Biomedical subjects
Publications and source records attributed to R Gokal.
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The benefits of using cyclosporin in organ transplantation to prevent graft rejection outweigh its potential disadvantages, but with the use of low-dose cyclosporin in relatively healthy individuals, such as those with psoriasis, the risk:benefit ratio is altered. The effects of low-dose cyclosporin (< 5 mg/kg body weight) on liver function and serum lipids and lipoproteins were examined in 40 normolipidaemic, normotensive psoriasis patients with normal renal function. After 3 months of treatment, serum cholesterol and bilirubin concentrations and alkaline phosphatase activity increased significantly (p = 0.001), and glomerular filtration rate (GFR) declined from 107 to 96 ml/min/1.73 m2 (p = 0.05). All these values returned to pretreatment levels 3 months after cessation of cyclosporin. In 15 patients in whom lipoproteins were isolated by ultracentrifugation, there was an increase in plasma low-density lipoprotein (LDL) cholesterol (p = 0.05), but very-low-density lipoprotein cholesterol, high-density lipoprotein (HDL) and HDL2 and HDL3 cholesterol concentrations did not change. The increases in serum bilirubin, alkaline phosphatase activity and LDL cholesterol, seen in individuals with normal baseline liver and renal function, which reverted to baseline following cessation of cyclosporin, suggest that cyclosporin-induced hypercholesterolaemia may be due to either decreased biliary excretion of cholesterol or impaired catabolism of LDL.
Based on correlation analysis with 24-h dialysis collections the peritoneal equilibration test (PET) has been promoted as an aid to prescribe and monitor dialysis dose. However correlation is an incorrect statistical technique to demonstrate the similarity of one measure to another. The closeness (or limits) of agreement should be measured using the technique of Bland and Altman. One hundred and nineteen patients underwent a 24-h dialysate collection and a PET. D/P ratios for urea and creatinine, dialysate volume, urea and creatinine clearance and KT/V (urea) were calculated using both methods and compared using correlation analysis. In addition the limits of agreement, reflecting the potential margins of difference between the two methods, were determined. When used to calculate a daily dialysate volume required to achieve adequacy targets, the PET was found to result in a prescription error range of -0.6 to +1.51/day for creatinine clearance and -0.9 to +0.61/day for urea clearance. The tendency of the PET to exaggerate clearance resulted in 14% of patients incorrectly achieving a target creatinine clearance of 50 1/week and 17% incorrectly reaching a target KT/V of 1.7. The PET cannot be used in place of 24-h dialysis collections to prescribe or monitor dialysis therapy.
Abnormalities of energy metabolism may exacerbate the high prevalence of protein-calorie malnutrition and inadequate calorie intake in continuous ambulatory peritoneal dialysis (CAPD) patients, leading to further nutritional depletion. In a controlled study, using indirect calorimetry, we evaluated oxygen consumption (VO2), CO2 production, resting energy expenditure, and respiratory exchange ratio (RER) in 12 CAPD patients at rest and during a standard CAPD exchange and in 11 healthy nonuremic control patients. In addition, we investigated the influence of nutritional status and dialysis adequacy on energy metabolism in the CAPD group. There was no significant difference in resting energy parameters between the two groups. Unlike the control group, blood glucose and RER were maintained during prolonged fasting in the CAPD patients. This observation indicates that all the absorbed glucose was used as a metabolic fuel preventing fat oxidation. There was no significant relationship between energy expenditure and dialysis adequacy. There was no significant relationship between nutritional state (including energy intake) and energy expenditure despite evidence of malnutrition in 41% of the patients. If maintenance of "normal levels" of energy expenditure occurs in dialysis patients with suboptimal calorie intake (especially with evidence of protein-calorie malnutrition), this inability to conserve energy may act as an additional risk factor for ongoing malnutrition.
For both hemodialysis and CAPD patients nutrition has been linked to mortality. Protein calorie malnutrition is present in 20 to 40% of CAPD patients. The normalized protein catabolic rate (NPCR), has been proposed as a useful measure of dietary protein intake and ultimately nutrition. However, the NPCR value has not been consistently predictive of outcome in CAPD patients. We have performed a cross sectional study on 147 clinically stable CAPD patients, who had a mean dialysis duration 22 months, to evaluate the relationship between the NPCR and conventional markers of nutrition. The NPCR was significantly correlated with normalized models of dialysis adequacy including KT/V (urea), total weekly creatinine clearance and the dialysis index. A significant negative correlation was found between individual anthropometric measures and the NPCR. Using a composite nutritional index to nutritionally categorize our population we found a significantly higher NPCR value in the severely malnourished group. The unadjusted protein catabolic rate (PCR) was significantly correlated with individual nutritional measures and was significantly greater in the well-nourished group. The NPCR, obtained by dividing the PCR by body weight (itself a nutritional measure), is lowest in well-nourished or obese patients, and thus as a marker of nutrition may be flawed. The PCR has nutritional relevance, however, adjusting its value to take into account patient size will require prospective evaluation of the influence of small solute removal on body composition.
The osmotic effectiveness of a large molecular weight glucose polymer fraction (Icodextrin) as a novel "colloid" osmotic agent in peritoneal dialysis was established, but the long-term safety remained undetermined. A randomized, controlled multicenter investigation of Icodextrin in ambulatory peritoneal dialysis (MIDAS) was undertaken to evaluate the long-term safety and efficacy by comparing daily overnight (8 to 12 hr dwell) use of isosmolar Icodextrin (282 mOsm/kg) with conventional 1.36% (346 mOsm/kg) and 3.86% (484 mOsm/kg) glucose exchanges over six months. Two hundred and nine patients were randomized from 11 centers, with 106 allocated to receive Icodextrin (D) and 103 to remain on glucose (control group; C); 138 patients completed the six month study (71 C, 67 D). All patients were divided into weak (1.36%) or strong (3.86%) subgroups based on their use of glucose solutions overnight during the pretreatment baseline period. The mean (+/- SEM) overnight ultrafiltration (UF) with D was 3.5 times greater than 1.36% glucose at eight hours [527 +/- 36 vs. 150 +/- 47 ml; 95% confidence interval (CI) for the difference +257 to +497 ml; P < 0.0001] and 5.5 times greater at 12 hours (561 +/- 44 vs. 101 +/- 48 ml, 95% CI for the difference +329 to +590; P < 0.0001) and no different from that of 3.86% glucose at eight hours (510 +/- 48 vs. 448 +/- 60 ml, 95% CI for the difference -102 to +226 ml; P = 0.44) and at 12 hours (552 +/- 44 vs. 414 +/- 78 ml, 95% CI for the difference -47 to +325 ml; P = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)
Patients with chronic renal failure show an excess mortality from cardiovascular disease (CVD). Over a 4-year period (1983-1986) we have prospectively studied 305 patients (177 men, 128 women) from a geographically constrained population entering a renal replacement therapy (RRT) programme. The development of new cardiovascular events and patient survival have been documented up to the end of 1990. We have determined the incidence of CVD amongst the patients compared to the general population of the region and assessed the predictive value for future cardiovascular events of risk factors present at the start of RRT. One hundred and fourteen patients experienced a new cardiovascular event. One hundred and fifteen patients died, 89 from CVD. Stratification by age and sex identified diabetes, previous coronary heart disease, and cardiomegaly to be significantly associated with an increased risk of a cardiovascular event, and diabetes, previous coronary heart disease, and accelerated hypertension to be significantly associated with an increased risk of cardiovascular death. Mortality from CVD was 10.1 times that of the corresponding general population, and was increased 44 times for patients with diabetes. Duration of RRT did not influence mortality rates. This excessive early mortality has significant implications for RRT programmes and further research is necessary to identify individuals at risk and the modifiable risk factors that could receive targeted interventional therapy.
The graft and patient survivals following renal transplantation in all Type 1 diabetic patients transplanted within the North-West of England between 1981 and 1990 at Manchester Royal Infirmary were studied. Fifty-two Type 1 (insulin-dependent) diabetic patients with end-stage renal failure due to diabetic nephropathy were transplanted during this period. They were compared to controls matched for age, sex, and year of transplantation and also to all 904 patients transplanted during the same period. Graft survival rates at 1 and 5 years in the diabetic patients were lower (80.8% and 62.1%, respectively), compared to controls (88.9% and 77.9%, respectively, p = 0.02) but were similar to those seen in all grafts (80.4% and 59.0%, respectively, p = NS). Actuarial patient survival rate at 5 years was lower in diabetic patients (76.3%) compared to the control group (94.2%, p = 0.003). Myocardial infarction was the main cause (60%) of death in diabetic patients. The results of this large recent series indicate that good graft and patient survival rates can be obtained in Type 1 diabetic patients, although they remain poorer than those of patients with non-diabetic renal disease. More rigorous pretransplantation cardiac assessment and treatment before acceptance of Type 1 diabetic patients for renal transplantation may help to improve patient survival.
Adynamic bone is being found with increasing frequency in dialysis patients. Little is known about its aetiology, and even less about its natural history. We found 10 cases of asymptomatic adynamic bone among a group of 32 continuous ambulatory peritoneal dialysis patients, most of whom had never been exposed to aluminium-containing phosphate binders. Compared to the remaining 22 patients, they had an older mean age (54 +/- 11.4 vs. 42 +/- 11.8 years; p < 0.05), probably a longer pre-dialysis duration of renal failure (10.9 vs. 7.1 years), higher mean ionized calcium (1.30 +/- 0.04 vs. 1.15 +/- 0.02 mmol/l; p < 0.01), and lower mean intact parathyroid hormone (31.5 vs. 200.3 pg/ml; p < 0.001). The bone density was not different between the two groups, but 9 of the 10 adynamic patients had significant vascular calcification seen on plain radiology as compared with only 7 of 20 in the comparison group (p < 0.05). Follow-up of the adynamic patients showed a close association with serum intact parathyroid hormone and ionized calcium levels. With one exception, adynamic bone did not appear to be associated with lower bone density than other types of osteodystrophy, but a longer-term study is required to determine the complete natural history of this lesion.
In 16 patients (9 on azathioprine, 7 not) the ineffective iron turnover (IIT) was much higher in the azathioprine group (62.7 +/- 6.7 vs. 23.5 +/- 3.5 mumol/l blood/day, p < 0.0001, 2-tailed t test), though the red cell iron turnover (RCIT) was similar (42.8 +/- 2.9 vs. 41 +/- 4.8). Erythropoietin improved the anaemia in all patients and raised the RCIT (4 still on azathioprine to 72.2 +/- 9.8, p < 0.003; 7 non-azathioprine patients to 62.7 +/- 5.3, p < 0.01); the IIT remained higher in the azathioprine-treated (85.5 +/- 19.3 vs. 37.1 +/- 5.4; p < 0.013). In 2 patients who discontinued azathioprine, the IIT declined markedly to normal. In summary, azathioprine exacerbates the anaemia of renal failure by augmenting ineffective erythropoiesis, while erythropoietin benefits those on azathioprine as much as other renal patients by stimulating both effective and ineffective erythropoiesis.
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The osmotic effectiveness of glucose polymer is now well established. The relative inertness of this macromolecular compound has been the key factor in its success as the first "colloid" osmotic agent in clinical use. In its present form it sustains ultrafiltration for up to 12 hours, and a daily overnight use would obviate the need for hypertonic exchanges, especially 3.86% glucose. In addition, it could be used in automated peritoneal dialysis regimens to enhance ultrafiltration and solute clearance during the daytime. Preliminary reports also indicate that it is beneficial in diabetic patients and in some patients who have lost ultrafiltration. Although systemic accumulation of glucose polymer breakdown products occurs, it reaches steady-state levels quickly (within 2 weeks) and remains stable throughout the duration of polymer use. In the long-term study these levels of maltose and oligosaccharides over 2.5 years represent the longest exposure of these substances in uremic patients without any clinical or metabolic adverse effects and provides important evidence of its safety. Future work based on ongoing studies suggests that a family of physiological solutions ("bimodal" preparations in iso-osmolar combination) could be available, and the individual's dialysis prescription could be tailored to take into account the ultrafiltration and metabolic needs. Icodextrin will be a key component of such solutions.
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With several hundred cases reported there is still much speculation about the etiology of idiopathic retroperitoneal fibrosis. We report an unusual case of retroperitoneal fibrosis with histologically identical lesion in the maxillary sinus, which has not been previously described. Both lesions showed dramatic response to corticosteroids but relapsed frequently on withdrawal of steroids, highlighting the importance of long-term follow-up.
The currently available glucose-containing peritoneal dialysis fluids (PDF), which are all hyperosmolar, are toxic to the cells present in the peritoneal cavity. However, glucose-polymer solutions, being isosmolar, may have improved biocompatibility in this respect. We therefore compared in vitro the effects of PDF containing glucose-polymers with that of glucose solutions on the function of donor granulocytes and monocytes (MN), and on the viability of mesothelial cells. In addition, the function of peritoneal macrophages (PMO) of eight patients was studied in a randomized cross-over setting following intraperitoneal exposure to glucose-polymer-versus glucose-monomer-containing fluid of comparable ultrafiltration capacity. Donor granulocytes, as well as MN, showed significantly better phagocytosis of both Staphylococcus epidermidis and Escherichia coli after incubation in the glucose-polymer solution as compared with the 3.86% glucose-containing fluid. Their oxidative metabolism, as measured by chemiluminescence, also showed that the glucose-polymer solution was less inhibitory than fluids containing 2.27 or 3.86% glucose. Patient-derived PMO showed a significantly better phagocytic capacity for S epidermidis and E coli, a significantly higher killing of E coli, and a significantly higher chemiluminescence response after intraperitoneal exposure to the glucose-polymer solution as compared with the glucose-monomer-based fluid. Increasing the osmolality of the glucose-polymer solution to that of the respective glucose solutions blunted the favorable effect on phagocyte function, suggesting the beneficial effect to be osmolality-mediated. However, no major difference was observed between the glucose-polymer solution and the glucose-based fluid in their effects on mesothelial viability.(ABSTRACT TRUNCATED AT 250 WORDS)
We analyzed transiliac bone biopsy specimens from 30 end-stage renal failure patients, taken at the time of admission for CAPD training. Results were compared with values of iPTH, bone alkaline phosphatase, 1,25-dihydroxyvitamin D3, skeletal survey, quantitative computed tomography (QCT) and single photon absorptiometry (SPA) bone density measurements. Osteitis fibrosa was the most common histological diagnosis, present in 15 of the 30 patients (50%), with eight classified as "severe" and seven as "mild." Eight patients (27%) had adynamic bone lesion, four mixed renal osteodystrophy (13%), and two (7%) osteomalacia. The mean age of the adynamic group was higher than the osteitis fibrosa group (41 +/- 12.1 vs. 56 +/- 10.2 years; P < 0.01), and than the mixed group (39 +/- 7.5 vs. 56 +/- 10.2 years; P < 0.02). Levels of iPTH enabled discrimination between groups, but not between individual patients, and values correlated with bone alkaline phosphatase (r = 0.62; P < 0.001). Erosion of the terminal phalanges was seen on the plain X-rays of 7 of 15 patients with mild or severe OF, and in three patients with another diagnosis. The majority of patients (> 90%) had bone density measurements within the normal range. No significant correlation existed between QCT or SPA scores and any of the histomorphometric parameters, or iPTH. We conclude that iPTH is the most helpful non-invasive investigation in this group of patients. Plain X-ray of the hands is the most useful radiological investigation, but single measurements of bone density are not diagnostic.