CsA Patients Research Articles

HLA-Identical Renal Transplants: Impact of Cyclosporine on Intermediate-Term Survival and Renal Function

Seventy-two and 34 consecutive HLA-identical sibling renal transplant recipients were treated with azathioprine/prednisone (AZA; follow-up, 5.0 years) and cyclosporine/prednisone (CSA; mean follow-up, 2.9 years), respectively. Both groups were similar in age, sex, race, and number of transplants, but there were more diabetics in the CSA group (34% v 8%). Actual patient survival at 1 year and actuarial patient survival at 5 years were 100% and 96%, respectively in the CSA group compared with an actual patient survival of 91% and 82% at 1 and 5 years, respectively, in the AZA group. Actual graft survival at 1 year improved from 85% in the AZA group to 97% in the CSA-treated recipients (P less than 0.05). Mean serum creatinine at 5 years remained stable in the AZA group at a mean of 123 mumol/L (1.4 mg/dL) compared with a progressive increase in this parameter to a mean of 212 mumol/L (2.4 mg/dL) after the same time interval in the CSA patients. Furthermore, the slopes of the serum creatinine against time were significantly different between the two groups (P less than 0.01). Mean daily CSA dose averaged 4 mg/kg 12 months following transplantation, with a decrease to 2.4 mg/kg by the fifth year. Causes of death in the AZA group were cardiovascular (eight), sepsis (three), cancer (one); and in the CSA group, Kaposi's sarcoma (one). Causes of graft failure in the AZA group were immunological (six), sepsis (three), technical (two), recurrence of disease (one), and patient death with a functioning graft (five). Technical (one), noncompliance (two), recurrence of disease (one), and patient death with a functioning kidney (one) caused graft failure in the CSA group. No difference in posttransplantation serum cholesterol or incidence of new onset diabetes was observed between the two groups, but hypertension was significantly more frequent (51% v 21%, P less than 0.01) when CSA was used. In conclusion, intermediate-term results of CSA-treated HLA-identical transplant recipients showed improved patient and graft survival with less complications apart from hypertension. However, the slow, but relentless, increase in serum creatinine in the CSA-treated patients compared with those treated with AZA is of concern.

POSTTRANSPLANT HYPERGLYCEMIA

The incidence of posttransplant diabetes mellitus (PTDM) was compared in two groups of renal allograft recipients. These were all nondiabetic patients who had been transplanted between 1979 and 1987 and received either azathioprine-methylprednisolone (group 1) or cyclosporine-methylprednisolone (group 2) therapy as maintenance immunosuppression. The incidence of PTDM in group 1 was 9.1% vs. 18.6% in group 2 (P less than .05). The mean daily dose of methylprednisolone during the initial 2 months posttransplant was not greater among the PTDM patients of groups 1 or 2. Cyclosporine levels and mean daily CsA doses during the initial 2 posttransplant months were also not different among the CsA-PTDM and euglycemic CsA patients. Posttransplant diabetes mellitus occurred rapidly (less than 2 months) and required insulin therapy in the majority of cases. Increased age (greater than 40 years) was associated with a higher risk for PTDM, however, the greater incidence accompanying increased body weight only approached significance. Patient gender and donor source were not associated with significant risk for PTDM. The development of PTDM was accompanied by a significant decrease in graft survival at 3 years in the entire PTDM population and at 4 years in the CsA-PTDM subgroup. Actuarial patient survival was not adversely affected. The current study suggests that CsA may be diabetogenic when administered with methylprednisolone to renal allograft recipients. The adverse effect on allograft survival requires further investigation. These results may also have important implications for pancreatic and islet cell transplantation.

Serum C-reactive protein concentrations in cyclosporine-treated renal allograft recipients.

Acute or persistent elevations in serum C-reactive protein (CRP) concentration have been shown to be of value in diagnosing acute rejection episodes in azathioprine (AZA)-treated renal transplant recipients. To assess whether changes in serum CRP level might assist in differentiating nephrotoxicity from acute rejection in cyclosporine (CsA)-treated renal transplant recipients, we measured changes occurring in serum CRP concentrations in 74 CsA patients in response to transplant operation, acute rejection, cyclosporine nephrotoxicity, and serious infection, and compared these values with changes in AZA patients. Serum CRP concentration rose in response to operation in virtually all patients, regardless of immunosuppressive regimen, from mean baselines of 5.9 +/- 2.7 mcg/ml (AZA) and 6.8 +/- 6.5 mcg/ml (CsA) to mean peak levels of 43.8 +/- 33.4 mcg/ml and 65.1 +/- 39.5 mcg/ml, respectively. CRP rose during 76% of acute rejection episodes in AZA patients by a mean of 29.7 +/- 37.4 mcg/ml. In contrast, in 80% of acute rejection episodes of CsA patients, CRP remained undetectable or failed to rise above a stable, minimally elevated baseline. Similarly, there was no elevation in CRP in 9 of 10 episodes of nephrotoxicity. In 14 CSA patients with serious infections (8 pulmonary, 3 intraabdominal, 3 genitourinary), CRP rose by a mean of 67.7 +/- 50.7 mcg/ml. Thus, although CRP rises significantly with operation or serious infection in CsA patients, CRP fails to rise with nephrotoxicity or acute rejection.

Immunohistologic analysis of human renal allograft dysfunction.

The value of percutaneous core needle biopsy in the immunohistological evaluation of renal allograft dysfunction was studied in 72 consecutive biopsies performed in 42 patients. The phenotypes of infiltrating cells mediating graft destruction were identified with monoclonal antibodies and immunoperoxidase staining techniques. Light microscopy, electron microscopy, and immunofluorescence staining were performed in all biopsies. Biopsies were divided into groups depending on their classification on the basis of standard histologic criteria, i.e., acute tubular necrosis (ATN), acute interstitial rejection, acute vascular rejection, chronic rejection and renal disease in native kidneys (RDNK) of nontransplant patients. Immunohistologic analysis of graft biopsies showed a significant increase in Leu 1 (pan-T cells), (P less than 0.001), Leu 2 (cytotoxic/suppressor cells) (P less than 0.001), and Leu 3 cells (P less than .05) in acute interstitial rejection. The expression of DR antigen was significantly increased in both acute (P less than .025) and chronic (P less than .05) rejection, when compared with the findings in ATN biopsies. Leu M1 (monocytes/activated T cells) and Leu 10 (B cells/macrophages) were significantly increased (P less than 0.05 and P less than .005, respectively) in acute interstitial rejection only. The helper/suppressor ratio of infiltrating cells showed no significant change in any clinopathologic category. There was no correlation between the cell populations infiltrating the graft and those monitored in the peripheral blood. Allograft mononuclear cell infiltrates in cyclosporine (CsA) vs. azathioprine-treated patients revealed significantly fewer Leu 2 (P less than .05) and Leu M1 (P less than .05) cell populations in CsA patients during acute rejection. In 32 of these 72 biopsies (44.4%), the biopsy results provided a direct contraindication to the use of steroids, by allowing differentiation between allograft rejection and other causes of graft dysfunction. A total of 38% of the biopsies yielded a histological diagnosis that contradicted the clinical pre-biopsy diagnosis. All allografts showing evidence of severe small vessel disease and/or antibody-mediated rejection eventually were lost. These data highlight the usefulness of needle biopsy material as a guide to the study of intragraft immune events and to clinical management of recipients.

Successful transplantation of cyclosporine-treated allograft recipients with serologically positive historical, but negative preoperative, donor crossmatches.

Eighteen renal allograft recipients (15 cadaveric and 3 haploidentical living-related donor transplants) with historically (Hx)3 positive, but pretransplant (pre-Tx) negative, donor crossmatches (XM) were treated postoperatively with cyclosporine (CsA) and prednisone (Pred). The one-year allograft survival for the 14 primary allograft recipients was 86% (12/14). This was comparable to, and not significantly different from, the 81% (51/63) graft survival for recipients of primary cadaveric donor allografts transplanted during the same period who displayed a negative donor crossmatch with both Hx and pre-Tx sera. All four retransplant recipients with (+) Hx, but (-) pre-Tx, donor Xms lost their grafts. This result was significantly different (P less than 0.05) from the 75% (27/36) graft survival for retransplant recipients displaying a negative donor crossmatch with both Hx and pre-Tx sera. A significant decrease in PRA of 52 +/- 19% to 19 +/- 16%, P less than 0.05, was displayed by 12/18 CsA patients when comparing (+) Hx to (-) pre-Tx sera, which could have influenced the allograft survival in those patients. However, a graft survival of 44% (4/9) was observed for azathioprine (Aza) and Pred-treated recipients of cadaveric donor renal allografts who also displayed a significant decrease in PRA of 50 +/- 22% to 5 +/- 4%, P less than 0.05 when comparing Hx to pre-Tx sera. The decreasing PRA did not beneficially affect these Aza-Pred patients' graft survival. Therefore, CsA-Pred afforded a beneficial effect when recipients of a primary cadaveric renal allograft displaying a (+) Hx, but (-) pre-Tx, XM were transplanted. Retransplant recipients, however, should receive a cadaveric donor allograft only when they are XM-unreactive, whether testing with pre-Tx or Hx sera.

Post-transplant acute renal failure in cadaver renal recipients treated with cyclosporine

The outcome of patients with acute renal failure following cadaveric renal transplant has been evaluated in a prospective, controlled trial, comparing treatment with cyclosporine (CSA) to prednisone, azathioprine, and antilymphocyte globulin (AZA). There was a high incidence of acute post-transplant renal failure in both groups: 37 of 51 CSA and 31 of 45 AZA patients, due to the long exposure of kidneys to warm and cold ischemia. Onset of adequate renal function was delayed for three or more weeks in 27 (53%) CSA and only nine (20%) AZA patients, and the only predisposing factor found was donor hypotension. All nine AZA and 18 of the 27 CSA patients with prolonged oliguria subsequently had a spontaneous diuresis. Nine of the CSA patients were changed to azathioprine and prednisone because of suspected CSA toxicity, and eight of these kidneys began functioning within days, even though they had been oliguric for 21 to 83 days. Of these nine patients, five had adequate long-term function on AZA, three developed CMV infections that were fatal to two individuals, and two rejected their grafts. Plasma CSA levels fluctuated widely in all patients, but were not higher in any group, including those with prolonged oliguria. During the oliguric period, biopsy specimens proved rejection was more common in the nine patients who had their CSA stopped than in the other CSA patients, and seven of these nine developed a diffuse interstitial fibrosis that was thought to be a manifestation of CSA toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Herniation of the heart: Bettman, R. B., and Tannenbaum, W. J.: Ann. Surg. 128:1012 (Nov.), 1948

Endothelial dysfunction in renal transplant recipients maintained on cyclosporine.Hypertension is almost universal following renal transplantation and may contribute to the already poor cardiovascular prognosis of this group. Cyclosporine-induced hypertension is a particular problem and has variously been attributed to increased sympathetic nerve activity, salt and water retention, and increased circulating endothelin levels. However, the effects of cyclosporine on the L-arginine/nitric oxide (NO) system in vivo in humans are unknown. In this present study, we examined basal and stimulated NO production from the vascular endothelium in cyclosporine-treated renal transplant recipients using the technique of forearm venous plethysmography.In study 1, stimulated NO production was assessed in 9 cyclosporine-treated renal transplant recipients (CsA), 7 azathioprine-treated renal transplant recipients (AZA), and 12 controls, using carbachol (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). In study 2, basal NO production was assessed in 9 cyclosporine-treated patients and 11 controls using L-NMMA (inhibits NO synthase), with norepinephrine as a control vasoconstrictor. Drugs were infused into the nondominant forearm through a sterile 27-gauge needle, and changes in forearm blood flow (FBF) were measured using venous occlusion plethysmography.In study 1, sodium nitroprusside caused a similar dose-dependent increase in FBF in all groups. However, the median (range) percentage increase FBF to carbachol (3 μg/min) was markedly reduced in the CsA patients (188.8; 72.5 to 385.1) compared with AZA patients (378.1; 124.0 to 548.9; P = 0.042) and to controls (303.8; 124.8 to 813.3; P = 0.028). In study 2, the maximum percentage reduction in FBF to L-NMMA (4 μmol/min) was less pronounced in CsA patients (-19.5; -4.7 to -63.1) compared with controls (- 39.5; -15.7 to -52.8; P = 0.056), and while controls vasoconstricted to the maximum dose of norepinephrine (240 pmol/min) as expected (-26.9; -1.4 to -38.6), CsA patients as a group tended to vasodilate (7.9; -36.8 to 92.6; P = 0.02).These data demonstrate impaired stimulated and basal NO production in CsA patients, indicating endothelial dysfunction. This may predispose patients to atherosclerosis and may be involved in the etiology of post-transplant hypertension.