyclosporin A). The control group consisted of 15 heart-transplant recipients who were treated with azathioprine and who had also survived for at least 12 months. Despite an equivalent cardiac output, the glomerular filtration rate was depressed (51 +/- 4 vs. 93 +/- 3 ml per minute, P less than 0.005) in transplant recipients treated with cyclosporine. Cyclosporine treatment was also associated with reduced renal plasma flow (320 +/- 21 vs. 480 +/- 30 ml per minute, P less than 0.001). A trend toward restricted transglomerular transport of neutral dextrans (radii, 2.4 to 5.8 nm) in cyclosporine-treated recipients suggested an intrinsic loss of ultrafiltration capacity by glomerular capillaries rather than a hemodynamic basis for the reduced glomerular filtration rate. Histopathologic examination of the kidneys of five cyclosporine-treated patients with glomerular hypofiltration revealed a variable degree of tubulointerstitial injury accompanied by focal glomerular sclerosis. Among the 32 heart-transplant recipients treated for more than 12 months with cyclosporine at our center, end-stage renal failure developed in 2. We conclude that long-term cyclosporine therapy may lead to irreversible and potentially progressive nephropathy. We recommend that cyclosporine be used with restraint and caution until ways are found to mitigate its nephrotoxicity.

Bioassay of Desoxycorticosterone-like Material in Urine.∗

Summary An assay for desoxycortieoster-one-like activity in biological fluids is presented, having a sensitivity in the order of 10 y of DOCA. The critical nature of solvent vehicle choice and of time-dosage of urinary extracts is presented and discussed. Urinary extracts from some edematous patients with heart failure and nephrosis show a sodium-retaining activity greater than that observed in normals and in non-edematous controls.

Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications.

Plasma renin exists in an active form or as an inactive zymogen that resembles a prorenin present in homogenates of human kidneys. We examined the relation of diabetes and its microvascular complications with the level of plasma inactive renin activated by dialysis to pH 3.3. Plasma inactive renin was measured in 235 diabetic patients and 90 nondiabetic controls. In the controls, the level of plasma inactive renin increased slightly with age but was never above 50 ng per milliliter per hour. In young diabetic patients studied within three years of the onset of diabetes the concentration of inactive renin was normal, and in some older diabetics without complications it remained within the age-adjusted normal range for many years. However, in patients with retinopathy or albuminuria, plasma inactive renin was above the normal range with few exceptions, reaching levels 50 to 200 per cent above the upper limits of normal in patients with nephropathy. The frequency of neuropathy was also significantly higher among patients with levels above the normal range. In 37 per cent of the diabetics followed during one to three years of conventional treatment, plasma inactive renin increased significantly, but in another group of diabetics under intensive treatment, the level rose in only 7 per cent and fell in 43 per cent. We conclude that there is a close association between a high level of plasma inactive renin and the presence of microvascular complications, and that the level of inactive renin can be modified by intensive treatment of diabetes.

Plasma Prorenin Activity and Complications in Children with Insulin-Dependent Diabetes Mellitus

BACKGROUND Renin, secreted into the blood by the juxtaglomerular cells of the kidneys, is derived from a larger precursor, prorenin. Plasma prorenin activity is increased in patients with insulin-dependent (Type I) diabetes mellitus who have microvascular complications of their disease. We undertook this study to determine prospectively whether rising prorenin activity can predict the development of complications in young patients with Type I diabetes. METHODS AND RESULTS Plasma prorenin was measured in 135 children and adolescents with Type I diabetes. The mean (+/- SE) plasma prorenin activity among the 32 patients over the age of 10 years who had had uncomplicated diabetes for 0.1 to 5 years was 8.43 +/- 0.58 ng of angiotensin I per liter.second, as compared with 7.06 +/- 0.32 in 37 control subjects of the same age (P less than 0.05). In the 9 patients older than 10 who had retinopathy or overt albuminuria, the mean plasma prorenin activity was 13.09 +/- 1.43 ng of angiotensin I per liter.second (P less than 0.0001). In 34 patients 10 years old or older with uncomplicated diabetes, 3 to 13 measurements of plasma prorenin activity were taken during a follow-up period of 6 to 39 months. Urinary albumin was determined at each visit, and the patients had regular retinal examinations. Only 1 of the 20 patients who had consistently normal plasma prorenin values had overt albuminuria (ratio of urinary albumin to creatinine, greater than 0.017) or retinopathy, whereas one or both of these complications appeared in 8 of the 14 who had at least one high prorenin value. The plasma prorenin value was significantly higher in these eight patients at least 18 months before a complication was found. CONCLUSIONS Increased plasma prorenin activity identifies a group of young patients with diabetes who are at high risk for retinopathy or nephropathy.

Abnormally sustained aldosterone secretion during salt loading in patients with various forms of benign hypertension; relation to plasma renin activity

Among 25 patients with benign, essential hypertension, and an equal number with other benign forms of hypertension, without serious cardiac, renal, or cerebrovascular impairment, 41 cases failed to reduce aldosterone excretion rates into the normal range (less than 5 mug/day) on a daily intake of 300 mEq of sodium. The hypertensive patients excreted slightly less than the normal fraction of labeled aldosterone as acid-hydrolyzable conjugate. Secretion rates were significantly higher in the hypertensive patients than in normotensive controls taking the high-sodium intake. On a 10 mEq sodium intake, the increase in excretion and secretion rates of aldosterone in the hypertensive patients could be correlated with plasma renin activity (PRA). The patients with the least increase in PRA had subnormal increase in aldosterone secretion and excretion, while unusually large rises in aldosterone secretion accompanied high PRA, especially in the cases with increased plasma angiotensinogen induced by oral contraceptives. The persistence of inappropriately high aldosterone secretion in most hypertensive patients during sodium loading could be related to a higher PRA than that found in normotensive controls under comparable conditions. In other hypertensives, whose PRA was unresponsive to sodium depletion, there was no significant correlation between PRA and aldosterone output, and no known stimulus to aldosterone production was detected. Five obvious cases of hyperaldosteronism were found among the 16 low-renin patients. The cause of the nonsuppressible aldosterone production in the other low-renin cases remains to be determined.

Hypertension induced by oral contraceptives containing estrogen and gestagen: effects on plasma renin activity and aldosterone excretion.

16 patients out of 53 referred for hypertension were taking oral contraceptives at the time of referral and were studied for blood pressure differentials plasma angiotensinogen levels plasma renin activity (PRA) and aldosterone excretion rates (AER) after cessation of the contraceptive treatment. Of the 11 patients who had normal blood pressure before taking the estrogen-gestagen contraceptives all of them showed reduced blood pressure levels within 1-3 months of stopping the treatment. 5 returned to and maintained normal limits for 6 months or longer while the remaining 6 showed reduced blood pressure levels that remained above the upper normal limits. In the 3 women who were hypertensive before treatment blood pressure fell to control levels after discontinuation. Angiotensinogen (renin substrate) concentration in the plasma of the patients receiving oral contraceptives was 2-5 times normal concentration. This also caused increase in angiotensinogen generation. These levels returned to normal within 3 months of cessation of contraception. PRA and AER were 2 times the normal rates under contraceptive therapy. PRA decreased but remained high in some cases 3 months after the treatment was stopped while AER returned to normal within the same period. It is concluded that oral contraceptives can cause hypertension in some patients and aggravate a pre-existing condition in others. Blood pressure therefore should be followed carefully in patients receiving oral contraceptives.

Increased Aldosterone Output During Sodium Deprivation in Normal Men.

Summary In 2 healthy men, restriction of sodium intake to 11 mEq./day was followed by increased aldosterone output, which mirrored the reduction of urine sodium. Insignificant changes were observed in renal clearance of inulin and endogenous creatinine and in the output of 17-hydroxy-corticoids and 17-ketosteroids.

Decreased Plasma Clearance and Hepatic Extraction of Aldosterone in Patients with Heart Failure

Inexperimental congestive heart failure indogs, thesecretion rateofaldosterone ismarkedly elevated (1).Ayersandhiscolleagues (2)demonstrated adecreased rateofaldosterone removal fromplasma, whichresults inafurther increase in circulating aldosterone indogswithpassive congestion oftheliver. Yates, Urquhart, andHerbst (3)showed thatconstriction oftheinferior vena cavaabove thehepatic veins lowers theA&-steroid reductase activity ofliver homogenates inrats. Increased levels ofsodium-retaining steroids can becorrelated withreduced renal excretion ofsodiumandwiththecollection ofascites indogs after stenosis ofthepulmonic valve orconstriction oftheinferior venacava(4,5).

Distribution, conjugation, and excretion of labeled aldosterone in congestive heart failure and in controls with normal circulation: development and testing of a model with an analog computer.

The distribution and clearance of aldosterone from plasma determine the fraction of secreted hormone reaching sites where the cellular actions of the hormone occur. Tait, Tait, Little, and Laumas (1) described the disappearance of aldosterone from plasma of normal man in terms of a two compartment system. Davis, Olichney, Brown, and Binnion (2) showed that the volumes of distribution and rates of clearance of aldosterone are reduced in dogs with experimental heart failure and low cardiac output. Our findings indicate that marked alterations in distribution and clearance of aldosterone are present in patients with congestive failure. Tait, Little, Tait, and Flood (3) estimated the mean plasma concentration of aldosterone in human plasma from the secretion rate and the plasma clearance rate. Ayers and his colleagues (4) and Tait and associates (5) showed that hepatic clearance of aldosterone is subnormal in dogs or in man in congestive failure (4). Camargo, Dowdy, Hancock, and Luetscher (6) demonstrated that reduced hepatic clearance and extraction of aldosterone may contribute to an increased concentration in plasma of patients with heart failure. The liver extracts aldosterone from plasma and returns conjugates and metabolites to plasma, in

Big renin: Identification, chemical properties and clinical implications

Big renin has a greater molecular weight (63,000 versus 43,000) than normal renin, but it shares the characteristic enzymatic and immunologic properties of normal renin. As it exists in the kidney or plasma of a patient, big renin is less active than normal renin, but its enzymatic activity is greatly enhanced by exposure to pH values of 3.0 to 3.6 or by brief incubation with pepsin or trypsin. Use of the terms prorenin and zymogen might be withheld until big renin is shown to exist in normal tissue or plasma and to be converted to normal renin in vivo. To date, big renin has been found in renal tumors and other abnormal kidney tissues as well as in the plasma of patients with renal disorders. The remarkable activation of big renin at pH levels of 3.3 can be used to detect its presence. If a method involving acidification is used to quantitate plasma renin activity of a patient with circulating big renin, the activated plasma renin activity greatly exceeds that measured in plasma maintained at neutral pH. Gel filtration of plasma is used to prove the presence of big renin. When large amounts of big renin are secreted by a renal tumor, hyperfusion may ensue and be cured by removal of the tumor. The secretion of small amounts of big renin does not necessarily result in any physiologic disorder. However, if there is a concomitant diminution or absence of normal renin a state of apparent hyporeninemia exists, as we have observed in diabetic nephropathy; this may be associated with hypoaldosteronism and hyperkalemia. Big renin does not appear to respond to physiologic changes that stimulate or suppress normal plasma renin activity. The finding of big renin may indicate the presence of certain renin-secreting renal tumors or other renal disorders, especially diabetic nephropathy.