Hyporeninemic hypoaldosteronism in diabetic patients with chronic renal failure

Plasma renin activity, plasma aldosterone levels and renal tubular capacity to excrete hydrogen ions were studied in 13 patients suffering from diabetes mellitus with a creatinine clearance of less than 40 ml/min. The results were compared with those obtained in a control group, in a group of nondiabetic subjects with chronic renal failure (CRF) and in a group of diabetic patients without CRF. Twelve of the thirteen diabetic patients with CRF had data characteristic of hyporeninemic hypoaldosteronism associated with type IV renal tubular acidosis. On comparing the results with those of the other two groups of patients, it was observed that the manifestations of the latter two groups considered separately were different from those of the problem group, although in the diabetic patients with normal glomerular filtration rate (GFR) hyporeninism but not hypoaldosteronism was present accompanied by a lower net acid excretion (p less than 0.001) due to a lower excretion of NH4 (p less than 0.05) and titratable acid (p less than 0.001) when the patients were challenged with an NH4Cl overload. We believe that a conjunction of diabetes and renal failure is necessary for the diabetic patients with a decrease in GFR to show hyporeninemic hypoaldosteronism and type IV tubular acidosis.     

Hyperkalemia in the elderly

Physiologic and pathologic events that occur in patients as they grow older may result in distal renal tubular dysfunction, as well as decreased levels of plasma renin activity and plasma aldosterone. Such alterations result in a tendency toward hyperkalemia. A syndrome termed hyporeninemic hypoaldosteronism, associated with hyperkalemia, has been frequently described in elderly patients. The common occurrence of hyperkalemia in the elderly may be aggravated by the use of drugs that either further suppress renin and/or aldosterone or interfere with distal tubular potassium excretion. Some patients with hyporeninemic hypoaldosteronism respond to diuretic therapy. The recognition of the possible development of severe hyperkalemia in the elderly patient may avoid serious and even fatal complications of this electrolyte disorder.     

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.     

A case of lupus nephritis with hyporeninemic hypoaldosteronism]

We report a case of 67-year-old woman with systemic lupus erythematosus presenting hyporeninemic hypoaldosteronism. She admitted because of anasarca in March, 1990. She manifested nephrotic syndrome, and hyperkalemia and hyperchloremic metabolic acidosis. The hyperkalemia was disproportionate to the degree of renal insufficiency. Basal levels of plasma renin activity and plasma aldosterone concentration were low. Renal tubular function studies revealed normal hydrogen ion secretion. Renal biopsy demonstrated diffuse proliferative lupus nephritis and prominent interstitial cell infiltration. There was no vasculitis of glomerular vascular poles. After treatment of lupus nephritis with prednisolone, levels of plasma renin activity and plasma aldosterone concentration were elevated. Hyperkalemia and metabolic acidosis were normalized and renal function improved. We conclude that the heperkalemia and metabolic acidosis could be attributed to hyporeninemic hypoaldosteronism.     

Isolated hypoaldosteronism and abnormalities in renin, kallikrein, and prostaglandin

To further define the pathophysiology of the syndrome of acquired isolated hypoaldosteronism, we determined plasma concentrations of active and inactive renin and urinary kallikrein and prostaglandin E2 excretion rates in 11 patients with the syndrome, 12 patients with similar serum creatinine levels, but without hyperkalemia, and in 12 normotensive patients with normal renal function and low plasma renin activities (PRA). Ten of 11 patients with the syndrome had low baseline PRA, and, unlike the control groups, six of 11 failed to double their PRA after furosemide stimulation. There were also consistent abnormalities in the percentage of inactive renin, no patient having a value less than and no control subjects having a value greater than 65%. Seven of 11 patients had prostaglandin E2 excretion rates lower than either control groups. Urinary kallikrein excretion rates in the patients with isolated hypoaldosteronism were significantly lower than in the control groups, but increased in response to therapy with fludrocortisone.     

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.     

Effect of dopaminergic blockade on plasma aldosterone in acquired hypoaldosteronism

The pathogenesis of acquired hypoaldosteronism, a frequent cause of hyperkalemia in patients with chronic renal failure, is poorly understood. The present studies were undertaken to investigate the role of dopamine in suppressing mineralocorticoid secretion in this syndrome. We studied the plasma aldosterone response to dopaminergic blockade with metoclopramide in 11 patients with chronic renal failure (5 of whom were hyperkalemic) and 7 normal controls. Following repetitive doses of metoclopramide, the normokalemic chronic renal failure patients showed an exaggerated aldosterone response (peak aldosterone 50 +/- 5 ng/dl or 1,385 +/- 138 pmol/l) compared to normal controls (24 +/- 4 ng/dl or 665 +/- 110 pmol/l). In the hyperkalemic chronic renal failure patients, however, metoclopramide failed to induce a significant increase in plasma aldosterone (peak aldosterone 13 +/- 3 ng/dl or 360 +/- 83 pmol/l). By contrast, metoclopramide stimulated prolactin secretion in both normokalemic and hyperkalemic chronic renal failure patients. The plasma renin activity and serum potassium values were unchanged in all 3 groups. Our data show that dopaminergic blockade with metoclopramide fails to stimulate aldosterone secretion in patients with acquired hypoaldosteronism. Thus this syndrome does not result from enhanced dopaminergic inhibition of aldosterone, but rather from an independent abnormality in aldosterone biosynthesis.     

Steroid-induced hypertension in patients with nephrotic syndrome

In 35 initially normotensive patients with chronic glomerulonephritis and lupus nephritis (including 27 patients with nephrotic syndrome; NS), blood pressure (BP), urinary sodium excretion, plasma renin activity (PRA), plasma aldosterone level (PA), urinary aldosterone excretion (Au and blood volume were measured before and during prednisolone treatment. In 7 patients (all with NS) steroid-induced hypertension has developed. The patients prone to develop hypertension were hypervolemic nephrotics with initial depression of PRA, PA, Au, and severe sodium retention. In these patients prednisolone did not produce diuresis of natriuresis nor did it decrease proteinuria. In normo- and hypovolemic patients prednisolone produced significant diuresis and natriuresis and failed to induce hypertension. Thus, two types of response to prednisolone could be observed in patients with NS.     

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.     

Glomerular filtration rate in streptozocin-induced diabetic rats. Role of exchangeable sodium, vasoactive hormones, and insulin therapy

The interrelationships of sodium and volume status, atrial natriuretic peptide (ANP), plasma renin activity (PRA), insulinlike growth factor I (IGF-I), and kidney weight and their influence on glomerular filtration rate (GFR) were investigated in rats during the first 4 wk of streptozocin-induced diabetes (STZ-D). In each of three experiments, untreated diabetic rats were compared with nondiabetic control rats and rats with varying degrees of glycemic control during insulin therapy. The first experiment evaluated exchangeable sodium, plasma volume, and GFR. In untreated diabetic rats, exchangeable sodium and plasma volume, but not GFR, were increased by approximately 25% compared with control rats. Insulin-treated diabetic rats with plasma glucose levels ranging from 12 to 30 mM had increased GFR, whereas exchangeable sodium and plasma volume were reduced toward control values. Daily insulin therapy, titrated to maintain euglycemia, further reduced exchangeable sodium and plasma volume and decreased but did not normalize GFR. The second experiment evaluated the relationship between vasoactive hormones and GFR. In untreated diabetic rats, plasma ANP levels increased 89% and urinary cyclic GMP (cGMP) excretion increased 94%, with an 85% decrease in PRA, whereas GFR was unchanged. Moderate hyperglycemia (plasma glucose 12-30 mM) was associated with normalized plasma ANP levels and urinary cGMP excretion, a 52% decrease in PRA, and a 13% increase in GFR. The third experiment studied serial changes in food and water intake and vasoactive hormones and end-point measurement of kidney weight, GFR, and plasma IGF-I. In the untreated diabetic group, urinary cGMP excretion was significantly elevated after 3 wk, whereas the reduction in PRA levels was apparent after 1 wk.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transient hyporeninemic hypoaldosteronism in acute glomerulonephritis

While hyporeninemic hypoaldosteronism (HH) has been well described in relation to chronic renal diseases, transient HH has rarely been reported. Here we present a 9-year-old boy with acute glomerulonephritis who developed hyperkalemia, which persisted for a period of 3 weeks despite normal values of creatinine clearance and an absence of acidosis. He was diagnosed as having HH because of low basal plasma renin activity and serum aldosterone level. Renal biopsy showed diffuse endocapillary proliferative glomerulonephritis. There were no apparent pathological changes in the juxtaglomerular apparatus (JGA). Rapid adrenocorticotropic hormone administration increased adequately both serum aldosterone and cortisol levels. Responses of both plasma renin activity and serum aldosterone level following the furosemide upright provocation were blunted in the hyperkalemic acute phase, but recovered in the normokalemic convalescent phase. Serum levels of human atrial natriuretic peptide were within normal range, both in the hyperkalemic and normokalemic phases. These results suggested that a transient dysfunction of the JGA, without volume expansion or structural damage of the JGA, caused HH in this patient.     

Sodium, renin, aldosterone, catecholamines, and blood pressure in diabetes mellitus

Interrelations among plasma renin activity (PRA), aldosterone and cortisole levels, 0lood volume, exchangeable sodium, urinary catecholamines, and blood pressure were studied in 35 normal subjects and 60 age-matched non-azotemic patients with diabetes mellitus (60% with hypertension, 15% with orthostatic hypotension). Basal PRA, plasma aldosterone, cortisol, blood volume, plasma potassium, and urinary electrolytes were comparable in diabetic and normal subjects. Diabetic patients, however, had a 10% increase in body sodium (P less than 0.01), and 8% of them showed normal postural PRA responses and subnormal aldosterone responses; 22% had subnormal PRA and normal aldosterone responses, and 17% had subnormal responses of PRA and aldosterone. Non-PRA-related aldosterone responses could not be explained by ACTH or electrolytes. Orthostatic decreases in blood pressure correlated (P less than 0.01) with both catecholamine excretion and basal PRA. This suggests that in diabetes mellitus, body sodium is increased. Basal PRA and plasma aldosterone are usually normal, but their postural responses are frequently impaired. Absent aldosterone responses, despite normal PRA responsiveness, may reflect an adrenal abnormality or an ineffective form of renin. Marked postural aldosterone stimulation, unrelated to PRA, ACTH, or electrolytes, points to a potent unknown factor in aldosterone control. Low levels of free peripheral catecholamines and PRA may be complementary factors contributing to postural hypotension.     

Impairment of diuresis in surgical intervention. Role of urinary prostaglandins

In 8 patients who underwent abdominal surgery for non-neoplastic reasons, we have evaluated some parameters of renal function (PRP, NaU, GFR and diuresis) plasma levels of PRA and ADH and urinary prostaglandins PGE2 and 6-keto-PGF1 alpha. In 4 patients we found that surgery per se was associated with enhancements of PRA, ADH and 6-keto-PGF1 alpha. In other 4 patients, Indomethacin, a specific inhibitor of prostaglandin synthesis was given and this was followed by impairment of natriuresis and RPF. These data confirm the central role of prostaglandins in the control of diuresis and natriuresis and suggest that use of drugs affecting prostaglandin synthesis should be avoided in patients who are undergoing surgery.     

Observations on the activity of the renin-angiotensin-aldosterone (RAA) system after low volume colloid resuscitation for burn injury

Studies of plasma renin activity (PRA) and plasma aldosterone in burn patients treated with a low volume colloid resuscitation regimen revealed very high levels of both hormones. Highest hormone levels occurred in the 5 days post burn with the correlation between PRA and plasma aldosterone r = +0.787 (p less than 0.001). The negative correlation between 24 hour urinary sodium excretion and PRA (r = +0.671, p less than 0.001), was closer than that between 24 hour sodium excretion and plasma aldosterone (r = -0.556, p less than 0.01). Secondary elevations of PRA and plasma aldosterone occurred in 2 patients (7-14 days after injury) associated with clinical deterioration and systemic sepsis.     

Hyperkalemia after acute metabolic decompensation in two children with vitamin B12-unresponsive methylmalonic acidemia and normal renal function

The patients affected by vitamin B12-unresponsive methylmalonic acidemia (MMA) on the long run develop chronic renal disease with interstitial nephropathy and progressive renal insufficiency. The mechanism of nephrotoxicity in vitamin B12-unresponsive MMA is not yet known. Chronic hyporeninemic hypoaldosteronism has been found in many cases of methylmalonic acidemia, hyperkalemia and renal tubular acidosis type 4. We report 2 patients affected by B12-unresponsive methylmalonic acidemia diagnosed at the age of 23 months and 5 years, respectively, with normal glomerular filtration and function. They showed hyporeninemic hypoaldosteronism and significant hyperkalemia requiring sodium potassium exchange resin (Kayexalate) therapy after an episode of metabolic decompensation leading to diagnosis of MMA. In both children, hyporeninemic hypoaldosteronism and hyperkalemia disappeared after 6 months of good metabolic control.     

The role of prostaglandins in gentamicin-induced nephrotoxicity in the dog

The effects of chronic gentamicin administration on renal function was studied in dogs receiving 4 mg/kg i.m. of gentamicin b.i.d. for 28 days. Administration of gentamicin resulted in a bimodal change in renal function. A decrease in urine osmolality was first noted on day 6 and declined progressively throughout the study. This decrease in urinary concentrating ability was preceded by a steady rise in urinary prostaglandin E2 (PGE) excretion and followed by a rise in plasma renin activity (PRA). Prior to an increase in azotemia, urinary PGE decreased precipitously while PRA continued to rise throughout the remainder of the study. The precipitous decrease in GFR was accompanied by a significant increase in FENa to seven times control. These studies suggest a dual effect of chronic gentamicin administration on renal function: (1) an early effect manifested by stimulation of urinary prostaglandin production with a concomitant loss of urinary concentrating ability and mild prerenal azotemia, and (2) a late effect, preceded by a decrease in urinary prostaglandin excretion while PRA continues to increase, and manifested by increase fractional excretion of sodium and progressive azotemia.     

Hyporeninemic hypoaldosteronism and diabetes mellitus:Pathophysiology assumptions,clinical aspects and implications for management

Patients with diabetes mellitus(DM) frequently develop electrolyte disorders,including hyperkalemia.The most important causal factor of chronic hyperkalemia in patients with diabetes is the syndrome of hyporeninemic hypoaldosteronism(HH),but other conditions may also contribute.Moreover,as hyperkalemia is related to the blockage of the renin-angiotensin-aldosterone system(RAAS) and HH is most common among patients with mild to moderate renal insufficiency due to diabetic nephropathy(DN),the proper evaluation and management of these patients is quite complex.Despite its obvious relationship with diabetic nephropathy,HH is also related to other microvascular complications,such as DN,particularly the autonomic type.To confirm the diagnosis,plasma aldosterone concentration and the levels of renin and cortisol are measured when the RAAS is activated.In addition,synthetic mineralocorticoid and/or diuretics are used for the treatment of this syndrome.However,few studies on the implications of HH in the treatment of patients with DM have been conducted in recent years,and therefore little,if any,progress has been made.This comprehensive review highlights the findings regarding the epidemiology,diagnosis,and management recommendations for HH in patients with DM to clarify the diagnosis of this clinical condition,which is often neglected,and to assist in the improvement of patient care.     

Disturbance in sodium regulating hormones in chronic obstructive uropathy.

Serum atrial natriuretic peptide (ANP), plasma renin activity (PRA), angiotensin II (AII) and aldosterone levels have been studied in patients with chronic bilateral ureteric obstruction resulting from high pressure chronic retention of urine (HPCR), both in the obstructed state and during the post-obstructed period. Increased ANP levels observed during chronic obstruction fell rapidly following urinary tract decompression by urethral catheterisation. Serum ANP resurged briefly within 24 h but stabilised thereafter at a lower level. PRA was initially suppressed but rose after catheterisation, the increase lagging behind the changes seen for ANP. Rising levels of AII and aldosterone followed this trend but, unlike PRA, levels were not completely suppressed in the obstructed state. The observed hormonal changes probably reflect homeostatic mechanisms directed to the maintenance of sodium and water balance during obstruction and to limitation of the diuresis following its relief.     

Aldosterone responsiveness in patients with diabetes mellitus

Plasma aldosterone (PA) and plasma renin activity (PRA) were determined in 44 diabetics, of whom nine were normotensive but not nephropathic (group 1), 10 were hypertensive but not nephropathic (group 2), and 25 were hypertensive and nephropathic (group 3); they were kept in balance on a diet composed of 10 to 20 mEq. of sodium (Na) and 100 mEq. of potassium (K). Supine PA in group 1 was 38 +/- 7 ng. per deciliter, whereas in normals it was 24 +/- 2 ng. per deciliter (P less than 0.05); beyond that, neither supine nor upright PA or PRA differed significantly from normal in groups 1 and 2. By contrast, in group 3, supine PA was 13 +/- 1 ng. per deciliter and PRA 2.0 +/- 0.2 ng./ml. and upright PA was 39 +/- 7 ng. per deciliter and PRA 3.8 +/- 0.5 ng./ml., all significantly lower than those in the other groups (P less than 0.01). Nine patients, one in group 1 and eight in group 3, had low supine and upright PA and PRA; four had hyperkalemia. An additional nine patients in group 3 had low upright PA, with normal or low PRA; two had hyperkalemia. Of the 18 patients with low upright PA, K correlated with glucose (R = 0.46, P less than 0.05). These results suggest (1) the renin-aldosterone system generally responds normally in diabetics without nephropathy but responds subnormally when nephropathy is present, (2) hyporeninemic hypoaldosteronism is frequent in diabetics with nephropathy but may occur in the absence of clinical nephropathy, and (3) hyperkalemia in some diabetic patients may be secondary to hypoaldosteronemia and hyperglycemia.     

Effects of Heparin-Induced Aldosterone Deficiency on Renal Function in Patients with Chronic Glomerulonephritis

The effects of heparin-induced aldosterone deficiency on renalsodium and potassium transport and renal function were studiedin 65 patients with chronic glomerulonephritis and initial hyperaldosteronism.Heparin-induced aldosterone deficiency resulted in increaseddiuresis, in natriuresis due to decreased sodium reabsorptionin the distal nephron, in a fall in serum sodium and an increasein serum potassium concentration. A transient reduction in potassiumexcretion occurred during the 2–4 days of heparin treatment.In patients with chronic glomerulonephritis and a compromisedrenin–angiotensin–aldosterone system, heparin maycause drug-induced selective hypoaldosteronism. The suppressiveeffect of heparin on aldosterone production was partially compensatedfor by increasing plasma renin activity. Heparin-induced aldosteronedeficiency did not change glomerular filtration rate in patientswithout renal failure. In those with chronic sclerosing glomerulonephritisand a glomerular filtration rate less than 35 ml/min, heparincaused a further decrease in renal function.