G. Gopal Krishna

Potassium Depletion Exacerbates Essential Hypertension

OBJECTIVE To determine the effect of potassium depletion on blood pressure in patients with essential hypertension. DESIGN Double-blind, randomized, crossover study, with each patient serving as his or her own control. SETTING Clinical research center at a university hospital. PATIENTS Twelve patients with hypertension. INTERVENTIONS Patients were placed on 10-day isocaloric diets providing a daily potassium intake of either 16 mmol or 96 mmol. The intake of sodium (120 mmol/d) and other minerals was kept constant. On day 11 each patient received a 2-litre isotonic saline infusion over 4 hours. MEASUREMENTS Blood pressure; urinary excretion rates for sodium, potassium, calcium, and phosphorous; glomerular filtration rate; renal plasma flow; and plasma levels of vasoactive hormones. MAIN RESULTS With low potassium intake, systolic blood pressure increased (P = 0.01) by 7 mm Hg (95% CI, 3 mm Hg to 11 mm Hg) and diastolic pressure increased (P = 0.04) by 6 mm Hg (CI, 1 mm Hg to 11 mm Hg), whereas plasma potassium concentration decreased (P less than 0.001) by 0.8 mmol/L (CI, 0.4 to 1.0 mmol/L). In response to a 2-litre isotonic saline infusion, the mean arterial pressure increased similarly on both diets but reached higher levels on low potassium intake (115 +/- 2 mm Hg compared with 109 +/- 2 mm Hg, P = 0.03). Potassium depletion was associated with a decrease in sodium excretion (83 +/- 6 mmol/d compared with 110 +/- 5 mmol/d, P less than 0.001). Plasma renin activity and plasma aldosterone concentrations also decreased in patients during low potassium intake, but concentrations of arginine vasopressin and atrial natriuretic peptide, glomerular filtration rate, and renal plasma flow were unchanged. Further, low potassium intake increased urinary excretion of calcium and phosphorus and of plasma immunoreactive parathyroid hormone levels. CONCLUSION Dietary potassium restriction increases blood pressure in patients with essential hypertension. Both sodium retention and calcium depletion may contribute to the increase in blood pressure during potassium depletion.

Natriuretic Effect of Calcium-Channel Blockers in Hypertensives

This double-blind, randomized, crossover trial characterizes the acute natriuretic response to calcium-channel blockers (CCB) and investigates the role of hemodynamic and hormonal factors in mediating the natriuresis. Thirteen male subjects with essential hypertension received a single oral 20-mg dose of nifedipine or 120 mg of diltiazem. Renal functional and hemodynamic measurements were performed prior to and hourly for 4 hours following medication. Subjects then received these medications for 4 weeks at which time the above studies were repeated. Urinary sodium excretion increased within 60 minutes of CCB administration and the natriuresis was sustained for 4 hours. Cumulative sodium loss during the 4 hours of study was greater with nifedipine (43 +/- 12 mmol) than with diltiazem (18 +/- 6 mmol) (P less than 0.05). Despite natriuresis, urinary potassium excretion was decreased by both agents. Even though both drugs decreased the mean arterial pressure, inulin and paraaminohippurate (PAH) clearances were not altered. Plasma aldosterone concentrations decreased, plasma catecholamine concentrations increased, whereas plasma-renin activity was unchanged with both drugs. Body weight, glomerular filtration rate (GFR), renal plasma flow, plasma-renin activity, plasma aldosterone, and catecholamine concentrations were unchanged following 4 weeks of therapy. The acute natriuretic response after 4 weeks of therapy was similar to the response noted after the first dose. This study concludes that CCB are acutely natriuretic. Despite systemic hypotension, renal hemodynamics are unaltered during CCB therapy. Suppression of aldosterone as well as direct tubular effects of these drugs may mediate the natriuresis. Chronic therapy with CCB does not modify the acute natriuretic response to these agents.

PRESERVATION OF RENAL RESERVE IN CHRONIC RENAL DISEASE

Protein-induced increases in glomerular filtration rate (GFR), termed renal reserve, is said to be abrogated with the onset of renal disease. However, this notion is inconsistent with the results from animal studies which suggest that alterations in protein intake modulate the glomerular hemodynamics in experimental renal disease. Accordingly, 12 normal subjects and 15 patients with renal disease received a protein meal providing 1 g/kg body weight protein. The subjects were pretreated with either placebo or an angiotensin I converting enzyme inhibitor, enalapril. A significant (P less than 0.05) increase in inulin and para-aminohippurate (PAH) clearance was noted in normal subjects as well as in patients with renal disease. The increase in GFR over basal values in normal subjects (28 +/- 9%), patients with moderate renal failure (20 +/- 13%), and advanced renal failure (21 +/- 14%) was not different. Plasma renin activity was unchanged following protein meal in the placebo studies although it increased following enalapril administration. Enalapril pretreatment did not alter the glomerular vasodilation and hyperfiltration following protein meal. We conclude that protein meal induces glomerular hyperfiltration in renal disease and that this protein-induced hyperfiltration is not mediated by angiotensin II. Because glomerular hyperfiltration is implicated in the progression of renal disease, these data suggest that even in patients who have advanced renal failure, high-protein diets may exert a detrimental effect on the kidney.

Parathyroid Carcinoma in a Chronic Hemodialysis Patient

G. Gopal Krishna, MD, Section of Nephrology, Temple University Hospital, 3401 North Broad Street, Philadelphia, PA 19140 (USA) Dear Sir, Hyperparathyroidism and parathyroid hyperplasia invariably accompany chronic renal failure [1]. However, parathyroid carcinoma rarely occurs in this setting. Indeed, our survey of the English language literature revealed only one patient developing this lesion during chronic renal failure [2]. We report a second patient manifesting such an association. A 64-year-old white female developed end-stage renal disease in 1976 secondary to idiopathic chronic interstitial nephritis. Her serum calcium at that time was 9 mg/dl (1.97 mmol/l), phosphorus 7.9 mg/dl (2.55 mmol/l) with a normal albumin concentration. Despite therapy with phosphate-binding agents, serum phosphate levels remained greater than 6 mg/dl (1.94 mmol/l). Over the next several years she developed multiple bone fractures (ribs, ankle and hip) from severe secondary hyperparathyroidism. Beginning in September 1983, serum calcium levels ranged from 10 to 11 mg/dl (2.50–2.74 mmol/l). Parathyroid hormone (PTH) levels (C-terminal assay) in February 1985 were greater than 10,000 pg/ml (normal 0–340 pg/ml). At parathyroidectomy in May 1985, the two inferior glands were hyperplastic while both superior glands revealed malignant changes with infiltration of adjacent thyroid tissue (fig. 1). Immunoperoxidase studies using monoclonal antibodies, positive for PTH and negative for thyroglobulin, confirmed that the tumor indeed originated from parathyroid tissue. No metastatic foci were identified in the seven paratracheal lymph nodes resected. As of June 1988 the patient is in a stable condition with no clinical evidence of metastatic disease. Parathyroid carcinoma is a rare cause of hyperparathyroidism, accounting for only 1–3% of patients with

Sjögren Syndrome and Cryoglobulinemic Glomerulonephritis

We report the case of a 53-year-old woman with Sjögren syndrome and cryoglobulinemia. The patient presented with nephrotic syndrome, hematuria, and reduced estimated glomerular filtration rate. The kidney biopsy revealed diffuse endocapillary proliferation and leukocyte exudation with focal intraluminal hyaline thrombi, prominent tubulointerstitial inflammation, and vasculitis. Diffuse granular mesangial and segmental to global capillary wall staining was observed on immunofluorescence with antisera to C3 and immunoglobulin M (IgM), with less intense staining indicative of IgG and κ and λ light chains. A biopsy diagnosis of Sjögren syndrome-related cryoglobulinemic membranoproliferative glomerulonephritis and vasculitis was rendered. Subsequent investigations revealed the presence of circulating type II cryoglobulins with cryocrit of 9%. Although rare, Sjögren syndrome is the most common cause of non-hepatitis C virus-related mixed cryoglobulinemia. We discuss the possible pathogenic mechanisms involved in the development of mixed cryoglobulinemia and its evolution to lymphoma, as best described in the setting of hepatitis C virus infection. Although the specific antigen involved is unknown, it is likely that the mixed cryoglobulinemia in Sjögren syndrome is triggered by the long-term B-cell stimulation, resulting in clonal proliferation of B cells. Additional chromosomal aberrations and cytokine milieu alterations, as seen in hepatitis C virus infection, may result in prolonged B-cell survival and progression to non-Hodgkin lymphoma.

Development and progression of chronic renal disease: Can it be prevented or attenuated?

Following its initiation, renal disease tends to progress relentlessly to end stage, necessitating dialysis or transplantation or causing death. Studies have shown that metabolic, hematologic and hemodynamic adaptations by the damaged kidney underlie the progressive nature of the disease. This review underscores the hemodynamic maladaptations and consequences and the evidence that suggests that glomerular hypertension is a necessary accompaniment to renal damage. The evidence reviewed indicates that high pressure develops in fragile glomerular capillaries after loss of a critical amount of renal mass and causes progressive sclerosis and destruction of remaining nephrons. This maladaptive renal response ensures progressive destruction in a variety of renal diseases including diabetes mellitus. Reduced protein intake and converting enzyme inhibitor therapy may prevent or attenuate the progression of these diseases.

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.

Effect of Dietary Protein on Glomerular Renin Secretion

Previous studies from our and other laboratories demonstrated that dietary protein restriction lowers plasma renin activity by impairing renin release. The effect of protein intake on glomerular renin secretion has not been investigated. Accordingly, we studied male Sprague-Dawley rats weighing 180 to 200 g for 3 weeks that were receiving isocaloric diets that provided either standard 20% protein (SP) or low 6% protein (LP). Renin secretion was measured in the glomeruli isolated from these rats, at baseline and following stimulation with arachidonic acid and isoproterenol. The activity of plasma renin (3.0 +/- 0.5 ng/mL/min on SP v 1.1 +/- 0.1 ng/mL/min on LP) was significantly (P < 0.02) lower on LP intake. In contrast, glomerular renin content (22.9 +/- 0.7 ng/micrograms protein on SP v 32.3 +/- 1.4 ng/micrograms protein on LP) was significantly (P < 0.01) higher on the LP diet. Furthermore, renin secretion (ng/mL/h) from the isolated glomeruli at baseline (3.9 +/- 1.0 on SP v 12.5 +/- 3.0 on LP, P < 0.02), and following incubation with arachidonic acid 10(-5) mol/L (5.9 +/- 1.7 on SP v 19.6 +/- 3.1 on LP, P < 0.005), and isoproterenol 10(-3) mol/L (6.0 +/- 0.5 on SP v 17.3 +/- 3.3 on LP, P < 0.01) was significantly higher on the LP diet. These studies suggest that dietary protein restriction impairs in vivo renin release. In contrast, in vitro glomerular renin release is augmented by protein restriction. The factors modulating in vivo renin release require further characterization.