Biomedical subjects
R G Luke
Publications and source records attributed to R G Luke.
Inhibition of angiotensin-converting enzyme in renal-transplant recipients with hypertension.
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Successful renal transplantation in hyperoxaluria. A report of two cases.
Two patients with documented primary hyperoxaluria have received renal allografts with successful function for 10 years and 25 months. The patient in case 1 required a ureterolithotomy 6 years post-transplantation to remove a renal calculus of calcium oxalate. This case illustrates that despite recurrence of oxalate stones in the allograft, satisfactory renal function can be maintained by careful follow-up and appropriate interventions. Factors that may be important in successful graft function include the occurrence of acute rejection episodes, avoidance of ischemic graft damage, trials of pyridoxine therapy to decrease oxalate excretion, and frequent evaluation with appropriate interventions as necessary. Renal transplantation is a suitable and possibly the preferred form of therapy of end stage renal disease in patients with primary hyperoxaluria.
Effects of NaCl on renin and aldosterone responses to potassium depletion.
We have previously suggested that renin secretion is inversely related to the magnitude of absorptive chloride transport in the thick ascending limb of the loop of Henle. Potassium depletion inhibits chloride transport at this site in the nephron. Consequently, we studied the effects of varying sodium and chloride intakes on the renin and aldosterone responses to potassium depletion. Potassium depletion prevented suppression of plasma renin activity (PRA) by dietary NaCl loading and augmented the PRA response to NaCl deprivation. PRA was stimulated (P less than 0.01) by selective chloride (without sodium) deprivation, and potassium depletion did not augment this response. Potassium depletion did not interfere with suppression of PRA by albumin-induced volume expansion. Plasma aldosterone was suppressed by potassium depletion, and the effect of potassium depletion on aldosterone was augmented by NaCl deprivation. In conclusion, the magnitude of PRA stimulation and aldosterone suppression by potassium depletion is modulated by dietary NaCl intake. The results are consistent with the hypothesis that potassium depletion stimulates renin release by inhibiting chloride transport in the loop of Henle.
Correction of acute chloride-depletion alkalosis in the rat without volume expansion.
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Effect of volume expansion and plasma chloride on function of the loop segment.
To determine the effect of acute volume expansion and changes in plasma chloride on fluid and chloride uptake in superficial loop segments of rats, this segment was microperfused in vivo at 22 nl/min with a fluid containing Na 145, Cl and 36Cl 130, and HCO3 15 meq/liter during hydropenia and after acute volume expansion with 0.15 M NaCl, 0.15 M NaHCO3, or an isotonic bicarbonate Ringer (Cl 106 meq/liter) solution. Fractional fluid, chloride, and 36Cl reabsorption and early distal chloride concentration did not change during maintained hydropenia (time control) or during volume expansion with NaCl (plasma chloride 120 meq/liter) or bicarbonate Ringer solution (plasma chloride 104 meq/liter). Absolute and fractional reabsorption of chloride and 36Cl increased, without change in fluid reabsorption, and early distal chloride diminished after infusion of NaHCO3 (plasma chloride 90 meq/liter). It is concluded that acute volume expansion, per se, has no effect on either net fluid or net chloride absorption in the superficial loop segment at the load studied. Hypochloremia is associated with increased net reabsorption of chloride and an increased unidirectional efflux of chloride from the loop segment during acute volume expansion, most likely due to a gradient effect on the thick ascending limb of the loop of Henle.
Chloride-depletion alkalosis with a normal extracellular fluid volume.
Current concepts hold that volume expansion is essential to the correction of chloride-depletion alkalosis (CDA) with chloride repletion in a permissive role. In this scheme, intranephronal fluid reabsorption would be redistributed with increased delivery to the distal nephron where the provided chloride is readily reabsorbed and the limited capacity for bicarbonate reabsorption would promote bicarbonate excretion and correction of CDA. In a model of CDA produced by peritoneal dialysis against 0.15 M NaHCO3, we have shown complete correction of CDA within 24 h without volume expansion by either oral isotonic sodium or chloride salts with 70 mM chloride and despite an obligatory bicarbonate load and negative sodium and potassium balance. During correction of CDA without volume expansion in rats by intravenous isotonic fluids containing 80 mM chloride, fractional fluid and chloride reabsorptions in the proximal convoluted tubule and in the loop segment of superficial nephrons were not different from controls but chloride reabsorption was enhanced in the collecting duct segment and probably within the distal convolution. Despite no differences in serial hematocrits, blood pressure, and measured plasma volume, kidney and nephron glomerular filtration rate (GFR) were reduced in CDA and returned to normal upon recovery 24 h later.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of chloride on renin and blood pressure responses to sodium chloride.
Both the inhibition of renin release by sodium chloride and salt-sensitive hypertension have been attributed to sodium. We evaluated the contribution of chloride to these responses to sodium chloride. In the Sprague-Dawley rat, acute and chronic administration of sodium salts other than sodium chloride failed to suppress plasma renin activity, whereas renin was inhibited by both sodium chloride and by selective chloride (without sodium) loading. Plasma renin activity was stimulated by selective chloride depletion. Similarly, in humans, plasma renin activity was suppressed by sodium chloride but not by sodium bicarbonate infusion. In a preliminary study in the Dahl salt-sensitive rat, in contrast to sodium chloride loading, sodium bicarbonate loading failed to produce hypertension. Thus, both the renin and possibly the blood pressure responses to sodium chloride are dependent on chloride.
Effect of alternate-day prednisone on plasma lipids in renal transplant recipients.
While numerous groups have reported high prevalences of plasma lipid abnormalities in their renal transplant recipients, we have been unable to confirm this finding. We have suggested that the routine use of alternate-day steroids (ADS) in our patients may be responsible. To test that hypothesis, a prospective controlled trial of equal total dose ADS versus daily steroids (DS) was conducted. Four months after transplant and before entering the trial, transplant study patients had significantly higher serum cholesterol (243 +/- 9 mg/dl) than either normal controls (cholesterol 200 +/- 7 mg/dl, alpha = 0.01) or hemodialysis patients (cholesterol 211 +/- 9 mg/dl, alpha = 0.01). They also had higher serum triglyceride than controls (129 +/- 7 mg/dl vs. 98 +/- 8 mg/dl, alpha = 0.01). After randomization to DS or ADS and 1 year of further followup study, the ADS group had a significant decrease in both serum triglyceride (139 +/- 9 to 100 +/- 7 mg/dl, P less than 0.01) and cholesterol (251 +/- 16 to 220 +/- 9 mg/dl, P less than 0.05) while the DS group's serum triglyceride and cholesterol values remained unchanged. Serum triglyceride and cholesterol in the ADS group had decreased to values that were not significantly different from 41 normal healthy controls. Dose spacing per se, and not the use of a lower total dose of prednisone, appears to result in a lower prevalence of abnormal plasma lipids after successful renal transplantation.
Effect of potassium depletion on renin release.
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Effect of pretransplant stored donor-specific blood transfusions on early renal allograft survival in one-haplotype living related transplants.
The effect of pretransplant stored donor-specific blood transfusions (DSBTs) on early renal allograft survival in 37 consecutive one-haplotype living related donor (LRD) transplants (group B) was compared with a similar consecutive series of 38 one-haplotype LRD recipients (group A) who did not receive DSBTs. All transplant recipients in both groups were treated with identical immunosuppressive protocols using azathioprine and prednisone. Forty patients received pretransplant DSBTs and three of these patients (8%) developed cytotoxic antibodies to their prospective donors. Neither hyperacute rejection nor hepatitis occurred in group B patients following DSBTs. One group B patient experienced a technical graft loss on the 1st postoperative day and was excluded from the rejection data. Graft survival at 3 and 6 months was 100 and 90% in group B recipients and 68% in group A recipients. All 12 group A graft failures resulted from acute nonreversible rejection episodes occurring during the first 3 months post-transplant. The three group B graft failures occurring at 6 months were attributable to chronic vascular rejection. Chronic rejection of the renal allograft was histologically documented in six group A and five group B patients by 6 months post-transplant. The use of stored donor blood offered a simple and easily monitored method of administering pretransplant DSBTs that was convenient to the donor and recipient. The administration of DSBTs did not appear to be harmful to the recipient. In fact, the use of pretransplant stored DSBTs in one-haplotype LRD renal transplantation appeared to improve the prospects of early graft survival in our experience.
Quantitative urinary protein excretion in chronic renal failure.
The diagnostic value of the measurement of quantitative proteinuria in patients with a creatinine clearance of less than 10 ml/min was determined in patients seen in a single center over a 5-year period. All 126 patients in whom a definitive renal diagnosis was possible were included. Patients with glomerular disease excreted 6.1 +/- 0.6 g/day and patients with interstitial disease 1.5 +/- 0.3 g/day (p less than 0.001). In individual patients with end-stage renal disease, however, measurement of urinary protein excretion excluded (with 95% confidence levels) patients with interstitial diseases only when greater than 2.9 g/day. To examine the natural history of proteinuria in progressive renal disease, urinary protein, absolute and factored for glomerular filtration rate (GFR; creatinine clearance), was determined at 10 ml/min decrements in GFR for patients with membranoproliferative glomerulonephritis, idiopathic membranous glomerulonephritis and focal glomerulosclerosis. Quantitative urinary protein excretion was relatively constant as GFR fell but did fall significantly at less than 10 ml/min but only to 4.8-7.0 g/day at even that level. Urinary protein excretion/GFR increased as GFR fell, particularly at end stage where a highly significant four-fold rise was seen; an increase also occurred in patients with primary interstitial disease. Similar data were obtained for 34 randomly selected patients after at least 1 year of chronic hemodialysis. Although a significant decline in absolute urinary protein excretion occurred during the year of dialysis to levels not different between glomerular and interstitial disease, urinary protein excretion/unit GFR remained elevated. Increased urinary protein excretion/unit GFR may result from a functional adaptation of remaining nephrons in response to declining renal mass.
Hereditary thrombotic thrombocytopenic purpura: microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency occurring in consecutive generations.
Microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency occurred in a mother an daughter when each was in her third decade. The mother had prominent neurological findings, fever, and expired from renal insufficiency. Her daughter's only major symptom was renal insufficiency. The similarity of the mother's illness to thrombotic thrombocytopenic purpura and of the daughter's to adult hemolytic uremic syndrome suggests that these diseases are variants of a single clinical disorder, while their occurrence in direct descendents strengthens the postulate that in selected instances a genetic predisposition to these disorders may be important.
Influence of aortic constriction on proximal chloride reabsorption during volume expansion.
Extracellular fluid volume expansion is associated with a decrease in the transepithelial chloride gradient in the proximal convoluted tubule. We have previously shown that this effect occurs in the presence of hypo- or hyperchloremia and is not dependent on a change in filtered chloride or bicarbonate load. To determine the influence of filtered fluid load on this effect of volume expansion, micropuncture studies were carried out during acute extracellular fluid volume expansion in rats with (group AC) and without (group CON) a reduction in renal perfusion pressure. Delayed aortic constriction prevented the increase in fluid load (49.7 +/- 2.4 and 49.0 +/- 3.9 nl/min for hydropenia and volume expansion, respectively), but reduced tubule fluid to plasma inulin ratios (2.25 +/- 0.13 and 1.84 +/- 0.8) were maintained. Tubule fluid to plasma chloride ratios did not change in group AC (1.27 +/- 0.03 and 1.25 +/- 0.01) as compared to group CON (1.25 +/- 0.02 and 1.18 +/- 0.02; p less than 0.05). Fractional chloride reabsorption fell in both groups. Absolute chloride reabsorption was highly correlated (p less than 0.001) with absolute fluid reabsorption. These results suggest that filtered fluid load or some related variable is an important determinant of the generation of the chloride gradient in the proximal tubule.
Uremia and the BUN.
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Comparison of daily and alternate-day prednisone during chronic maintenance therapy: a controlled crossover study.
To determine if dose spacing of low dose chronic suppressive corticosteroid therapy would result in different effects on circulating T lymphocytes and hypothalamic-pituitary-adrenal (HPA) axis suppression, a crossover trial of two maintenance steroid regimens was performed. Twenty stable renal allograft recipients were treated for 6 mo with daily prednisone (DS) and then the same patients were abruptly converted to alternate-day prednisone (ADS) for another 6 mo. Total prednisone dosage was identical during the 6-mo study periods and only dose spacing differed. Both circulating T lymphocyte numbers and responsiveness to mitogens were less on the DS regimen. Patients gained weight on DS and lost weight on ADS. Five of the 20 patients developed infections on DS. However, HPA suppression was not different on the two regimens. These findings suggest that dose spacing alters the immunosuppressive and metabolic response to prednisone, even at low dose.
Pathophysiology of acute Bence-Jones protein nephrotoxicity in the rat.
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Effect of hypochloremia on loop segment chloride and solute reabsorption in the rat during volume expansion.
Hypochloremia has been associated by inference from clearance studies with disturbances in free water reabsorption and renal renin release by a macula densa mechanism. To examine directly these relationships, we studied chloride, fluid, and solute transport in the loop segment (LS) of rat superficial nephrons by micropuncture techniques following acute volume expansion with 0.15 m sodium chloride (CVE) or sodium bicarbonate (BVE). Plasma renin activity was suppressed in group CVE but not in group BVE. Blood pressure, plasma volume expansion, whole kidney GFR, urinary sodium excretion, late proximal and early distal SNGFR, and fluid delivery to the LS were no different between groups CVE and BVE despite different plasma chloride concentrations (102 +/- 5 mEq/liter for CVE vs. 74 +/- 3 for BVE; P less than 0.001). Absolute LS chloride reabsorption was less in BVE than it was in CVE (2030 +/- 120 pEq/min vs. 2454 +/- 136; P less than 0.025). This was associated with significantly lower fractional absolute LS solute reabsorption and higher early distal tubule fluid osmolality. These data demonstrate directly and in vivo that a decrease in chloride reabsorption in the LS of superficial nephrons is associated with impaired solute reabsorption in that segment and a failure to suppress plasma renin activity by sodium loading.