J. Landmann

Prevention of cancellous bone loss but persistence of renal bone disease despite normal 1,25 vitamin D levels two years after kidney transplantation.

Osteopenia has been observed to occur frequently after renal transplantation. The present study was undertaken to assess whether an immunosuppressive regimen combining cyclosporine with no or the lowest possible maintenance doses of glucocorticoid may prevent osteopenia after kidney transplantation. Thirty-four patients were prospectively followed for two years. Serial blood drawings were done for determination of serum indices of calcium and bone metabolism and an iliac crest bone biopsy was performed at time of transplantation. A second bone biopsy was done in 20 patients during the second year of observation. Creatinine clearance was 56 +/- 6 ml/min one year and 46 +/- 6 ml/min two years after transplantation. Serum parathyroid hormone levels were elevated in 24 patients at time of grafting, decreased significantly thereafter, but remained above the normal range. Ten patients had low or normal serum parathyroid hormone levels at time of transplantation and showed a significant increase after grafting. Two years after transplantation, the mean cumulative dose of prednisone was 5.9 +/- 0.5 g. After the first six months, 30-40% of the patients were not on maintenance doses of steroids. None of the patients experienced fractures, and cancellous bone volume was within or above the normal range in all repeat bone biopsies. It is of note that metabolic bone abnormalities did not resolve 1-2 years after transplantation despite normalization of serum 1,25 vitamin D levels. The histologic abnormalities at the time were consistent with the bone findings in renal failure suggesting resistance of bone to normal circulating levels of 1,25 vitamin D.

Glomerular hyperfiltration after unilateral nephrectomy in living kidney donors

Glomerular hyperfiltration, which is expected to occur after uninephrectomy, could potentially damage the non-transplanted donor kidney in living donor transplantation. We therefore prospectively measured renal function (inulin and PAH clearance), albumin excretion and blood pressure in the donors of 30 consecutive living donor kidney transplants before uninephrectomy (n = 29) and 1 week (n = 27) and 1 year (n = 16) after. Hyperfiltration was defined as: (post-nephrectomy inulin clearance)/(0.5 x pre-nephrectomy inulin clearance); hyperperfusion was defined in an analogous way for PAH clearance. Hyperfiltration averaged 128 +/- 5% [SEM] and hyperperfusion 133 +/- 6% 1 week after uninephrectomy. Hyperfiltration was nearly unchanged (126 +/- 7%) 1 year after nephrectomy, whereas hyperperfusion had significantly decreased to 118 +/- 8% (P < 0.02). There was no significant change in blood pressure after nephrectomy, and no new cases of hypertension were observed during the 1-year follow-up. The degree of hyperfiltration did not correlate with donor age. Microalbuminuria > 30 mg/24 h was found in two donors 1 week after nephrectomy (one of which normalized at 1 year) and in one additional donor 1 year after nephrectomy. The degree of hyperfiltration did not correlate with albumin excretion rate. In conclusion, no adverse consequences of hyperfiltration were demonstrable during the 1-year observation period, but the prognostic role of occasional microalbuminuria should be further investigated.

Cyclosporin A‐induced transient rise in plasma alkaline phosphatase in kidney transplant patients

In 1981 cyclosporin A (CyA) became available and replaced azathioprine (Aza) as the immunosuppressive agent in kidney transplantation at the University Hospitals in Basel, Switzerland. Patients on CyA and prednisone (CyA/p) therapy frequently demonstrated an isolated rise in bone-derived serum alkaline phosphatase (aP) concentration, but patients on Aza and prednisone (Aza/p) therapy did not. On the basis of long-term aP concentration and using noninvasive means, the present retrospective study was designed to investigate biochemical markers and radiographic signs of bone disease after successful kidney transplantation in patients on Cya/p treatment. Similar investigations were performed in patients on Aza/p and the results were compared. Follow-up examinations included clinical examination, radiography of the hand, and biochemical analysis of serum and urine. In 139 renal transplant patients on CyA/p, aP increased transiently after successful grafting (at transplantation 84±43 U/l; on day 90, 112±82 U/l). In 50 patients aP levels were higher at the time of transplantation (120±80 U/l) and aP peaked after 8±6 months, at a mean concentration of 242±103 U/l. In these patients aP concentrations exceeded the normal range for 16±10 months. None of the patients on CyA/p showed symptoms of bone disease when aP was increased. Radiological surveys revealed more pronouced osteodystrophy in patients at the time of transplantation, which increased aP to above the normal range after transplantation. Despite this rise in aP, over the long term bone lesions improved radiographically while bone mass remained stable. In constrast, patients treated with Aza/p demonstrated a significant decrease in aP level after transplantation from 75±33 U/l to 54±29 U/l on day 90. In addition, radiographic bone changes persisted and bone mass decreased significantly. After a 2-year follow-up, serum parathyroid hormone, 1,25-(OH)2-vitamin D3, calcium, and phosphorus concentrations, urinary excretion of hydroxyproline, and tubular reabsorption of phosphate did not differ between patients on CyA/p and controls on Aza/p. We conclude that after successful kidney transplantation and initiation of CyA/p therapy, a transient increase in bone-derived aP frequently occurred. These patients more often demonstrated radiographic signs of pre-existing osteodystrophy. However, over the long term, these changes improved.

Protective effect of allopurinol and superoxide dismutase in renal isografts in cyclosporin A-treated rats.

Acute tubular necrosis (ATN) after renal transplantation is related to the duration of warm and cold ischemia and leads to temporary or permanent impairment of graft function. An increased incidence of ATN has been reported since the introduction of cyclosporin A. Kidney damage resulting from hypothermic storage is generated in part during reperfusion rather than during ischemia itself. Potential mediators of the reperfusion injury are oxygen-derived free radicals. Therefore, the influence of two oxygen radical antagonists, allopurinol and superoxide dismutase, was evaluated in syngeneic rat kidney transplantation with and without concurrent administration of cyclosporin A. At 15 h cold ischemia, 28-day survival increased from 8% (no treatment) to 22% (superoxide dismutase), 33% (superoxide dismutase and allopurinol), and 73% (allopurinol). Cyclosporin A cotreatment (10 mg/kg over 14 days) resulted in survival rates of 0%, 25%, 17%, and 50% for the respective treatment groups. The results of serum creatinine values and morphological evaluation of biopsies paralleled the survival rates. Cyclosporin A nephrotoxicity was evidenced by significant serum creatinine elevations throughout the 28-day period of observation. In conclusion, allopurinol significantly protects syngeneic rat kidney transplants against a critical duration of cold ischemia. Under the conditions of this experiment, allopurinol was clearly superior to superoxide dismutase treatment. Cyclosporin A nephrotoxicity was, however, not ablated by the oxygen radical antagonists employed.

The efficacy and tolerability of cyclosporine G in human kidney transplant recipients.

Twelve consecutive first cadaveric kidney transplant recipients received cyclosporine G (CsG)(initial dose 12 mg/kg per day) as basic immunosuppressive treatment along with prednisone (initial dose 0.5 mg/kg per day) for the first three months after transplantation. Thereafter CsG was replaced by Sandimmun (cyclosporine, CsA). Evaluation of the immunosuppressive efficacy and assessment of possible side effects of CsG was made and compared with the results in 38 historical control patients starting with the same dose of CsA as part of the same immunosuppressive dosage schedule. Statistically, there was no difference in patient survival at three (91% in CsG group versus 95% in CsA group) and twelve months (91% in CsG group versus 92% in CsA group), or in graft survival at three (75% in CsG group versus 89% in CsA group) and twelve months (75% in CsG group versus 84% in the CsA group). At equivalent oral doses of CsG and CsA significantly higher blood levels of CsG were observed (2P less than 0.05). Nephrotoxicity assessed by graft biopsy could be demonstrated to a similar extent in both groups, whereas hepatotoxicity was more pronounced during CsG treatment. Sequential measurements of bilirubin revealed a significant increase in all patients but median values were significantly higher in the CsG patients. A pronounced and concordant elevation of liver enzymes occurred during CsG treatment in three out of 12 patients. Liver biopsies performed in these patients revealed histological alterations consistent with toxic liver injury. Thus, in human kidney transplant recipients CsG and CsA appeared to be equally immunosuppressive and nephrotoxic but more hepatotoxic. On the basis of this limited experience we conclude that in human kidney transplant recipients CsG has no advantage over CsA.

Dosage of OKT3 independent of body weight: a mistake?

Comparing OKT3 and antithymocyte globulin (ATG) in a prospective study, the dosage difference in regard to body weight (ATG: dependent on body weight/OKT3: independent) does not introduce any obvious source of mistake concerning clinical effectiveness or side effects. One explanation for the lack of influence of body weight may be the high effectiveness of 5 mg of OKT3, reaching a maximal effect even with lower plasma levels in heavier patients. We wonder, therefore, whether the OKT3 dosage could be lowered.

276. Nierentransplantation — 7 Jahre mit Cyclosporin

SummaryDuring our 7-year experience with cyclosporine in kidney transplantation, the dosage has been reduced from 17 mg/kg per day to 3 mg/kg per day. In parallel, the original monotherapy has been changed to triple therapy. The 1-year graft survival rate has improved from 74% to 90%. The additional advantages are: a reduction in the initial acute tubular necrosis rate, accelerated reduction of serum creatinine values, and a reduction in late nephrotoxicity.ZusammenfassungWährend der siebenjährigen Erfahrung mit Cyclosporin bei der Nierentransplantation hat sich die Dosierung von anfänglich 17 mg/kg/Tag auf 3 mg/kg/Tag reduziert, wobei gleichzeitig von der Monotherapie auf die Trippeltherapie übergegangen wurde. Die Transplantat-Überlebenszeit nach einem Jahr konnte von 74% auf 90% gesteigert werden. Als zusätzliche Vorteile werden die Abnahme der initialen Oligo-Anurie und die weniger häufige Spättoxizität angeführt.

228. Tumoren nach Nierentransplantation

SummaryOf 271 patients with 304 kidney transplants, between 1967 and 1981, 20 (7y.) have developed a malignant tumor and 7 patients (2.6 %) have died of it. A minimal time interval for tumor induction has to be assumed. Of 154 patients under immunosuppression with a functioning graft for over 1 year, 19 have developed a tumor. The figure of 12.3 % is probably more realistic than the usual 5 %– 7 % incidence, based on all transplanted patients. Of these 154 patients, 6 (3.9 %) died of their tumor that is 15.4 % of all deaths among the 154 patients exposed to immunosuppression for over 1 year.Zusammenfassung20 von 271 Patienten mit 304 Nierentransplantationen zwischen 1967 und 1981 haben ein Malignom entwickelt. Von diesen 7 % der 271 Patienten sind 7 oder 2,6 % am Tumor gestorben. Da eine minimale Induktionszeit zur Tumorauslösung anzunehmen ist, wurden nur jene Patienten berücksichtigt, die mindestens 1 Jahr mit dem Transplantat unter Immunsuppression standen: 19 Tumoren bei 154 Patienten oder 12,3 %, eine wohl realistischere Zahl als die üblichen 5–7 %, die sich auf alle Transplantierten überhaupt beziehen. 6 der 154 erliegen ihrem Tumor (3,9% statt 2,6%) oder 15,4% aller 39 Todesfälle bei diesen 154 Patienten. Die Tumoren waren: 9 viscerale, 7 Hauttumoren, 4 Lymphome.