J. Douglas Briggs

Analysis of factors that affect outcome of primary cadaveric renal transplantation in the UK

BACKGROUND In the UK, kidneys are exchanged between centres on the basis of matching for HLA. We analysed various factors that might affect graft outcome to establish whether exchange of kidneys on this basis remains valid. METHODS 6363 primary cadaveric renal transplants carried out in 23 centres in the UK between 1986 and 1993 were used in the analysis. 6338 (99.6%) patients who underwent transplantation were followed up at 1 year. 5-year follow-up data were available for 2907 (97.8%) of the 2972 patients who survived to 5 years. We made random checks to validate the data. A multifactorial analysis with Coxs proportional hazards models was used to analyse factors that had a possible effect on graft outcome. To ensure that the analysis of matching was constant during the 8-year study, our analysis was based on the HLA antigens used for organ exchange (11 A locus antigens, 27 B locus antigens, and 12 DR locus antigens). We assessed overall outcome at 5 years and during three periods after transplantation at: 0-3 months, 3-36 months, and after 36 months. FINDINGS The following factors were significantly associated with graft outcome in the multifactorial analysis: year of graft, age of donor, age of recipient, whether the recipient had diabetes, cause of donors death, cold ischaemic time, transport of kidneys, transplant centre, and matching for HLA. The best outcome was achieved with kidneys that had no mismatches at HLA-A, HLA-B, and HLA-DR loci (000 mismatches). The next most favourable outcome was achieved with one mismatch at either A or B loci or one mismatch at both the A and B , but no mismatch at the DR locus (100, 010, or 110 mismatches). Age of the donor and recipient had a significant effect on transplant outcome: older age was associated with increased risk of graft failure. INTERPRETATION Various factors affect the outcome of primary cadaveric renal transplantation, particularly the age of the donor and the recipient. However, the effect of matching for HLA remains a strong one and fully justifies the continuing policy in the UK of exchanging kidneys on the basis of HLA matching, especially to recipients when there is a 000 mismatch for HLA between donor and recipient. On the basis of this analysis, a new allocation scheme for kidneys was introduced in the UK in 1998. During the first 9 months of the scheme, there has been a doubling of the number of HLA-000 mismatched kidneys transplanted.

EFFECT OF ACUTE ALUMINIUM OVERLOAD ON CALCIUM AND PARATHYROID-HORMONE METABOLISM

Accidental exposure of 25 patients on continuous ambulatory peritoneal dialysis to a high aluminium level in the dialysate for a month provided an opportunity to investigate the interrelation between the metabolism of parathyroid hormone (PTH), calcium, and aluminium. After exposure to the high-aluminium dialysate, the mean serum aluminium had risen from 1.85 to 7.11 mumol/l and serum calcium from 2.27 to 2.44 mmol/l, and serum PTH had fallen from 744 to 580 ng/l. After a further 2 months, during which time the dialysate was aluminium-free, the mean serum aluminium and calcium fell to previous levels. There were no changes in calcium or vitamin-D therapy which could have influenced these results. The rise in serum calcium and fall in PTH during a period of aluminium toxicity strongly support the hypothesis that aluminium suppresses PTH through an elevation of serum calcium.

Adhesion molecule expression (ICAM-1, VCAM-1, E-selectin and PECAM) in human kidney allografts

Expression of the cellular adhesion molecules ICAM-1, VCAM-1, E-selectin and PECAM in human kidney allografts was assessed by immunoperoxidase labelling of cryostat sections. Biopsies from 10 kidneys immediately prior to transplantation and 58 biopsies from 51 kidney transplants with graft dysfunction were studied. Allograft dysfunction was due to acute tubular necrosis (n = 5), acute rejection (n = 30), cyclosporin A (CyA) nephrotoxicity (n = 6), acute pyelonephritis (n = 3), recurrent glomerulonephritis (n = 4) and chronic rejection (n = 10). There was variability in the distribution of ICAM-1, VCAM-1 and E-selectin expression in pretransplant kidneys but the principal observation was a marked increase in the expression of ICAM-1 and VCAM-1 by the renal vasculature and the proximal tubules during acute rejection. By contrast, grafts with dysfunction not attributed to rejection showed a pattern of ICAM-1 and VCAM-1 expression similar to that observed prior to transplantation. E-selectin was expressed only weakly by occasional intertubular capillaries during acute rejection but the three grafts with pyelonephritis displayed strong expression of E-selectin on intertubular capillaries. There was no change in the pattern of PECAM expression following transplantation. The induction of ICAM-1 and VCAM-1 during rejection may contribute to the recruitment of mononuclear cells and render endothelial and tubular renal cells more susceptible to cell-mediated injury.

RENAL TRANSPLANTATION IN THE UNITED KINGDOM AND IRELAND—THE CENTRE EFFECT

A detailed audit was done of eight of the twenty-nine transplant centres serving the UK and Ireland. These 8 centres account for one-third of the total renal transplant operations in these two countries. Information was obtained from each centre by means of a comprehensive questionnaire, a 1 1/2 day visit by the three authors, and an analysis of 50 consecutive first cadaver transplants. The 8 centres were chosen in the knowledge that 4 had high and 4 had low 3-month graft-survival rates. Our audit confirmed a centre effect, with a range in 1-year patient survival of from 82% to 96% and of first cadaver graft survival of from 54% to 82%. The two main factors affecting success rate were the rate of irreversible acute rejection and death with a functioning kidney. Our investigations suggested that the centre variation in acute rejection was influenced by blood transfusion and the variation in mortality by steroid dose and recipient age. Careful and well-organised clinical management cannot be easily quantified but was thought to have an important influence. Widespread adoption of pre-transplant blood transfusion and increasing use of cyclosporin will probably contribute to the further lessening of the centre effect which has already been observed over the past few years.

Osteonecrosis and fractures following renal transplantation

Skeletal radiological surveys in 161 renal transplant recipients identified 36 patients with 115 lesions of osteonecrosis. A further two patients with osteonecrosis found at autopsy had had no radiographic abnormality. The total incidence of osteonecrosis was, therefore, 38 (24%) out of 161. The lesions were frequently multiple and bilateral with structural failure being the most common initial abnormality and the femoral head the most frequent site. Lesions also occurred in the femoral condyles, the talus, the humeral heads and the metatarsals, many being symptom-free. Calcification was demonstrated in the femoral and tibial shafts. The initial radiological abnormality appeared at a mean interval of 19 months after transplant but could occur as late as 75 months. Significantly fewer patients, three (7%) out of 41, developed osteonecrosis following a low-dose prednisolone regimen (0.8 g) compared with a high-dose group (2.8 g) where 35 (29%) out of 120 were affected. More females than males developed osteonecrosis, but no correlation could be demonstrated with regard to age, primary renal disease, number and type of transplant and duration of dialysis prior to transplant. Osteonecrosis is a complication which can be reduced with a low-dose prednisolone regimen. Most lesions will be demonstrated by radiological survey undertaken during the second and fourth years after transplantation.

The diagnosis of Helicobacter pylori infection in uremic patients

Two urease-based tests--the urease slide test and the radiolabeled urea breath test, are commonly used for the diagnosis of Helicobacter pylori infection of the stomach. The reliability of these tests in chronic uremia was compared with serological tests for H pylori antibodies, and with direct detection of the organism by microscopy or culture of gastric antral biopsies. Twenty-seven patients with chronic renal failure and dyspepsia underwent upper gastrointestinal endoscopy. Twelve of these patients (46%) were judged to be infected with H pylori on the basis of identification of the organism on microscopy or culture of antral biopsy. Both urease-based tests were able to determine H pylori status, despite the markedly increased concentrations of urea in the gastric juice found in chronic renal failure. The urease slide test performed on antral biopsies obtained at endoscopy proved reliable in determining H pylori status with no false-positive nor false-negative results after 20 minutes and 24 hours of incubation. The 14C-urea breath test also differentiated the infected from the uninfected patients. The 20-minute 14CO2 excretion (kg %dose/mmol CO2 x 100) ranged from 50 to 834 in the H pylori-infected patients, compared with 0.3 to 27 in the H pylori-noninfected patients (P < 0.0001); the 90-minute values ranged from 88 to 398 in the former, compared with 1 to 79 in the latter (P < 0.0001). The excretion of 14CO2 (derived from bacterial hydrolysis of ingested 14C-urea) was higher in all the uremic patients compared with nonuremic controls, and in half of the H pylori-noninfected uremic patients there was a late increase in 14CO2 excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

DINITROCHLOROBENZENE SKIN TESTING PREDICTS RESPONSE TO HEPATITIS B VACCINE IN DIALYSIS PATIENTS

The pattern of seroconversion and anti-HBs titres after 3 doses of hepatitis B vaccine was studied in 40 haemodialysis patients who had been grouped on the basis of their cell-mediated immune (CMI) response into strong or weak reactors. CMI response was determined by means of a dinitrochlorobenzene (DNCB) skin test. Titres of anti-HBs were comparable to those in healthy controls in 13 of 14 (93%) strong reactors but in only 9 of 26 (35%) weak reactors. Strong reactors had an equally satisfactory seroconversion rate with either 20 micrograms or 40 micrograms of vaccine whereas weak reactors had a negligible seroconversion rate with the 20 micrograms dose. In terms of hepatitis B prophylaxis, haemodialysis patients with a well preserved CMI response require only 20 micrograms of vaccine, with a consequent saving in cost. In contrast, it will be necessary to devise more effective immunisation schedules for most patients with a poor CMI response.

A critical review of immunosuppressive therapy

Low-dose Prednisolone probably has a useful role in combination with other drugs, but is ineffective on its own in prophylaxis. Side effects are relatively mild in contrast to high-dose steroids. Azathioprine is a relatively non-toxic drug whose main side-effects are on the bone marrow and liver. As with steroids, it is ineffective on its own. Cyclosporin is undoubtedly the most potent of the currently available immunosuppressives. Careful monitoring is essential to avoid toxicity, in particular nephrotoxicity. Its value is enhanced by relative sparing of suppressor wells and B lymphocytes. While concern still exists regarding progressive long-term nephrotoxicity, it seems now more likely that this can be avoided by careful dose regulation. Hirsutism and cost are two important disadvantages. ALG, ATG and monoclonal antibodies directed against T lymphocytes (e.g., OKT3) or surface receptors such as IL-2 receptors are increasingly being used and there is hope of the development of an increasing range of new, more specific monoclonals.

Persistent dipstick haematuria following renal transplantation.

Abstract:  Despite widespread testing for dipstick haematuria following renal transplantation, there are no published series describing the prevalence and possible causes of this complication in an adult population. A cross‐sectional study of 640 renal transplant recipients under review at our follow‐up clinic was performed. Persistent haematuria was defined as a minimum of 1+ of blood on urinalysis stick testing detected at not fewer than 75% of clinic visits since its onset, or since the start of routine testing, present over a period of at least 4 weeks. The prevalence of persistent dipstick haematuria was 13.3%. Median serum creatinine was higher in patients with persistent haematuria but age, gender and length of time since transplantation were not significantly different. Potential explanations for persistent haematuria in 21 of 85 affected patients were chronic infection, ureteric stent without chronic infection, regular or intermittent self‐catheterization, persistent menstrual bleeding, anticoagulant therapy, graft calculus, and allograft renal cell carcinoma. Recurrent or de novo glomerular disease was confirmed by graft biopsy in 10 of 85 patients. Among the 41 recipients whose original cause of renal failure was IgA nephropathy (IgAN), the prevalence of persistent haematuria was 31.7% compared with 12% in the remaining patients (relative risk 2.6, 95% CI: 1.6–4.3). Persistent haematuria in IgAN patients was not associated with gender, age or time since transplantation. After 29 months of follow‐up, 20% of patients with haematuria had progressed to graft failure or death compared with 11.6% of the unaffected group (p = 0.029). However, despite the association with earlier graft failure, haematuria did not predict this endpoint independently of renal function.

A Bayesian Kinetic Control Strategy for Cyclosporin in Renal Transplantation

Although cyclosporin has brought about a dramatic improvement in graft survival after transplantation, its use in this therapeutic setting may be associated with considerable control problems. Many clinically oriented studies have shown remarkable fluctuations in cyclosporin blood concentrations and this has presented a challenge primarily to those interested in pharmacokinetics. This presupposes, of course, that the fluctuations are in large part due to pharmacokinetic variability of one sort or another. There may well be other reasons. An excellent overview of the topic — including suggestions for one pharmacokinetic strategy — has been provided recently by Kahan and Grevel [1]. In response to the often quoted and observed wide range of cyclosporin concentrations, these authors stress that a dosing strategy that achieves uniform drug levels by compensating for pharmacokinetic variability is essential for the promotion of rational cyclosporin regimens. While their comments were directed at renal transplantation, there is no doubt that such comments are equally applicable to the use of cyclosporin in other transplant situations.