Ram Gokal

The textbook of peritoneal dialysis

In 1986 the first edition of Continuous Ambulatory Peritoneal Dialysis, edited by R. Gokal, was published. In 1989 the third edition of Peritoneal Dialysis, edited by K.D. Nolph, was published. Both books were widely recognized for their comprehensive discussion of this particular field. Rather than edit new editions of each of these books separately, two of the most prominent figures in this field have decided to combine their knowledge and enthusiasm in this single book: The Textbook of Peritoneal Dialysis. The book is unique in its detailed discussion of a complete range of topics, including new advances in our understanding of the physiology of peritoneal dialysis, peritoneal dialysis kinetics, clinical results and a chapter dealing with the concepts of intraperitoneal chemotherapy. These examples of the dynamic nature of the field further illustrate the importance of this textbook, and make it required reading for everybody working within the field of peritoneal dialysis.

Textbook of peritoneal dialysis

Maintaining the nutritional status of the patient is recognized as an important aspect of peritoneal dialysis therapy. Patients commencing dialytic therapy are at risk of malnutrition due to factors inherent in progressive renal failure including the metabolic and hormonal effects of uraemia, comorbid disease, the effects of drugs prescribed, and psychosocial factors associated with chronic disease. It has been estimated that up to two-thirds of patients on peritoneal dialysis may be malnourished, and this group has a higher risk of both morbidity and mortality. Several groups of patients appear to be a higher risk of complications of malnutrition, in particular the elderly and patients with renovascular disease, where the risk of vascular disease may be magnified. Once dialysis is commenced additional mechanisms which promote progressive malnutrition occur. In peritoneal dialysis these include inadequate dialysis, loss of protein and amino acids during dialysis, which may be more marked in patients with increased peritoneal permeability, and the catabolic efects of peritonitis. Glucose-based dialysate may displace other food sources and amplify abnormalities in carbohydrate metabolism. Bioincompatible dialysate and peritonitis may stimulate cytokine production and promote malnutrition. Nutritional adequacy is not easy to assess in peritoneal dialysis, largely due to dependence of traditional markers of nutrition on body water content, which varies in end-stage renal failure. Total body nitrogen (TBN) provides the most accurate means of measuring protein stores and has significant and predictable prognostic value. In the absence of access to measurement of TBN, several parameters should be considered in parallel to achieve an overall assessment of nutrition, as all other methods may be variably affected by the presence of renal failure, the mode and adequacy of dialysis delivery and fluid status at the time of assessment. Serum albumin is the visceral protein marker most well established as having important prognostic value and should be regularly assessed, but both its sensitivity and specificity in detecting nutritional impairment prior to severe malnutrition are poor. However, no single alternative serum protein measure confers improved sensitivity in detecting malnutrition in dialysis patients. Alternative measures of lean body mass, such as bioelectrical impedance and dual-energy X-ray absorptiometry when measured with an accurate determination of total body water may well prove to be useful, but as yet their prognostic usefulness is unclear. The subjective global assessment is a useful prognostic tool, but is not specific for nutritional adequacy and is likely to be significantly affected by comorbid illness. Nutritional supplementation in small studies with either oral, intravenous intradialytic parenteral nutrition or intraperitoneal amino acids has been shown to improve several nutritional markers, provided the profile of the supplemental solution is appropriate to the deficiencies observed in renal failure and adequate energy is concurrently supplied. However, the impact of improving nutrition in benefiting prognosis awaits confirmation.

Posttransplant antidonor lymphocytotoxic antibody production in relation to graft outcome.

Serial serum samples from 266 recipients of primary renal allografts were monitored posttransplant for the presence of panel reactive lymphocytotoxic antibodies (PRA). The minimum posttransplant follow-up period was 18 months. Patients were classified according to whether or not they produced PRA before and/or after transplantation. The groups were as follows: PRA negative before and after transplant, -/-, 171; PRA positive before and negative after transplant, +/-, 5; PRA positive before and positive after transplant, +/+, 27; PRA negative before and positive after transplant, -/+, 63. Actuarial graft survival at 1 year for each group was 81.3%, 100%, 70.4%, 47.6%, respectively. Fifty-five of the 63 -/+ recipients were retrospectively crossmatched with posttransplant sera against stored donor lymphocytes. Of these, 50 (91%) were posttransplant cross match positive, and 37 (67%) have lost their grafts. In 23 of the 26 cases where an anti-HLA specificity was defined, the antibody was directed against antigens present in the donor but not in the recipient. These results clearly indicate that the production of PRA in recipients of renal transplants is associated with antidonor reactivity and poor graft outcome. The fact that these PRA were often directed against donor HLA antigens emphasizes one of the hazards of mismatching for HLA at transplantation.

Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation

To investigate the effect of calcitriol plus calcium carbonate on the bone loss associated with long-term renal transplantation, 30 patients with serum creatinine levels less than 2.0 mg/dL were randomly allocated to a control (n = 14) or treatment group (n = 16) and studied with bone biopsy and densitometry at baseline and after 1 year of follow-up. Calcitriol (0.25 microg/d) plus calcium carbonate (500 mg/d of elemental calcium) were administered to patients in the treatment group. Comparing the baseline and final data of each group at a time, no change in bone mineral density (BMD) z score was observed at the distal radius (control, -0.8 +/- 0.8 versus -0.6 +/- 0.9; treatment, -1.0 +/- 1.0 versus -1.0 +/- 1.1). However, a significant increase (P < 0.05) was found at the lumbar spine in both groups (control, 0.1 +/- 1.6 versus 0.4 +/- 1.6; treatment, -0.1 +/- 1.5 versus 0.3 +/- 1.5) and only in the treatment group at the femoral neck (control, -0.9 +/- 1.0 versus -0.8 +/- 1.0; treatment, -0.5 +/- 0.9 versus -0.3 +/- 1.1). When BMD was compared between groups, no significant differences were observed at the evaluated anatomic sites at baseline or after 1 year of follow-up. After 1 year of follow-up, adjusting for age and sex (z score), the control group showed a trend to reduce the value of several histomorphometric parameters, including osteoblast surface (-2.2 +/- 6.1 versus -3.4 +/- 3.9), osteoid surface (-2.3 +/- 3.5 versus -3.1 +/- 3.9), and osteoclast surface (0.2 +/- 5.0 versus -1.3 +/- 3.3). Consequently, there was a significant reduction (P < 0.05) in mineralizing surface (-9.8 +/- 11.0 versus -15.8 +/- 12.3) and appositional rate (-5.8 +/- 2.7 versus -7.6 +/- 2.2). In the treatment group, a significant reduction (P < 0.05) in osteoclast surface was observed at the end of the study (3.9 +/- 6.8 versus -1.2 +/- 4.1), and although a trend to reduce osteoblast surface (-2.5 +/- 2.6 versus -3.2 +/- 5.7) and osteoid surface (-2.1 +/- 2.5 versus -3.2 +/- 2.8) was also found, patients maintained approximately the same level of wall thickness (-5.2 +/- 5.3 versus -5.3 +/- 3.3) and bone volume (-2.7 +/- 1.8 versus -2.5 +/- 1.7). However, there was no improvement in mineralizing surface (-4.2 +/- 2.9 versus -10.4 +/- 3.6) or appositional rate (-5.8 +/- 3.1 versus -8.1 +/- 2.6). No significant differences in bone histomorphometric variables were observed between groups after 1 year of follow-up. In conclusion, 1,25-dihydroxyvitamin D3 and calcium carbonate did not significantly improve bone loss in long-term renal transplant recipients. However, significant osteoclast suppression and a trend to maintain trabecular bone volume and wall thickness as well as improve the axial BMD were observed in the treatment group.

Bone histopathology and densitometry comparison between cyclosporine a monotherapy and prednisolone plus azathioprine dual immunosuppression in renal transplant patients.

Background. No study has compared the bone histopathologic findings in renal transplant patients receiving cyclosporine A (CsA) monotherapy with those in patients receiving a non-CsA regimen. The aim of this study was to compare bone densitometry and histomorphometry findings in patients receiving CsA monotherapy versus those receiving azathioprine + prednisolone dual therapy. Methods. A bone biopsy and densitometry were performed in 13 patients receiving CsA monotherapy and 12 patients receiving azathioprine + prednisolone, who had been on these regimens since the time of transplantation. Fourteen men and 11 women, age 51±12 years, with 140±75 months since transplantation, were included. Results. A low bone mineral density (BMD) was observed in patients on both immunosuppressive schemes—most notably at the distal radius and less significantly at the lumbar spine. No significant differences in BMD were observed between immunosuppressive groups. Histopathologic analysis of the group as a whole revealed mixed uremic bone disease in 42%, adynamic bone in 29%, hyperparathyroid disease in 17%, and normal bone in 12%. Patients showed a slight increase in osteoclast number and function, decreased osteoblast number and function, and retardation of dynamic parameters. No differences in histopathologic diagnosis or histomorphometric findings were observed between the immunosuppressive therapy groups. In addition to the immunosuppressive drugs, male gender and old age negatively affected bone mass. Conclusions. Both prednisolone and CsA were associated with slight osteoclast stimulation and osteoblast suppression and marked retardation of mineral apposition and bone formation rates. Both drugs were also associated with reduced BMD at the axial and appendicular skeleton, even though a nonsignificant trend to a better-preserved lumbar spine BMD was observed in the CsA group.

Risk Factors for Non‐ischaemic Foot Ulceration in Diabetic Nephropathy

It is recognized that diabetic patients with nephropathy frequently have macrovascular disease leaving them at risk of ischaemic foot lesions. In order to assess non‐vascular risk factors for foot ulceration 64 patients were stratified into four groups: microalbuminuria, albuminuria with creatinine clearance > 40 ml min−1, chronic renal failure (clearance < 40 ml min−1), and a non‐nephropathic diabetic control group. Vibration perception threshold was measured by biothesiometry, peroneal nerve conduction velocity by conventional methods, and dynamic foot pressure by pedobarography. Vibration perception threshold was elevated in all three groups when compared with age‐matched normal and diabetic control groups. Mean vibration perception threshold was 20.8 ± 8.6 (±SD) in the microalbuminuria group (p < 0.001 compared with age‐matched normal control group), 28.1 ± 5.6 (p < 0.001) in the albuminuria group, 38.9 ± 9.4 (p < 0.001) in the renal failure group, 14.8 ± 5.2 in the diabetic control group and 12.3 ± 2.9 in the normal control group. Peroneal motor conduction velocity was reduced in all three groups when compared with normal control subjects, microalbuminuria 38.6 ± 4.2 m s−1 (p < 0.001), albuminuria 38.0 ± 6.1 m s−1 (p < 0.01), renal failure 35.5 ± 1.2 m s−1 (p < 0.001), diabetic control 40.6 ± 1.8 m s−1, and normal 43.1 ± 2.3 m s−1. Mean peak plantar foot pressure was elevated in all three groups when compared with age‐matched normal anddiabetic control groups (p < 0.01), microalbu‐minuria 12.2 ± 3.1 kg cm−2, albuminuria 14.1 ± 2.6 kg cm−2, renal failure 15.2 ± 4.3 kg cm−2, diabetic control 11.4 ± 4.1 kg cm−2, and normal 8.2 ± 2.7 kg cm−2. A previous history of foot ulceration was recorded in 5 % of the diabetic control group, 10 % of patients with microalbuminuria and albuminuria, and 40 % with renal failure. We conclude that patients at all stages of diabetic nephropathy are at increased risk of non‐vascular foot ulceration.

Gustatory Sweating in Diabetes Mellitus

Gustatory sweating has been only rarely reported in diabetes mellitus and is thought to be due to axonal regeneration within the autonomic nervous system. We investigated the relationship of gustatory sweating to other diabetic complications. 196 patients in four groups (diabetic nephropathy, diabetic neuropathy, diabetic controls, and non‐diabetic renal failure) were questioned about gustatory sweating. Somatic and autonomic neuropathy were assessed by clinical signs, vibration perception threshold, and heart rate variability. Sixty‐nine percent of patients with nephropathy and 36% of those with neuropathy reported gustatory sweating, whereas less than 5% reported it in the other two groups. Five subjects reported that gustatory sweating either disappeared or significantly improved immediately after renal transplantation. Analysis of the nephropathy and neuropathy groups separately showed a strong correlation between gustatory sweating and degree of neuropathy (p < 0.01). This study shows that gustatory sweating is much more common than previously believed and demonstrates that it is often very closely linked with diabetic nephropathy.

Limitations of Kinetic Models as Predictors of Nutritional and Dialysis Adequacy in Continuous Ambulatory Peritoneal Dialysis Patients

Nutrition has been shown to predict clinical outcome in continuous ambulatory peritoneal dialysis (CAPD) patients. However, despite the positive relationship between KT/V (urea) and the normalised protein catabolic rate, the ability of urea kinetic modelling to predict clinical outcome or nutrition remains inconclusive. We have evaluated the relationship between nutrition and achieved dialysis in a cross-sectional study of 147 stable CAPD patients on dialysis for a mean period of 22 months. Protein-energy malnutrition was present in 22-32% of the study population. 39 and 41% of the population failed to achieve suggested adequacy targets of 50 liters/week for total creatinine clearance and a weekly KT/V (urea) of 1.7, respectively. Severely malnourished patients had significantly greater normalised clearance and adequacy values than well-nourished patients. Intrinsic actual peritoneal clearance bore no relation to patient size. The subsequent normalisation of this value by a component of patient mass results in a mathematical bias against well-nourished or obese patients. This may explain the failure of such adequacy values to reflect outcome and argues against accepting such values as measures of dialysis well-being.

Evidence that matching for HLA antigens significantly increases transplant survival in 1001 renal transplants performed in the northwest region of England

In the 20-year period from March 1968 to March 1988, 860 patients received 1001 renal transplants in the Northwestern Regional Renal Transplant Unit at Manchester Royal Infirmary. Through a continuing policy of avoiding mismatches for HLA antigens and lymphocytotoxic antibody crossmatching, transplant survival rates were found to correlate with the degree of HLA-A and B antigen mismatching from 1968 to 1978 and with HLA-B and DR antigen mismatching from 1979 to 1988. Mismatching for HLA-B and DR antigens was also found to correlate with transplant survival in highly sensitized patients and in patients transplanted since 1981, the “cyclosporine era.” Recipients who were HLA-DR1 positive were found to have the highest graft survival compared to recipients negative for this antigen. In contrast, HLA-DR3 positive recipients had the poorest outcome. Transplants from HLA-DRw6 positive donors showed higher transplant survival rates than donor kidneys positive for any other HLA-DR antigen. A correlation of transplant survival with HLA-B and DR mismatching was seen whether kidneys were collected within our region or received through the UK Transplant Service. We conclude that avoidance of mismatching for HLA-B and DR antigens confers high transplant survival rates (91.1% at 5 years for 0 HLA-B and DR mismatches), and in order to achieve this rate for most recipients exchange of donor kidneys between transplant centers will be essential.

Quality of Life in CAPD, Transplant, and Chronic Renal Failure Patients with Diabetes

Although quality of life (QoL) is an important outcome measure, there are few studies of QoL in diabetic patients. We performed a cross-sectional study to assess QoL in such patients comparable for age, sex, and co-morbidity. Patients. Group CAPD: DM (n = 19, 12 males), diabetic CAPD patients; group CAPD: no DM (n = 26, 15 males) CAPD patients without diabetes; group TXP (n = 20, 10 males), diabetic transplant patients; and group CKD: DM (n = 20, 11 males), diabetics with chronic kidney disease. Two valid QoL instruments were used: a generic one (SF-36) and one that is disease-specific (RQLP). Results. As a whole, CAPD patients scored badly as far as concerned the physical domain, but with a good mental adaptation. Diabetic CAPD patients exhibited worse QoL for physical functioning, energy, vitality, leisure activity, and eating/drinking limitations. Diabetic transplant patients exhibited the best QoL. The RQLP instrument had better discriminative power for domains such as eating/drinking, treatment effects, and psychosocial aspects. Using analysis of co-variance and adjusting for age, sex, and co-morbidity, QoL differences disappeared. In conclusion, diabetic CAPD patients exhibited the worst QoL though with a satisfactory mental adaptation, a renal-specific instrument had better discriminative power, and the prevention of co-morbidity is likely to improve QoL in such patients.