The use of D-penicillamine in patients with rheumatoid arthritis undergoing hemodialysis.

D-penicillamine and its major metabolites cysteine-penicillamine disulphide (CP) and penicillamine disulphide (P2) concentrations were measured in plasma from a hemodialysis patient with rheumatoid arthritis. CP and P2 alone were measured in plasma and a plasma ultrafiltrate from a second patient. On penicillamine 250 mg thrice weekly taken after dialysis pre-dialysis penicillamine concentrations were in the range 5.9-9.9 mumol/l. CP and P2 concentrations remained stable (range 139-197 mumol/l and 10-20 mumol/l) over 5 weeks and were of the same order as previously found in patients with normal renal function on higher doses of the drug. On penicillamine 250 mg daily concentrations of metabolites CP and P2 reach 193 mumol/l and 59.2 mumol/l after 2 and 3 weeks respectively. Concentration of metabolites fell by about half and of penicillamine by about a third after dialysis. Concentration of metabolites in ultrafiltrate were on average 75% lower than in plasma. Penicillamine 250 mg thrice weekly given after dialysis appears to be an appropriate dose for hemodialysis patients with rheumatoid arthritis.

Assessment of arteriovenous fistulae from pressure and thermal dilution studies: clinical experience in forearm fistulae.

Knowledge of useful fistula flow (UFF), the maximum blood flow available using twin needles within acceptable pressure limits and without recirculation, is essential for the optimal management of patients receiving maintenance hemodialysis or hemofiltration. A technique for the measurement of UFF employing thermal dilution for the detection of recirculation has been developed. Using this technique, 94 studies were carried out in 69 forearm fistulae. UFF exceeded 400 ml/min in 45 fistulae. In these satisfactory fistulae a normal range was defined for basal intrafistula pressures (60 mmHg being the approximate upper limit of normal). Analysis of arterial and venous line pressure recordings with increasing extracorporeal blood flow and knowledge of the presence or absence of recirculation allowed us to define the functional problem in unsatisfactory fistulae. The functional diagnosis was supported in 16 of 24 fistulae by angiography or surgery or both. In all but two of the remainder, satisfactory UFF was obtained by repositioning the patients' needling sites. Fistulae were divided into different clinical groups. Of 35 fistulae which were thought to be clinically acceptable, 7 were found to be unsatisfactory. In 17 fistulae in patients with poor biochemical control, recirculation was detected in 8. Of 11 fistulae reported to produce poor flows on dialysis, 4 had UFF above 400 ml/min. Of 6 fistulae in patients experiencing needling difficulties, 5 had satisfactory UFF. These studies which take only a few minutes and can be carried out immediately preceding a routine dialysis session not only identify unsatisfactory fistulae, but yield valuable diagnostic information in these cases. This has reduced dependence on angiography and has led to more careful selection of patients for surgery.

Dialysis-induced change in erythrocyte volume: effect on change in blood volume calculated from packed cell volume.

Blood volume (BV) change during hemodialysis is often monitored by packed cell volume (PCV). This assumes erythrocyte volume is constant. We tested this by dialyzing 5 patients for 2 hours against high (154 mmol/l), normal (140 mmol/l) and low (126 mmol/l) dialysate sodium concentrations. Erythrocyte water content, calculated from measured blood and plasma water contents, decreased with high and increased with low dialysate sodium concentrations. Erythrocyte volume, calculated from mean corpuscular hemoglobin concentration (MCHC) decreased 3.8% with high concentration dialysate and increased 2.5% when dialysate concentration was low. These changes correlated significantly (r = 0.80, p less than 0.01) with alterations in plasma sodium. Mean corpuscular volume (MCV), measured with a Coulter-S Plus Counter did not alter because of a methodological artefact. BV change can be calculated from PCV when plasma concentrations of osmotically active substances are changed only if allowance is made for altered erythrocyte volume.

Controlled trial of calcitriol in hemodialysis patients.

We report on a 5-year, prospective, double-blind trial of 1,25 dihydroxycholecalciferol (calcitriol) versus placebo in 76 hemodialysis patients without biochemical or radiological evidence of bone disease. Calcitriol, 1 microgram daily, regularly induced hypercalcemia. Doses of 0.25 microgram daily or less proved satisfactory in most patients. During calcitriol treatment, plasma calcium concentration was significantly higher and serum parathyroid hormone concentration significantly lower than on placebo. There was no difference in the rates of development or of progression of vascular calcification in the two groups. Significantly more patients on placebo (17 vs. 6, p less than 0.05) developed a sustained elevation of plasma alkaline phosphatase concentration. Calcitriol appeared to protect against the development of histological evidence of osteitis fibrosa but not of osteomalacia, but accumulation of aluminum in bone occurred during the study. We conclude that calcitriol delays and may prevent the development of osteitis fibrosa in patients receiving regular hemodialysis and may reasonably be prescribed routinely in hemodialysis patients without biochemical or radiological abnormality, unless there is a substantial prospect of early renal transplantation.

The assessment of arteriovenous fistulae created for haemodialysis from pressure and thermal dilution measurements.

A technique is described for the assessment of arteriovenous fistulae created for haemodialysis. This involves the measurement of intrafistula pressures and 'useful fistula flow' (UFF). The latter we define as the maximum blood flow available for twin needle haemodialysis without recirculation and without unacceptable pressures in the arterial ('A') and venous ('V') lines. The test circuit resembles that used for conventional haemodialysis except there is 'A' and 'V' line pressure and temperature monitoring and no dialyser. Intrafistula pressures are first measured at the time of insertion of the fistula needles. 'A' and 'V' line pressures are then recorded as the extracorporeal blood flow rate is increased in increments from zero to 500 ml/min. A check for recirculation is made at each flow rate. A bolus of cold saline injected into the 'V' line causes a momentary decrease in 'A' line temperature when recirculation is present; when there is no recirculation, 'A' line temperature remains constant. The blood flow rate at which recirculation is first detected will be above the useful fistula flow by definition. This technique allows identification of those patients who obtain high blood flows at the expense of recirculation and thus dialyse inefficiently. Combined pressure and thermal dilution measurements yield valuable information in the investigation of failing or problem fistulae.

Fluid balance modelling in patients with kidney failure.

In patients with kidney failure, adequate control of fluid status remains one of the most difficult routine issues to be addressed in the modern style of dialysis. This is primarily due to the lack of quantitative methods for the assessment of fluid status and the reliance on subjective criteria. Fluid is removed from the blood during dialysis treatments using a process called ultrafiltration. The last decade has seen considerable developments in blood volume monitoring (BVM) technology which has enabled responses to ultrafiltration to be continually monitored on an individual basis. This has enabled feedback control of patients' blood volume to be applied with partial success, reducing the number of symptoms. The feedback control algorithms employed have been relatively unsophisticated, using simple proportional control with no attempt to include models of the patient fluid dynamics. This paper describes the development of some prototype fluid kinetic models which may be used in a more advanced control system. Initial results demonstrate the importance of active control processes in the patients' physiological compensatory mechanisms.

Is there a rationale for rationing chronic dialysis? A hospital based cohort study of factors affecting survival and morbidity.

OBJECTIVES: To determine factors influencing survival and need for hospitalisation in patients needing dialysis, and to define the potential basis for rationing access to renal replacement therapy. DESIGN: Hospital based cohort study of all patients starting dialysis over a 4 year recruitment period (follow up 15-63 months). Groups were defined on the basis of age, comorbidity, functional status, and whether dialysis initiation was planned or unplanned. SETTING: Renal unit in a district general hospital, which acts as the main renal referral centre for four other such hospitals and serves a population of about 1.15 million people. SUBJECTS: 292 patients, mean age 61.3 years (18-92 years, SD 15.8), of whom 193 (66%) were male, and 59 (20%) were patients with diabetes. Dialysis initiation was planned in 163 (56%) patients and unplanned in 129 (44%). MAIN OUTCOME MEASURES: Overall survival, 1 year survival, and hospitalisation rate. RESULTS: Factors affecting survival in the Cox's proportional hazard model were Karnofsky performance score at presentation (hazard ratio 0.979, 95% confidence interval 0.972 to 0. 986), comorbidity severity score (1.240, 1.131 to 1.340), age (1.036, 1.018 to 1.054), and myeloma (2.15, 1.140 to 4.042). The Karnofsky performance score used 3 months before presentation was significant (0.970, 0.956 to 0.981), as was unplanned presentation in this model (1.796, 1.233 to 2.617). Using these factors, a high risk group of 26 patients was defined, with 19.2% 1 year survival. Denying dialysis to this group would save 3.2% of the total cost of the chronic programme but would sacrifice five long term survivors. Less rigorous definition of the high risk group would save more money but lose more long term survivors. CONCLUSIONS: Severity of comorbid conditions and functional capacity are more important than age in predicting survival and morbidity of patients on dialysis. Late referral for dialysis affects survival adversely. Denial of dialysis to patients in an extremely high risk group, defined by a new stratification based on logistic regression, would be of debatable benefit.

The machine and the therapy concept.

Maintenance haemodialysis became established in mainstream clinical practice in the 1960s. For pragmatic reasons, diffusive dialysis was the technique which underpinned its success. Over the next 15 years it was shown that short- and medium-term survival depended only on a critical level of urea clearance being achieved. Uncomplicated technology with negligible capacity for middle molecule removal could deliver this and the case for developing more sophisticated machines able to broaden the spectrum of solute removal was unconvincing. Dialysis-related amyloidosis which was recognised in the mid-1980s as a devastating complication in long survivors disturbed this complacency. The journey to develop machines which could deliver broad-spectrum solute removal while exposing patients only to ultrapure fluids and biocompatible materials is described elsewhere in this text. The Lister Renal Unit was established in 1988. A fruitful collaboration between the multidisciplinary clinical team and engineering colleagues in the R&D Department of Fresenius contributed to a steady and in-depth understanding of the effect of superimposing convection on diffusive dialysis. From the outset only high-flux dialysis using ultrapure fluids was employed. Haemodiafiltration (HDF) was introduced in 1993. This paper summarises our observations regarding the relative contributions of natural renal function and convective blood purification to long-term outcomes. We have recently reported a 19-year experience which has allowed us to more clearly define the rationale for HDF in modern clinical practice. HDF is an engineering triumph which is likely to universally supersede diffusive dialysis. The challenge for clinicians moving forward is to learn in which treatment schedules this technology can best be deployed to improve the health prospects of patients with kidney failure.

Posture and central venous pressure measurement in circulatory volume depletion.

The effect of posture on central venous pressure (CVP) was studied in 16 patients with circulatory volume depletion before and after fluid replacement. At presentation, measurement of CVP when supine did not reflect circulatory volume depletion, with a mean (SEM) of 0.1 cm H2O (0.6), but when sat at 45 degrees the CVP showed a striking fall in all patients to -9.7 cm H2O (1.1). After fluid replacement, the CVP was 2.3 cm H2O (0.4) when supine, and -0.4 cm H2O (0.4) at 45 degrees. In the assessment of circulatory volume depletion, CVP should be measured with the patient sat at 45 degrees, if possible: measurement of CVP in a supine patient may not detect or severely underestimate circulatory volume depletion.

Serial blood water estimations and in-line blood viscometry: the continuous measurement of blood volume during dialysis procedures.

It has been shown in vitro that serial measurements of blood water during ultrafiltration accurately reflect changing blood volume. It has been shown that minute changes in blood hydration produce detectable changes in blood viscosity. An 'in-line' capillary viscometer has been constructed which can be placed in parallel with an extracorporeal circuit to give a continuous semi-quantitative measure of blood viscosity during ultrafiltration or haemodialysis. By making serial measurements of blood water each 'viscometer curve' can be corrected to permit calculation of blood volume provided that the starting blood volume is known. Blood volume changes of less than 1% can be detected in vitro and provided that blood volume changes solely as a result of the removal or influx of water it can be measured continuously to within an accuracy of 4% for volume changes up to 30% irrespective of starting packed cell volume or blood water.

Kinetic modelling and underdialysis in CAPD patients.

Kinetic analysis was performed in all 58 patients undergoing standard CAPD. The urea distribution volume was estimated from anthropomorphic measurements (Watson formulae). Normalized protein catabolic rate (NPCR), daily protein leak (PL), urea and creatinine Kt/Vs, clearances and peritoneal mass transfer coefficients (Kp) were calculated from measurements on serum, 24-h urine and PD fluid effluent. The mean total (renal+PD) daily creatinine and urea Kt/Vs (KT/V) were 0.31 (range 0.15-0.79) and 0.31 (0.18-0.65). There was no relationship between KT/V and serum urea or Kp. The strongest determinant of the urea KT/V was the residual renal urea clearance (KrU)(R = 0.79, P < 0.001) which decreased with time on dialysis (R = -0.38, P < 0.005). There was a significant correlation between the hospital admissions per year and both the urea and creatinine KT/V and KrU (R = -0.30, -0.32, P < 0.05). Patients with urea KT/V < 0.25 (n = 22) had more hospital admissions/year than those with KT/V > 0.25 (mean of 2.6 versus 1.5, P < 0.05). NPCR correlated with urea KT/V (R = 0.62, P < 0.001) but not with serum albumin or the PL. Patients identified by UKM to be less well dialysed have a lower residual renal function and are more likely to be hospitalized. Undernutrition in CAPD patients appears to be related to underdialysis rather than protein loss.

Maintaining adequacy in CAPD by individualizing the dialysis prescription.

Urea kinetic modelling (UKM) has been proposed as a tool for auditing the adequacy of CAPD and a total fractional daily urea cleared volume (Kt/V) of 0.25 suggested as the minimum adequate level. At the start of CAPD the kidneys contribute significantly to the total clearance and Kt/V often falls below 0.25 as renal function declines. We performed 3-monthly UKM measurements in 56 CAPD patients. These results were used to individualize exchange volume and frequency in an attempt to achieve a Kt/V > 0.25 and compensate for declining renal function in all patients over a study period of 1 year. The mean Kt/V was maintained over 0.29 over the study period. During this time the residual renal component of Kt/V fell significantly from 0.09 (SD +/- 0.07) to 0.06 +/- 0.08 (P < 0.001) while the dialysis component increased significantly from 0.20 +/- 0.05 to 0.24 +/- 0.05 (P < 0.005). This was achieved by increasing the mean daily exchange volume from 8.12 +/- 1.22 to 10.39 +/- 2.68 litres (P < 0.001). After a year, 15 patients had Kt/V < or = 0.25 despite maximum practical exchange volumes. Twelve patients dropped out of the study due to death (4), transplantation (2), and transfer to haemodialysis (6 patients, of whom 4 had frank uraemic toxicity). In most CAPD patients it is possible to compensate for declining renal function by increasing exchange volume, at least over 1 year. However, CAPD was unable to provide Kt/V > 0.25 in 40% of patients, despite individualization of the dialysis prescription.

Extensive pelvic malacoplakia: observations on management.

A case of malacoplakia of the bladder is described. During a 4-year interval the disease progressed from a small intravesical lesion to a large pelvic mass. The disease eventually was controlled by carefully supervised antibiotic treatment of the recurrent urinary tract infections. Patients with urinary malacoplakia require careful long-term followup to control urinary tract infections and help prevent the occasionally aggressive course of this disease.

Renal biopsy in patients with unexplained renal impairment and normal kidney size.

We report renal biopsy findings in 109 patients with unexplained renal impairment (serum creatinine greater than 0.15 mmol/l) and normal-sized non-obstructed kidneys. The most common histological lesions were interstitial nephritis, rapidly progressive glomerulonephritis and a variety of other types of glomerulonephritis. The groups could not be distinguished by the presence or absence of hypertension, haematuria, proteinuria, or features of systemic disease. However interstitial nephritis was found more frequently in patients presenting with one or none of these features and rapidly progressive glomerulonephritis in patients presenting with three or more. All four patients with none of these features had interstitial lesions. Fifty-two per cent of patients with interstitial nephritis improved and 60 per cent of the patients with rapidly progressive glomerulonephritis who received immunosuppressive treatment improved or remained stable with treatment. The benefits of a biopsy diagnosis were almost wholly confined to these two groups. Complications were recorded in nine patients - prolonged macroscopic haematuria in six and symptomatic perirenal haematomata in three. Six required blood transfusion. One required nephrectomy to control haemorrhage and subsequently died. Percutaneous renal biopsy is not without risk in patients with renal impairment but the benefits of diagnosing interstitial nephritis and rapidly progressive glomerulonephritis outweigh the disadvantages.

The post-hemodialysis rebound: predicting and quantifying its effect on Kt/V.

Immediately after hemodialysis, the urea concentration rebounds upwards as urea continues to be transferred into the arterial circulation from peripheral body compartments. This rebound takes at least 30 minutes to complete. Hemodialysis is quantified as the Kt/V, calculated prom pre- and post-dialysis urea samples. Unless the post-dialysis sample is taken at least 30 minutes after dialysis, the Kt/V will be overestimated. This overestimation will be relatively greater in short high-efficiency dialyses, which have greater post-dialysis rebounds. We propose a method of correction that uses only the conventional pre- and immediate post-dialysis samples and is based on the physiologically-appropriate patient clearance time (tp). This is the time needed to clear all body compartments when the dialyzer clearance is infinite. The tp can be calculated from the pre-, immediate post- and 30-minute post-dialysis urea concentrations and was 35 minutes (SD 16) in 29 patients undergoing short (149 min) hemodiafiltration and standard (243 min) hemodialysis the following week. There was no significant difference between tp values calculated during the two treatments. Standard Kt/V can be corrected by multiplying by t/(t + tp) and dialysis time should be increased by tp x Kt/V minutes to compensate for the rebound. Despite individual variations in tp, a value of tp = 35 was sufficient to correct Kt/V in all patients. Kt/V corrected in this way agreed with Kt/V calculated using a 60-minute post-dialysis sample (r = 0.856, P < 0.001). The method predicted the 60-minute post-rebound concentration (SE 0.5 mM, r = 0.983, P < 0.001) and the addition of 35 minutes to the treatment time corrected for the rebound in both conventional and short treatments. Similar simple equations corrected the error in V caused by rebound effects.

Alkalosis and hypomagnesaemia: unwanted effects of a low-calcium CAPD solution.

We studied 43 CAPD patients for 4 months during the change from a high-calcium dialysis fluid (Baxter PD1) to a low-calcium fluid (Baxter PD4), which also contained low magnesium (0.25 mmol/l) and high lactate concentrations (40 mmol/l). Serum calcium fell significantly as did the incidence of hypercalcaemia, whilst the proportion of patients taking calcium-containing phosphate binders increased. There was a non-significant increase in serum i-PTH levels but the proportion with i-PTH > 150 pg/ml (normal range 10-65 pg/ml) increased significantly. There was a significant fall in serum magnesium level and seven patients developed hypomagnesaemia. Serum bicarbonate increased significantly and progressively and 17 patients were alkalotic at 4 months, five severely (bicarbonate 35-40 mmol/l). One patient developed recurrent episodes of painful subcutaneous and periarticular calcification, which may have been related to the alkalosis. Initial serum bicarbonate levels correlated significantly with dialysis adequacy assessed by daily Kt/V (r = 0.458, P = 0.002). The relationship to adequacy was abolished during the period of use of the high-lactate dialysis fluid. Use of low-magnesium CAPD fluids must be supported by regular monitoring of serum magnesium levels. The high lactate concentration in such fluids may not be appropriate and is potentially hazardous when individualization of dialysis dose demands the use of relatively high exchange volumes. Low serum bicarbonate levels in CAPD patients reflect inadequate dialysis, which use of these fluids serves to mask.