Diastolic dysfunction and abnormality of the Na+/Ca2+ exchanger in single uremic cardiac myocytes.

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease, possibly due to a specific "uremic cardiomyopathy". This study investigated the function of the Na(+)/Ca(2+) exchanger in single cardiac myocytes from a model of early renal impairment. Mild uremia was induced by partial (5/6) nephrectomy in male Wistar rats. After 4 weeks, ventricular myocytes were isolated, loaded with the fluorescent Ca(2+) indicator indo-1, and contractile function and calcium transients recorded following electrical pacing at 0.2 Hz. Relaxation from rapid cooling contractures (RCCs) was also studied. Cells from uremic animals (U) were hypertrophied compared with controls (C), with a significant increase in width (14%; P<0.02) and cross-sectional area (13%; P<0.03). There was a significant increase in diastolic intracellular Ca(2+) ratio in the uremic cells (C, 0.33+/-0.00 vs U, 0.37+/-0.02; P<0.02), although the amount of calcium released per twitch was similar. Uremic cells were slower to relax following RCCs, however when Na(+)/Ca(2+) exchange was inhibited using a Na(+)-free/Ca(2+)-free solution, this difference was abolished. Under these conditions, there was little difference in the relaxation rate of control cells, indicating that the Na(+)/Ca(2+) exchanger plays only a minor role in relaxation in normal rat myocytes. However in uremia, the data indicate that the Na(+)/Ca(2+) exchanger actively interfered with relaxation, possibly by working in reverse rather than forward mode. These results indicate that myocyte relaxation and Ca(2+) handling are abnormal in early uremia and may provide further evidence for the existence of a specific "uremic cardiomyopathy".

Maintenance of normal agonist-induced endothelium-dependent relaxation in uraemic and hypertensive resistance vessels.

BACKGROUND: The nitric oxide system has been implicated in several diseases with vascular complications including diabetes mellitus and hypertension. Despite the high prevalence of hypertension and cardiovascular complications in renal failure few studies have examined vascular and endothelial function in uraemia. We therefore chose to study possible abnormalities of the nitric oxide vasodilator system in an animal model of chronic renal failure. METHODS: Adult spontaneous hypertensive rats and Wistar Kyoto rats were subjected to a 5/6 nephrectomy with control animals having sham operations. After 4 weeks blood pressure was recorded and the animals were sacrificed. Branches of the mesenteric arteries were isolated and mounted on a Mulvany myograph. All experiments were performed in the presence of indomethacin (10(-5) M). The vessels were first preconstricted with noradrenaline, exposed to increasing concentrations of acetylcholine (10(-8) to 10(-4) M) and subsequently to sodium nitroprusside (10(-5) M). RESULTS: There was no difference in the relaxation of the four groups of vessels to any of the concentrations of acetylcholine used nor was there any significant difference in the EC50s (control Wistar Kyoto 6.1+/-1.4 x 10(-8) M; uraemic Wistar Kyoto 5.4+/-0.8 x 10(-8) M; control spontaneous hypertensive rats 4.5+/-0.6 x 10(-8) M; uraemic spontaneous hypertensive rats 6+/-0.7 x 10(-8) M). Vasodilatation in response to sodium nitroprusside was unchanged in uraemic vessels. In addition the vascular responses to both acetylcholine and sodium nitroprusside were unaltered in spontaneous hypertensive rats. CONCLUSIONS: We conclude that normal agonist-induced endothelium-dependent relaxation is maintained in experimental uraemia and hypertension.

Calcified plaque is common in the carotid and femoral arteries of dialysis patients without clinical vascular disease.

BACKGROUND: Cardiac and vascular mortality are common in end-stage renal disease (ERSD) and are often attributed to accelerated atherosclerosis. SUBJECTS AND METHODS: We studied 24 non-diabetic ESRD patients without cardiac or vascular disease (M = 12, F = 12) and 24 age-, sex- and race-matched healthy controls. All underwent B-mode ultrasound for carotid and femoral intima media thickness (IMT) and plaque (% stenosis) together with blood pressure (BP), and echocardiograms to determine left ventricular mass. RESULTS: Both BP and mean IMT were similar in patients and controls. However, discrete plaque was present in 71% (17/24) of patients compared with 21% (5/24) of controls (P = 0.001), and % stenosis was greater in patients (carotid 12.2 +/- 11% vs 2.3 +/- 5.9%, P < 0.0004; femoral 16.4 +/- 19.1% vs 3.1 +/- 6.4%, P < 0.003). Plaque was soft/atheromatous in 3 of the 5 controls, but not in any of the 17 patients (P = 0.007), all of whom had calcified lesions. BP and cholesterol were not correlated with IMT or plaque in patients, but in control subjects carotid IMT was correlated with systolic BP (r = 0.66, P < 0.0005) and diastolic BP (r = 0.45, P < 0.03). In patients, the only independent variables related to vascular morphology were serum albumin which was inversely related to IMT (P < 0.03) and to plaque (carotid P < 0.05, femoral P < 0.02) and age, which was related to femoral plaque only (P < 0.04). Left ventricular end-diastolic internal dimension, not LVMI, correlated positively with carotid IMT (P < 0.04). CONCLUSION: Our results show that calcified plaque is common in ESRD patients and hypoalbuminaemia may be an associated factor.

Gender differences in mediators of left ventricular hypertrophy in dialysis patients.

Left ventricular hypertrophy (LVH) is known to be a strong predictor of cardiovascular death in dialysis patients, but the mediators for its development remain to be clarified. In the non-renal population risk factors for LVH differ between the genders. We therefore studied 46 non-diabetic patients (26 male, 19 female) on maintenance hemodialysis (n = 25) or continuous ambulatory peritoneal dialysis (CAPD) (n = 20) all free from clinically evident cardiac disease, who underwent 48-hour ambulatory blood pressure (BP) monitoring, 2-D and M-mode echocardiography for left ventricular mass index (LVMI) and bloods for hemoglobin, parathyroid hormone (PTH), urea and electrolytes and liver function tests. Thirty-two out of 45 patients were taking antihypertensive drugs at the time of the study. The mean 48-hour BP was 135 +/- 19/83 +/- 13 mmHg and the mean LVMI was 144 +/- 50 g/m2. LVH (LVMI > 131 g/m2 men, > 100 g/m2 women) was present with equal frequency in both sexes: men 72% (18/25) and women 68% (13/19). Simple regression analysis showed that LVMI was correlated with 48-hour pulse pressure (r = 0.52, p < 0.00033), 48-hour systolic BP (r = 0.37, p < 0.05), PTH (r = 0.31, p < 0.04) and inversely with serum calcium (r = -0.29, p < 0.05) and hemoglobin (r = -0.33, p < 0.03). However, on multiple regression analysis pulse pressure (R2 = 28.7%), day systolic BP (R2 = 15.4%) and 48-hour systolic BP (R2 = 14.1%) were the only variables linked to LVMI. When the patients were split by gender, stepwise linear regression in the men showed a highly significant relationship between LVMI and pulse pressure (R2 = 37.1%) which was stronger at nighttime (R2 = 42.6%), but in females this was not apparent (R2 = 4.39%) and indeed no variable was linked to LVMI. Our study confirms that LVH is not only prevalent in dialysis patients but is present with equal frequency in both sexes. However the determinants of its development are different for each gender. In males pulse pressure, and therefore by implication vascular compliance, is important but in females, other unidentified factors predominate.

Interdialytic weight gain and 48-h blood pressure in haemodialysis patients.

BACKGROUND: Hypertension, which is often associated with hypervolaemia, is common in haemodialysis patients and is a known determinant of target organ damage. Interdialytic weight gain due to volume overload has also been associated with mortality in haemodialysis patients. METHODS: We therefore studied 27 chronic haemodialysis patients who underwent 48-h ambulatory blood pressure monitoring between two midweek dialysis sessions, and 2D and M-mode echocardiography for determination of left ventricular mass index. RESULTS: Left ventricular hypertrophy (left ventricular mass index in men > 131 g/m2, women > 100 g/m2) was present in 70% (19/27) patients despite a mean 48-h blood pressure of 132 +/- 19/81 +/- 15 mmHg. Mean interdialytic weight gain was 1.6 +/- 0.8 kg and was not related to left ventricular mass index. Two patterns of interdialytic blood pressure change were apparent: in group 1 (16 patients) 48-h blood pressure increased (+19 +/- 12/13 +/- 9 mmHg), whereas in group 2 (11 patients) blood pressure fell (-10 +/- 13/-8 +/- 10 mmHg P < 0.0001). In both groups the number of hypertensive patients (group 1, 10/16; group 2, 6/11), the 48-h blood pressure (132 +/- 20/80 +/- 15 vs 132 +/- 18/82 +/- 15 mmHg) and interdialytic weight gain (+1.9 +/- 0.7 vs +1.3 +/- 0.7 kg) were similar. There was also no correlation between interdialytic blood pressure change and weight gain in either group. CONCLUSIONS: We conclude that interdialytic blood pressure changes cannot be directly related to interdialytic fluid gain, even in apparent volume-dependent hypertension, emphasizing the importance of additional factors in the control of blood pressure in end-stage renal disease.

Acute reversal of cyclosporine nephrotoxicity by neutral endopeptidase inhibition in stable renal transplant recipients.

BACKGROUND: Atrial natriuretic peptide and cyclosporine have opposing effects on renal hemodynamics and excretory function. METHODS: Twelve male stable cyclosporine-treated renal transplant recipients received a single 100-mg i.v. dose of the neutral endopeptidase EC 24.11 inhibitor candoxatrilat in a double-blind, placebo-controlled cross-over study. Each study day consisted of 2 hr of baseline and 7 hr of postdose evaluation. RESULTS: After administration of candoxatrilat, plasma atrial natriuretic factor rose from 12.8+/-1.6 (mean +/- SEM) to 44.1+/-6.8 pmol/L (P<0.001) in association with a threefold increase in urine cGMP excretion (573+/-195 pmol/min baseline to 1823+/-545 pmol/ min; P<0.001), marked natriuresis (207+/-34 micromol/min baseline to 416+/-62 micromol/min; P<0.001), fractional sodium excretion (3.3+/-0.5% baseline to 5.6+/-0.7%; P<0.01), and diuresis (3.4+/-0.5 ml/min baseline to 7.4+/-1 ml/min; P<0.001). All parameters remained elevated above baseline for the remaining 7-hr study period. In response to candoxatrilat, the glomerular filtration rate rose by 19% (P=0.01), renal plasma flow by 7% (P=0.04), renal blood flow by 13% (P=0.03) in association with an increase in filtration fraction from 24+/-2% to 28+/-2% (P=0.002) and small fall in renal vascular resistance from 0.38+/-0.04 to 0.30+/-0.04 mmHg x min x 1.73 m2 x ml(-1) (P=0.02). There was a fall in plasma angiotensin II without a change in plasma renin concentration or plasma aldosterone. Median urinary albumin excretion increased after candoxatrilat administration from 48 (3-131) to 114 (32-641) microg/min (P<0.01). CONCLUSIONS: Acute neutral endopeptidase inhibition with candoxatrilat appears to reverse the adverse renal hemodynamic and renal excretory effects of cyclosporine in stable renal transplant recipients.

Enhanced natriuretic response to neutral endopeptidase inhibition in patients with moderate chronic renal failure.

Atrial natriuretic factor (ANF) has natriuretic, renin-suppressing and chronic hypotensive actions that may be utilized by inhibition of ANF degradation by neutral endopeptidase, E.C.24.11 (NEP). Three groups of 8 male patients [GFR 103 +/- 8 (Normal), 64 +/- 6 (Moderate CRF), and 16 +/- 2 ml/min (Severe CRF)] received 100 mg i.v. bolus of the NEP inhibitor candoxatrilat or placebo in random order in a double-blind crossover study. GFR (51CR-EDTA), ERPF (125I-hippuran). ANF (IRMA), urinary cGMP (RIA) and albumin (RIA) and sodium excretion and flow rate were measured hourly for two hours before and for seven hours after candoxatrilat administration. After candoxatrilat plasma ANF rose two- to threefold from baseline, and remained elevated for 5(N) and 7(M,S) hours (P < 0.01(N,S), P < 0.03(M)) associated with an immediate rise in urine cGMP excretion from 23.5(N), 25.4(M) and 10.4(S) nmol/hr (base) to 51.7(N), 73.8(M) and 27.5(S)(peak) lasting 7(N,M,S) hours (P < 0.01(N,M,S)). There was a marked natriuresis in all three groups, the cumulative sodium excretion at seven hours post-candoxatrilat being 104(N), 140(M), 102(S) mmol (P < 0.05(N,M,S)). This was greatest in those with moderate CRF (moderate CRF vs. normal, P = 0.036, moderate vs. severe CRF, P = 0.01, normal vs. severe CRF, P = 0.74). Following candoxatrilat there was a near doubling of the urine flow rate (P < 0.01(N,S), P < 0.02(M)). Urine albumin excretion increased in patients with renal failure (P < 0.01), but there was no change in GFR, ERPF or systemic blood pressure. We conclude that the marked natriuretic effects of acute NEP inhibition seen in normal subjects are enhanced in the presence of moderate CRF and sustained even in severe renal impairment.

Left ventricular hypertrophy and ambulatory blood pressure monitoring in chronic renal failure.

BACKGROUND: Left ventricular hypertrophy (LVH) is both common and an important predictor of risk of death in end-stage renal failure (ESRF). In mild to moderate chronic renal failure (CRF), the timing of onset of LVH and the factors involved in its initial development have not been fully elucidated. The present study was undertaken to examine the prevalence and potential determinants of echocardiographically determined LVH in this connection, and to compare 24-h ambulatory blood pressure (BP) recordings with BP measured at a previous clinic visit. METHODS: From a cohort of 120 non-diabetic patients who had been attending a nephrology clinic, 118 agreed to participate in the study. Of these we selected for analysis 85 stable patients (37 male). Patients with known cardiovascular disease, those with a history of poor compliance with antihypertensive medication, and those in whom such medication had been changed in the previous 3 months were excluded. Clinic BP, 24-h ambulatory BP, echocardiography, body mass index (BMI), serum creatinine (SCr), creatinine clearance (CrCl), haemoglobin (Hb), fasting cholesterol (CHOL), triglyceride TRIGL), plasma glucose, calcium (Ca), phosphate (PO4), alkaline phosphatase (ALK PHOS), parathyroid hormone (PTH) concentrations, and 24-h urinary protein were assessed in all patients. Seventy-seven per cent were on antihypertensive medication. RESULTS: LVH was detected in 16% of patients with CrCL > 30 ml/min, and 38% of patients with CrCl < 30 ml/min. By stepwise regression analysis, ambulatory systolic BP (P < 0.0001), male gender (P < 0.0001), BMI (P < 0.0002), and Hb concentration (P < 0.002) were the only independent determinants of left ventricular (LV) mass. Nocturnal systolic BP (P < 0.02) was the main determinant of LVH in the group of patients with advanced CRF. The correlation between left ventricular mass index (LVMI) and mean 24-h ambulatory systolic BP (r = 0.52, 95% confidence interval 0.50-0.54) was statistically significantly stronger than with outpatient systolic BP (r = 0.25, 95% confidence interval 0.23-0.27). The same was true for the correlation between LVMI and mean 24-h ambulatory diastolic BP (r = 0.42, 95% confidence interval 0.40-0.44), and outpatient diastolic BP (r = 0.22, 95% confidence interval 0.20-0.24). CONCLUSIONS: Twenty-four hour ambulatory BP recording and echocardiography are required for accurate diagnosis of inadequate BP control and early LVH in patients with chronic renal impairment, independent determinants of which are hypertension, male sex, BMI, and anaemia.

Serum C-reactive protein as a marker for infection and inflammation in regular dialysis patients.

Serum C-reactive protein (CRP) concentration was measured in 98 hemodialysis (HD) patients and 68 continuous ambulatory peritoneal dialysis patients (CAPD). The effect, if any, of a HD session on serum CRP level and the usefulness of CRP in diagnosing and monitoring proven inflammatory disease were studied. Seventy-five percent of CAPD patients without evidence of inflammation had CRP levels within the quoted normal range (< 10 mg/l), as compared with only 47% of HD patients also without evidence of overt inflammation (p < 0.001). No significant change in the CRP level was detected during a hemodialysis session. Twenty-four patients with overt inflammation (due mainly to infection) were studied, 22 of whom had CRP levels of > 50 mg/l. These increased CRP levels fell with treatment. A CRP level of > 50 mg/l proved highly suggestive of a significant inflammatory process and a value of < 10 mg/l always excluded it. The total period of time on the regular dialysis program was not related to the CRP level. A subclinical inflammatory response resulting in a raised CRP is very common in our hemodialysis patients and less so in CAPD patients. Possible reasons for this are discussed. However, CRP is still useful in the diagnosis and monitoring of response to treatment of inflammatory disease if the level is > 50 mg/l or serial/baseline measurements are available for comparison. Whether any relationship exists between elevation of CRP and the well-documented increased risk of cardiovascular death in dialysis patients is currently unknown.

A randomized controlled study of iron supplementation in patients treated with erythropoietin.

In view of current uncertainty regarding the optimum route for iron supplementation in patients receiving recombinant human erythropoietin (EPO), a prospective randomized controlled study was designed to investigate this issue. All iron-replete renal failure patients commencing EPO who had a hemoglobin concentration < 8.5 g/dl and an initial serum ferritin level of 100 to 800 micrograms/liter were randomized into three groups with different iron supplementation: Group 1, i.v. iron dextran 5 ml every 2 weeks; Group 2, oral ferrous sulphate 200 mg tds; Group 3, no iron. All patients were treated with 25 U/kg of EPO thrice weekly subcutaneously. The hemoglobin concentration, reticulocyte count, serum ferritin, transferrin saturation, and EPO dose were monitored every two weeks for the first four months. Thirty-seven patients entered the study (12 i.v., 13 oral, 12 no iron). The three groups were equivalent with regard to age, sex, and other demographic details. Even allowing for dosage adjustments, the hemoglobin response in the group receiving i.v. iron (7.3 +/- 0.8 to 11.9 +/- 1.2 g/dl) was significantly greater than that for the other two groups (7.2 +/- 1.1 to 10.2 +/- 1.4 g/dl and 7.3 +/- 0.8 to 9.9 +/- 1.6 g/dl for Groups 2 and 3, respectively; P < 0.005 for both groups vs. Group 1 at 16 weeks). There was no difference between the groups supplemented with oral iron and no iron. Serum ferritin levels remained constant in those receiving i.v. iron (345 +/- 273 to 359 +/- 140 micrograms/liter), in contrast to the other two groups in which ferritin levels fell significantly (309 +/- 218 to 116 +/- 87 micrograms/liter and 458 +/- 206 to 131 +/- 121 micrograms/liter for Groups 2 and 3, respectively; P < 0.0005 for Group 1 vs. Group 2, and P < 0.005 for Group 1 vs. Group 3 at 16 weeks). Dosage requirements of EPO were less in Group 1 (1202 +/- 229 U/kg/16 weeks) than in Group 2 (1294 +/- 314 U/kg/16 weeks) or Group 3 (1475 +/- 311 U/kg/16 weeks; P < 0.05 vs. Group 1). The results of this study suggest that, even in iron-replete patients, those supplemented with i.v. iron have an enhanced hemoglobin response to EPO with better maintenance of iron stores and lower dosage requirements of EPO, compared with those patients receiving oral iron and no iron supplementation.

Contractile dysfunction of isolated ventricular myocytes in experimental uraemia.

In order to clarify the mechanism underlying impaired cardiac performance in uraemia, the contractile function of isolated cardiac myocytes from chronically uraemic and control rats has been compared. Rats were made uraemic by sub-total nephrectomy in a two-stage surgical procedure, and left for 4 weeks. Sham-operated controls were prepared at the same time. Animals were pairfed, and final body weights were not significantly different between the groups. Ventricular myocytes were isolated and their contraction amplitude and velocity were measured using a video-based edge-detection system. Contraction was depressed in myocytes from uraemic animals, with contraction amplitude in maximum Ca2+ reduced from 16.3 +/- 0.6% shortening, to 13.0 +/- 0.8% (p < 0.01, n = 10 animals for each group). There was a concomitant decrease in the velocity of shortening (5.6 +/- 0.4 vs. 3.9 +/- 0.5 micron s-1 change in sarcomere length, p < 0.02) and of relaxation (4.6 +/- 0.4 vs. 3.2 +/- 0.4 micron s-1 p < 0.02). Similar depression was seen at lower perfusate Ca2+ concentrations (1-2 mM) and the EC50 for Ca2+ was unchanged. The response to beta-adrenoceptor stimulation was decreased by the same magnitude as that to Ca2+, with no change in the EC50 for isoproterenol or the ratio of maximum response to isoproterenol or to Ca2+ in the same cell (isoproterenol/Ca2+ ratio). There was no shift in the myosin isozyme composition in uraemic cells, with both groups showing a heterogeneous V1/V2/V3 pattern. We conclude that chronic uraemia is associated with a depression of contractile function in the isolated myocyte but no shift in myosin isoforms or specific beta-adrenoceptor desensitisation.

The susceptible patient.

Acute hypotension is a common complication of haemodialysis, occurring in 20-33% of patients in different series. Although the immediate cause is increasing intravascular hypovolaemia related to the dialysis procedure, no constant relationship exists between volume status or degree of volume loss and development of hypotension, emphasizing the importance of additional factors which render certain patients susceptible to this complication. These may include autonomic neuropathy, left ventricular hypertrophy (LVH) and diastolic dysfunction, inappropriate activation of cardiovascular reflexes, and abnormal vascular compliance. In contrast to earlier studies implicating autonomic neuropathy in intradialytic hypotension, recent reports have failed to confirm differences in autonomic function or baroreflex sensitivity in patients with and without hypotensive episodes. However, there is a strong association between LVH and dialysis hypotension. LVH is very common in ESRD, increases with time on dialysis, and is present in up to two-thirds of chronic dialysis patients. A close relationship exists between LVH and impaired diastolic relaxation, which is also common in ESRD patients. Patients prone to hypotension are characterized by both LVH and diastolic dysfunction, with an impaired early to late ventricular filling ratio, together with virtual complete cessation of passive ventricular filling prior to development of hypotension. Impaired cardiac filling and reduced cardiac output do not fully explain dialysis hypotension; in most subjects the response is reflex sympathetic activation and peripheral vasoconstriction, with maintenance of blood pressure. Syncope may result from activation of ventricular mechanoreceptor afferents as a response to left ventricular underfilling, with a resulting paradoxical withdrawal of sympathetic activity and of reflex vasoconstriction. Other potential factors increasing susceptibility to hypotension include impaired venous compliance, which predisposes to reduced venous return, seen particularly in elderly hypertensive and diabetic ESRD patients. Anaemia, inadequate vascular refilling rate, and overactivity of the NO vasodilator pathway have also been proposed to contribute to the pathogenesis of intradialytic hypotension. Excessive interdialytic weight gain is not directly related to hypotension, but EDTA data have shown it to be associated with increased cardiovascular mortality. Despite this, interdialytic weight gain is not related either to interdialytic blood pressure change, nor to development of LVH.

Effects of parathyroid hormone and 1,25(OH2)D3 on protein glycation in moderate uraemia.

Glucose intolerance in uraemia may be a consequence of secondary hyperparathyroidism. In this study fructosamine and glycated albumin have been used as markers of long-term glycaemic control in a group of pre-end-stage, non-diabetic uraemic patients with secondary hyperparathyroidism. The serum fructosamine level (mumol/100 g total protein) was significantly higher (p = 0.005) in uraemic patients (364 +/- 42) than in a group of 25 non-uraemic controls (332 +/- 27), but the content of glycated albumin did not differ (p > 0.05; 1.6 +/- 0.5 vs. 1.5 +/- 0.3%). In the uraemic patients, there was a significant relationship between serum 1,25-dihydroxycholecalciferol [1,25(OH2)D] (median 4.2, range 1.0-38 ng/l) and fructosamine (r = -0.66, p < 0.01; fructosamine = -2.76 1,25(OH2)D + 389), but not glycated albumin (r = -0.22, p > 0.1). No relationship existed between serum parathyroid hormone (median 15.4, range 7.0-55 pmol/l) and either glycated albumin or fructosamine (p > 0.1). In patients treated with oral calcitriol (0.25 microgram/day), significant reductions in serum parathyroid hormone after both 4 (p = 0.03) and 8 weeks (p = 0.02) and concomitant increases in serum 1,25(OH2)D (p < 0.02) after 8 weeks of treatment were not accompanied by any change in fructosamine, glycated albumin, total calcium, or ionized calcium (p > 0.05). Elevation of serum fructosamine in these patients is consistent with the impaired glucose tolerance of uraemia. The evidence presented supports a relationship between long-term glycaemic control and 1,25(OH2)D3, but not parathyroid hormone, in moderately uraemic patients with secondary hyperparathyroidism; however, serum fructosamine was not altered by treatment with calcitriol over an 8-week period.

Recombinant erythropoietin increases blood pressure in experimental hypertension and uraemia without change in vascular cytosolic calcium.

The mechanism of erythropoietin-induced hypertension in dialysis patients is unclear. Intracellular calcium ([Ca2+]i) may be altered in both hypertension and uraemia, and the effects of both uraemia and r-HuEPO on vascular smooth muscle [Ca2+]i and blood pressure (BP) in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were therefore studied. Male WKY and SHR underwent partial nephrectomy or sham operation. Three weeks later a 28-day period of treatment with either r-HuEPO 100 U/kg, s.c., 3 times/week or buffer was commenced (n = 10-12 for each subgroup). BP was measured weekly, by noninvasive Doppler tail-cuff assessment. [Ca2+]i was measured following loading with fura-2 in pooled, primary aortic vascular smooth muscle cells (VSMC). Serum urea and creatinine rose 3- to 4-fold after partial nephrectomy. Treatment with r-HuEPO did not change renal function further in either uraemic or control WKY or SHR. Haemoglobin increased in both non-uraemic WKY (16.2-20.3 g/dl) and SHR (16.4-20.5 g/dl) and uraemic animals (WKY 13.9-20.9; SHR 13.8-18.8 g/dl; p < 0.01 for all changes) following 4 weeks of r-HuEPO treatment. BP was unaffected by r-HuEPO in WKY but increased in nonuraemic SHR (210-250; p < 0.01) and in uraemic SHR (224-251 mm Hg; p < 0.001) at 4 weeks. VSMC [Ca2+]i was higher in SHR than WKY (121 vs. 83 nmol/l; MANOVA p < 0.05) but no effect of uraemia or r-HuEPO on [Ca2+]i was detected. In conclusion, the hypertensive effects of r-HuEPO are augmented both in a genetic model of hypertension and in uraemia. Although VSMC [Ca2+]i was elevated in SHR, the further increase in BP induced by r-HuEPO was not associated with alterations in VSMC cytosolic calcium.

Does antihypertensive therapy modify chronic allograft failure?

Hypertension after renal transplantation continues to affect 50% or more of patients, despite use of modern immunosuppressive regimens. Relationships between poor control of blood pressure and reduced chronic allograft survival have been clearly demonstrated, and are analogous to the well-known acceleration of progressive renal disease by coexisting hypertension. It is likely, although to date it has not been formally proven by prospective study, that effective blood pressure control has a beneficial effect on chronic allograft outcome, as in progressive dysfunction of native kidneys. A further key question is whether differing classes of antihypertensive therapy may have differing effects on long-term graft outcome. It has been proposed that glomerular hypertension, hyperfiltration and hypertrophy, secondary both to inadequate nephron mass and to loss of functioning nephrons, may contribute to chronic allograft failure. If this is true, then use of converting enzyme inhibitors may particularly benefit long-term graft outcome. However, post-transplant hypertension in cyclosporine-treated patients is associated with sodium retention and renin system suppression, and a relative lack of renoprotective action of ACE inhibitors might be predicted in this context. An alternative hemodynamic factor underlying chronic allograft failure is glomerular ischemia, secondary to the vascular changes associated with chronic rejection and to cyclosporine-related afferent arteriolar vasoconstriction. In this setting, calcium channel blockers which lower systemic blood pressure in combination with afferent arteriolar vasodilatation may improve long-term allograft outcome. New strategies with a similar rationale include endothelin receptor antagonists and neutral endopeptidase inhibitors such as candoxatril, which in acute experimental and clinical studies reverse cyclosporine-induced reductions in renal blood flow and glomerular filtration rate. Long-term prospective controlled comparative studies are needed to assess the effect of all these differing therapeutic approaches on chronic allograft outcome.

Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis associated with anti-thyroid drug treatment.

Two cases of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis following treatment with propylthiouracil and carbimazole are described. Both patients had crescentic glomerulonephritis proven by renal biopsy and responded to immunosuppressive therapy and withdrawal of the anti-thyroid drugs. Though systemic vasculitis associated with propylthiouracil is reported, this is the first report to our knowledge of renal biopsy-proven vasculitis associated with either of these drugs.

Prostate-specific antigen levels in patients receiving long-term dialysis.

OBJECTIVE: To investigate the effect, if any, of renal failure upon prostate-specific antigen (PSA) levels and the validity of PSA estimation as a marker of prostatic disease in renal failure. PATIENTS AND METHODS: PSA was measured in 65 men (median age 67 years, range 39-84) on regular haemodialysis and 37 men (median age 70 years, range 42-77) on continuous ambulatory peritoneal dialysis (CAPD). Patients with a PSA level > 4 ng/mL underwent prostatic biopsy guided by transrectal ultrasonography. RESULTS: There was no evidence of an artefactual elevation of PSA attributable solely to renal failure. All eight patients with a PSA level > 4 ng/mL had prostatic disease. CONCLUSION: PSA measurements in patients with end-stage renal failure treated by dialysis remain a useful marker of prostatic disease.

Identification of auto-transplanted parathyroid tissue by Tc-99m methoxy isobutyl isonitrile scintigraphy.

Parathyroid tissue is sometimes auto-transplanted into the forearm after 'total' parathyroidectomy in patients with renal failure. Recurrent hyperparathyroidism demands identification of the source of PTH secretion which cannot be assumed to be the forearm. To this end, Tc-99m methoxy isobutyl isonitrile (MIBI) scintigraphy was used to identify functioning auto-transplanted parathyroid tissue in seven patients undergoing renal replacement therapy (five with functioning renal transplants and two on haemodialysis). Serum PTH was estimated in venous blood taken proximal and distal to the forearm graft and from the contralateral arm, and subsequent Tc-99m MIBI scanning was carried out without knowledge of the PTH results. Five patients had a significant gradient in PTH levels between sites proximal and distal to the graft, and between the proximal site and the contralateral arm, suggesting functioning parathyroid tissue in the graft. Subsequent Tc-99m MIBI scintigraphy confirmed the activity of the auto-transplanted parathyroid tissue in these five patients. In the remaining two patients without a significant PTH gradient between the sampling sites, Tc-99m MIBI scintigraphy did not identify any functioning forearm parathyroid tissue. The scan results therefore correlated well with the gradients in PTH levels, suggesting that MIBI scintigraphy can be used to identify functioning auto-transplanted parathyroid tissue. The results also indicate that any patient who has undergone auto-transplantation of parathyroid tissue must have blood samples taken from veins proximal to the graft and either distal to it, or from the contralateral arm when parathyroid status is re-assessed, particularly when surgery is being considered for recurrent hyperparathyroidism.