Antonio Tarantino

Risk factors for late kidney allograft failure

BACKGROUND While graft survival rates in the short term have improved dramatically, only a modest improvement has been shown in long-term graft survival rates. We evaluated the causes of late failure in renal allograft recipients treated with cyclosporine A (CsA). METHODS A total of 864 adults with a functioning graft at one year were evaluated. The end points were dialysis or death with a functioning graft. RESULTS The 13-year patient and graft survival probabilities were 0.82 and 0.64, respectively. The graft half-life was 20.1 years and the pure graft half-life was 31.1 years. At multivariate analysis, plasma creatinine at one year (P = 0.0006; RR 1.72), low-density lipoproteins (LDL) at one year (P = 0.0014; RR 1.65), older age (P = 0.0128; RR 1.50) and delayed graft function (P = 0.0350; RR 1.45) were associated with the end point. Chronic allograft nephropathy was the cause of failure in 97 patients, death in 70, recurrence of glomerulonephritis in 24, other events in 6. Cardiovascular complications were the most frequent cause of death. Post-transplant cardiovascular events were associated with: pre-transplant cardiovascular events (P = 0.0012; RR 2.65), older age (P = 0.0001; RR 2.46), pre-transplant arterial hypertension (P = 0.0249; RR 1.57), smoking (P = 0.0235; RR 1.29), duration of dialysis (P = 0.0229; RR 1.28). Mean serum cholesterol, LDL and triglycerides were each significantly associated post-transplant cardiovascular events. CONCLUSIONS The graft half-life was 20 years. Chronic allograft nephropathy was the leading cause of late failure, followed by death. If the data were censored by death, the projected pure graft half-life would be 31.1 years. Pre-transplant selection and preparation of the candidate as well as appropriate life style are recommended to improve life expectancy and extend graft survival.

Cutaneous Lesions in 67 Cyclosporin-Treated Renal Transplant Recipients

Sixty-seven out of 100 kidney transplant recipients treated with cyclosporin and methylprednisolone were evaluated for the presence of dermatological manifestations. Only 2 patients had no dermatological lesions; 80% had iatrogenic lesions, 38% infectious, 13% miscellaneous, 3% cancerous lesions, while 28% had cutaneous manifestations related to previous uremic state. Most of the lesions concerned the pilosebaceous unit: hypertrichosis (60%), epidermal cysts (28%), pilar keratosis (21%), acne (15%), folliculitis (12%) and sebaceous hyperplasia (10%). Among infectious manifestations, viral lesions were the most frequent and were very severe in the first month after transplantation. Two patients developed a squamous-cell epithelioma and a probable cutaneous lymphoma, respectively.

Clinical Features and Course of Kaposi’s Sarcoma in Kidney Transplant Patients: Report of 13 Cases

We retrospectively evaluated the prevalence of Kaposis sarcoma (KS) in 820 kidney transplant recipients with a follow-up period of at least 6 months. Thirteen patients developed a KS (1.6%): 2 were under conventional therapy and 11 under ciclosporin A. The onset of KS was 38.7 +/- 38.3 (range 6-124) months after transplantation in the whole population and after 33.9 +/- 19.7 months in the patients treated with ciclosporin A only. Nine were men and 4 women (male/female ratio: 2.25:1). The mean age at KS occurrence was 36.8 +/- 11.1 years. The mean follow-up period since KS diagnosis was 35.9 +/- 19.5 months. Clinical manifestation and severity of KS were heterogeneous: 5 patients had a KS with cutaneous involvement only, 8 patients a KS with multiple skin and mucosal and/or visceral lesions. Only 2 patients from the second group died of peritonitis due to intestinal lesions. In these 2 patients, immunosuppressive therapy had either been increased or reintroduced after a partial regression of KS. In all other patients, therapy was promptly reduced or withdrawn. In 1 patient local radiation therapy plus intralesional bleomycin administration were started and 1 patient received intralesional vincristine. Nine patients had a complete and 2 a partial remission of lesions. After therapy reduction, 4 patients lost their kidney (these patients however, had an already ongoing chronic rejection at KS diagnosis), in 2 there was an improvement of graft function, and in the other patients it remained stable. Our experience confirms that in most cases reduction or withdrawal of immunosuppression halts the evolution of both cutaneous and visceral lesions, without compromising graft function.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension After Renal Transplantation

In 212 cyclosporine-treated renal transplant recipients with stable graft function at 1 year and with potential follow-up of 5 years the prevalence of arterial hypertension was 81.6% at 1 year and 81.2% at 5 years. The logistic regression analysis showed that the presence of hypertension before transplantation (P = 0.0001; odds ratio 3.5), a plasma creatinine level higher than 2 mg/dL at 1 year (P = 0.0001; odds ratio 3.8), and a maintenance therapy with corticosteroids (P = 0.008; odds ratio 3.3) were positively associated with hypertension at 1 year after transplantation. The mean number of graft failures between 1 and 5 years was significantly higher and the mean reciprocal of plasma creatinine was significantly worse at 1 and 5 years in patients with noncontrolled hypertension than in normotensive patients or in patients with hypertension well controlled by drugs. We also investigated the potential protective role of nifedipine. The episodes of acute tubular necrosis (four versus three), of acute rejections (28 versus 29), the mean arterial pressure at 1 year (105 +/- 9 versus 104 +/- 9 mm Hg) and 5 years (105 +/- 10 versus 108 +/- 12 mm Hg), and the mean plasma creatinine level at 1 year (1.4 +/- 0.4 versus 1.6 +/- 0.4 mg/dL) and 5 years (1.8 +/- 1 versus 1.9 +/- 1 mg/dL) were similar in 52 patients who were given nifedipine for at least 4 years and 58 hypertensive patients who never took calcium channel blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history of hepatitis B and C in renal allograft recipients.

Background. In renal allograft recipients, most cases of liver dysfunction are caused by hepatitis B virus and hepatitis C virus (HCV). The natural history of hepatitis C and B was studied in 286 renal allograft recipients who received a kidney allograft between 1972 and 1989 when tests for anti-HCV became available. Methods. In all patients, hepatitis B (HB) surface (s) antigen (Ag) was tested before and anti-HCV (by enzyme-linked immunosorbent assay II) after transplantation. Results. At enrollment in 1989 (5.5±4 years after transplantation), 209 patients were anti-HCV positive (C+), 42 patients were HBsAg-positive (B+), and 35 patients were both B+ and C+ (C+B+). One hundred four patients were receiving azathioprine (AZA) and 182 were on cyclosporine A (CsA). Since transplantation, the median follow-up was 18 years in AZA-treated and 13 years in CsA-treated patients. Liver biopsy showed chronic hepatitis in 73 patients, cirrhosis in 20 patients, and fibrosing cholestatic hepatitis in 2 patients. In 34 patients, liver biopsy was repeated, and progression of fibrosis was observed in 24 patients. The 12-year patient survival rate was similar in B+, C+, and B+C+ patients (67%, 78%, and 71%, respectively; P=not significant). Liver-related death was the first cause of death in B+ and B+C+ infected patients (58% and 72%, respectively), whereas cardiovascular disease was the leading cause of death in C+ patients (40%). Multivariate analysis showed that older age (>40 years) (relative risk [RR], 2.8), B+ status (RR, 2.36), and C+ status (RR, 1.65) were independently associated with a worse patient survival. Conclusions. In the long term, B+ patients had a higher risk of death related to liver disease than C+ patients, and co-infection did not worsen patient survival.

Oxidative stress in kidney transplant patients.

Background. Little information is available about the role of oxidative stress in renal transplant patients. To evaluate the prevalence and severity of oxidative stress in renal transplantation, the authors conducted a cross-sectional study. Methods. In 112 cadaver or living-donor kidney transplant recipients with a follow-up of at least 6 months and with plasma creatinine less than or equal to 2.5 mg/dL, complete blood count, serum vitamin B12, serum folate (s-F), reactive oxygen species (ROS), thiol groups (−SH), total antioxidant activity (TAOC), serum homocysteine (Hcy), and intraerythrocyte folate (ery-F) were measured. Results. The mean levels of Hcy (21.1 &mgr;M vs. <10 &mgr;M), ROS (302.7 U. Carr (Carratelli units) vs. 250–300 U. Carr), and TAOC (410.6 &mgr;mol/HclO/mL vs. >350 &mgr;mol/HclO/mL), were higher than the reference interval, whereas −SH groups, vitamin B12, s-F, and ery-F were within the normal range. In the multivariate model, plasma creatinine (P =0.0062), vitamin B12 (P =0.0121), and TAOC (P =0.0007) were independently associated with oxidative stress. At multiple regression analysis, −SH groups and ROS were directly and inversely related to hematocrit (P =0.0007 and P =0.0073). There was also a negative correlation between −SH groups and blood pressure levels (P =0.0095). Conclusions. Renal transplant patients have a pattern of increased oxidant stress that is counterbalanced by an enhancement of the antioxidant mechanisms. Besides the well-known risk factors, the authors found that anemia is an independent risk factor for an increase of ROS. Further studies are needed to evaluate whether the correction of anemia might prevent or reduce the oxidative stress in renal transplant patients.

A randomized prospective trial comparing cyclosporine monotherapy with triple-drug therapy in renal transplantation

In a prospective trial 151 recipients of renal transplants were randomly assigned to treatment with CsA alone (74 patients) and to low dose of AZA, prednisolone, and CsA (77 patients). At two years, graft survival was 84% for the monotherapy and 90% for the triple therapy. This difference was not statistically significant. The number of rejection episodes was similar in the two groups, but the severity of rejection was significantly worse among the patients on monotherapy. More kidneys were lost because of rejection (6 versus 3), and a higher number of methylprednisolone pulses was used for treating rejection (5.2±2.3 versus 4.3±2.9; P=0.0077). CsA nephrotoxicity episodes were more frequent among patients on monotherapy (23 versus 7; P<0.02). Infectious episodes were equally distributed between the two groups. Creatinine clearance was poorer in the monotherapy-treated patients at the third month (42±16 ml/min versus 48±15 ml/min; P=0.02), but no differences were observed between the two groups since the sixth month after transplantation. Many patients on monotherapy required changes in maintenance therapy. In fact, one patient was switched to conventional immunosuppression because of Cremophor-induced anaphylaxis. Another patient who developed Kaposis sarcoma 4-months after surgery was switched to steroids alone. Excluding 5 patients who lost their grafts a few days after transplantation, only 30 of 74 patients (40%) could be kept without steroids. We conclude that both the therapeutic protocols can give good results in renal allotransplantation; however, monotherapy could create some problems in keeping the balance between drug toxicity and significant immuno-suppression. On the contrary, triple therapy is easier to handle, especially in the early posttransplant period when the differential diagnosis between acute rejection and CsA-related nephrotoxicity can be difficult even for a skilled clinician.

THE MILAN CLINICAL TRIAL WITH CYCLOSPORINE IN CADAVERIC RENAL TRANSPLANTATION: A THREE-YEAR FOLLOW-UP

Between February and November 1983, 108 recipients of cadaveric renal transplants entered a randomized multicenter trial and were treated either with cyclosporine (CsA) and prednisone (n=55) or with conventional treatment based on azathioprine (Aza) and glucocorticoids (n=53). The graft survival probability at 3 years was 76% for CsA patients and 48% for Aza patients (P<0.001). The cumulative number of acute rejections was significantly lower in the CsA group (32 vs. 104, P<0.001). Incidence of early posttransplant anuria was similar in both groups and did not affect renal function after three years. Nephrotoxicity in CsA patients, when present, was handled by reducing the dose of CsA, but in 12/55 patients a change to conventional therapy was thought to be necessary. However, in this group of 12, one patient lost the allograft because of irreversible rejection and one patient died 14 months later because of an infection. Mean creatinine clearance after three years was significantly lower in the CsA patients (54.7±2.6 ml/min) than in Aza patients, (67.2± 4.9 ml/min, P<0.05). Considering only patients with grafts functioning after three years and still on the original randomized therapy, the mean creatinine clearance was similarly and significantly decreased from 1 to 3 years in both groups. There were no significant differences in occurrence of severe infections. Side effects such as hypertension, hypertrichosis, tremor and gum hyperplasia were more frequent in CsA patients.

Cutaneous Manifestations in Renal Transplant Recipients

Out of 105 renal transplant recipients 100 had skin lesions: 55% iatrogenic, 74% infectious, 12% precancerous or cancerous and 4% miscellaneous. Many of these lesions were at least in part transient, and steroid-related skin lesions became less frequent as years progressed. The more frequent infections were the fungal ones, followed by viral and bacterial infections with different patterns of onset. All the precancerous lesions appeared late and were almost exclusively represented by actinic keratoses; 2 evolved into squamous cell epitheliomata. 2 patients died due to Kaposis sarcoma and melanoma. The high incidence of skin cancers in transplanted patients and the rapid evolution of dyskeratoses into spinaliomas warrants close dermatological surveillance.

Porokeratosis and immunosuppression

Immunosuppression may favour the development of disseminated superficial porokeratosis (DSP). We report the clinical features and the outcome of DSP in 24 patients receiving immunosuppressive treatment (group A), and compare the characteristics of the disease with those of 13 immuno‐competent patients with DSP (group B). The two groups were similar with regard to age, sex, area of skin involvement and mean follow‐up. There was a family history of DSP in only two patients in group A, compared with five patients in group B (P= 0.03). The skin type, based on the tanning response to sunlight, was not significantly different between the two groups. Two of the 24 patients in group A had high sun exposure, compared with five of the 13 patients in group B (P = 0.03). Moreover, 10 patients in group A and 11 in group B (P = 0.01) exhibited worsening of the disease after exposure to sunlight, usually during the summertime. These observations appear to support the hypothesis that sun exposure is not always essential for the development of porokeratosis in immunosuppressed patients.