HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, SR-B1, and ACAT in diet-induced syndrome X

BACKGROUND: Long-term consumption of Western diets can lead to acquired syndrome X, which presents with obesity, insulin resistance, hypertension, hyperlipidemia, and risk of atherosclerotic cardiovascular disease. While plasma lipid abnormalities in syndrome X have been well characterized, their molecular basis remains unclear. This study explored potential mechanisms of hypercholesterolemia in diet-induced syndrome X. METHODS: Female Fischer rats were fed a high-fat, refined-carbohydrate (sucrose) diet (HFS) or standard rat chow (low-fat, complex carbohydrate, LFCC) for 20 months. Plasma lipids and hepatic tissue mRNA, protein, and/or activities of the key enzymes and receptors involved in cholesterol metabolism were determined. RESULTS: The HFS group exhibited hypertension, hyperlipidemia, insulin resistance, obesity, significant down-regulation of hepatic cholesterol 7alpha-hydroxylase (the rate-limiting step in cholesterol catabolism) and low-density lipoprotein (LDL) receptor (LDL-R, the primary pathway of LDL clearance). In contrast, hepatic tissue acyl-coenzyme A:cholesterol acyltransferase (ACAT-2, the primary enzyme involved in intracellular esterification of cholesterol) and scavenger-receptor class B, type 1 (SR-B1 or HDL receptor) were up-regulated. While 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase mRNA expression was increased, its protein abundance and activity were unchanged, and HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio was increased in HFS-fed animals. CONCLUSION: Hypercholesterolemia in diet-induced syndrome X is associated with depressed cholesterol 7alpha-hydroxylase, diminished LDL-R, elevated ACAT, and increased HMG-CoA reductase-to-cholesterol 7alpha-hydroxylase ratio. These findings point to impaired hepatic catabolism and uptake of cholesterol and inappropriate cholesterol production capacity as the underlying causes of hypercholesterolemia in rats with diet-induced syndrome X.     

HMG-CoA reductase,cholesterol 7alpha-hydroxylase,LCAT, ACAT,LDL receptor,and SRB-1 in hereditary analbuminemia

BACKGROUND: Hereditary analbuminemia is associated with hypercholesterolemia, which has been shown to be primarily caused by increased extrahepatic production of cholesterol. Nagase rats with hereditary analbuminemia (NAR) have been used as a model to dissect the effect of primary hypoalbuminemia from that caused by proteinuria in nephrotic syndrome. The present study was undertaken to explore the effect of hereditary analbuminemia on protein expression of the key factors involved in cholesterol metabolism. METHODS: Hepatic tissue protein abundance of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7alpha-hydroxylase (a rate-limiting enzyme in cholesterol catabolism), low density lipoprotein (LDL) receptor, high density lipoprotein (HDL) receptor (SRB-1), acyl-coA cholesterol acyltransferase-2 (ACAT-2), and plasma concentration of lecithin cholesterol acyltransferase (LCAT), as well as HMG-CoA reductase, ACAT, and LCAT activities were determined in fasting male NAR and Sprague-Dawley control rats. RESULTS: The NAR group exhibited significant up-regulation of HMG-CoA reductase protein abundance but normal HMG-CoA reductase enzymatic activity. This was coupled with a significant up-regulation of cholesterol 7alpha-hydroxylase and a mild up-regulation of ACAT protein abundance and activity. However, hepatic LDL receptor and HDL receptor and plasma LCAT protein concentration and activity were normal in NAR. CONCLUSION: Hypercholesterolemia in NAR is associated with elevated hepatic HMG-CoA reductase protein abundance, but normal HMG-CoA reductase activity. These findings point to post-translational regulation of this enzyme and favor an extrahepatic origin of hypercholesterolemia in NAR. The observed up-regulation of cholesterol 7alpha-hydroxylase represents a compensatory response to the associated hypercholesterolemia. Unlike nephrotic syndrome, which causes severe LDL receptor, HDL receptor, and LCAT deficiencies, hereditary analbuminemia does not affect these proteins.     

Hepatitis B vaccination and interleukin 2 receptor expression in chronic renal failure

Only 50 to 60% of dialysis patients develop anti-HBs antibodies following hepatitis B vaccination. The nonresponder state correlates with impaired monocyte function, decreased interleukin-2 (IL-2) production of T cells, and an upregulation of the IL-2 receptor system. In the present study we examined anti-HBs production after hepatitis B vaccination and the in vitro expression of IL-2 receptors in nondialyzed patients with various degrees of chronic renal failure. Forty-four patients with impaired renal function were immunized with 2 micrograms recombinant hepatitis B vaccine and boostered after one and six months. Prior to the first injection IL-2 receptor expression of activated T cells was studied by an in vitro proliferation assay. Sixty-four healthy subjects served as controls. After completion of the third vaccination 55.0% of the patients acquired antibody titers greater than 10 U/liter. The seroconversion rate did not differ between patients with lower (less than 3.5 mg/dl) and higher (greater than 3.5 mg/dl) creatinine levels. In nonresponders IL-2 receptor expression (stimulation index, SI = 10.09 +/- 1.80) was elevated compared to healthy controls (SI = 4.62 +/- 0.35, P less than 0.002) or patients who responded with a high antibody titer (greater than 50 U/liter, SI = 3.12 +/- 0.43, P less than 0.001). Patients who produced low antibody titers (less than 50 U/liter) also presented with enhanced IL-2 receptor expression. These data show that an impaired antibody production following hepatitis B vaccination and an enhanced IL-2 receptor expression of T cells may already be present in early stages of chronic renal failure.     

Autoantibodies against oxidized LDL in chronic renal failure: role of renal function, diet, and lipids

Lipid peroxidation (LP) has recently been suggested to trigger the atherosclerotic process as well as to worsen the progression of renal disease. Autoantibodies against oxidized low-density lipoproteins (Ox-LDLAb) were considered to provide a sensitive marker to detect LDL oxidation in vivo. To date few studies have been reported on Ox-LDLAb levels in patients with different degrees of renal failure. The aim of this study was to evaluate the influences of renal function, dietary manipulation, and lipids on Ox-LDLAb concentrations in uremic patients either on conservative or replacement therapy. Seventy-one patients (42 males, 29 females) aged 60 +/- 19 years with chronic renal failure (CRF) of different etiology and degree were divided into four groups according to serum creatinine levels [sCr(mg/dl)] and diet: CRF I > or = 1.5-3.0, CRF II > 3.0-5.5, and CRF III > 5.5 were all patients on a conventional low-protein diet, while a fourth group included patients on a vegetarian diet supplemented with keto analogues and amino acids (CRF SD >3.0). A further group was represented by patients on dialysis therapy. All patients were examined for Ox-LDLAb, triglycerides (TG), total cholesterol, HDL and LDL cholesterol, and apolipoproteins Apo A1, Apo B, and Lp(a). The results were compared with those of 20 controls (9 males and 11 females) aged 52 +/- 11 years with sCr <1.5 mg/dl. Ox-LDLAb increased, although not significantly, with TG and Lp(a) from the early stages of CRF along with the deterioration of renal function. However, TG and Lp(a) levels were significantly higher in all groups of patients except those on vegetarian diet (CRF SD). This group also showed the lowest Ox-LDLAb levels. No relationship was observed between lipids or apolipoproteins and Ox-LDLAb. Hyperlipidemic patients did not show higher Ox-LDLAb levels than normolipidemics. Our results show a progressive increase of LP as the renal function declines, which may account for the increased risk of cardiovascular disease reported in uremia. Dialysis does not correct significantly the oxidative state observed in patients with end-stage renal disease. Vegan diet, by reducing LP, TG, and Lp(a), is supposed to decrease the risk of cardiovascular disease and worth being reconsidered as an alternative effective therapeutic tool in patients with advanced CRF.     

Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure.

BACKGROUND: Chronic renal failure (CRF) is associated with hypertriglyceridaemia and depressed plasma high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-I (Apo A-I) concentrations. Uraemic hypertriglyceridaemia is due, in part, to lipoprotein lipase and hepatic lipase deficiencies, which are causally linked to excess parathormone (PTH). This study was designed to test the hypothesis that depressed plasma concentration and abnormal composition of HDL in CRF may be due to dysregulation of hepatic expression of Apo A-I and/or the newly discovered HDL receptor. METHODS: Hepatic Apo A-I and HDL receptor mRNA abundance (Northern blot), and HDL receptor protein mass (Western blot) were determined in CRF rats (5/6 nephrectomy), parathyroidectomized CRF rats (CRF-PTx) and sham-operated controls. RESULTS: The CRF group exhibited normal hepatic HDL receptor mRNA and HDL receptor protein abundance coupled with reduced hepatic Apo A-I mRNA. Hepatic Apo A-I mRNA, HDL receptor mRNA and protein abundance were not affected by PTx. CONCLUSIONS: CRF results in the down-regulation of hepatic Apo A-I gene expression, which accounts for the known reduction in plasma Apo A-I concentration. However, CRF does not affect HDL receptor mRNA or protein expression in this model. Neither Apo A-I nor HDL receptor expression were modified by PTx in CRF rats.     

Selective estrogen receptor modulators in chronic renal failure

BACKGROUND: In addition to renal osteodystrophy, postmenopausal women on dialysis could be at risk of osteoporosis. Hormone replacement therapy (HRT) could have beneficial effects as well as potentially serious risks, especially in uremic women, due to the pharmacokinetics of estradiol in renal failure. Therapeutic alternatives, such as the selective estrogen receptor modulators (SERMs), have shown the benefits of estrogen on bone and serum lipid levels, without its adverse effects on the breast and endometrium, in nonuremic women. METHODS: Recent data on the effect of the SERM raloxifene in bone and lipid metabolism in osteoporotic postmenopausal women on dialysis is reviewed. Since the estrogen receptor (ER) gene has been suggested as a candidate marker for osteoporosis, we investigated whether ER polymorphism could have predicted the BMD response to raloxifene. RESULTS: Hemodialyzed women on raloxifene demonstrated increased trabecular bone mineral density (BMD) and decreased bone resorption markers. Similarly, LDL-cholesterol values dropped significantly. ER gene polymorphism analysis of baseline BMD parameters did not differ between PP/xx or Pp/Xx groups. Nevertheless, patients on raloxifene with PP/xx genotypes, but not those with Pp/Xx, showed a higher trabecular BMD after one year on treatment, suggesting that homozygous women for P or x alleles of the ER have a better BMD response to raloxifene. CONCLUSION: Raloxifene and, most likely, other SERMs, could represent a good alternative to HRT in postmenopausal uremic women.     

Blood pressure reduction with HMG-CoA reductase inhibitors in renal transplant recipients

BACKGROUND: Besides lowering lipid levels, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) modulate endothelial function and decrease vascular tone. The effect of statin therapy on blood pressure has not been previously examined in renal transplant recipients. METHODS: We identified 113 stable recipients with graft survival>1 year and started on a statin >or=1 year post-transplant with no subsequent alteration in type or dose, as well as >or=6 months' follow-up post-statin introduction along with no changes in antihypertensive medication type or dosage. This "statin" group was compared to a control group matched 1:1 by age, gender, donor source, year of transplant, and time since transplant who met identical criteria but were not begun on a statin. Baseline, 6 months, and 12 months outpatient blood pressure were reviewed and compared along with other possible blood pressure predictors. A multivariate analysis was performed controlling for other influences on blood pressure change. RESULTS: Blood pressure and baseline characteristics other than lipid levels were similar in the two groups. The systolic, diastolic, and mean arterial blood pressure decreased by 7 mm Hg (P = 0.005), 3 mm Hg (P = 0.05), and 4 mm Hg (P = 0.007), respectively, at 12 months' post-statin introduction, while no blood pressure change was seen in the control group (P = NS). At 12 months, the systolic, diastolic, and mean arterial blood pressures were lower in the statin group compared to the control group (P = 0.05, 0.03, and 0.02, respectively). These changes in blood pressure were independent of changes in serum lipid levels. CONCLUSION: Renal transplant recipients exhibit a significant blood pressure reduction associated with statin therapy. This finding has important mechanistic and clinical implications in the management of cardiovascular disease risk factors in this population.     

Platelet vasopressin receptor in patients with chronic renal failure

The vasopressin binding to intact platelet from patients with chronic renal failure (CRF) was investigated in relation to the abnormalities in platelet aggregation. The immunoreactive arginine vasopressin (AVP) in platelet-free plasma (PFP) but not in platelets was significantly higher in non-dialyzed patients with CRF than in normal subjects. Binding studies using [3H]AVP demonstrated a decreased number of binding sites (Bmax) on platelets from patients with CRF compared to normal controls with no significant difference in affinity (Ka). A significant diminution of the maximal percentage aggregation with AVP was found in patients with CRF. An inverse relation between Bmax and the PFP AVP levels and a highly significant relation between Bmax and the maximal percentage aggregation with AVP in patients with CRF and normal controls were observed. At 4 weeks after the introduction of hemodialysis in patients with CRF, the PFP AVP levels decreased and Bmax increased significantly, and the maximal percentage aggregation tended to increase. The present findings suggest that a reduced number of AVP receptors on platelets might account for decreased platelet aggregation with AVP, and the elevated plasma AVP levels might induce a down-regulation of the AVP receptor number on platelets in patients with CRF.     

Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia-reperfusion injury

BACKGROUND: Increasing evidence supports an important role for inflammation in the pathogenesis of renal ischemia-reperfusion injury (IRI). Recently, HMG-CoA reductase inhibitors, 'statins', have demonstrated anti-inflammatory effects independent of cholesterol-lowering. HYPOTHESIS: We tested the hypothesis that a statin would improve outcome in a murine model of renal IRI. Upon finding a protective effect, we tested the hypothesis that the mechanisms by which statins protected in renal IRI was by reducing neutrophil and macrophage infiltration and upregulating the anti-inflammatory cytokine IL-6. METHODS: Cerivastatin at various dosing regimens was administered to NIH Swiss mice to evaluate the effects on renal IRI. Analysis of renal structure, function, neutrophil and macrophage infiltration, cytokine production, as well as mortality was performed in cerivastatin- and saline-treated groups. RESULTS: PRIMARY: Cerivastatin pretreatment for 3 days led to a significant improvement in renal function, tubular injury as well as survival after IRI compared to saline-treated mice. SECONDARY: Neutrophil and macrophage infiltration into kidney tissue was similar in both groups. IL-6 was markedly upregulated early in the kidneys of statin-treated compared to saline-treated mice. CONCLUSION: These data demonstrate that a statin compound can improve the course of ischemic acute renal failure. Induction of protective molecules such as IL-6 may underlie this effect.     

Ezetimibe in renal transplant patients with hyperlipidemia resistant to HMG-CoA reductase inhibitors

Hyperlipidemia affects the majority of renal transplant patients. Multiple risk factors contribute to elevated serum cholesterol including the use of certain immunosuppressant agents. HMG-Co A reductase inhibitors have become the preferred class of cholesterol-lowering medication with an increasing body of evidence to support their safety, efficacy, and outcomes in both the normal and renal transplant populations. New guidelines recommend lowering previous LDL-c goals as outcomes appears to continually improve. As a result, ezetimibe has been added to patients with persistently elevated triglycerides and/or LDL-c in individuals who possessed a renal transplant and were deemed to be on a maximum safe dose of statin agent. After the addition of ezetimibe, total cholesterol, LDL-c, and triglycerides fell by 21%, 31%, and 13%, respectively. Creatinine phosphokinase, liver enzyme serum levels, and renal function were not affected to any level of clinical significance with the addition of ezetimibe. Large interpatient variability of measurable immunosuppressant levels was seen but no serious adverse events were attributed to a change in levels.     

Effect of aluminium on calcium-sensing receptor expression,proliferation, and apoptosis of parathyroid glands from rats with chronic renal failure

BACKGROUND: To assess the effect of aluminium on the calcium-sensing receptor expression, proliferation, and apoptosis in parathyroid glands from rats with chronic renal failure, 2(1/2)-month-old male Wistar rats were 7/8 nephrectomized. METHODS: Eight weeks after surgery the rats were divided into two groups, one receiving intraperitoneal AlCl3 for 8 weeks and the other receiving intraperitoneal placebo. Serum Al, Ca, P, creatinine, and PTH were measured. Parathyroid glands were removed, formaldehyde-fixed, and paraffin-embedded. Calcium-sensing receptor and proliferation were detected by immunohistochemistry and apoptosis by TUNEL and propidium iodide uptake. RESULTS: At the end of the study, despite higher levels of serum P in the aluminium group (6.27 +/- 0.63 vs. 5.56 +/- 0.58 mg/dL; P = 0.045), serum PTH was lower (89.6 +/- 57.7 vs. 183.1 +/- 123.8 pg/mL; P = 0.059). No significant differences were found in the calcium-sensing receptor expression between groups (aluminium: 27.1 +/- 7.6; placebo: 25.4 +/- 3.5 RU). Rats receiving aluminium showed a significantly lower cell proliferation rate than the control rats (0.54 +/- 0.69 vs. 4.43 +/- 3.10 cells/mm2; P = 0.003). No apoptotic events were detected. CONCLUSION: Aluminium was able to reduce the cell proliferation of the parathyroid glands. Due to the low apoptosis rate, however, it was not possible to find any change. Aluminium had no effect on the calcium-sensing receptor expression.     

Expression of scavenger receptor CD36 in chronic renal failure patients

BACKGROUND: Patients with chronic renal failure (CRF) are at increased risk of atherosclerosis development. One of the major steps in pathogenesis of atherosclerosis is formation of foam cells. Scavenger receptor CD36 is among the major receptors for oxidized low density lipoproteins (oxLDL) and therefore it plays a crucial role in foam cell formation. The aim of the present study was to investigate the expression of CD36 on blood monocytes of CRF patients. METHODS: Expression of CD36 on blood monocytes of CRF patients treated with hemodialysis (HD), peritoneal dialysis (PD), those not yet on dialysis (predialysis), and controls was assessed with the use of flow cytometry. Additionally, the major lipid peroxidation markers, malondialdehyde (MDA) and 4-hydroxyalkenals (HAE), were measured. Further, impact of treatment with HMG-CoA reductase inhibitors (statins) on CD36 expression in CRF patients was evaluated. RESULTS: Expression of monocyte CD36, measured as mean fluorescence intensity (MFI) was significantly higher in HD and PD patients, when compared to controls without renal insufficiency (respectively: 1011 +/- 288 and 1000 +/- 309 vs. 710 +/- 313; P < 0.01 for both groups). This was not the case in predialysis group (828 +/- 363 vs. 710 +/- 313). Higher concentrations of lipid peroxidation indicators, MDA and HAE were observed in all three subgroups of CRF patients (2.1 +/- 0.51, 2.02 +/- 0.27, and 1.81 +/- 0.53 microm in HD, PD, and predialysis group, respectively, vs. 1.13 +/- 0.59 microm in controls; P < 0.01). Patients treated with statins showed significantly lower CD36 expression than patients without statin therapy. CONCLUSIONS: The present study, for the first time, demonstrates increased expression of CD36 scavenger receptor in CRF patients. This may be a possible risk factor for accelerated atherogenesis observed in this group of patients.     

Effect of chronic renal failure on arginase and argininosuccinate synthetase expression

BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including urea and nitric oxide synthesis. Sources of L-arg include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase. L-arg is converted to urea by arginase I in the liver and arginase II in the kidney. Normally, the liver fully consumes L-arg for urea generation and does not contribute to its circulating pool. Instead, much of the circulating L-arg is produced by the kidney. If true, plasma L-arg should be severely reduced in chronic renal failure (CRF); however, plasma L-arg is frequently unchanged in CRF. We hypothesized that preservation of plasma L-arg in CRF may be, partly, due to downregulation/inhibition of arginase. METHODS: Argininosuccinate synthetase, arginase I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, arginase activity was measured in the presence of different urea concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as arginase activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by urea in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in urea concentration inhibits its enzymatic activity. The latter, in turn, attenuates L-arg catabolism and urea production and, thereby, mitigates the fall in plasma L-arg.     

Renoprotective effect of angiotensin II receptor antagonists in experimental chronic renal failure

We compared the antihypertensive and renoprotective effects of the angiotensin II receptor antagonist losartan and the calcium channel blocker verapamil in the rat with chronic renal failure. One month after five-sixths nephrectomy, male WKY rats were treated for 2 months with either losartan or verapamil. Both resulted in a similar reduction in blood pressure: from 147.1 to 112 mm Hg in losartan-treated and from 155 to 118 mm Hg (p = NS) in verapamil-treated rats. Losartan improved the creatinine clearance (difference + 17.1% as compared with + 6.6% for verapamil, p = 0.039) and prevented the increase in proteinuria: 12.26 +/- (SE) 2.33 mg/day before and 18.48 +/- 2.19 mg/day (p = NS) after therapy in the losartan-treated and 17.27 +/- 2.73 mg/day before and 32.27 +/- 10.29 mg/day after therapy (p = 0.0484) in the verapamil-treated group. In addition, losartan resulted in minimal mesangial proliferation and significantly less glomerular sclerosis and thickening of the small arterial and arteriolar walls. The changes in interstitial fibrosis and tubular hypertrophy, however, were similar in both the verapamil- and losartan-treated groups. Treatment with losartan 1 month after five-sixths nephrectomy in male WKY rats resulted in reduced blood pressure, similar to that of the verapamil-treated group. However, despite similar antihypertensive properties, losartan improved creatinine clearance and reduced proteinuria. The losartan-treated group also had a marked reduction in mesangial proliferation and less glomerular sclerosis and less reduced vascular wall thickness in renal small arteries and arterioles. However, losartan did not totally eliminate nephrosclerosis. The tubular and interstitial changes were fewer in the losartan-treated group. Thus losartan has an additional, although only partial, renoprotective effect when compared with verapamil.     

Parathyroidectomy in chronic renal failure

Parathyroidectomy was carried out in 26 patients over a 14-year period. Excellent results were obtained in patients with severe hyperparathyroidism. Vascular calcification, hypercalcaemia and pruritus did not justify surgery unless associated with unequivocal hyperparathyroidism. 13 patients required intravenous calcium infusion for up to 2 weeks to control post-operative hypocalcaemia. Calcium requirements could be predicted from the pre-operative plasma alkaline phosphatase level. Following operation continued treatment with vitamin D was necessary to prevent hypocalcaemia. Hyperparathyroidism recurred in 1 patient after 8 years and 4 patients developed osteomalacia. Since parathyroid hormone may have toxic effects other than those on bone, maintenance of normal levels should be a long-term objective in the treatment of patients with chronic renal failure. Where large parathyroid glands are present, surgical reduction in gland mass is a logical prelude to long-term suppression of parathyroid hormone with vitamin D and phosphate-binding agents.     

Parathyroidectomy in chronic renal failure

Between 1978 and 1984, 19 patients at Royal Perth Hospital (RPH) underwent parathyroidectomy for secondary (renal) hyperparathyroidism. This represented 6.0% of the overall dialysis population treated at RPH during this period of time. The mean duration of pre-operative dialysis for these 19 patients was 48 months, compared with a mean duration of 30 months for the overall dialysis population. The principal indications for parathyroidectomy were symptomatic hyperparathyroid bone disease (10), hypercalcaemia (six), progressive lower limb ischaemia (two) and painful peri-articular calcification (one). The complications of chronic renal failure that were most consistently improved by parathyroidectomy were the clinical, radiological and biochemical manifestations of hyperparathyroid bone disease and hypercalcaemia. Features such as pruritus, soft tissue calcification, vessel wall calcification and peripheral ischaemia responded less predictably. Hyperparathyroid bone disease and hypercalcaemia remain the principal indications for parathyroidectomy in chronic renal failure. Profound postoperative hypocalcaemia was the major early postoperative management problem (seven patients) and was closely linked with the severity of pre-operative hyperparathyroid bone disease. It was also seen more frequently in those patients undergoing total parathyroidectomy with immediate autotransplantation of parathyroid tissue (TP-A), than in those in whom residual parathyroid tissue was left in situ (subtotal parathyroidectomy or STP). Recurrent hyperparathyroidism (four patients) was the major late postoperative complication, but was more frequently the result of a supernumerary or previously overlooked fourth parathyroid gland (three), than due to hyperplasia of residual parathyroid tissue (one). STP and TP-A were equally effective in controlling or reversing renal hyperparathyroidism, but the former was associated with a lower incidence of postoperative management problems and should be the preferred operation in this group of patients.     

In vitro production of interleukin-1 receptor antagonist in chronic renal failure, CAPD and HD.

Dialysis-related symptoms are believed to be mediated, at least in part, by monocyte/macrophage-derived pro-inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor (TNF). Measuring the production of interleukin-1 receptor antagonist (IL-Ra), a naturally occurring inhibitor of IL-1, opens avenues to study the balance between these two cytokines in patients. We studied the cell content and production of IL-1 beta and IL-Ra by unstimulated and endotoxin- or IgG-stimulated peripheral blood mononuclear cells (PBMC) in undialyzed patients with chronic renal failure (CRF), patients on continuous ambulatory peritoneal dialysis (CAPD) and patients on chronic hemodialysis with reuse cuprophan membranes (HD), and compared them to healthy controls. IL-1 beta and IL-Ra were measured by specific radioimmunoassay. IL-1 beta was undetectable in freshly harvested PBMC from healthy controls, CRF, CAPD or HD. In contrast, the content of IL-Ra in HD patients (2828 +/- 466 pg/ml) was significantly higher than that in healthy controls (643 +/- 53 pg/ml, P < 0.01), CRF (1097 +/- 320 pg/ml, P < 0.01) or CAPD (1398 +/- 390 pg/ml, P < 0.05). In endotoxin-stimulated PBMC, IL-1 beta production by HD patients (9375 +/- 1687 pg/ml) was not significantly different from healthy controls (8429 +/- 1621 pg/ml). However, endotoxin-stimulated IL-Ra production by HD patients (32,350 +/- 8276 pg/ml) was greater than that from healthy controls (11,284 +/- 1250 pg/ml, P < 0.001), CRF (12,263 +/- 2680 pg/ml, P < 0.01) or CAPD patients (11,822 +/- 1797 pg/ml, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)