Comparison of transplant listing strategy in two renal dialysis centers within a regional transplant alliance.

AIMS: An increasing dialysis population and insufficient supply of transplant organs necessitate that patients are carefully evaluated prior to registration on the national waiting list to ensure effective utilization of a scarce resource. We have assessed listing practice in two renal units within the North of England Transplant Alliance. METHODS: Demographic, ethnic and clinical data were recorded at initiation of dialysis for patients from two northern English cities, Bradford (n = 209) and Hull (n = 202) between 1994-2000. Patients were stratified by two co-morbidity scoring systems. Multivariate and survival analyses were undertaken by registration status. RESULTS: Overall, 159 patients were registered onto the waiting list. Stratification by co-morbidity predicted listing at high and low risk, but with overlap at medium scores. There was no difference in overall co-morbid burden between the two centers (p = 0.161 and 0.316, respectively, for two scoring systems). Logistic regression analysis demonstrated a center effect, Hull having an odds ratio for listing of 0.48 compared to Bradford (p = 0.041). Short- and medium-term survival in the listed group was high regardless of co-morbid score (22 vs 174 deaths in the non-listed group). In this cohort, five patients died with grafts, another three died whilst active on the waiting list. The remaining 14 patients had been removed from the list prior to death. SUMMARY: Co-morbidity scoring schemes are unlikely to be sophisticated enough to accurately identify those who would most benefit from transplantation, and the value of clinical judgment is well-shown in this study. Standardization of registration will result in more equitable allocation of organs. However, this study has demonstrated that there are differences in listing practices even within a single alliance. Continuous assessment will allow judicious removal from the waiting list of patients who have developed an unacceptable co-morbid burden.

Re-establishment of erythropoietin responsiveness in end-stage renal failure following renal transplantation.

Re-establishment of erythropoietin (EPO) secretion following renal transplantation is poorly understood. The development of sensitive EPO radioimmunoassay has enabled further study of this phenomenon. Forty-one adult patients were studied during the first 16 weeks following renal transplantation. Twenty six received cyclosporin monotherapy and 15 also received prednisolone and azathioprine. Serum creatinine, haemoglobin (Hb), ferritin and EPO were assayed pre-operatively, daily for 1 week, weekly for 1 month, and fortnightly to 16 weeks. An expected EPO value, for any Hb level, was derived by linear regression analysis in 144 patients with iron deficiency anemia. An observed to expected ratio (O/E) was calculated, a value of 1.0 implying appropriate responsiveness. Hb increased from 8.6 +/- 2.0 (SD) to 12.3 +/- 2.1 g/dl (p < 0.001) over 16 weeks, an increase unaffected by ferritin status. Mean EPO concentration increased during the first week with a peak at day 4 (22.1 +/- 13.3 to 44.6 +/- 40.0 mu/ml, p < 0.05), a change apparent only in patients with immediate graft function (24 cases). There was no correlation between EPO and Hb pre-operatively; however a significant inverse relationship was established by week 16 (r = -0.404, p < 0.02). The median O/E ratio (0.22) at baseline increased progressively to 1.0 at 16 weeks (p < 0.001); ratios were significantly greater in the immediate versus delayed function group throughout (p < 0.05). In the former group an O/E ratio of 1.0 was reached at 10 weeks when mean serum creatinine was 142 +/- 48 mumol/l. Patients with poor ongoing renal function (9 cases, serum creatinine > 250 mumol/l at 16 weeks) had impaired Hb recovery (10.1 +/- 1.6 vs 12.7 +/- 2.0 g/dl at 16 weeks, p < 0.05). EPO values were not different in those patients but median O/E ratios were significantly depressed (p < 0.05) throughout, the maximum O/E ratio being 0.75. Recovery of renal function is accompanied by a beneficial Hb response driven by EPO synthesis in the transplant. The O/E ratio provides a useful index to assess EPO responsiveness. Appropriate secretion was achieved during the first 4 months and optimized by immediate and satisfactory graft function.

Quantitative reticulocyte analysis may be of benefit in monitoring erythropoietin treatment in dialysis patients.

Reticulocyte responses to low-dose erythropoietin (EPO) were monitored using automated flow cytometric analysis. Sixteen adult dialysis patients were treated with 1,000 U of recombinant human EPO (rHuEPO), subcutaneously, thrice weekly (mean dose 15.7, SD 3.7 U/kg). The reticulocyte count (baseline 31.1, SD 19.1 x 10(9)/L) increased in 14 patients in the first week, with a peak response occurring at Week 2 (mean 57.3, SD 26.5 x 10(9)/L, p < 0.01). There was a wide spectrum of response, the maximal absolute increment ranging from 6.8-69.7 x 10(9)/L (maximal percentage increase 19-863%). Overall there was no relationship between the early increment in reticulocyte count and hemoglobin (Hb) response over the ensuing 4 months. Nine patients became transfusion independent (mean Hb increasing from 6.9, SD 0.8-9.2, SD 1.2 g/dl). Two patients had poor reticulocyte increments and no significant change in Hb. The remaining 5 patients responded partially with a brisk reticulocyte response and a marked reduction in transfusion dependency, but without a sustained increase in Hb. On investigation, all had gastrointestinal bleeding (melena in 1, commencing after initiation of treatment, positive fecal occult bloods in 4), whereas none of the other patients showed evidence of blood loss. It is notable that the erythron was sensitive to this modest dose of rHuEPO in the majority of patients as evidenced by the reticulocyte response. The results provide useful information in the management of patients on rHuEPO. A small or inapparent reticulocyte response suggests a confounding factor; a poor Hb response in the presence of active reticulocyte synthesis points to occult blood loss or hemolysis.

Renal disease associated with antineutrophil cytoplasmic antibody: 39 patients over a 5-year period.

We have reviewed 39 adult patients who presented over a 5-year period with biopsy confirmed renal disease in association with positive antineutrophil cytoplasmic antibody (18 with C-ANCA, 21 with P-ANCA). Twenty-three (59%) had primary systemic vasculitis, typically with aggressive renal histology including focal necrotising and crescentic glomerulonephritis. In the remaining patients a wide range of clinical syndromes and renal histological appearances were apparent: 30 had abnormal renal function (serum creatinine > 140 mumol/l), including 17 who were initially dialysis-dependent. Intensive immunosuppression was administered in 33 cases. When response was assessed at 3 months, renal function was stable or improved in 17 (52%), 5 of whom were able to discontinue dialysis. There was, however, an appreciable early mortality and, at latest follow-up (1-57 months), 12 patients had died and 8 were on the dialysis programme. On immunosuppression, ANCA became negative in the majority (median time 1.5 months) but recurred during clinical relapse in 11 cases. In asymptomatic patients (12 cases), the reappearance of ANCA positivity did not herald clinical relapse. The ANCA assay has increased awareness of systemic vasculitis but not removed the need for histological confirmation before instituting immunosuppression.

A comparison of molecular clearance rates during continuous hemofiltration and hemodialysis with a novel volumetric continuous renal replacement system.

We developed a continuous, volumetrically controlled veno-venous renal replacement system that can be operated in filtration or dialysis modes. We compared the clearances of substances with a range of molecular weights (MW) in each mode. Ten patients with acute renal failure underwent serial postdilutional hemofiltration and hemodialysis, for 30 min each, in sequence and in randomized order. All were receiving vancomycin for concurrent sepsis. The system incorporated a Filtral 10 AN69 artificial kidney; blood flow rate was 200 ml/min, and dialysate/filtrate flow rate was 25 ml/min. Sieving (SC) and diffusion (DC) co-efficients, for hemofiltration and hemodialysis, respectively, were identical for urea (MW 60; 1.01 +/- 0.05 vs 1.01 +/- 0.07) and creatinine (MW 113; 1.00 +/- 0.09 vs 1.01 +/- 0.06), and clearance equated with dialysate/filtrate flow. There was a modest difference in uric acid clearance (MW 168; SC 1.01 +/- 0.04 vs DC 0.97 +/- 0.04; p < 0.05). Vancomycin (MW 1,800) removal was 19% greater during filtration compared with dialysis (SC 0.87 +/- 0.10 vs DC 0.74 +/- 0.06; p < 0.01). For small solutes, the two modalities were equivalent. Vancomycin clearance was appreciably greater with hemofiltration, which is consistent with a greater potential for convection-based therapy in the removal of uremic and other middle molecules.

Anticoagulation with low molecular weight heparin (Fragmin) during continuous hemodialysis in the intensive care unit.

A preparation of low molecular weight heparin (Fragmin) was administered to patients with multiorgan failure receiving continuous venovenous hemodialysis. Three patients received a high-dose regimen (35 IU/kg bolus followed by 13 IU/kg infusion), and 7 received a low-dose regimen (8 and 5 IU/kg, respectively) for 36 h. High-dose Fragmin was associated with minimal clotting in the extracorporeal circuit. Plasma fibrinopeptide A levels declined, and mean anti-Xa activity was in the range 0.47-0.79 IU/ml. The urea equilibration coefficient (UEC) (100% at initiation) remained above 90% throughout. All 3 patients had mild bleeding episodes, which led to discontinuation of Fragmin in 1. During all low-dose treatments, marked thrombus formation occurred in the extracorporeal circuit, and in 2, the circuit clotted within the study period. Fibrinopeptide A levels further increased in 4 patients, and mean anti-Xa activity was in the range 0.27-0.53 IU/ml. UEC declined appreciably in 3 treatments (including the 2 in which early circuit clotting occurred). One patient experienced a mild bleeding episode. The low-dose Fragmin regimen produced safer anticoagulation in patients at risk from bleeding and is suitable for prolonged renal support although the tendency to thrombosis may necessitate more frequent circuit changes.

Crescentic glomerulonephritis: experience of a single unit over a five year period.

Crescentic glomerulonephritis is a well defined pathological lesion occurring in a range of renal and systemic diseases. We have retrospectively reviewed the aetiology, clinical features and outcome in 60 patients presenting over a five and a half year period. Most patients were elderly (median age 61 years, range 16-84 years). The majority presented with severe renal impairment, 32 requiring dialysis at admission. The degree of glomerular crescent formation on biopsy was closely related both to initial dialysis dependence and the ensuing response to immunosuppression. Forty-three patients received immunosuppressive treatment. A beneficial response was seen in 40% of patients requiring dialysis, and in 88% of those with less severe renal impairment. A high early mortality was apparent (30% within three months), exclusively affecting elderly patients (all > 60 years), with advanced renal failure (all dialysis dependent), the majority of whom (15 out of 18) had been immunosuppressed. The results suggest that the benefits of immunosuppression in this group may be outweighed by the complications of treatment.

Comparison of colour Doppler ultrasound with venography in the diagnosis of axillary and subclavian vein thrombosis.

The primary imaging technique in suspected venous occlusive disease has for many years been contrast venography. Recent studies have shown ultrasound with the addition of colour Doppler imaging to be a suitable alternative method in the diagnosis of lower limb venous thrombosis. We have applied these techniques to the upper limb venous system, and have performed a prospective study of 19 patients (30 limbs) comparing colour Doppler ultrasound with venography in the diagnosis of axillary and subclavian vein thrombosis, for which colour Doppler ultrasound has a sensitivity and specificity of 100%. If vein stenosis is included, the sensitivity falls to 89%. We propose that colour Doppler ultrasound is a suitable first-line alternative to venography in the diagnosis of axillary and subclavian vein thrombosis. In addition to showing the major venous drainage of the upper limb, ultrasound routinely assesses patency of the internal jugular vein, which is, on occasion, of clinical relevance when determining possible future sites of venous access. If, however, colour Doppler ultrasound is normal then bilateral upper limb venography is indicated to exclude a more central venous problem or localized stenotic lesion.

A single dose study of the effects of fenoldopam and enalapril in mild hypertension.

To clarify the contribution made by the renin-angiotensin system activation to the short lived hypotensive response to fenoldopam, the haemodynamic effects of a combination of fenoldopam (100 mg) and enalapril (5 mg) were compared with fenoldopam alone, enalapril alone and placebo in a balanced, randomised, double blind, single dose study in eight hypertensive patients. Fenoldopam caused an acute fall in blood pressure which lasted approximately 3 h after dosing and was associated with a reflex tachycardia. Enalapril caused a more gradual fall in blood pressure (onset 2 h) without a reflex tachycardia. The combination of drugs produced greater reductions in blood pressure sustained for a longer period than fenoldopam alone and with a more rapid onset than enalapril alone. In combination the hypotensive effects of fenoldopam and enalapril were clearly additive and not synergistic. Activation of the renin-angiotensin system does not antagonise significantly the hypotensive effect of fenoldopam.

Effects of felodipine on atrial natriuretic peptide in hypertensive non-insulin dependent diabetes mellitus.

Eighteen patients with non-insulin dependent diabetes mellitus and hypertension were treated during two 4 week periods with the calcium antagonist felodipine or placebo in a double-blind, randomised, cross-over study. Mean systemic blood pressure was significantly lower on felodipine, without producing a deleterious effect on diabetic control. Felodipine was associated with an increment in plasma renin concentration but plasma aldosterone and the renal outputs of sodium and dopamine were similar on both treatments. Plasma atrial natriuretic peptide levels were significantly reduced following felodipine treatment.

Effect of lithium on the renal actions of alpha-human atrial natriuretic peptide in normal man.

1. alpha-Human atrial natriuretic peptide (7.5 pmol min-1 kg-1) was infused intravenously into eight healthy men after pretreatment with lithium carbonate (750 mg) or placebo. 2. Baseline sodium excretion was significantly increased after lithium, but the natriuresis during infusion of alpha-human atrial natriuretic peptide was attenuated. 3. Similar decreases in plasma renin activity with infusion of alpha-human atrial natriuretic peptide occurred on both days. 4. Administration of lithium may be associated with pharmacological effects and further work is required to validate the use of lithium clearance as a marker of proximal renal tubular sodium handling.

A preliminary study of the dopamine DA1 agonist fenoldopam in the treatment of chronic left ventricular failure due to ischaemic heart disease.

The effects of chronic oral fenoldopam in the treatment of NYHA grade II-III heart failure secondary to ischaemic heart disease, were studied in a placebo controlled, double blind, randomised, parallel group fashion in 20 patients. Nine patients taking placebo and six taking fenoldopam completed the study. Adverse events were similar in each group. There were no significant changes in exercise capacity, ejection fraction, body weight or symptom questionnaires with either treatment. This preliminary study has not revealed any benefit of fenoldopam in heart failure due to ischaemic heart disease.

Relationship between urinary excretion of sodium and dopamine in type 1 diabetic patients with an without microalbuminuria.

The relationship between urinary sodium and dopamine excretion was investigated in 40 normal males and in 48 normotensive, Type 1 diabetic males, 11 with microalbuminuria and 37 with normal albumin excretion. In all three groups a significant correlation was demonstrated and the regression lines were similar. Thus, no evidence was found that a defect in dopamine mobilization contributes to the early renal pathophysiological changes of Type 1 diabetes.

The renal and haemodynamic effects of a 10 h infusion of glutamyl-L-dopa in normal man.

1. gamma-L-glutamyl-L-dopa (gludopa) and placebo were given by intravenous infusion to 12 healthy salt replete men for 10 h in a single-blind randomised fashion. 2. Gludopa caused a cumulative natriuresis of 46.5 mmol compared with placebo with a biphasic pattern and this was associated with a small reduction in body weight. 3. A small fall in arterial blood pressure and rise in pulse rate was seen with gludopa. 4. Plasma renin activity, atrial natriuretic peptide and urine kallikrein excretion were unchanged by gludopa but a small fall in urine aldosterone excretion, urine flow rate and free water clearance occurred. 5. The renal effects of gludopa are modest and last for only a few hours after the start of infusion.

The renal effects of atrial natriuretic peptide in man are not attenuated by (+)-sulpiride.

1. Human alpha atrial natriuretic peptide (ANP) was infused intravenously for 1 h in eight healthy salt-replete men on two occasions, with and without pretreatment with (+)-sulpiride. 2. ANP increased sodium excretion and urine flow rate but did not alter blood pressure or plasma renin activity. 3. (+)-sulpiride had no significant effect on baseline creatinine clearance, sodium excretion or urine flow rate and did not alter the increases in these parameters with ANP. 4. It is unlikely that the renal effects of ANP are mediated by dopamine DA1-receptors in man.

The effect of carbidopa and lithium on the systemic and renal response to acute intravenous saline loading in normal man.

To assess a possible role for endogenous renal dopamine in sodium excretion, the dopa decarboxylase inhibitor carbidopa was given during intravenous salt loading. In addition, the effect of lithium on tubular sodium handling was separately determined. Nine males were studied randomly on three occasions, receiving placebo, lithium carbonate (1000 mg, 11 h prior to study) or carbidopa (100 mg x 2). On each day a baseline period was followed by infusion of isotonic saline (20 ml/kg per hour) over 3 h, and 6 h recovery. With placebo, sodium excretion increased markedly to a peak in the hour after infusion (0.15 +/- 0.03 to 0.73 +/- 0.12 mmol/min, P less than 0.01). Urine dopamine excretion increased modestly (1.33 +/- 0.12 to 1.67 +/- 0.13 mmol/min, P less than 0.01). Carbidopa effectively blocked dopamine output during the study. However, the natriuretic response was comparable to values on placebo at all time points. Fractional lithium clearance, a proposed measure of proximal tubular fluid rejection, increased significantly during saline infusion. However, baseline sodium excretion was greater in the presence of lithium, and plasma renin activity (PRA) was significantly elevated. In addition, the peak natriuretic response was smaller and cumulative sodium excretion reduced by 40% (P less than 0.01) compared to placebo. This study provides no evidence for a facilitatory role for dopamine in the natriuretic response to intravenous salt loading. Lithium, at subtherapeutic levels, cannot be presumed to be an inert marker, and clearance data must be interpreted with caution.

The effect of lithium on the renal response to the dopamine prodrug gludopa in normal man.

1. The effect of oral lithium on the renal response to gamma-L-glutamyl-L-dopa (gludopa, 25 micrograms kg-1 min-1) was investigated in seven normal males. 2. Gludopa at this dose produced an 800-fold increase in urine dopamine excretion. It was natriuretic and suppressed plasma renin activity without altering blood pressure and pulse. 3. Lithium alone increased sodium excretion and stimulated plasma renin activity. However, it abolished the natriuresis produced by gludopa. 4. Gludopa did not significantly affect lithium clearance. 5. This study suggests that lithium interacts with dopamine at the proximal tubule and that the lithium clearance method is not suitable for investigating dopaminergic mechanisms in the kidney.

The effect of carbidopa and indomethacin on the renal response to gamma-L-glutamyl-L-dopa in normal man.

1. The renal response to gamma-L-glutamyl-L-dopa (gludopa, 25 micrograms kg-1 min-1) was investigated in seven normal male volunteers. The effects of oral carbidopa (100 mg) and indomethacin (100 mg) on the response to gludopa were studied in the same group. 2. Gludopa at this dose level produced a 900-fold increase in urine dopamine excretion and caused a natriuresis and suppression of plasma renin activity with only minor effects on pulse rate and blood pressure. 3. Carbidopa inhibited the increase in dopamine excretion by 97% and abolished the renal actions of gludopa. 4. The increase in urine dopamine produced by gludopa was not altered by indomethacin and the urine sodium output was similar to that caused by gludopa alone. 5. Gludopa is an effective renal dopamine prodrug whose activity can be blocked by the dopa decarboxylase inhibitor carbidopa. The results with indomethacin suggest that dopamine and the prostaglandins form separate natriuretic systems in the kidney.