Prospective study of calcium homeostasis after renal transplantation.

Nineteen consecutive patients receiving renal transplants underwent prospective evaluation of their calcium homeostasis for 1 year after transplantation to characterize indices of hyperparathyroidism (HPT) amelioration. All but one underwent dialysis, and six had vitamin D supplementation before grafting. The rapid falls in serum creatinine concentrations and increased creatinine clearances the first weeks after grafting were accompanied by rapidly reversed hypercalcemia and hypermagnesemia, induced hypophosphatemia, maintained parathyroid hormone (PTH) excess and calcitriol deficiency, and decreased alkaline phosphatases. At 3 months when the serum calcitriol had started to rise, serum PTH levels were the lowest and parathyroid responses to induced hypocalcemia the least abnormal. This was coupled to peaks in serum calcium, 24-hour urine calcium excretions, and serum alkaline phosphatase levels. All patients had subnormal creatinine clearances at the study end, and normal serum PTH occurred in only seven of them. Arbitrary subgrouping of the material was performed according to posttransplant creatinine clearance and serum PTH levels. More satisfactory graft function related to lower serum PTH values and less abnormal parathyroid responses to induced hypocalcemia, earlier and higher rises in serum calcitriol, and higher urine calcium excretion. Patients with mild HPT at the study end generally had higher creatinine clearance, lower serum PTH, calcium, and alkaline phosphatase values, and lower urine calcium excretion. Moreover, they had fewer prevalent signs of radiologic bone involvement before grafting. These temporal diversities in conjunction with the variable graft function and intensity of immunosuppression provide a complex interaction in renal transplant recipients, which should be considered in the light of improved function of the PTH/PTHrP receptor in bone and kidney and cation receptors in the parathyroid and kidney.

Is kidney transplantation in sensitized recipients justified?

The objective of the study was to determine if it is justified to use the scarce resources of cadaveric kidneys on HLA-sensitized patients, by reviewing the initial and long-term outcome of cadaveric renal transplantation at Uppsala University Hospital, Sweden. Between January 1988 and December 1994, 402 renal transplantations were performed. The patients were divided into one group of sensitized recipients (peak panel antibody reactivity > or = 25%; n = 84) and a second of non-sensitized recipients (panel reactive antibodies < 25%; n = 318). The groups were comparable in terms of recipient and donor age, gender, HLA-A, -B and -DR mismatches and numbers of diabetics. None of the sensitized patients received a six-antigen-matched kidney. For the non-sensitized group, life table analysis showed a 1-year actuarial graft survival (GS) of 91.8% and a 4-year GS of 84.4%. The corresponding GSs for the sensitized group were 79.9% and 68.7%, respectively (P < 0.01). The statistical significance vanished if patients with primary non-function were excluded. When excluding donors above 55 years of age, kidneys with cold ischemia time above 20 h, and two-antigen (HLA-DR) mismatches, there was no detectable difference between the non-sensitized and sensitized groups at 1-year or 4-year GS. Although there is a statistical significance in GS between non-sensitized and sensitized recipients of a kidney transplant, this does not differ from other risk groups such as diabetics, rheumatoid disease sufferers or elderly recipients. We therefore conclude that the sensitized patient should be accepted on the waiting list for a kidney transplant and that it is worthwhile to do the utmost to transplant this category of patients. Our data indicate that kidney GS in sensitized recipients is more affected by negative risk factors such as older donors, long cold ischemia time and two-antigen HLA-DR mismatch, than the non-sensitized recipient. To improve the outcome, those negative factors should be avoided or reduced.

Ischemic heart disease--major cause of death and graft loss after renal transplantation in Scandinavia.

Causes of graft loss and death were studied in 1347 recipients of primary renal transplants followed for 5 years after transplantation irrespective of graft function. Immunosuppression consisted of high or medium dose CsA and prednisolone or low dose CsA and prednisolone and azathioprine. In recipients of cadaver grafts, death with a functioning transplant was more common than graft rejection after the first posttransplant year, accounting for 49% and 41% of the graft losses, respectively. Of deaths with a functioning graft, 53% were due to ischemic heart disease (IHD) and 10% were due to other vascular disease. In the 55- to 64-year-old age group, the risk of death from IHD was 6.4 times higher in the transplanted nondiabetic patients, 8.6 times higher in the dialysis patients (European Dialysis and Transplant Association figures), and 20.8 times higher in the transplanted diabetic patients than in the general population (national figures). A multivariate Cox regression analysis showed that old age, diabetes mellitus, occurrence of acute rejection, pretransplant transfusions, delayed onset of graft function, and male gender were significant for death in IHD. We conclude that, in comparison to reports from other regions, Scandinavian renal transplant recipients are at high risk of dying of IHD. Future advances in long-term renal graft survival will depend largely on the success of preventing myocardial infarction and death in this patient population.

Cancer risk after renal transplantation in the Nordic countries, 1964-1986.

The theory that cancer may arise under conditions of reduced immune capacity is supported by observations of humans with immune deficiencies such as occur following organ transplants. However, no study on humans has been done in which the reference population was the same as that in which the cancer cases arose and in which there was a sufficiently long period of follow-up. Information on 5,692 Nordic recipients of renal transplants in 1964-1982 was linked with the national cancer registries (1964-1986) and population registries. Person-years at risk were calculated from the date of first transplantation until death or the end of the study period and were multiplied by the appropriate age- and calender-specific incidence rates to obtain the expected numbers of cancers. Standardized incidence ratios (SIR) were calculated after stratification by a number of recorded variables. Altogether, 32,392 person-years were accrued, and 471 cancers occurred, yielding overall SIR of 4.6 (95% CI, 4.0 to 5.2) for males and 4.5 (95% CI, 4.0 to 5.2) for females. Significant overall 2- to 5-fold excess risks in both sexes were seen for cancers of the colon, larynx, lung and bladder, and in men also for cancers of the prostate and testis. Notably high risks, 10-fold to 30-fold above expectation, were associated with cancers of the lip, skin (non-melanoma), kidney and endocrine glands, also with non-Hodgkin's lymphoma, and in women also with cancers of the cervix and vulva-vagina. Among a number of donor and recipient variables studied, including tissue types and compatibility (ABO, HLA, DR), age below 45 years at the time of transplantation was the most important determinant for increased risk at most sites. Kidney transplantation increases the risk of cancer in the short and in the long term, consistent with the theory that an impaired immune system allows carcinogenic factors to act. The tumor risk is small in comparison with the benefits of transplants, but patients should be followed up for signs of cancer.

A randomized multicenter trial of cyclosporin and prednisolone versus cyclosporin, azathioprine, and prednisolone following primary living donor renal transplantation.

A total of 195 consecutive recipients of primary living donor renal transplants were randomized to receive either cyclosporin (CyA) and prednisolone (double therapy) or CyA, prednisolone, and azathioprine (triple therapy). There was no significant difference in patient or graft survival, incidence of acute rejection episodes, or major complications between the groups. The graft survival at 5 years was 71.5% in patients receiving double therapy and 71.6% in patients receiving triple therapy. In a Cox regression analysis, recipient age and occurrence of acute rejection were the only independently significant variables affecting graft survival, whereas treatment schedule did not. Renal function was stable throughout the observation period and did not differ between the double and triple therapy groups. A linear regression analysis showed that recipient age, donor age, gender, and occurrence of acute rejection significantly influenced the serum creatinine level. This and previous similar prospective studies in cadaveric renal transplantation indicate that there is no advantage of routinely adding azathioprine to a double drug regimen.

Safety aspects and diagnostic findings of serial renal allograft biopsies, obtained by an automatic technique with a midsize needle.

Percutaneous biopsy is an important diagnostic procedure in evaluating the renal allograft with compromised function. Graft losses and haemorrhagic complication are major risks. To minimize these problems we used a midsize TruCut needle, controlled by an automatic firing device (Biopty-Cut), fixed to an ultrasound guidance system. Core biopsies of 1.2 x 20 mm were obtained from 1,421 kidney grafts. On 5 occasions a haemorrhagic complication that required prolonged hospitalization or intervention occurred. No grafts were lost as a consequence of the biopsy procedure. Typical histological morphological parameters found during allograft rejection has earlier been established. Using a protocol with 27 histological parameters this study confirms that recognized criteria for rejection can be relied upon even with this smaller needle. The results showed that the degree of oedema and lymphocytic infiltration of the interstitium and in the arterial wall discriminated best between rejecting grafts and non-rejection grafts.

Is repeated mismatching at regrafting deleterious?

We reviewed our clinical experience of allowing kidney regrafting with a repeated HLA mismatch. We also permitted a weakly positive B-cell cross-match. All patients who received a second or subsequent renal graft (n = 92) between January 1985 and June 1990 were analysed for graft survival. The overall 1-year graft survival was 70%. A repeated mismatch occurred in 29 of the patients at at least one HLA locus and their 1-year graft survival was 66%. The balance of the regrafts (63) were performed without a repeated mismatch, and their 1-year graft survival was 70%. Even a weakly positive B-cell cross-match was deleterious; when a grafting with a repeated mismatch was performed only one out of five grafts survived. Our results indicate that retransplantation of renal grafts with a repeated mismatch in the HLA A or B locus can be performed without a negative influence on transplant outcome provided that both the T- and B-cell cross-matches are negative.

Influence of the age of cadaveric kidney donors on transplantation outcome and rate of surgical complications.

Cadaveric kidney graft recipients, treated according to a strict, high dose CyA protocol, were followed prospectively for one year. The aim was to study the impact of donor age on transplantation outcome in a homogenously immunosuppressed patient material. The patients were divided into 2 groups; G1: donor age less than or equal to 50 years (mean 34.5 y; range 10-50; n = 49) and G2; donor age greater than 50 years (mean 58.1 y; range 51-68; n = 37). The groups were comparable in terms of recipient age, warm and cold ischemia time, number of HLA A, B, DR mismatches and number of rejection episodes. The result showed no difference in mortality between the 2 groups (12% vs. 13%). One year graft survival was 70% vs. 51% (NS), immediate onset of function was 76% vs. 46% (p less than 0.01), creatinine concentration at one year was 146 +/- 39 vs. 206 +/- 73 mumol/l (p less than 0.05) for G1 and G2, respectively. The most striking finding was a highly significant difference in the rate of graft-related surgical complications, 12% vs. 35% (p less than 0.01) for G1 and G2, respectively. We conclude, that a patient receiving a graft from an elderly donor, runs a higher risk of graft-related complications and that long term graft survival and function also might be influenced by the age of the donor. A possible reason for the inferior results in group 2 might be an increased sensitivity for the toxic effects of CyA of aging kidneys.