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.

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.

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.

Cardiac function and energetics in experimental renal failure in the rat (5/6 nephrectomy) have been investigated by means of an isolated perfused working heart preparation and an isometric Langendorff preparation using 31P nuclear magnetic resonance (31P NMR). 4 wk after nephrectomy cardiac output of isolated hearts perfused with Krebs-Henseleit buffer was significantly lower (P < 0.0001) at all levels of preload and afterload in the renal failure groups than in the pair-fed sham operated control group. In control hearts, cardiac output increased with increases in perfusate calcium from 0.73 to 5.61 mmol/liter whereas uremic hearts failed in high calcium perfusate. Collection of 31P NMR spectra from hearts of renal failure and control animals during 30 min normoxic Langendorff perfusion showed that basal phosphocreatine was reduced by 32% to 4.7 mumol/g wet wt (P < 0.01) and the phosphocreatine to ATP ratio was reduced by 32% (P < 0.01) in uremic hearts. During low flow ischemia, there was a substantial decrease in phosphocreatine in the uremic hearts and an accompanying marked increase in release of inosine into the coronary effluent (14.9 vs 6.1 microM, P < 0.01). We conclude that cardiac function is impaired in experimental renal failure, in association with abnormal cardiac energetics and increased susceptibility to ischemic damage. Disordered myocardial calcium utilization may contribute to these derangements.

It is known that atrial natriuretic peptide (ANP) is synthesized, stored and released from the myocytes of mammalian heart, but the role of cardiac autonomic nerves in triggering the release of ANP has not been fully assessed. We have therefore measured plasma ANP concentrations in the right atrium and the main pulmonary artery, together with pulmonary haemodynamics in 10 heart transplant (HT) recipients who underwent graded submaximal bicycle exercise during right-heart catheterisation. Pulmonary arterial blood samples and haemodynamic measurements were obtained at rest, on peak of exercise, and after ten minutes of recovery. A radioreceptor of alpha-human ANP was used to measure ANP levels. Exercise significantly increased ANP levels in both the right atrium from 24 pM (resting values) to 48.5 pM, and the main pulmonary artery from 27.1 pM (resting values) to 58.4 pM. We conclude that HT recipients still retain the ability to increase ANP release in response to graded submaximal dynamic exercise, and that the mechanisms underlying ANP release depend on other factors than the integrity of cardiac innervation in man.

1. In cirrhosis the kidney tends to retain salt and water abnormally. Two theories have been proposed to account for this: the 'underfilling' theory, in which sodium retention is thought to occur secondary to perceived underfilling of the circulation, and the 'overflow' theory, in which sodium retention is considered to be due to a primary renal defect. 2. Using the model of cirrhosis produced by carbon tetrachloride administration in the rat, the ability of the kidney to excrete sodium has been examined in vivo and during isolated perfusion. 3. Cirrhotic animals demonstrated a reduced ability to excrete an acute sodium load: 6 h after 2 mmol of sodium was given by gavage, 27.5 +/- 10.5% had been excreted by the cirrhotic rats and 62.5 +/- 7.0% by control rats (P less than 0.025). 4. In contrast, during isolated perfusion, kidneys from cirrhotic animals excreted the same amount of sodium as control animals over a range of perfusion pressures from 90 to 150 mmHg (12 to 20 kPa). 5. The data are consistent with the view that in cirrhosis the kidney retains sodium in response to immediate external factors.

Correction of the anaemia of chronic renal failure by recombinant human erythropoietin results in a rise in packed cell volume with a consequent increase in blood viscosity, predisposing to increased vascular resistance and the development of hypertension.Increases in blood pressure have occurred in almost half the patients treated so far with erythropoietin,' but of more serious concern is the development of seizures in seven of these patients in the United Kingdom.2Although these bear similarities to hypertensive encephalopathy, their mechanism remains unclear.An episode of seizures associated with erythro- poietin treatment in one of our patients has been reported.We describe here a subsequent seizure suffered by this patient 11 days after a blood transfusion and two similar episodes suffered by an anephric patient undergoing continuous ambulatory peritoneal dialysis.These episodes are of interest because of their resemblance to the seizures reported in association with erythropoietin treatment.

The effect of alteration in renal perfusion pressure on the response of the isolated perfused rat kidney to concentrations of alpha-human atrial natriuretic peptide (ANP) within the pathophysiological range has been examined. At a perfusion pressure of 90 mmHg ANP concentrations of 50, 200, and 1,000 pmol/l were without effect on any parameter tested. At a perfusion pressure of 130 mmHg 50 pmol/l ANP produced an increase of 3.13 +/- 0.68 mumol/min in sodium excretion (UNa V), compared with a fall of 0.33 +/- 1.04 mumol/min in controls (P less than 0.02); fractional excretion of sodium (FENa) rose by 1.45 +/- 0.36% vs. -0.12 +/- 0.47% (P less than 0.05); glomerular filtration rate (GFR) was unchanged. At 200 and 1,000 pmol/l larger changes in UNa V and FENa were seen; only at 1,000 pmol/l was a significant effect on GFR observed. In contrast, frusemide (furosemide) at concentrations of 10 and 100 mumol/l was natriuretic at both 90 and 130 mmHg, with lesser absolute but greater proportional changes being seen at the lower pressure. It was concluded 1) the response of the isolated kidney to ANP is critically dependent on perfusion pressure, 2) at elevated levels of perfusion pressure the isolated kidney can respond to levels of ANP within the upper physiological and pathophysiological range.

A patient receiving long-term haemodialysis developed systemic amyloidosis, which was shown immunohistochemically to be of beta 2-microglobulin type, a previously unrecognised form of systemic amyloidosis. Histologically, the amyloid deposits were closely associated with foci of acute and granulomatous inflammation and vasculitis, although it was not clear if the amyloid deposits directly caused the inflammatory process, or if amyloid was deposited preferentially in areas of inflammation of uncertain aetiology.

Forearm vasodilator responses to atrial natriuretic peptide (ANP) were studied in twelve untreated patients with essential hypertension and twelve normotensive subjects. Alpha-human ANP (0.005 to 1.5 micrograms/min per 100 ml forearm volume) infused into the brachial artery increased forearm blood flow dose-dependently. This was paralleled by a decrease in forearm vascular resistance (FVR) which, at lower doses, was greater in essential hypertensives than in normotensives (P less than 0.001), and showed a lower ED50 for ANP in essential hypertensives (P less than 0.01). At higher doses of ANP the difference in vasodilator response between hypertension and normotension disappeared; the response to ANP was associated with a fall (P less than 0.01) in systemic blood pressure in hypertensives but not normotensives. At lower doses, the decreases in FVR were correlated directly with plasma renin activity in hypertensives (r = 0.656; P less than 0.05) but not normotensives. These data suggest greater vasodilator responsiveness to infusions of low doses of ANP in essential hypertensives, which is greater in low-renin states and blunted in high-renin states.

This pilot study was undertaken to examine the safety and efficacy of enalapril in the treatment of hypertension associated with impaired renal function. Forty-one patients with glomerular filtration rate (GFR) < or = 50 ml/min received enalapril for up 12 weeks. Blood pressure, renal function, biochemistry and haematology were monitored weekly for 4 weeks and then monthly. Blood pressure was effectively reduced within 4 weeks; this reduction was maintained for at least 12 weeks. Renal function remained stable and there was no significant sustained alteration in any biochemical or haematological parameter. Requirement for additional antihypertensive drugs was reduced during enalapril therapy. These data suggest that enalapril may have a useful role in the management of hypertension associated with renal impairment.

We compared pressure-natriuresis in isolated perfused kidneys of spontaneously hypertensive rats (SHR), and age-matched controls, and studied the effect of frusemide on sodium excretion. Okamoto SHR and age-matched Wistar-Kyoto controls (WKY) were used. Conscious BP was measured in a tail artery cannulated before the experiment. Isolated kidneys were perfused at 37 degrees C and glomerular filtration rate, urinary sodium excretion (UNaV) and percentage sodium reabsorption (%TNa) were measured as mean perfusion pressure was increased in steps from 100 to 180 mmHg and repeated after addition of frusemide. At all perfusion pressures GFR and UNaV were lower in SHR and %TNa higher, consistent with a 50 mmHg rightward shift of the pressure-natriuresis relationship in SHR. However, at intrarenal perfusion pressure equal to MBP, sodium excretion was the same (2.9 microEq/min/g WKY; 2.7 microEq/min/g SHR). Subsequent response to frusemide was markedly reduced in SHR. We conclude that resetting of pressure-natriuresis in SHR compensates exactly for increased renal perfusion pressure. The mechanism by which these are so precisely linked is not known, nor is the reason for the blunted sensitivity to frusemide in SHR, but it is possible that Na-K-Cl cotransport in Henle's loop may be altered in this genetic model of hypertension.

In order to study cation transport in vivo the changes in plasma and red cell rubidium concentrations were measured following an oral load of rubidium chloride. Eight patients receiving short-term digoxin therapy, 10 patients with chronic renal failure and 22 patients with untreated essential hypertension were studied, and the findings were compared with those in healthy control subjects matched for age, sex, race, obesity index, and plasma and red cell potassium concentrations. In patients receiving short-term digoxin therapy, and in patients with chronic renal failure, the increases in plasma rubidium concentrations after the oral load of rubidium chloride were significantly enhanced and the increases in red cell rubidium concentrations were significantly attenuated. These findings are consistent with a generalized reduction in Na+, K+-ATPase activity in vivo. In contrast, in patients with untreated essential hypertension the increases in both plasma and red cell rubidium concentrations following the oral load were significantly enhanced. These data do not support the hypothesis that essential hypertension is associated with reduced Na+, K+-ATPase activity in vivo, at least in the red cell.