Protein-induced glomerular hyperfiltration: role of hormonal factors

High protein diets acutely elevate the glomerular filtration rate. To characterize this response we administered 1 g of protein/kg body weight as a beef steak meal to nine, healthy male subjects and measured glomerular filtration rate (inulin clearance), renal plasma flow (p-amino hippurate clearance), plasma renin activity, aldosterone and plasma and urinary catecholamines. The subjects ingested the meal on three separate days and were pretreated with either placebo, 50 mg indomethacin (to inhibit renal prostaglandin synthesis), or 10 mg enalapril (to inhibit angiotensin II synthesis). Following placebo treatment protein feeding significantly increased the glomerular filtration rate, from a pre-meal level of 101 +/- 7 ml/min/1.73 m2 to a post-meal level of 130 +/- 6 ml/min/1.73 m2, P less than 0.005. A parallel rise in renal plasma flow and a fall in renal vascular resistance were noted. Indomethacin pretreatment attenuated the increase in glomerular filtration rate following the protein meal, 105 +/- 6 ml/min/1.73 m2 pre-meal level to 118 +/- 4 ml/min/1.73 m2 post-meal, P greater than 0.1. Enalapril pretreatment had no significant effect on protein-induced glomerular hyperfiltration. Protein feeding following placebo increased plasma aldosterone concentration while the concentrations were unchanged in the studies where enalapril or indomethacin was administered. Protein feeding following placebo or indomethacin did not alter plasma renin activity while plasma renin activity rose following enalapril administration. Urinary norepinephrine excretion rose while plasma norepinephrine concentration was unchanged in all three study groups. A decrease in urinary dopamine excretion was also noted four hours after the protein meal was ingested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of renal prostaglandin E2 in chronic renal disease hypertension

The role played by renal prostaglandin E2 in the maintenance of hypertension in chronic renal disease has been investigated through studying the response of body weight, blood pressure, glomerular filtration rate (GFR), 24-hour natriuresis, plasma renin activity (PRA), plasma aldosterone and urinary PGE2 excretion to the administration of indomethacin (2mg/kg daily, during 3 days). A group of 37 patients diagnosed as having chronic renal parenchymatous disease with creatinine clearance above 25 ml/min was included in the study. 21 of them were hypertensive (BP greater than 160/95). 27 normotensive volunteers were also studied and considered as the control group. The initial study disclosed similar levels of PGE2, PRA and plasma aldosterone in volunteers, normotensive patients and hypertensive patients, although the sodium intake was lower in the last two groups. A positive correlation between PRA and urinary PGE2 was found both in normotensive (r = 0.507, p less than 0.01) and in hypertensive patients (r = 0.609, p less than 0.01). The administration of indomethacin induced a diminution of PRA, plasma aldosterone and urinary PGE2 levels together with an increase in diastolic blood pressure (p less than 0.05-0.01) in both volunteers and patients. The remaining parameters measured did not change in volunteers or in normotensive patients. On the contrary, in hypertensive patients, during indomethacin administration, lower values of creatinine clearance (p less than 0.005) and 24-hour natriuresis (p less than 0.05) together with an increase in body weight (p less than 0.01) were observed. These results point to the existence of a protective role of renal prostaglandin E2 upon renal function when hypertension appears in the course of chronic renal parenchymatous disease.     

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.     

Renal tubular function in cirrhotic patients with ascites: special reference to lithium clearance following the human atrial natriuretic peptide administration]

Synthetic alpha-human atrial natriuretic peptide (alpha-hANP), 1 micrograms/kg, was intravenously given to 16 cirrhotic patients with ascites and 9 control subjects (CS) to investigate major factors responsible for sodium retention and refractory ascites. The following parameters were measured before and after alpha-hANP administration; such as lithium clearance (CLi) as an index of fluid delivery to the distal tuble, mean arterial pressure (MAP), urinary sodium excretion rate (UNaV), urine volume (V), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), plasma renin activity (PRA), plasma aldosterone concentration (PAC), urinary excretion of prostaglandin (PG)E2, 6-keto-PGF1 alpha (6-k-PGF1 alpha), and thromboxane B2 (TxB2). Patients were divided following alpha-hANP administration into 2 groups as "good responders (GR)" and "poor responders (PR)", in which GR was defined as the group showing 2-fold-increase in UNaV. In contrast, PR had significant lower MAP (71.8 +/- 5.04 mmHg), GFR (21.3 +/- 3.90 ml/min), ERPF (158.0 +/- 43.8 ml/min), FELi (CLi/GFR; 12.6 +/- 1.26%), and higher PRA (8.72 +/- 0.99 ng/ml/h) and PAC (12.2 +/- 3.13 ng/dl) than GR. GR demonstrated almost same natriuretic response as CS with an increase of GFR and renal PGs synthesis, and a decrease of FELi despite reduction in blood pressure. However, alpha-hANP did not suppress PRA, PAC, and distal tubular reabsorption of sodium (FDRNa = 1-FENa/FELi) in cirrhotic patients, whereas suppressed in CS. UNaV correlated with FELi (r = 0.687, p = 0.01) and GFR (r = 0.777, p = 0.01). PRA correlated with FELi r = 0.669, p = 0.015), GFR (r = -0.634, p = 0.018), and MAP (r = 0.858, p = 0.001) only in cirrhosis. These results therefore indicated that hypotension caused by hemodynamic alteration and extremely stimulated renin release might effect on proximal tubular sodium reabsorption and GFR, leading to sodium retention and diuretic resistance in cirrhosis.     

The long-term effects of a new converting enzyme inhibitor, delapril hydrochloride, on renal function, renin-angiotensin-aldosterone system and kallikrein-kinin prostaglandin system in hypertensive patients

The effects of a new angiotensin converting enzyme inhibitor, delapril hydrochloride, (delapril) on renal function, and the renin-angiotensin-aldosterone and kallikrein-kinin prostaglandin systems were studied in 10 hypertensive patients. After 4 to 12 months (7.6 +/- 0.9 [SE]) of treatment with 15-60 mg/day (36 +/- 6.8) of delapril (b.i.d.), mean arterial pressure was decreased from 126 +/- 3.0 to 110 +/- 4.4 mmHg (p less than 0.01). Although renal blood flow (RBF), assessed by PAH clearance and hematocrit, was increased from 437 +/- 51 to 490 +/- 49 ml/min (p less than 0.05) and renal vascular resistance was decreased (p less than 0.05), glomerular filtration rate, measured by endogenous creatinine clearance, did not change significantly. Thus, filtration fraction was reduced (p less than 0.01). Plasma renin activity was increased from 1.5 +/- 0.3 to 4.4 +/- 1.1 ng/ml/hr (p less than 0.01). Plasma aldosterone concentration tended to decrease (p less than 0.1), and urinary aldosterone excretion showed on significant change. Although urinary kallikrein and prostaglandin E2 excretions were increased (p less than 0.05), urinary thromboxane B2 excretions was reduced (p less than 0.05). In addition, the changes in RBF were significantly correlated with those in urinary PGE2 excretion (r = 0.63, p less than 0.05). These results suggest that the antihypertensive effect of delapril is multifactorial and that the improvement of RBF seen during delapril administration in the present study may be partly due to the suppression of the renin-angiotensin-aldosterone system and the activation of kallikrein-kinin-prostaglandin system.     

Effect of demeclocycline on renal function and urinary prostaglandin E2 and kallikrein in hyponatremic cirrhotics

8 cirrhotics with hyponatremia were given demeclocycline (DMC) 900 mg/day to investigate its effect on renal function, plasma renin activity, aldosterone and urinary excretion of prostaglandin E2 and kallikrein. In 7 patients DMC induced an increase of free water clearance (from -0.36 +/- 0.06 to 0.13 +/- 0.06 ml/min) and serum sodium concentration (from 125.4 +/- 0.09 to 131.1 +/- 1.0 mEq/l, mmol/l). In 5 of these patients DMC also induced a marked reduction of glomerular filtration rate (from 72.2 +/- 6.2 to 31,2 +/- 4.7 ml/min) and renal plasma flow (from 468 +/- 98 to 195 +/- 55 ml/min) which could not be explained on the basis of hypovolemia. In each case this renal impairment was not associated with changes in urinary concentration of beta 2-microglobulin, urinary casts excretion, fresh urine sediment or urine protein content and disappeared after discontinuation of the drug. DMC induced a marked increase in the urinary excretion of prostaglandin E2 (from 0.82 +/- 0.27 to 6.16 +/- 1.91 ng/min) in 6 out of the 7 patients who responded to DMC and a marked reduction in urinary kallikrein (from 16.1 +/- 4.4 to 4.2 +/- 1.6 pkat/min) in the 5 patients who developed renal insufficiency. The serum DMC concentration was greater than 5 micrograms/ml in all patients who responded to DMC, greater than 8 micrograms/ml in all cases who developed renal insufficiency and of 3 micrograms/ml in the case not responding to DMC. (ABSTRACT TRUNCATED AT 250 WORDS)     

Functional relationships in the nephrotic syndrome

An analysis of 70 observations in patients with the nephrotic syndrome (NS) on a low sodium diet is presented. The following parameters were determined: plasma volume, plasma renin activity, plasma aldosterone concentration, serum albumin, urinary sodium and protein excretion, and creatinine clearance. In 41 instances glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined on the basis of 51Cr-EDTA and 125I-hippuran clearances, and the filtration fraction (FF) was calculated. The results in patients with minimal lesions (ML) and those with histological glomerular lesions (HL) were compared to determine whether these groups can be separated on the basis of signs of hypovolemia and primary renal sodium retention. Although a higher proportion of the ML patients showed extreme sodium retention and elevated plasma renin and aldosterone levels, these values tended to overlap and no differences were found for blood volume, blood pressure, and overall renal function between the groups. FF was markedly and equally depressed in both groups: 13.5 +/- 1.6% in the ML and 14.2 +/- 1.1% SEM in the HL group (NS). Analysis of the within-group relationships between the parameters under study revealed relatively few correlations, which supports the hypothesis that primary impairment of renal water and salt excretion is an important if not overruling factor in patients with the NS.     

Abnormal antidiuretic hormone secretion in patients with systemic lupus erythematosus

There have been anecdotal reports describing patients with systemic lupus erythematosus (SLE) and inappropriately elevated secretion of antidiuretic hormone (ADH), but no systematic studies of ADH and its metabolism in SLE have been performed. We measured plasma ADH levels in 36 stable SLE patients with normal renal function and examined the relationship of the circulating ADH concentration to clinical disease activity and effective extracellular fluid volume as reflected by peripheral plasma renin activity (PRA) and plasma aldosterone concentration. The mean ADH level was elevated, 11.4 +/- 1.0 microU/ml (normal 0.4-1.4 microU/ml), while mean PRA and aldosterone were 5.4 +/- 0.6 ng/ml/h and 10.6 +/- 1.6 ng/100 ml, respectively. When patients were divided into two groups according to disease duration, those with SLE for 2 years or more had significantly higher plasma ADH levels (13.9 +/- 1.4 vs. 7.7 +/- 0.9 microU/ml; p less than 0.001 and urinary osmolality (697 +/- 63 vs. 445 +/- 49 mosm/kg; p less than 0.02) compared to those with SLE of less than 2 years duration. No differences in serum Na+, K+, PRA, plasma aldosterone concentration, C3, or 24-hour urinary protein excretion were noted between these two groups. Six patients with SLE for less than 2 years underwent a standard water load (20 ml/kg); in 3/6 there was a paradoxical increase in the plasma ADH concentration. These findings indicate that SLE is associated with elevated plasma ADH levels that increase with prolonged disease duration. This abnormality is unrelated to the usual serologic indices of SLE activity, effective extracellular fluid volume status, or any apparent renal unresponsiveness to ADH.(ABSTRACT TRUNCATED AT 250 WORDS)     

No involvement of antidiuretic hormone in acute antidiuresis during PEEP ventilation in humans

Decreased urinary output (Vu ml/min) after institution of PEEP is attributed to a variety of mechanisms including decreased cardiac output and renal blood flow (RBF), activation of neurohormonal reflexes, increased catecholamines, plasma renin activity (PRA), and antidiuretic hormone (ADH) release. To evaluate these factors, seven normovolemic patients (36 yr +/- 13 SD), free of preexisting lung, cardiac, or renal disease, requiring continuous mandatory ventilation for neurologic reasons were studied. The authors measured or calculated: total blood volume (TBV) (51Cr); right atrial, pulmonary arterial, pulmonary wedge, and systemic pressures, cardiac index (CI); renal plasma flow (RPF) (iodohippurate sodium 131I [131I PAH] clearance); glomerular filtration rate (GFR) (creatinine clearance), free water clearance (CH2O), osmolal clearance (Cosm), fractional excretion of sodium (FENa+) and potassium (FEK+); and plasma renin activity (PRA) (ng X ml-1 X h-1), plasma ADH (pg/ml; radioimmunoassay), epinephrine (E in pg/ml), and norepinephrine (NE in pg/ml) (double-isotope radioenzymatic assay). Two conditions were studied after 90-min steady state: 1) zero PEEP (ZEEP); and 2) 15 cmH2O PEEP. PEEP caused a significant decrease in CI (-21%; P less than 0.01) and RPF (-19%; P less than 0.05) without significant decrease in GFR. A significant decrease in Vu (-55%; P less than 0.05), FENa+ (-39%; P less than 0.05) and Cosm (-36%; P less than 0.25) occurred without modification in CH2O. Plasma ADH remained in the normal range and did not increase when PEEP was applied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal tubular function in children and adolescents with Gitelnian's syndrome, the hypocalciuric variant of Bartter's syndrome

Renal tubular function was studied in 14 patients with Gitelman'ssyndrome and 14 control subjects. Apart from the biochemicalhallmarks of Gitelman's syndrome, namely alkalaemia, hyperbicarbonataemia, hypokalaemia, hypomagnesaemia (with increasedmagnesium over creatinine ratio), increased urinary chlorideover creatinine ratio, and low urinary calcium over creatinine,the patients were found to have hyperproteinaemia, hypochloraemia,high total plasma calcium concentration, reduced plasma ionizedcalcium concentration, and high urinary sodium excretion. Astatistically significant negative linear relationship betweenplasma magnesium concentration and magnesium excretion correctedfor glomerular filtration was observed in patients. The fractionalcalcium clearance and the urinary excretion of calcium correctedfor glomerular filtration was significantly decreased in patients.In patients the urin ary osmolality after overnight water deprivationranged from 526 to 1067 mmol/kg. Glucosuria and aminoacid uriawere similar in patients and controls. The results of the studydemonstrate the renal origin of hypomag nesaemia and hypocalciuriain Gitelman's syndrome. The failure to demonstrate hyperaminoaciduria,hyperglucosuria, hyperphosphaturia, hyperuricosuria, and severelyimpaired urinary concentrating ability provide evidence fora defect residing in the distal convoluted tubule.     

Effects of Nva2-cyclosporine on glomerular filtration rate and renal blood flow in the rat

The effects of Nva2-cyclosporine on glomerular filtration and renal blood flow in rats were studied and compared with those of cyclosporine. An infusion of Nva2-cyclosporine (20 mg/kg) caused a 53% fall in glomerular filtration rate (1.0 +/- 0.08 to 0.47 +/- 0.09; P less than 0.001) and renal plasma flow (3.2 +/- 0.4 to 1.6 +/- 0.4; P less than 0.005). Nva2-cyclosporine when infused in a dose of 10 mg/kg caused a nearly identical fall in inulin clearance and renal plasma flow. By comparison an infusion of cyclosporine (20 mg/kg) caused a 50% decrease in inulin clearance and a fall in renal plasma flow from 2.6 +/- 0.3 to 0.9 +/- 0.3. Nva2-cyclosporine or cyclosporine was given chronically in a dose of 20 mg/kg intraperitoneally for seven days. Cyclosporine produced a 27% fall in creatinine clearance, whereas Nva2-cyclosporine produced a 19% decrease in creatinine clearance (NS). These studies suggest that Nva2-cyclosporine has adverse effects on renal blood flow and glomerular filtration rate similar to those seen with cyclosporine.     

Mechanisms of hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone

Hypouricemia seen with hyponatremia related to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) results from an increase in uric acid renal clearance. We studied the mechanism of the increase of uric acid excretion in 6 SIADH patients through pyrazinamide (PZA), which decreases tubular secretion of uric acid, and sulfinpyrazone (SPZ) which decreases post-secretory reabsorption of uric acid. 3 g of PZA decreased the absolute uric acid excretion from 428 +/- 244 to 105 +/- 47 micrograms/min (mean +/- SD, p less than 0.01), and 300 mg of SPZ increased the uric acid to creatinine clearance ratio from 0.31 +/- 0.05 to 0.52 +/- 0.05 mg/dl glomerular filtration rate (mean +/- SEM, p less than 0.001), which represent an increment about half of that observed in the control group. The increase of uric acid clearance in SIADH seems to result from a decrease in the post-secretory reabsorption of uric acid. After SPZ, we saw a decrease of natriuresis from 5.6 +/- 1.4 to 1.8 +/- 0.3 mmol/h (p less than 0.001), without any change of urinary flow or urinary potassium excretion.     

Renal handling of enalaprilat.

Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean +/- SE, 33.1 +/- 2.8) were studied. They had representative height (178.6 +/- 1.99 cm) and weight (73.3 +/- 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 +/- 0.3 mmol/L [17 +/- 0.8 mg/dL]), plasma creatinine (88 +/- 3 mumol/L [1.0 +/- 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 +/- 6.2 mL/min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P less than 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85, (P less than 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion.     

Nocturnal blood pressure is elevated with natriuresis and proteinuria as renal function deteriorates in nephropathy

BACKGROUND: We reported that patients with sodium sensitive type of hypertension exhibited the lack of nocturnal fall in blood pressure with enhanced natriuresis during night. Sodium sensitivity is caused by diminished glomerular filtration capability and/or augmented tubular reabsorption of sodium, and seems tightly linked with glomerular capillary hypertension. In the present study, we investigated the relationship between glomerular filtration rate and circadian rhythms of these parameters in patients with glomerulopathy. METHODS: Twenty six patients (15 men and 11 women; aged 17 to 72 years; mean age 47 +/- 3 years), whose diagnosis was confirmed as glomerulopathy with renal biopsy, were studied during hospitalization. Ambulatory blood pressure for 24 hours was monitored, while urinary samples were collected for both daytime (6:00 a.m. to 9:00 p.m.) and nighttime (9:00 p.m. to 6:00 a.m.) to estimate circadian rhythms of urinary sodium and protein excretion rates (UNaV, UproV). Then night/day ratios of mean arterial blood pressure (MAP), UNaV, and UproV were analyzed in relation to 24-hour creatinine clearance as a marker of glomerular filtration rate. RESULTS: Serum creatinine and creatinine clearance were 1.1 +/- 0.1 mg/dL and 89 +/- 7 mL/min/1.73 m2. There were significant day-night differences in MAP (96 +/- 2 mm Hg vs. 92 +/- 2 mm Hg; P= 0.006), UNaV (6.7 +/- 0.9 mmol/hour vs. 3.6 +/- 0.3 mmol/hour; P= 0.003), and UproV (161 +/- 27 mg/hour vs. 128 +/- 28 mg/hour; P= 0.02). Creatinine clearance had significantly negative relationships with night/day ratios of MAP (r=-0.49; P= 0.01), UNaV (r=-0.43; P= 0.03,) and UproV (r=-0.41; P= 0.04). In addition, night/day ratio of MAP had significantly positive relationships with night/day ratios of UNaV (r= 0.49; P= 0.01) and UproV (r= 0.45; P= 0.02). CONCLUSION: Our results show that as renal function deteriorates in glomerulopathy the nocturnal dip in blood pressure is lost, resulting in enhanced urinary sodium and protein excretions during night. These findings are compatible with our proposal that impaired natriuresis during daytime makes nocturnal blood pressure elevated to compensate for diminished natriuresis by pressure natriuresis. We speculate that nocturnal glomerular capillary hypertension contributes, at least in part, to enhanced urinary sodium and protein excretions during night.     

Atrial natriuretic peptide and other vasoactive hormones in nephrotic syndrome

Plasma levels of atrial natriuretic peptide (ANP), arginine vasopressin (AVP), renin activity (PRA), aldosterone (PA), catecholamines and urinary prostaglandins (PG), as well as renal function were measured in children in the edematous state of the nephrotic syndrome before and after infusion of human serum albumin. Before albumin infusion, plasma levels of AVP, PRA, PA and noradrenaline (NA) and urinary excretion of PGE2, PGE-Met, PGF2 alpha were elevated. The mean value of plasma ANP was in the normal range. Albumin infusion produced a 36% increase in the calculated plasma volume. It was associated with a fivefold rise in the plasma level of ANP (31.6 +/- 22.6 vs. 151.4 +/- 52 fmol/ml mean, SD), and a significant fall in the levels of PRA, AVP, PA, and NA. Similarly, urinary concentration of PGE2, PGE-Met and PGF2 alpha fell. Urine flow, GFR, UNaV, FENa, and COsm increased significantly, while CH2O remained unchanged. The diuresis, natriuresis and GFR correlated with the level of plasma ANP, while urinary sodium excretion did not correlate with PA or NA levels. These findings suggest that ANP plays an important role in albumin induced natriuresis in children with nephrotic syndrome.     

Effects of indomethacin on the renal function and renin-aldosterone system in chronic glomerulonephritis

The effects of indomethacin on plasma renin activity (PRA), plasma and urine aldosterone levels and on renal function were studied in 37 patients with chronic glomerulonephritis (GN). Indomethacin produced a significant decrease in PRA, in plasma and urinary aldosterone levels and an increase in serum potassium levels. In 4 patients indomethacin induced the clinical syndrome of hyporeninemic hypoaldosteronism with hyperkalemia, which developed during the first weeks of treatment, persisted during treatment and disappeared without any additional drugs when indomethacin was stopped. In 14 patients with chronic GN, indomethacin caused a decrease in glomerular filtration rate (GRF). Their pretreatment PRA was significantly higher than that of patients with unchanged or increased GFR and most of them had prominent sclerotic changes on biopsy. Indomethacin considerably depressed diuresis and urinary sodium excretion. The antidiuretic and antinatriuretic effects of indomethacin were more pronounced in patients with the nephrotic syndrome. The results suggest that indomethacin exerts an effect on the renin-aldosterone axis, may be a cause of drug-induced hyporeninemic hypoaldosteronism and may cause a decrease in GFR in patients with high PRA.     

Renal Potassium Excretion: Comparison between Chronic Renal Disease Patients and Old People

Senescence and chronic renal failure bring about a progressive glomerular filtration reduction. Moreover, a reduction in glomerular filtration usually modifies the potassium renal excretion. In the present study, we compared the renal potassium handling between old and chronic renal disease populations. Materials and Methods: Fifty-five volunteers were studied, 43 of them were healthy old persons and 12 were predialysis chronic renal disease patients. Exclusion criteria were: presence of altered plasma potassium (Kp), diabetes mellitus, obstructive uropathy, drugs that could alter plasma potassium levels. All volunteers were on a diet with a potassium content around 50 mmol/day (3-day dietary register). We measured potassium, creatinine, urea in plasma and 24 hours urine. We also measured creatinine clearance (CrCl) and fractional excretion of potassium (FEK), and we studied the relationship between these parameters. Statistical analysis was made using Student’s test. Results: Slopes of the correlation curves between CrCl and FEK. Conclusion: The relationship between creatinine clearance and fractional excretion of potassium in old and chronic renal disease groups were different with the excretion of potassium being lower in the elderly.     

Urinary excretion of glutathione S transferases alpha and pi in patients with proteinuria: reflection of the site of tubular injury

In patients with renal diseases, proteinuria is a major determinant of progressive renal failure, probably by causing tubular cell injury. Little is known on extent and site of tubular cell injury in patients with proteinuria. Glutathione S transferases (GST) are cytosolic enzymes. The alpha isoform is present only in proximal tubular cells, whereas the pi isoform is confined to distal tubular cells. We have studied the urinary excretion of both isoenzymes in 56 (38 male and 18 female) patients with glomerular diseases and proteinuria. The mean age was 45 +/- (SD) 16 years, the median creatinine clearance was 80 (range 27-159) ml/min, and the median albuminuria was 4.2 (range 0.7-16.9) g/10 mmol creatinine. The excretions of both GST alpha (median 35.9 ng/10 mmol creatinine) and GST pi (median 24.8 ng/10 mmol creatinine) were elevated as compared with control values (upper limits 10 and 12 ng/10 mmol creatinine, respectively). The urinary excretion of GST pi, but not that of GST alpha, was inversely correlated with the creatinine clearance. The highest levels of GST alpha were found in patients with a well-preserved renal function, whereas highest levels of GST pi were found in patients with renal failure. In a small number of patients we performed immunofluorescent studies of renal tissue. An increased urinary excretion of GST alpha correlated with brush border damage and decreased staining of proximal tubules for that isoenzyme. Our data suggest that in patients with proteinuria initial injury is apparent at the proximal tubules. Measurements of GST alpha and GST pi appear useful to study longitudinal timing and site of proteinuria-induced tubular cell injury.     

Acute physiological changes in canine kidneys following exposure to extracorporeal shock waves

Nine anesthetized dogs were studied for four to five hours after administration of extracorporeal shock waves to one kidney, the contralateral organ serving as control. Urinary excretion of electrolytes, N-acetyl-beta-glucosaminidase (NAG) and kallikrein, clearances of creatinine, inulin and para-amino-hippuric acid (PAH), serum aldosterone level and plasma renin activity (PRA) were determined. On the exposed side there was a significant increase in urinary flow and urinary NAG excretion, and a significant fall in urinary osmolality. Effective renal plasma flow (ERPF) was reduced and glomerular filtration rate (GFR) unchanged, thus filtration fraction (FF) was increased. Extraction of PAH was significantly reduced compared with the control kidney. On the control side there was a significant increase in urinary flow and excretion of electrolytes, and a significant fall in urinary osmolality. GFR was increased and ERPF unchanged. FF therefore increased also on this side. The mean rise of PRA in the exposed kidney was higher than in the control kidney, the difference being not significant (p = 0.09). Our results may indicate a triggering of the renin-angiotensin system, and an effect on proximal tubular function following exposure of extracorporeal shock waves.     

Lithium treatment reduces the renal kallikrein excretion rate

Lithium salts are widely used agents for the prophylactic treatment of affective disorders. Lithium salts may be associated with distal nephron dysfunction. Kallikrein is a protease which is generated by the distal nephron. We used an amidolytic assay of chromatographically purified enzyme to determine the urinary excretion rate of active kallikrein in relation to lithium treatment. All plasma lithium concentrations were within the therapeutic range (0.4 to 0.9 mmol/liter). In 15 patients the urinary excretion rate of active kallikrein was 267.4 +/- 65.6 mU/24 hrs before lithium treatment, and fell to 117.8 +/- 39.6 mU/24 hrs (P less than 0.05) on day 14 of lithium treatment. This reduction was associated with a decrease of immunoreactive kallikrein in the same urines by 66%. In another 15 patients who had undergone lithium therapy for an average period of 5.6 years, the urinary excretion rate of active kallikrein was 86.1 +/- 14.5 mU/24 hrs, while 21 age-matched healthy controls had an excretion rate of 364.1 +/- 58.4 mU/24 hrs (P less than 0.05). Measurements of immunoreactive kallikrein in the same urine samples demonstrated a reduction of kallikrein after long-term lithium treatment by 78%. These observations could not be attributed to changes in creatinine clearance, renal sodium or potassium excretion rates or plasma concentrations of aldosterone and vasopressin. Addition of lithium to the urine in vitro had no demonstrable effect on kallikrein measurement by amidolytic assay. We conclude that lithium in therapeutic plasma concentrations may directly suppress the secretion of kallikrein by renal connecting tubule cells.