Meyer D. Lifschitz

Studies on the Mechanism of Sodium Excretion during Drug-induced Vasodilatation in the Dog

The administration of vasodilating agents such as bradykinin and acetylcholine cause an increase in urinary sodium excretion. Yet the mechanisms involved in this natriuretic effect are not clear. Recent studies with another renal vasodilator, secretin have shown this drug also causes a profound increase in renal blood flow but without major changes in sodium excretion. To attempt to delineate the basis of this difference in sodium excretion with these drugs, the renal functional effects of secretin and bradykinin were compared at an equivalent vasodilating dose. Bradykinin increased renal blood flow from 222 to 342 ml/min, urine volume from 0.2 to 1.2 ml/min, and urine sodium excretion from 28 to 115 mueq/min. Urine osmolality fell from 1,230 to 401 mosmol/kg. Secretin caused a comparable increase in renal blood flow (216 to 325 ml/min) while changes in urine flow, sodium excretion, and urine osmolality were significantly less. In further studies papillary plasma flow was estimated using the albumin accumulation technique. Control papillary plasma flow was 29 ml/min per 100 g. Bradykinin increased urinary sodium excretion 108 mueq/min and decreased urinary osmolality from 1,254 to 516 mosmol/kg in association with a rise in papillary plasma flow to 62 ml/min per 100 g. Urine sodium excretion, urinary osmolality, and urine flow rate, as well as papillary plasma flow rate (32 ml/min per 100 g) were unchanged from control when secretin was administered. Studies with acetylcholine were qualitatively similar to those of bradykinin. Renal blood flow increased from 150 to 248 ml/min, urinary sodium excretion increased from 20 to 243 mueq/min, urinary osmolality decreased from 1,237 to 411 mosmol/kg and papillary plasma flow increased from 39 to 52 ml/min per 100 g. It is suggested that the natriuretic effect of some vasodilators is due, at least in part, to alterations in medullary hemodynamics, as evidenced by the increase in papillary plasma flow seen with bradykinin and acetylcholine, but not secretin.

Effect of prostaglandins on renal salt and water excretion

There are several important mechanisms by which renal prostaglandins modulate renal salt and water excretion. The role of endogenous renal prostaglandins in facilitating urinary sodium excretion and the individual nephron segments that are affected by renal prostaglandins are reviewed. The role of the administration of nonsteroidal anti-inflammatory agents on the kidneys ability to excrete salt and water both physiologically and clinically is summarized. The potential role for endogenous prostaglandins to antagonize the effect of antidiuretic hormone and to alter renal water excretion is also described. The clinical consequences of taking nonsteroidal anti-inflammatory drugs in terms of hyperkalemia, sodium retention with associated edema, and possible hyponatremia are all discussed. Although these clinical consequences are quite uncommon statistically, there are certain subsets of patients for whom additional concern is important.

Gastrointestinal Blood Loss in Patients With Chronic Renal Failure

In the management of patients with chronic failure one of the persistent medical problems is that of anemia. Since iron deficiency can be an important component of this anemia, this study was designed to evaluate the possible contribution of gastrointestinal blood loss to their anemia. Blood loss was quantitated by 51 chromium labeling red cells in normals and in patients with chronic renal failure both before and during chronic hemodialysis. Four normal volunteers had a gastrointestinal blood loss of 0.83 ml/day, six azotemic patients not yet on hemodialysis had significantly greater gastrointestinal blood loss of 3.15 ml/day (p less than 0.05). Ten patients on chronic regular hemodialysis had a daily gastrointestinal blood loss of 6.27 ml/day which was significantly greater than both the normals (p less than 0.01) and the predialysis azotemic patients (p less than 0.05). Complete gastrointestinal tract evaluation in the chronic dialysis patients revealed several upper gastrointestinal tract mucosal abnormalities although discrete bleeding sites were not identified. In conclusion, azotemic patients both before and after chronic hemodialysis have increased gastrointestinal blood loss. This increased blood loss contributes to the increased iron loss in this patient population.

Suprofen-Related Nephrotoxicity: A Distinct Clinical Syndrome

We describe a unique clinical syndrome of flank pain and acute renal failure that is associated with suprofen, a nonsteroidal anti-inflammatory drug that has recently been made available in the United States. In the initial 6 months of the drugs distribution in this country, at least 16 patients developed this syndrome. All 16 had acute flank pain and 13 developed mild reversible renal failure within 12 hours of ingestion of one to three suprofen capsules. This syndrome is unlike other nephrotoxic syndromes related to nonsteroidal anti-inflammatory drugs. The mechanism is not known.

Effect of eplerenone on blood pressure and the renin-angiotensin-aldosterone system in oligo-anuric chronic hemodialysis patients - a pilot study.

INTRODUCTION AND AIMS Recent studies have suggested that aldosterone has many effects in addition to its ability to cause the kidney to retain sodium. To test the hypothesis that aldosterone can cause hypertension in a manner that does not involve renal sodium retention, we administered eplerenone, a specific aldosterone antagonist, to oligo-anuric chronic hemodialysis patients who had HTN. METHODS 220 chronic hemodialysis patients underwent initial screening. Of these, 8 patients were followed for 8 weeks and their blood pressure, weight, plasma potassium, aldosterone levels and plasma renin activity were recorded. After a 4 week run in period, each patient received eplerenone 25 mg twice daily for another 4 weeks. RESULTS Administration of eplerenone for 4 weeks decreased predialysis systolic blood pressure from 166 ± 14 to 153 ± 10 mmHg (p < 0.05). Eplerenone had no effect on diastolic blood pressure, potassium, predialysis weight, intradialytic weight gain, plasma aldosterone or PRA. CONCLUSION Eplerenone significantly reduces systolic blood pressure in oligo-anuric hypertensive hemodialysis patients without effect on plasma aldosterone concentrations or plasma renin activity. Plasma potassium increases minimally after 4 weeks of therapy, a finding that raises some concern for long-term eplerenone use in chronic hemodialysis.

B2-Microglobulin and Associated Amyloidosis Presenting as Bilateral Popliteal Tumors

Chronic hemodialysis has led to the prolongation of life in many patients with end-stage renal disease, but has also allowed for the development of new diseases that are a consequence of this clinical setting. B2-microglobulin accumulation leading to systemic amyloidosis may be the most recent disease in this category. This case report documents the development of bilateral popliteal tumors in a patient undergoing chronic hemodialysis for 9 years. Removal of one of the tumors and pathological examination demonstrated amyloid that was positive for B2-microglobulin by specific antibody testing. This case adds further support to the suggestion that B2-microglobulin amyloidosis in chronic hemodialysis patients is truly a systemic disorder. The development of popliteal tumors, particularly in proximity to joints, in a chronic hemodialysis patient, must include amyloidosis in the differential diagnosis.

Acute Renal Failure: Clinical Aspects and Pathophysiology1

: Acute renal failure may be caused by multiple conditions including those which are due to some direct hemodynamic or nephrotoxic insult. In considering the pathophysiology of these entities, it seems appropriate to differentiate between the initiating and the maintenance phase of the disorder. In the former, renal ischemia and/or a direct effect of a given nephrotoxic agent seems to be the basis for the underlying renal damage. In the maintenance phase, renal functional impairment is maintained by a number of factors which include persistent renal vasoconstriction, tubular obstruction, a leakage of filtrate across damaged tubular epithelium, and a reduction in glomerular capillary permeability. The therapy and possible preventive aspects of these entities are discussed.

Effect of saralasin in hypertensive patients on chronic hemodialysis.

Hypertension in patients on chronic hemodialysis is thought to be largely of two types--volume dependent or renin dependent. If renin-dependent hypertension is mediated by angiotensin II, then angiotensin II antagonism should lower blood pressure. To test this hypothesis, the angiotensin II antagonist saralasin was given to 15 hypertensive patients on chronic hemodialysis. Patients were separated into two groups by their blood pressure response. In responders blood pressure was 191/112 mm Hg and fell to 147/85 during saralasin administration (P less than 0.01). In contrast, nonresponders had blood pressures of 190/111 mm Hg before and 188/110 during saralasin administration. Five responders subsequently ahd nephrectomies with normalization of their blood pressures. Plasma renin activity averaged 70 ng/ml . 3 h of angiotensin I in responders and increased to 110 after saralasin (P less than 0.05), while nonresponders had values of 21 before and after saralasin. These results offer strong support for the hypothesis that renin-dependent hypertension is an important mechanism in certain patients on chronic hemodialysis and that such patients will respond to angiotensin II antagonism.

Renal Physiology of the Prostaglandins and the Effects of Nonsteroidal Anti-Inflammatory Agents on the Kidney

The prostaglandins are a series of fatty acid products derived from the cellular metabolism of arachidonic acid. The kidney makes prostaglandins and the endogenous renal prostaglandins appear to play a role in the regulation of renal hemodynamics, renal salt and water excretion, and control of the level of activity of the renin-angiotensin system. The administration of nonsteroidal anti-inflammatory drugs blocks cyclooxygenase activity, an early step in the synthesis of prostaglandins. This class of drugs, under certain circumstances, leads to sodium retention, hyperkalemia and several different forms of acute and chronic renal failure. The potential role of altered prostaglandin synthesis in leading to these clinical syndromes is reviewed.

Urinary prostaglandin E excretion: Effect of chronic alterations in sodium intake and inhibition of prostaglandin synthesis in the rabbit

On the basis of acute experiments in animals, a role for prostaglandin E (PGE) in the regulation of urinary sodium excretion has been suggested. Limited information is available, however, concerning the possible role of PGE in chronic adjustments to sodium intake. These studies were designed to determine whether chronic changes in sodium balance would modify renal PGE excretion and whether partial inhibition of prostaglandin synthesis would alter the ability of the kidney to adjust to an alteration in sodium intake. Thus, we measured sodium and PGE excretion in rabbits on chronic high and low salt diets before and after inhibition of prostaglandin synthesis with indomethacin or meclofenamate. Although the alterations in salt intake resulted in large changes in sodium excretion there was no significant change in urinary PGE excretion. After administration of either indomethacin or meclofenamate for several days there was a significant fall in PGE excretion, but no significant change in sodium excretion. These results suggest that in the rabbit 1) chronic changes in sodium excretion can occur without modifying PGE excretion (and presumably renal PGE synthesis) and 2) inhibition of PGE synthesis does not impair the kidneys ability to adjust to a chronic high or low sodium intake.