Biomedical subjects
Publications and source records attributed to M J Bia.
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A case of posttransplant erythrocytosis in a 51-year-old diabetic man is described. This problem, which can occur in 5 to 15% of renal transplant patients, can result from a contracted plasma volume (diuretics, pressure natriuresis, or glycosuria) or from a true elevation in red blood cell mass. Once the diagnosis of true erythrocytosis is made by a radiolabeled red blood cell mass study, secondary causes such as hypoxia, liver disease, polycythemia rubra vera, renal artery stenosis, and cystic kidney disease should be excluded. Posttransplant erythrocytosis has only been observed in renal transplant recipients and appears to be more frequent with cyclosporine compared with azathioprine therapy. An inappropriately high level of erythropoietin has been described in some, but not all patients, suggesting stimulation of erythropoietin production as the mechanism. Posttransplant erythrocytosis can be associated with an increased incidence of thrombotic events. The presence of this potential complication has prompted intervention to maintain the hematocrit below 50 to 55%. Measures such as discontinuation of diuretics as well as better control of blood pressure and plasma glucose should be used to facilitate the correction of extracellular volume contraction. Phlebotomy has been the most accepted intervention to intermittently lower the hematocrit when needed, but this can lead to iron deficiency. Newer therapeutic modalities are now being used to treat the problem medically. Theophylline, which reduces adenosine-mediated erythropoietin synthesis, is effective but may be associated with side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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A 47-year-old patient presented with hypercalcemia secondary to sarcoidosis and was successfully treated with 1 year of corticosteroids leading to improvement in his hypercalcemia, hypercalcuria, and elevated levels of 1,25-dihydroxyvitamin D. Angiotensin-converting enzyme levels (ACE) normalized and serum creatinine improved. When hypercalcemia recurred after a 3-year symptom-free interval, the patient refused repeat corticosteroid treatment and was placed on ketoconazole (initially 600 and eventually 800 mg/d). Ketoconazole controlled the patient's hypercalcemia (serum calcium, 3.2 to 2.6 mmol/L [12.8 to 10.4 mg/dL]), but only the larger dose suppressed serum 1,25-dihydroxyvitamin D levels into the normal range. Hypercalcuria was markedly improved with ketoconazole, decreasing from a peak of 23 mmol/d (940 mg/d) to less than 8.7 mmol/d (350 mg/d) on a dose of 800 mg. However, serum ACE levels remained elevated on ketoconazole. An attempt to taper the ketoconazole after 1 year resulted in rapid recurrence of hypercalcemia (serum calcium, 2.8 mmol/L [11.1 mg/dL]) and hypercalcuria (urinary calcium excretion, 11 mmol/d [451 mg/d]). After a total of 2 years of ketoconazole treatment, his defect in calcium metabolism remains well controlled despite persistent elevation in ACE levels. Serum cortisol levels and liver function tests remain normal on therapy, although there has been a slight decrease in serum testosterone levels accompanied by some decrease in libido. These data suggest that long-term use of ketoconazole may be a safe and effective alternative to corticosteroid treatment for sarcoid-associated hypercalcemia. Further study is needed to determine whether the long-term side effects of ketoconazole therapy or its failure to control disease activity in sarcoidosis outweigh its advantages in avoiding the known side effects of glucocorticoids.
The following study was performed to determine whether calcium channel blockers, delivered before or after an ischemic insult, were effective at reducing cyclosporine-induced exacerbation of renal ischemic injury. When cyclosporine (5 mg/kg) was administered intravenously to rats after 30 min of renal ischemia, GFR fell by 60% compared with values observed in rats subjected to ischemia alone (190 +/- 30 vs. 330 +/- 40 microliters/min/100 g; P less than 0.05). Pretreatment with verapamil (10 micrograms/kg/min delivered intravenously) prevented the fall in GFR (320 +/- 70 microliters/min 100 g), as did pretreatment with nitrendipine, 1 micrograms/kg/min (460 +/- 90 microliters/min/100 g). Verapamil was less effective if given after the ischemia-cyclosporine insult (GFR 260 +/- 90 microliters/min/100 g), and nitrendipine given at this time had no beneficial effect at all (GFR 180 +/- 10 microliters/min/100 g). The doses of calcium channel blockers used had no protective effect on renal ischemic injury alone. Blood pressure during study ranged between 105 and 119 mm Hg with minor differences between groups. Sodium and potassium excretion and urinary flow rates were similar in all groups, except for a slight increase in sodium excretion in verapamil-treated rats. These values demonstrate that calcium channel blockers ameliorate the exacerbation or renal ischemic injury induced by cyclosporine if given before but not after the ischemia-cyclosporine insult. The protective effect of these agents, used preischemia in cyclosporine-treated rats, is observed with intravenous use of the drugs at doses that have no protective effect on renal ischemic injury alone.
Fourteen of 39 dialysis patients (36%) became hypercalcemic after switching to calcium carbonate as their principal phosphate binder. In order to identify risk factors associated with the development of hypercalcemia, indirect parameters of intestinal calcium reabsorption and bone turnover rate in these 14 patients were compared with results in 14 eucalcemic patients matched for age, sex, length of time on dialysis, and etiology of renal disease. In addition to experiencing hypercalcemic episodes with peak calcium values of 2.7 to 3.8 mmol/L (10.7 to 15.0 mg/dL), patients in the hypercalcemic group exhibited a significant increase in the mean calcium concentration obtained during 6 months before the switch, compared with the mean value obtained during the 7 months of observation after the switch (2.4 +/- 0.03 to 2.5 +/- 0.03 mmol/L [9.7 +/- 0.2 to 10.2 +/- 0.1 mg/dL], P = 0.006). In contrast, eucalcemic patients exhibited no change in mean calcium values over the same time period (2.3 +/- 0.05 to 2.3 +/- 0.05 mmol/L [9.2 +/- 0.2 to 9.2 +/- 0.2 mg/dL]). CaCO3 dosage, calculated dietary calcium intake, and circulating levels of vitamin D metabolites were similar in both groups. Physical activity index and predialysis serum bicarbonate levels also were similar in both groups. However, there was a significant difference in parameters reflecting bone turnover rates between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of chronic beta adrenergic blockade on potassium homeostasis during moderate intensity exercise (40% of VO2 max) was examined in seven end-stage renal patients who were being maintained on chronic dialysis treatment. Subjects participated in three study protocols: 1) exercise alone, 2) exercise plus propranolol (a nonselective beta-1, beta-2 antagonist), and 3) exercise plus metoprolol (a specific beta-1 antagonist). The basal potassium concentration was similar in all three studies and averaged 4.95 +/- 0.12 mEq/liter. During Study 1 (exercise alone), plasma potassium rose by 0.26 +/- 0.09 mEq/liter. During exercise with propranolol, plasma K concentration rose significantly higher (delta plasma K = 0.44 +/- 0.26 mEq/liter; P less than 0.05 vs. exercise alone). In contrast, the rise in plasma K during exercise with metoprolol (delta plasma K = 0.20 +/- 0.08 mEq/liter) was similar to that observed with exercise alone. Differences in potassium homeostasis between metoprolol and propranolol could not be explained by differences in hemodynamic parameters, levels of potassium regulatory hormones, or acid base status. Thus, the higher rise in potassium concentration during exercise with propranolol could only be explained by adrenergic blockade at the beta-2 receptor site. These results support the concept that adrenergic control of extrarenal potassium homeostasis in dialysis patients is mediated at the beta-2 receptor. Since a deterioration in potassium homeostasis during exercise is observed with beta-2, but not beta-1 blockade, selective beta-1 adrenergic blocking agents may be safer in dialysis patients.
The baseline hematologic status of 27 patients with modest degrees of aluminum overload was examined. In addition, hematologic data were evaluated in 19 of these patients during and after treatment with DFO. Although neither severe anemia nor microcytosis was observed pretreatment, there was a significant correlation between hemoglobin level and degree of aluminum burden as determined by bone surface aluminum staining (r = -0.58; P less than 0.007). Following treatment with DFO, hemoglobin concentration increased dramatically by 1.3 to 4.4 g/dl in eight patients but did not change in the remaining eleven. Responders and nonresponders were similar with regard to the degree of aluminum overload both before and after chelation therapy but differed with regard to baseline levels of erythropoietin (higher in responders) and degree of iron overload (greater in nonresponders). Pretherapy levels of red cell ALA dehydratase were depressed in all patients (32 +/- 4 vs. 56 +/- 5 U/g Hb in normals) but did not correlate with the degree of aluminum overload and did not change with chelation therapy. Pretherapy levels of red cell protoporphyrin were elevated in 15 of 24 patients (62%) and were higher in responders than in nonresponders. Following DFO therapy, levels fell by 25 to 50% in 7 of 8 patients with elevated pretherapy values, despite the tendency in several patients to develop iron deficiency with treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
H2-receptor antagonists have been frequently avoided in cyclosporine-treated transplant patients because of concern regarding possible exacerbation of nephrotoxicity. To determine whether the reported increase of serum creatinine levels in cyclosporine-treated transplant patients receiving H2-receptor antagonists was due to a true decrease in glomerular filtration rate or was secondary to altered renal tubular handling of creatinine, simultaneous inulin and creatinine clearances were analyzed in 11 cyclosporine-treated renal transplant recipients before and after H2-receptor antagonist administration. Seven patients received one week of cimetidine 300 mg p.o. four times daily and eight received one week of ranitidine 150 mg p.o. two times daily. Prior to study, all patients had stable renal function and were maintained on prednisone (mean dose 0.2 +/- 0.01 mg/kg/day) and cyclosporine (mean dose 5 +/- 0.6 mg/kg/day). Four patients were also receiving azathioprine (2 mg/kg/day). Cimetidine administration resulted in a significant increase (P less than 0.05) in mean serum creatinine concentration from 2.0 +/- 0.3 mg/dl to 2.4 +/- 0.3 mg/dl and a significant reduction (P less than 0.05) in mean creatinine clearance remained unchanged during this same period. Serum creatinine levels returned to baseline values for all patients following discontinuation of the drug. Ranitidine administration had no consistent effect on serum creatinine concentration, creatinine clearance or inulin clearance. Cyclosporine trough levels and BUN were unchanged by either drug. These results confirm previous observations demonstrating an increase in serum creatinine and a reduction in creatinine clearance following administration of H2 receptor antagonists, especially cimetidine. Failure to document a simultaneous reduction in inulin clearance is consistent with the hypothesis that H2-receptor antagonists do not exacerbate cyclosporine nephrotoxicity and lower GFR, but rather compete with creatinine for tubular secretion.
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Duplex Doppler ultrasound (US) examination of the renal vasculature has proved valuable in assessing the kidney transplant. The normal renal allograft exhibits low-impedance arterial inflow similar to that seen in the normotopic kidney. The authors and others previously reported that a high vascular impedance, defined as either a pulsatility index (PI) greater than 1.8 or a resistive index greater than 0.9, indicates acute vascular rejection (AVR). Although AVR remains the most common cause of increased PI, the authors noted ten episodes among 180 serially followed-up transplants in which abnormal waveforms were clearly not due to rejection. Four other causes of increased vascular impedance are reported, including renal vein obstruction, severe acute tubular necrosis, pyelonephritis, and extrarenal compression of the graft. These new causes only slightly decrease the specificity of high vascular impedance for rejection. Furthermore, the cause can usually be recognized from the clinical history or other US findings.
In order to determine whether the proteinuria observed in some renal donors was glomerular or tubular in origin, and to determine whether creatinine clearance was an accurate index of glomerular filtration rate (GFR) in subjects with reduced nephron mass, 29 donors were evaluated 9-18 years after uninephrectomy. Results were compared with those in 31 age-, sex-, and race-matched controls evaluated at the same time. Mean creatinine clearance (Ccreat) in donor was 78% that of controls, which was similar to the 85% ratio of inulin clearance (Cin) in donors compared with that of controls. Furthermore, the ratio of Ccreat/Cin was similar in both donors and controls. One third of the renal donors had an elevated albumin excretion compared with controls (microalbuminuria [12-220 mg/24 hr] in seven patients; 301 and 1084 mg/24 hr in two patients). There was no correlation between albuminuria and blood pressure, nor was there a demonstrable clinical cause for the albuminuria in most patients. In contrast to these results, excretion of beta-2 microglobulin, an index of tubular proteinuria, was normal in all but one patient. The prevalence of hypertension was higher in donors compared with the expected prevalence adjusted for age, sex, and race. These results verify that creatinine clearance is a reliable measure of GFR in long-term renal donors. They also demonstrate an increased frequency of glomerular proteinuria and hypertension in renal donors. Despite these mild abnormalities, GFR is well preserved for up to 18 years postuninephrectomy.
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To determine whether cyclosporine exacerbated renal ischemic injury and whether or not the timing of cyclosporine administration was important, rats were subjected to 30 or 45 min of ischemia. Cyclosporine was administered either before or after the renal ischemic insult. A single intravenous dose of cyclosporine, 20 mg/kg, before ischemia had no additional deleterious effect on inulin clearance compared with rats subjected to ischemia alone. In contrast, a significant exacerbation of the diminished glomerular filtration rate (GFR) produced by ischemia occurred when a low dose of cyclosporine (5 mg/kg) was given after ischemia. With 30 min of ischemia, GFR was 160 +/- 40 microliter/min/100 g in rats receiving cyclosporine (5 mg/kg) after ischemia compared with 280 +/- 40 microliter/min/100 g in rats subjected to ischemia alone. After 45 min of ischemia, cyclosporine (5 mg/kg) markedly reduced GFR to 20 +/- 10 microliter/min/100 g, a value significantly lower (P less than 0.05) than that observed in rats subjected to 45 min of ischemia alone (290 +/- 100 microliter/min/100 g). Plasma potassium concentrations tended to be higher and urinary potassium and sodium excretion lower in rats subjected to ischemia plus cyclosporine compared with ischemia alone. These findings indicate that even a single low dose of parenteral cyclosporine can exacerbate renal ischemic injury if given immediately after the ischemic insult. This interaction may contribute to the acute renal failure observed with cyclosporine use. In contrast, the kidney appears to be relatively resistant to a single dose of cyclosporine injury when the drug is administered prior to ischemia. These data suggest that the administration of parenteral cyclosporine immediately after transplantation could have deleterious effects and should probably be avoided.
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Beta adrenergic control of extrarenal potassium disposal was evaluated by examining the effects of physiologic doses of beta adrenergic agonists and antagonists on potassium tolerance in acutely nephrectomized rats. Following an acute intravenous potassium load (0.17 mEq/100 g over 60 min), the plasma potassium concentration rose significantly less in animals concomitantly treated with epinephrine at a dose that raises plasma epinephrine concentration to levels found during surgical stress (maximum plasma K 2.2 vs. 2.9 mEq/1 in controls receiving KCl alone; p less than 0.005). Similar results were observed with the selective beta-2 agonists salbutamol and terbutaline. Conversely, the rise in plasma potassium concentration was significantly greater in rats treated with low-dose propranolol (beta-1 + beta-2 blockade) and with butoxamine (beta-2 blockade) compared to control animals. In contrast, the selective beta-1 blocking agent metoprolol had no effect on potassium tolerance. Alterations in potassium tolerance following the administration of various beta adrenergic agonists and antagonists could not be explained by changes in plasma insulin, renin, or glucose concentration or by differences in the acid-base or hemodynamic status of the animals. The data suggest that beta adrenergic control of extrarenal potassium disposal occurs with physiologic stimulation or blockade of the beta-2 receptor site.