Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial.

Renal transplant recipients (RTR) have a 50-200-fold higher risk for nonmelanoma-skin cancer (NMSC) causing high rates of morbidity and sometimes mortality. Cohort-studies gave evidence that a sirolimus-based immunosuppression may inhibit skin tumor growth. This single-center, prospective, assessor-blinded, randomized trial investigated if switching to sirolimus treatment inhibits the progression of premalignancies and moreover how many new NMSC occur compared to continuation of the original immunosuppressive therapy. Forty-four RTR (mean age 59.9 years, mean duration of immunosuppression 229.5 months) with skin lesions were randomized to sirolimus or continuation of their original immunosuppression. Blinded dermatological assessment at month 6 and 12 by the same dermatologist evaluated the clinical change compared to baseline. Biopsy was performed in suspected malignancy. Already the 6-month-assessment showed significant superiority of sirolimus-therapy: a stop of progression, even regression of preexisting premalignancies (p < 0.0005). This effect was increased at month 12 (p < 0.0001). Nine patients developed histologically confirmed NMSC: one in the sirolimus group, eight in the control group, p = 0.0176. Sirolimus-based immunosuppression in RTR, even when established many years after transplantation, can delay the development of premalignancies, induce regression of preexisting lesions and decelerate the incidence of new NMSC.

Hypertension is associated with hyperlipidemia, coronary heart disease and chronic graft failure in kidney transplant recipients.

BACKGROUND: Hypertension is a common concomitant condition in renal transplant recipients. There is accumulating evidence that this disorder is an important risk factor for chronic renal graft failure and other cardiovascular complications in these patients. SUBJECTS AND METHODS: The current retrospective study in 330 patients treated with cyclosporin or azathioprin covered 5 years and aimed to further characterize the interrelation between hypertension and renal graft failure. Furthermore, the association of hypertension with hyperlipidemia and the prevalence of coronary heart disease was evaluated. RESULTS: Altogether, before transplantation 182 patients were normotensive (no antihypertensive medication except diuretics) and 105 were hypertensive (blood pressure > 160/95 mmHg or patients requiring antihypertensive medication); for the remaining 43 patients no data were available. After transplantation the prevalence of hypertension in the cyclosporin group was 71, 76 and 70% after 1, 3 and 5 years, respectively. The respective numbers for the azathioprin group were 60, 59 and 58%. Hypertension was associated with graft dysfunction both in cyclosporin- and azathioprin-treated patients. Hyperlipidemia (cholesterol, triglycerides) was more severe in hypertensive than in normotensive patients. The prevalence for hypertension was higher in patients with coronary artery disease than in patients without the disease. CONCLUSION: The results further support the view that hypertension may be a risk factor for the development of chronic renal graft failure and coronary artery disease in this population. Furthermore, the association of hypertension with hyperlipidemia hints to an unfavorable accumulation of renal and cardiovascular risk factors in a large number of renal allograft recipients.

Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients.

To delineate the pathogenesis of the reduction in hemoglobin occurring in renal transplant patients treated with angiotensin converting enzyme inhibitors (ACEI) and azathioprine (AZA) a controlled, prospective trial of ACEI withdrawal was conducted. The ACEI was replaced by nifedipine or clonidine in 15 kidney transplant patients immunosuppressed with AZA and prednisone (enalapril in 14 and captopril in 1). Before and during 10 to 12 weeks after withdrawal of the ACEI, AZA metabolites, renal function parameters and hematological parameters including erythropoietin and reticulocytes were evaluated. Enalaprilat levels were measured and compared with 15 similar patients matched for transplant function and enalapril dosage immunosuppressed with cyclosporine and prednisone. AZA metabolites did not differ significantly in the presence or absence of the ACEI. Enalaprilat levels also showed no significant difference between the two patient groups treated with AZA or cyclosporine. Hematocrit and hemoglobin increased significantly from 37.5 +/- 6.4 to 39.7 +/- 3.6% (mean +/- SD, P = 0.02) and 12.8 +/- 2.2 to 13.5 +/- 1.2 g/dl, P = 0.04, respectively, 10 to 12 weeks after ACEI treatment had been discontinued. Simultaneously numbers of reticulocytes and erythropoietin concentrations rose significantly after 2, 4 and 10 weeks, with a peak at two weeks (from 14.1 +/- 3.8 to 20.6 +/- 8.0/1000, P < 0.05 and from 14.3 +/- 12.4 to 29.3 +/- 54.5 mU/ml, P < 0.05, respectively). In conclusion, ACEI-related anemia in renal transplant recipients seems to be due to the erythropoietin-lowering effect of this group of drugs. A pharmacokinetic interaction between AZA and enalapril is not likely since plasma enalaprilat levels were independent of the immunosuppressive regimen and AZA metabolite levels were unchanged in the presence and absence of the ACEI. Several mechanisms by which angiotensin converting enzyme blockade may cause a decrease in circulating erythropoietin are discussed.

Anemia in renal transplant recipients caused by concomitant therapy with azathioprine and angiotensin-converting enzyme inhibitors.

Immunosuppression of recipients of renal transplants with azathioprine has been associated with two major side effects: hepatotoxicity and myelotoxicity, mainly in the form of leukopenia. Reports of isolated anemia in these patients have been rare. We now observed the development of severe anemia in 9 out of 11 renal transplant recipients whose immunosuppressive regimen was converted from cyclosporine plus prednisone to azathioprine plus prednisone. A significant (P = 0.001) drop in hematocrit (from 34 +/- 4% to 27 +/- 3%, mean +/- SD) and hemoglobin (from 11.6 +/- 1.3 g/dl to 9.5 +/- 1.0 g/dl) was found. Since a common variable of all these patients was their use of an angiotensin-converting enzyme (ACE) inhibitor as antihypertensive medication, we speculated that the combination of azathioprine and ACE blocker might be the reason for the anemia. We then compared 2 groups of 10 patients each who had been on azathioprine as their regular immunosuppressive agent and who did or did not take an ACE inhibitor. Hematocrit and hemoglobin were significantly (P = 0.01) lower in the group of patients taking ACE inhibitors (33 +/- 6% versus 41 +/- 5% and 11.5 +/- 2.0 g/dl versus 14.0 +/- 1.6 g/dl, respectively). Haptoglobin levels were also significantly (P = 0.05) lower in the ACE inhibitor group (116 +/- 65 mg/dl versus 210 +/- 114 mg/dl). Erythropoietin concentration in the serum and the reticulocyte index were slightly, but not significantly, higher in the ACE inhibitor group but the values were probably too low for their degree of anemia. Comparing hematological parameters of the patients in the ACE inhibitor group before and after beginning of the antihypertensive treatment confirmed a significant reduction of hematocrit and hemoglobin following therapy with an ACE inhibitor. Hematocrit fell from 41 +/- 7% to 36 +/- 6% and hemoglobin from 14.0 +/- 2.3 g/dl to 11.3 +/- 1.5 g/dl (P < 0.05 for both). We conclude that the combination of these two drugs should probably be avoided.

[Porphyria cutanea uraemica: an obligate systemic disease in chronic kidney insufficiency?]. / Porphyria cutanea uraemica: eine obligate Systemerkrankung bei chronischer Niereninsuffizienz?

Patients with chronic renal failure, especially those receiving maintenance haemodialysis, have a number of dermatological alterations. Some of them are similar to those seen in porphyria cutanea tarda (PCT). Whereas early studies showed normal plasma porphyrin levels, a striking elevation of plasma porphyrins, and particularly of uroporphyrin, has recently been found. We measured the concentrations of porphyrins in the plasma and erythrocytes of 55 patients with chronic renal failure and receiving maintenance haemodialysis and also in 7 patients with PCT and 100 healthy volunteers. The mean concentration of porphyrins in plasma was 2.7-fold, and the maximum concentration, 6-fold the highest value measured in plasma of controls. The mean plasma concentration of uroporphyrin was 6-fold higher up to a maximum value of 37-fold the upper limit of the controls. The plasma porphyrin values of 3 of 7 patients with PCT were on the same high level as those measured in patients undergoing haemodialysis. The mean porphyrin concentration in the erythrocytes of haemodialysis patients were 1.5-fold the control values. Because of the known pathophysiological effect of uroporphyrin, especially its stimulation of the collagen synthesis and the activation of the complement system, we suppose that the porphyria cutanea tarda like skin lesions in patients with chronic renal failure are due to the highly increased uroporphyrin concentration.

[Normalization of uremic skin changes following kidney transplantation]. / Normalisierung der urämischen Hautveränderungen nach Nierentransplantation.

A clinical dermatological examination was performed on 49 patients (30 males, 19 females; 24-64 years of age) 3.1 years after successful kidney transplantation. Some patients underwent skin biopsy procedures for examination by light and electron microscopy, as well as immunohistological methods. Six patients had already been examined using these methods prior to the transplantation. When sufficient renal function was restored after successful kidney transplantation, the uremic skin alterations disappeared. The increase in sweat secretion, a common symptom in uremic patients was not observed after renal transplantation. The ichthyosiform feature of uremic skin and the increased vulnerability of the skin was observed in only a minority of the transplanted patients examined. In addition, the generalized pruritus and Raynaud phenomenon that are seen so frequently among uremic patients disappeared completely. However, the uremic-induced alterations of the connective tissue, like severe actinic elastosis and Dupuytren's contractures, persisted after renal transplantation. Histological examinations revealed renormalization of the uremic altered skin; in particular, the severe microangiopathy of skin vessels in long-term hemodialysis patients vanished.

[Microangiopathy, connective tissue changes and amyloid deposits in chronic renal failure]. / Mikroangiopathie, Bindegewebsveränderungen und amyloidartige Ablagerungen bei chronischer Niereninsuffizienz.

Skin biopsies were taken from 59 patients with chronic renal failure (52 patients were on regular dialysis treatment, and seven patients were predialytic). The histological examination of the skin biopsies revealed microangiopathy and pericollageneous deposition of a substance with the histochemical behavior of amyloid. In electron microscopy studies these deposits were found to be fine granular, but microfibrillar structures could also be detected. The alterations of the vessel walls are obviously caused by a non-reactive deposition of immunoglobulins, complement components, and fibrinogen. The alteration of the connective tissue mainly imposes as actinic elastosis. These findings could be demonstrated in both predialytic patients and patients on regular dialysis. The extent of the observed alterations seemed to be dependent on the duration of uremia. Atrophy of sweat and sebaceous glands also characterizes the skin lesions of patients with chronic renal failure.

[Skin changes in long-term dialysis patients. clinical study]. / Hautveränderungen bei Langzeitdialysepatienten. Eline klinische Studie.

Fifty-one regular hemodialysis patients underwent clinicodermatologic examination. Twenty-three of them were on regular hemodialysis for 2-3 years (group I), 28 patients for more than 8 years (group II). Both groups were matched in regard to primary kidney disease, age, and sex. A characteristic feature found was a marked premature aging of the skin, mainly imposing as actinic elastosis. The incidence was related to the duration of hemodialysis (56.5% of patients of the first group and 100% of patients of the second group). There was also a correlation between time on hemodialysis and an increase of skin pigmentation. Other phenomena like xeroderma, decrease of sebaceous and sweat gland secretion, and Raynaud syndrome were also seen more frequently in the second group, but the extent of these alterations was equal in both groups. Seventy-eight percent of the patients of the first group and 43% of the second group suffered from generalized pruritus. Two different froms of pruritus could be observed, one possibly atopic, only occurring during regular hemodialysis, the other occurring independent of hemodialysis. accumulation of rare phenomena like carpal-tunnel syndrome and Dupuytren's contractures in group II together with the frequent occurrence of actinic elastosis implies systemic disturbance of collagen metabolism in long-term regular hemodialysis patients.