Verapamil worsens rate of development and hemodynamic effects of acute hyperkalemia in halothane-anesthetized dogs: effects of calcium therapy

The hemodynamic effects of verapamil pretreatment versus no pretreatment were evaluated in five acutely hyperkalemic dogs. Using ECG evidence for severe hyperkalemia, the halothane-anesthetized dogs were rendered acutely hyperkalemic to similar plasma levels of K+ (K+ = 8.2 +/- 0.8 mEq/l verapamil plus hyperkalemia, K+ = 9.4 +/- 0.2 mEq/l hyperkalemic controls). The verapamil-hyperkalemic group had significantly lower cardiac indexes (CI) (CI = 1.3 +/- 0.5 1 X min-1 X m-2 verapamil plus hyperkalemia vs. CI = 3.0 +/- 0.2 1 X min-1 X m-2 hyperkalemic controls) and lower mean arterial pressures (MAP = 60 +/- 13 mmHg verapamil plus hyperkalemia vs. MAP = 96 +/- 7 mmHg hyperkalemic controls). Calcium therapy for hyperkalemia that returned CI to control levels in hyperkalemic controls only partially reversed the severe hemodynamic depression and did not improve the AV block seen during hyperkalemia in the presence of the calcium entry blocker verapamil. Surprisingly, the total mEq of KCl infused at the same rate into verapamil-pretreated dogs to result in similar high serum potassium levels was only one-third that required in dogs not pretreated with verapamil (1.6 +/- 0.3 mEq/kg KCl in verapamil-hyperkalemia group vs. 5.0 +/- 0.7 mEq/kg KCl in hyperkalemic controls).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of dietary potassium in the hyperaldosteronism and hypertension of the remnant kidney model

The remnant kidney model of progressive renal disease is marked by arterial hypertension, especially when produced by nephrectomy and partial infarction. Hyperaldosteronism sustains much of the hypertension, but the stimuli to the increased aldosterone levels are uncertain. It is hypothesized that the hyperaldosteronism attending this model stems from the combination of fixed dietary potassium load in the face of reduced filtration on the one hand, and persistent renin secretion from the scarred remnant kidney on the other. This hypothesis predicted that dietary potassium restriction would lower aldosterone and BP in this model. To test this prediction, two groups of rats with a remnant kidney were studied. Group 1 consumed 0.4 +/- 0.06 mEq (mean +/- SD) of potassium chloride daily, and group 2 ate 4.8 +/- 1.0 mEq daily. Two sham-operated groups with intact kidneys also were studied. Group 3 consumed 1.7 +/- 0.2 mEq daily and group 4 ate 15.2 +/- 1.4 mEq daily. These levels of intake were designed to provide at least as much potassium per liter of GFR in the sham groups as in the remnant kidney rats. Systolic BP (SBP), 24-h protein excretion, plasma aldosterone levels, 24-h urinary aldosterone excretion, and plasma renin activity (PRA) were determined in all groups at 2 wk. At 4 wk, after SBP and protein excretion measurements, remnant kidneys were perfusion-fixed for morphometric analysis. SBP was normal in both sham-operated groups and was not different between the groups (113 +/- 13 versus 117 +/- 2 mmHg, group 3 versus group 4). In the remnant animals, SBP at 2 wk followed potassium intake: Group 1 had a lower SBP than group 2 (140 +/- 26 versus 170 +/- 34 mmHg, P = 0.005). The same SBP pattern persisted at 4 wk (153 +/- 25 versus 197 +/- 27 mmHg, group 1 versus group 2, P = 0.0006). However, 24-h urinary protein excretion was not different between the two groups with remnant kidneys at either 2 or 4 wk. Both plasma and 24-h urinary aldosterone excretion at 2 wk followed potassium intake (120 +/- 124 versus 580 +/- 442 pg/ml for plasma aldosterone, group 1 versus group 2, P = 0.03, and 2.6 +/- 1.8 versus 23.2 +/-9.8 ng/d for urinary aldosterone, group 1 versus group 2, P = 0.0001). PRA, however, followed a reverse pattern in which dietary potassium restriction resulted in higher levels (16 +/- 6 versus 6 +/- 3 ng angiotensin I/ml per h, group 1 versus group 2, P = 0.01). A similar pattern for PRA and aldosterone excretion was also observed in the sham groups, in which lower potassium intake also resulted in a significantly higher PRA and lower aldosterone excretion. The constancy of BP in the sham groups likely reflects their lack of nephron reduction and greater sodium excretory capacity. Morphometric analysis in remnant animals revealed no significant difference between the two dietary groups in the prevalence of glomerular sclerosis, glomerular volume, or interstitial volume. It is concluded that dietary potassium is a potent determinant of hypertension in the remnant kidney model probably through the actions of aldosterone and that the high aldosterone secretion in this model is a function of the dietary potassium load. In this model, reduction in nephron number is also critical in promoting hypertension in conjunction with hyperaldosteronism.     

Effects of ciclosporin on plasma renin activity, catecholamines and prostaglandins in patients with idiopathic uveitis

Animals and humans undergoing treatment with ciclosporin (CS) show a reversible increase in renal vascular resistance and a decrease in glomerular filtration rate. The causes of these abnormalities have not yet been established. We evaluated the effects of a 1-week treatment with CS on creatinine clearance, renal arachidonic acid metabolites, plasma renin activity (PRA), plasma aldosterone levels, urinary excretion and plasma levels of catecholamines in 7 patients with idiopathic uveitis. We show that CS treatment induces a significant (p less than 0.05) decrease in creatinine clearance (from 132 +/- 0.5 to 108 +/- 8 ml/min); urinary 6-keto-PGF1 excretion (from 17.8 +/- 4.9 to 10.9 +/- 3.3 ng/mmol creatinine), urinary thromboxane B2 excretion (from 7.0 +/- 1.0 to 3.6 +/- 0.9 ng/mmol creatinine), upright PRA (from 4.2 +/- 0.9 to 2.3 +/- 0.8) and supine PRA (from 2.0 +/- 0.5 to 1.1 +/- 0.3). We found no change in plasma aldosterone levels and plasma levels and urinary excretion of catecholamines. We suggest that the reversible renal vasoconstriction observed in patients treated with CS may be induced by inhibition of renal prostacyclin synthesis. In this setting inhibition of PRA and angiotensin II formation may impair autoregulation of effective filtration pressure and therefore glomerular filtration rate.     

Effect of potassium chloride on plasma renin activity and plasma aldosterone during sodium restriction in normal man

The present study was designed to evaluate the spectrum of responses of PRA and plasma aldosterone (PAldo) to a range of oral potassium intakes (0 to 300 mEq of potassium chloride per day) in 20 normal human subjects receiving an electrolyte-free diet. Potassium exhibited a dose-dependent natriuretic effect. The results of the PRA studies indicate that normal dietary amounts (50 mEq/day) of potassium chloride do not prevent the increase in PRA with absolute sodium deprivation and that PRA is maximally stimulated on 150 mEq of potassium chloride per day. The rise in PRA is directly correlated with serum potassium concentration. The results of the PAldo studies indicate that potassium chloride deprivation attenuates PAldo increases due to sodium deprivation and that PAldo is maximally stimulated on 150mEq of potassium chloride per day. The rise in PAldo is directly correlated with serum potassium concentration and with PRA. The administration of 300 mEq/day of potassium chloride caused significant hyperkalemia and blunted both PRA and PAldo increases. Our results suggest that potassium chloride has an important role in the regulation of PRA and PAldo, and that only following potassium chloride deprivation is the PRA/PAldo response dissociated.     

Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy.

BACKGROUND: A point mutation in the plasminogen activator inhibitor-1 (PAI-1) gene and a three-allelic variation in the apolipoprotein-E (ApoE) gene have been suggested as risk factors for the development of diabetic micro- and macrovascular complications. METHODS: We studied 198 type 1 diabetic patients with diabetic nephropathy [121 men, age (mean+/-SD) 41+/-10 years, diabetes duration 28+/-8 years] and 192 patients with persistent normoalbuminuria (118 men, age 43+/-10 years, diabetes duration 27+/-9 years). RESULTS: Male patients with nephropathy had elevated plasma PAI-1 levels [geometric mean (95% CI)], 70 (62-79) ng/ml, compared with normoalbuminuric men, 43 (38-47) ng/ml, P<0.001. Even though nephropathic patients with the 4G4G genotype tended to have higher plasma PAI-1 levels, P=0.06, no difference in allele frequency (4G/5G) was seen between patients with and without nephropathy: 0.538/0.462 vs 0.539/0.461, respectively. Nor did ApoE allele frequencies (epsilon2/epsilon3/epsilon4) differ between nephropathic and normoalbuminuric patients: 0.099/0.749/0. 152 vs 0.081/0.745/0.174, respectively. Genotype distributions were also similar, n.s. Coronary heart disease was more prevalent (36%) among nephropathic patients carrying the atherogenic epsilon4-allele compared with 12% in patients with the epsilon3,epsilon3 genotype, P<0.001. No associations between diabetic retinopathy and PAI-1 or ApoE polymorphisms were observed, n.s. CONCLUSIONS: The ApoE polymorphism may accelerate the development of coronary heart disease often seen in Caucasian patients with type 1 diabetes and diabetic nephropathy, a condition characterized by elevated plasma PAI-1 in men. Neither the PAI-1 nor the ApoE gene polymorphism contributes to the genetic susceptibility to diabetic nephropathy or retinopathy.     

Arterial blood pressure and the renin-angiotensin-aldosterone system during postural changes in hypertensive patients with unilateral renal mobility

Unilateral renal mobility was identified in 27 out of 100 essential hypertensive patients by examination of renal scintiphotos. The pattern of response to postural changes of blood pressure (BP), plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was investigated in 11 patients with renal mobility and without treatment and compared with that of an age- and sex-matched group of untreated hypertensives without renal mobility. The patients with renal mobility had higher BP levels (X +/- SD mm Hg: supine 185 +/- 39/112 +/- 18 vs. 149 +/- 18/97 +/- 14; upright 167 +/- 38/108 +/- 17 vs. 144 +/- 7/93 +/- 10; p less than 0.05). Significant correlations were obtained in the patients with renal mobility (but not in those without renal mobility) between upright PRA and PAC (p less than 0.001), their postural variations (p less than 0.01) and between upright PRA (and PAC) and BP levels (p less than 0.05). The high prevalence of renal mobility in hypertension and the relationship observed between the activated renin-angiotensin-aldosterone system and BP in this condition suggest the importance of searching for unilateral renal mobility when examining the renin-angiotensin-aldosterone system in hypertensive patients, particularly during postural manoeuvres.     

The paradox of the low-renin state in diabetic nephropathy.

Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.     

Atrial natriuretic factor in the acute nephritic and nephrotic syndromes

Because the role of systemic hormones in the pathophysiology of edema in acute renal disease remains incompletely understood, we compared the levels of atrial natriuretic factor (ANF) and plasma renin activity (PRA) in patients with acute glomerulonephritis (AGN), nephrotic syndrome (NS), and normal individuals during salt deprivation and salt loading. Sixteen patients with AGN (10 males) and nine patients with NS and hypoalbuminemia (7 males) were studied on admission, and after recovery (12 AGN patients) or remission (4 NS patients). Eighteen normal controls were each studied after five days on a low (20 mEq Na/day), regular (120 mEq Na/day) and high (300 mEq Na/day) dietary salt intake. Patients with AGN and NS had comparable edema (AGN 2.8 +/- 0.53 kg; NS 3.36 +/- 0.47 kg; SE) and urinary Na excretion (mean +/- SEM: AGN 0.97 +/- 0.11 mEq/hr; NS 1.06 +/- 0.16 mEq/hr), but AGN patients had five times higher ANF (AGN 27.2 +/- 4.06 fmol/ml; NS 5.51 +/- 1.02 fmol/ml; P less than 0.001) and six times lower PRA ng/liter.sec levels (AGN 0.187 +/- 0.047; NS 1.144 +/- 0.222; P less than 0.001) than NS patients. The degree of edema was correlated with ANF levels in AGN patients (P less than 0.001) but not in NS patients. There was a strong exponential negative correlation (r = -0.773, P less than 0.0001) between ANF and PRA, in which AGN patients and Na-restricted controls were located in the opposite ends of the volume sensing-response, and NS patients in the middle, alongside controls with regular Na intake.(ABSTRACT TRUNCATED AT 250 WORDS)     

Predictors of the development of hyperkalemia in patients using angiotensin-converting enzyme inhibitors

BACKGROUND/AIMS: Angiotensin-converting enzyme inhibitors (ACEI) are the antihypertensives of choice in patients with chronic renal failure (CRF). ACEI by decreasing the synthesis of aldosterone, the main regulator of serum potassium, predispose to the development of hyperkalemia. Although hyperkalemia with administration of ACEI is uncommon in patients with a normal renal function, a preexisting abnormality in potassium hemostasis, as seen in patients with chronic renal failure, may increase the risk of hyperkalemia. METHOD: To determine the predictors of development of hyperkalemia (K >5.1 mEq/l) in patients on ACEI, we retrospectively reviewed medical records of 119 patients followed in our renal clinic. RESULTS: The mean age of the patients was 56 +/- (SD) 13 (range 20-84) years. Sixty-three percent were males, and 37% were females. Sixty-seven percent had a history of diabetes. Eighty five percent of the patients had CRF [creatinine clearance (CrCl) <80 ml/min]. The baseline serum Cr was 2.3 +/- 1.2 (range 0.6-6.9) mg/dl, and the CrCl was 50 +/- 27.5 ml/min. Of the 119 patients 46 (38.6%) developed hyperkalemia (mean K 5.68 +/- 0.3, range 5.2-6.7 mEq/l). Ninety-six percent of the patients who developed hyperkalemia had CRF, and 84% were diabetics. Pearson product-moment correlation revealed a significant positive correlation of hyperkalemia with Cr and a negative correlation of hyperkalemia with CrCl and HCO(3) (Cr: r = 0.42, p < 0.0001; CrCl: r = -0.34, p < 0.0001; HCO(3): r = -0.41, p < 0.0001). Multivariate logistic regression analysis revealed diabetes and serum creatinine to be the main predictors of hyperkalemia. In 31 patients hyperkalemia resolved either with a low-potassium (2 g/day) diet or with diet and a decrease in the dose of ACEI. In 15 patients ACEI had to be discontinued due to persistent hyperkalemia. CONCLUSIONS: We conclude that hyperkalemia is common in patients with CRF on ACEI. The majority of the patients who develop hyperkalemia on ACEI have CRF and diabetes. A large number of patients with CRF require discontinuation of ACEI due to hyperkalemia and are deprived of their renoprotective effects.     

Rapid increase in plasma levels of atrial natriuretic peptide after common bile duct ligation in the rabbit.

Previous studies have shown that common bile duct ligation in the rabbit is followed by a reduction of the extracellular water compartment. To further elucidate the mechanisms leading to volume depletion in this model, water and sodium balances and changes in plasma concentrations of atrial natriuretic peptide (ANP), vasopressin (ADH), plasma renin activity (PRA) and aldosterone (Ald) were investigated during the first 4 days after common bile duct ligation (group OJ,) or sham operation (group SO). Water and chow intakes were lower in group OJ (148 +/- 30 versus 226 +/- 40 mL/4 days; p = 0.004 and 12 +/- 9 versus 171 +/- 40 g/4 days; p = 0.0001). There were no differences in urine output. Sodium urinary losses were marginally higher in group OJ (12.4 +/- 7 versus 6.7 +/- 5 mEq/4 days; p = 0.06). Water balance was lower in group OJ (-50 +/- 56 versus 101 +/- 71 mL/4 days; p = 0.0001). At 24 hours, plasma ANP (41 +/- 7 versus 10.7 +/- 1 fmol/mL, p = 0.0001), ADH (21.8 +/- 7 versus 12.3 +/- 6 pg/mL, p = 0.008) and Ald (14.5 +/- 5 versus 3.7 +/- 3 ng/dL, p = 0.001) were higher in group OJ. These alterations persisted 72 hours after bile duct ligation, when a concomitant increase in PRA (10.7 +/- 5 versus 3 +/- 1.6 ng/dL, p = 0.006) was also observed. A group of pair-fed pair-watered sham-operated controls (group SO2, n = 13) showed a metabolic profile similar to group OJ but a low ANP concentration. Multiple venous sampling in five rabbits 24 hours after bile duct ligation showed the highest plasma levels of ANP in the aorta and infrarenal vena cava. These results suggest that common bile duct ligation in the rabbit is followed by marked hypodipsia and hypophagia, possibly mediated by ANP, leading to isotonic volume depletion and secondary activation of the water and sodium retaining hormones.     

Associations of serum testosterone with microvessel density,androgen receptor density and androgen receptor gene polymorphism in prostate cancer

PURPOSE: We investigate potential associations of serum testosterone with microvessel density, androgen receptor expression and AR gene polymorphism in men with untreated prostate cancer. MATERIAL AND METHODS: Serum luteinizing hormone, follicle-stimulating hormone, estradiol and testosterone were determined in men with newly diagnosed prostate cancer. The number of tumor vessels per 0.46 mm. and androgen receptor density (as the percent positive nuclei) were quantified immunohistochemically on prostate cancer areas of prostate biopsy specimens. Polymorphisms within the AR gene (number of CAG repeats) were determined by polymerase chain reaction and restriction fragment length polymorphism analysis using DNA from peripheral blood. RESULTS: The 39 men entered into this study were grouped into 16 with low (3 ng./ml. or less, group 1) and 23 with normal (greater than 3 ng./ml., group 2) serum testosterone. Mean prostate specific antigen +/- SD was significantly lower in group 1 than in group 2 (18.8 +/- 11.1 versus 27.2 +/- 12.2 ng./ml., p = 0.03). Mean Gleason score (7.4 +/- 1.3 versus 6.0 +/- 1.2, p = 0.01), androgen receptor density (96.6% +/- 2.8% versus 84.8% +/- 7.2%, p = 0.03) and tumor vessel density (63.0 +/- 30.8/0.46 versus 39.0 +/- 22.9/0.46 mm.2, p = 0.007) were significantly higher in group 1 than in group 2. The number of CAG repeats within the AR gene did not correlation with serum androgen. CONCLUSIONS: Low serum testosterone in men with newly diagnosed prostate cancer is associated with higher tumor microvessel and androgen receptor density as well as with higher Gleason score, suggesting enhanced malignant potential.     

Perinatal complications and three-year follow up of infants of diabetic mothers with diabetic nephropathy stage IV

The objective of the study was to evaluate differences in the perinatal complications and in the 3-year follow up of infants of diabetic mothers with and without diabetic nephropathy stage IV. We compared the fetal and maternal complications and the early postpartal development until 3 years after delivery in 10 children of nephropathic diabetic mothers and 30 children of diabetic mothers without nephropathy. The mean (+/-SD) birthweight of the infants of nephropathic women was 2,250 +/- 496 g versus 3,544 +/- 435 g in the women without nephoropathy (p < 0.01). Births were premature in six pregnancies (60%) of the nephrotic women but in none of the women without nephropathy (p < 0.01). Three infants (30%) of the women with nephropathy showed respiratory distress syndrome in contrast to two babies (6%) of the women without nephropathy. Pre-eclampsia or eclampsia occurred in 6 (60%) pregnant women with and in two women (6%) without diabetic nephropathy (p < 0.01). Nephrotic syndrome was observed in 7 nephrotic women (70%) in contrast to none women without nephropathy. Three years postpartum, six of the children (60%) of nephropathic women had a body weight < the 50th percentile but none of the children of the women without nephropathy did so (p < 0.01). In addition, the children of nephropathic mothers started to speak significantly later (15 +/- 3 versus 12 +/- 13 months postpartum, p < 0.05) and had infectious diseases more commonly (60% versus 6%, p < 0.01) than the children of women without nephropathy. It can be concluded that in pregnancies of diabetic women the birth weights of the infants are significantly smaller and the fetal as well as maternal complication-rates significantly higher than in those of women without nephropathy. Also 3 years after delivery, the body weight of the children of nephropathic diabetic women is significantly lower than that of children of diabetic women without nephropathy. Additionally, children of nephropathic women are retarded in terms of linguistic development and their resistance to infections is reduced.     

Augmented aldosterone and insulin responses to potassium infusion in dogs with renal failure

The present study examines acute potassium-induced insulin and aldosterone responses in renal failure, and the role of chronic dietary potassium intake in modifying these acute responses. Plasma aldosterone (PA) and insulin (IRI) responses to acute KCl infusion were examined in control and remnant kidney dogs on two potassium intakes. Dogs (N = 8) received the KCl infusions after 10 days of a 60, and then 10 days of a 200, mEq daily potassium intake during control and after surgical-induced renal failure (CRF). A one hour intravenous infusion of KCl (2 mEq KCl/kg/hr) in dextrose and water was performed with blood samples for PA, IRI, creatinine and electrolytes, and urine for electrolytes and creatinine at 20 minute intervals one hour preceding, during, and after the infusion. Preinfusion PA was higher (P less than 0.05) in controls and CRF dogs on 200 mEq potassium intake compared to 60 mEq potassium intake. The peak incremental responses of PA to KCl infusion were increased (P less than 0.01) in CRF compared to controls on 60 mEq (PA 36 +/- 4.2 vs. 26 +/- 3.0 ng/dl) and 200 mEq (delta PA 49 +/- 5.6 vs. 37 +/- 2.8 ng/dl) potassium intakes. Differences in incremental PA responses in CRF were not due to altered aldosterone metabolic clearance rates, changes in renin, or ACTH activity. Pre-infusion IRI was higher (P less than 0.05) in CRF than control dogs on both potassium diets.(ABSTRACT TRUNCATED AT 250 WORDS)     

Perioperative management of patients on maintenance hemodialysis: serum potassium and hemodynamic changes during anesthesia]

Serum potassium and hemodynamic changes were studied during anesthesia in 32 patients on chronic hemodialysis (HD) who received the last HD either 24 hours (12 patients; Group A) or 3 hours (20 patients; Group B) prior to surgery. Preanesthetic removal of body water by HD in Group A (2,400 +/- 1,100 ml) was significantly greater than that of Group B (1,200 +/- 500 ml). Preanesthetic serum potassium values were 4.7 +/- 0.6 and 4.1 +/- 0.4mEq.l-1 in Groups A and B respectively. Anesthesia was induced and maintained with N2O-O2 plus halothane or enflurane. Six patients in Group A (50%) developed hypotension during anesthesia. In contrast, hypotension was noted in only one patient (5%) in Group B. On the other hand, in Group B, 3 patients (15%) developed hyperkalemia (serum K greater than 6mEq.l-1), although no patient had hyperkalemia in Group A. The excessive removal of body water by preoperative HD should be avoided because hypotension often develops during anesthesia. Since the risk of hyperkalemia is not low, we should measure serum potassium during anesthesia when HD is performed immediately before anesthesia and removal of body water appears to be inadequate even if preanesthetic serum potassium value is normal.     

Quantitation of human pancreatic beta-cell function by immunoassay of C-peptide in urine.

Human proinsulin connecting peptide (C-peptide) was measured by immunoassay in urine from 25 normal subjects, 18 patients with diabetes mellitus, and 34 patients with various degrees of renal insufficiency. Assay validation studies showed that pancreatic C-peptide was quantitatively recovered when added to urine. Fractionation of urine by gel filtration indicated that most endogenous C-peptide eluted in fractions that corresponded to the C-peptide standard. In 34 nondiabetic subjects with normal kidney function or various renal diseases, C-peptide clearance was independent of creatinine clearance over a range of 6 to 190 ml./min. Urine C-peptide clearance (5.1 +/- 0.6 ml./min.) is greater than that of insulin (1.1 +/- 0.2 ml./min.), and the total quantity of C-peptide excreted in the urine per day represents 5 per cent of pancreatic secretion, as against only 0.1 per cent of secreted insulin. Healthy subjects excreted 36 +/- 4 mug. C-peptide per 24 hours, while this value in juvenile-onset diabetics was only 1.1 +/- 0.5 mug. Adult-onset diabetics excreted 24 +/- 7 mug./24 hr., the range overlapping the excretory rates of both normal subjects and juvenile-onset diabetics. Two insulin-requiring adult-onset diabetics showed significant beta-cell reserve during the course of acute infections. These results suggest that urine C-peptide provides a useful means of assessing beta-cell secretory capacity over a period of time and is especially advantageous when frequent blood sampling is not feasible.     

Renin-angiotensin-aldosterone system in mild diabetic nephropathy

The mechanism of lowered renin-aldosterone system was investigated in 17 patients with diabetic nephropathy (serum Cr less than 3 mg/100 ml) with concomitant control of the blood sugar level. The response of plasma renin activity (PRA) to upright stimulation was lower in the low renin group (group I) than in the normal to high renin group (group II) and in the control group. The PRA response to theophylline was delayed in group I. The percentage of the luminal area of the arteriole in the biopsy specimens was larger in group I and the control group than in group II. Plasma aldosterone concentration (PAC) was not increased by angiotensin II in group I. Low PRA in diabetic nephropathy with slightly to moderately impaired renal function may not be due to hyaline destruction of the arteriolar walls, but to other factors such as sympathetic nervous dysfunction. The adrenal responses of PAC to angiotensin II may also be impaired.     

Investigation of insulin sensitivity in treated subjects with ketosis-prone diabetes mellitus.

Two similar intravenous infucion techniques have been utilized to investigate insulin sensitivity in young subjects with recent-onset ketosis-prone diabetes mellitus. All subjects presented initially with mild to moderately severe ketoacidosis and had been treated with daily insulin therapy for two to eight weeks at the time of study. Six diabetics and 10 normal subjects (group A) received intravenous infusions of glucose (6 mg./kg./min), insulin (80 mU./min.) for 150 minutes. Steady-state plasma glucose (SSPG) and insulin levels (SSPI) were reached by 90 minutes and maintained through the end of the study. As all subjects achieve simolas SSPI while simultaneously receiving similar glucose loads, the SSPG can be used to measure individual insulin sensitivity. Under these conditions the diabetics in group A had a mean SSPG (+/-S.E.) of 99+/-26 mg./100ml., which was not different from the level of 98 +/-14mg./100 ml. for their control subjects. Six diabetics and six normal subjects (group B) received infusions of only glucose (6 mg./kg./min.) and insulin (80 mU./min.). Similar SSPI levels were attained in both the diabetic and control subjects, and their mean SSPG (+/-S.E.) levels were not significantly different (83+/- 13 vs. 61 +/-6 mg./100 ml.). One diabetic in group A and two diabetics in group B had SSPG levels above the highest values measured in their control groups. However, all three had markedly elevated fasting plasma glucose levels on the day of study. In contrast, nine well-controlled diabetics had normal insulin sensitivity. These results suggest that well-controlled subjects with ketosis-prone diabetes mellitus have normal sensitivity to insulin.     

Plasma atrial natriuretic peptide and natriuretic response to water immersion in patients with nephrotic syndrome.

Eight nonnatriuretic (daily Na excretion less than 50 mEq), 4 natriuretic (daily Na excretion greater than 50 mEq), and 4 steroid-responsive nephrotic patients, and 12 normal controls were studied with a 4-hour water immersion with measurements of electrolytes, plasma atrial natriuretic peptide (ANP), plasma renin activity (PRA), and plasma aldosterone (PA) [corrected]. Four nonnatriuretic patients further received 25 g albumin infusion, with a subsequent 2-hour water immersion study. The results are as follows: (1) In the nonnatriuretic patients, the extremely low basal Na excretion rate, high PRA, and PA levels indicated a state of active Na retention. In spite of the water-immersion induced suppression of PRA and PA and a comparable magnitude of plasma ANP increment, the natriuretic response to water immersion was blunted in the nonnatriuretic patients. (2) In the natriuretic patients, water immersion resulted in a similar magnitude of natriuresis but a higher degree of plasma ANP increment in comparison to the normal controls. (3) Natriuretic and plasma ANP responses to water immersion were not different between the steroid-responsive patients and normal controls. (4) The increase in plasma ANP and the suppression of PRA and PA after 25 g albumin infusion did not result in natriuresis until the further suppression of PRA and PA and the further stimulation of plasma ANP by subsequent water immersion. The above results indicate that the natriuretic and plasma ANP responses to water immersion are related to the basal Na status in nephrotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of insulin on the exaggerated glucagon response to arginine stimulation in diabetes mellitus.

The effect of insulin on the glucagon response to intravenous arginine was studied in eight juvenile-type and six adult-onset diabetics. In the juvenile-type diabetics, concomitant administration of insulin significantly blunted the glucagon response from a mean maximal rise of 310 +/- 54 pg./ml. to only 184 +/- 39 pg./ml. (p less than 0.01), about the same as in nondiabetics. In the adult-onset patients, however, insulin had no effect, the mean maximal rise being 250 +/- 50 pg./ml. without insulin and 307 +/- 71 pg./ml. with insulin (N.S.). This study demonstrates that in juvenile-type diabetics concomitant administration of supraphysiologic quantities of insulin can reduce the exaggerated glucagon response to intravenous arginine to normal, whereas in the adult-type group, it has no apparent effect.     

Plasma renin activity in juvenile diabetes mellitus and effect of diazoxide.

Low plasma renin activity (PRA) has been reported in patients with long-term diabetes mellitus complicated by hypertension and nephropathy. We have assayed PRA in twelve normal subjects and in eight age- and sex-matched juvenile diabetics of greater than twelve years' duration without hypertension and nephropathy under control conditions and following stimulation with diazoxide. During control conditions PRA did not decrease with time in the diabetics as it did in the normals. Following diazoxide infusion, PRA increased in both groups, and although the levels were often higher in diabetics than in normals, the mean differences were not statistically significant. The findings are consistent with the suggestion that PRA is normal or possibly elevated in clinically uncomplicated insulin-dependent diabetes mellitus and decreases with establishment of hypertension and nephropathy.