Switching to sirolimus in renal transplant recipients with hepatitis C virus: a safe option.

INTRODUCTION: The presence of hepatitis C virus (HCV) in renal transplant recipients is an independent risk factor for death and graft failure. Chronic allograft nephropathy (CAN) favored by the use of calcineurin inhibitors (CNI) is one of the main causes of graft loss, whereas sirolimus (SRL) has proven to maintain better graft function with lower rates of CAN. OBJECTIVES AND METHODS: We developed a protocol to evaluate the safety of SRL in transplant recipients with respect to HCV. We studied 5 patients (3 men) of mean age 52 +/- 9.2 years with HCV who had not received antiviral treatment. The viral genotypes were 1b in 4 cases and 2a/2c in 1 case. Basic immunosuppression was mycophenolate mofetil (MMF) and corticosteroids in all patients, cyclosporine (CsA) in 4 cases, and tacrolimus (Tac) in 1 case. Before the switch, a renal biopsy was performed and viral replication and cryoglobulins determined. RESULTS: Biopsy provided a diagnosis of CAN in 1 case, CNI toxicity-associated CAN in 2 cases, CNI toxicity in 1 case, and no renal damage in the remaining case. We observed a nonsignificant decrease in the number (log) of viral copies with a stabilization of renal function but with a slight to moderate increase in proteinuria. CONCLUSIONS: The switch seemed to be safe with no increase in viral copies. Graft renal function remained stable with increased proteinuria that must be supervised, even though it did not reach statistical significance.

Calcineurin inhibitor reduction based on maintenance immunosuppression with mycophenolate mofetil in renal transplant patients: POP study.

Since calcineurin inhibitors (CNI) have been introduced, they have become the cornerstone of immunosuppression for renal transplant patients, but their cardiovascular and neurological toxicities, and primarily their renal toxicity, have brought about an increased effort to find combinations of immunosuppressants that are either CNI-free or that use minimum doses of these drugs. The weight of immunosuppression therefore lies with drugs that have a better toxicity profile. The POP observational transverse study including 213 renal transplant patients was designed to study CNI minimization strategies. The mean time of transplant evolution to the time of reduction was 9.9 +/- 11.8 months. The acute rejection rate to the start of reduction was 9.4%. Almost all the patients were undergoing treatment with CNI + mycophenolate mofetil (MMF) + steroids in the immediate posttransplantation period. When reduction was chosen, all patients were undergoing treatment with MMF (mean dose at the start of reduction = 1490.7 +/- 478.0 mg/d). Among the cohort, 66.7% of patients were being treated with tacrolimus (mean C0 levels 13.3 +/- 6.6 ng/mL) and 33.3% with cyclosporine (mean C0 levels 192.2 +/- 94.0 ng/mL; mean C2 levels 1097.5 +/- 457.6). The main reasons for withdrawal were nephrotoxicity (55.9% of the cases), as well as prevention of adverse effects (21.6%). The mean target CNI dose reduction was 41.4% +/- 21.45% in the tacrolimus group and 28.6 +/- 10.0% in the cyclosporine group. In conclusion, CNI toxicity, primarily renal toxicity, makes reduction of these drugs based on the use of full MMF doses an alternative to manage renal transplant patients.

Gastrointestinal complications in renal transplant recipients: MITOS study.

INTRODUCTION AND METHODS: An epidemiologic multicenter study was performed to evaluate the prevalence and management of gastrointestinal (GI) complications in solid organ transplant patients. A total of 1788 recipients were included, 1132 of which corresponded to renal transplanted patients. RESULTS: The mean age for the renal transplanted patients was 52 +/- 13.2 years. The mean time from the transplantation was 5.4 +/- 5.4 years. 17.7% showed some pretransplant GI disease, while 53% presented this type of complication in the posttransplant period. Diarrhea was the most prevalent GI complication (51.5%) and digestive perforation was the GI disorder that affected the patients daily living the most. From the patients with GI complications, 71% received pharmacological treatment, using gastric protectors in 91.3% of the cases. Regarding immunosuppressive drugs, in 30.9% of the cases the dose of the drug was reduced, in 9.3% discontinued temporarily and in 7.5% discontinued permanently. These changes mainly affected the MMF (89%, 83% and 74% for dose change, temporary and permanent discontinuation, respectively). CONCLUSIONS: The prevalence of GI complications in renal transplant exceeded 50%, and affected patients' daily living. The management of these complications was based on treatment with gastric protectors, dose reduction and/or partial or definitive MMF discontinuation.

Steroids and bone density in patients with functioning kidney allografts.

INTRODUCTION: Osteopenia and osteoporosis after renal transplantation have been associated with factors related to the cause of end-stage renal disease, as well as to clinical events and therapeutic factors in the posttransplant period. We studied the prevalence of low bone density (LBD) according to WHO criteria. METHODS: A cross-sectional study was performed in a cohort of 106 patients (54 men and 52 women) with functioning renal allografts, who underwent bone densitometry (DEXA) of the lumbar spine and femoral neck. Patients were grouped according to DEXA into those with normal bone density (NBD) or LBD. We studied clinical, analytical, and therapeutic variables. RESULTS: Thirtysix patients (34%) had NBD and 70 patients (66%) LBD. Weight was the only parameter showing a significant difference (P = .034), namely, among NBD it was 80.44+/-15.13 versus LBD 73.94 +/- 14.54 kg, respectively. Creatinine clearance (CCr) tended to be lower among patients with LBD 59.62 +/- 22.73 versus 69.59 +/- 28.15 mL/min in patients with NBD (P = .052). PTHi levels were higher in patients with LBD (149.39 +/- 110.75) than those with NBD (110.94 +/- 82.61) (P = .069). In the multivariate analysis the important determinants were weight Exp(ss) = 0.967 [CI = 0.939 to 0.996] (P = .036); CCr Exp(ss) = 0.982 [CI = 0.965 to 1.000] (P = .055); and PTHi levels Exp(ss) = 1.003 [CI = 0.932 to 0.994] (P = .059). CONCLUSIONS: Osteopenia and osteoporosis are frequent among kidney transplant patients (66%), with a similar distribution between the lumbar spine and femoral neck. Excess weight and possibly better renal function may be protective factors. The cumulative steroid dose showed a significant effect on bone density. As expected, secondary hyperparathyroidism in patients with renal impairment seemed to be a risk factor for LBD.

Multifactorial thrombotic-type microangiopathy with skin ulcers and hepatitis C infection.

The case of a patient with hepatitis C virus infection who presented with symmetric ulcers of the legs is reported. She was found to have type III mixed cryoglobulinemia, high titers of anticardiolipin antibodies, lupus anticoagulant, and a free protein S deficiency. To our knowledge, this is the first reported case of such an association. The role of these factors in the pathogenesis of skin lesions in the setting of hepatitis C virus infection is discussed.

[Epidemiologic study of infection by hepatitis C virus in a hemodialysis unit]. / Estudio epidemiológico de la infección por el virus de la hepatitis C en una Unidad de Hemodiálisis.

OBJECTIVE: To analyze the prevalence of infection, the frequency of HCV genotypes and the epidemiology characteristics among the patients in hemodialysis treatment in one 25 years old hospital hemodialysis center and one 15 years old secondary unit by a transversal cross-section study in 1998. PATIENTS AND METHODS: 171 hemodialyzed-patients were studied. Patients sera were analyzed by the presence of HCV antibodies anti-VHC by a enzymoimmunoassay (Abbott Cientifica) and the presence of antibodies was confirmed by a line immunoassay (Inno-LIA HCV AbIII) and by the presence of VHC-RNA by reverse transcriptase PCR (Cobas Amplicor HCV). Genotypes were determinate by reverse hybridization (Inno-LIA HCV III). RESULTS: Fifty (29.2%) of the patients were HCV antibody positive. Forty-five (26.3%) were HCV-RNA positive, all of them with antibodies positive. The distribution of genotypes was: 1b, 34 (75.5%); 4f, 4 (8.9%); 1a, 3 (6.7%); 1, 3 (6.7%) and 1 case could not be typed (2.2%). In 14 patients (28.0%), seroconversions were documented Twenty-one patients (42.0%) were diagnosed when the routine tests were available and 15 patients (30.0%) were diagnosed pre-dialysis. The multivariate analysis showed that the risk of HCV infection was greater for patients who had been more 8 years on dialysis (OR: 6.22; 95% CI: 1.24-31.07). CONCLUSIONS: Data presented indicate that the prevalence of HCV infections in our hemodialysis units and the number of seroconversions were high and the HCV subtype 1b was more frequent; because of this, the screening by both serological and molecular methods is necessary, at least twice a year, to identify all the infected patients. Besides, we think that is necessary to increase the control of the completion of the Universal Precautions.

The PlA2 polymorphism of the platelet glycoprotein IIIA gene as a risk factor for acute renal allograft rejection.

Glycoprotein IIIa/IIb is a membrane receptor for fibrinogen and von Willebrand factor that plays an important role in platelet aggregation. The beta integrin chain of this receptor, GPIIIa, is polymorphic, and the allele known as PlA2 has been associated with coronary thrombosis. The GPIIIa genotype of a cohort of 119 consecutive renal allograft recipients (46.3 +/- 13 yr; 85 M/34 F; 24.4% diabetic patients) was determined by PCR-restriction fragment length polymorphism, and those patients were followed for at least 12 mo. From 119 patients with at least 1 yr of follow-up, those who suffered an acute rejection (n = 52) showed a lower proportion of HLA-DR beta1 identity with the donor (7.7% versus 23.9%; P = 0.03), a higher proportion of cytomegalovirus-positive (CMV+) donors/CMV- recipients (21% versus 7.5%; P = 0.05), and the PlA2 allele was more frequent (48.1% versus 26.9%; P = 0.02) compared with patients free of acute rejection (n = 67). No other variable was associated with acute rejection in the univariate analysis. The impact of the three above-mentioned significant variables on acute rejection was analyzed by stepwise logistic regression. The presence of the PlA2 allele yielded an odds ratio of 2.75 (95% confidence interval, 1.01 to 7.93) and an HLA-DR beta1 identity of 0.2 (95% confidence interval, 0.06 to 0.99) for suffering an acute rejection episode. In addition, the serum creatinine at discharge was higher in PlA2-positive versus PlA2-negative patients (2.2 +/- 1.6 versus 1.5 +/- 0.6 mg/dl, respectively; P = 0.01), and the prevalence of proteinuria >1.5 g/d 1 yr after transplantation was significantly higher among patients showing the PlA2 allele (16% versus 3%; P = 0.02). Finally, in the entire cohort of patients, the 2-yr graft survival was significantly lower in PlA2-positive (n = 43) compared with PlA2-negative (n = 76) patients (85.7% versus 97.2%; P = 0.015). No differences were found in patient survival (95.2% versus 98.7%, respectively). Proportional hazards regression analysis (Cox regression model) confirmed that serum creatinine level at discharge is the best predictor of allograft survival, followed by CMV status, delayed graft function, and the glycoprotein IIIa/IIb genotype. The PlA2 polymorphism is an independent risk factor for acute renal graft rejection, affecting short-term graft survival. Future studies aimed at preventing the hemostatic imbalance favoring platelet aggregation associated with this polymorphism may be important in preventing acute rejection and its impact on chronic rejection.

Nutritional status of CAPD patients at three years.

A nutritional assessment was carried out in 63 patients starting treatment from April 1990 up to December 1993. Anthropometric measurements were performed showing a prevalence of protein-calorie malnutrition (PCM) of 21% in a total of 142 clinical surveys carried out in the above-mentioned sample. A steady state of albumin levels in plasma was verified during a three-year follow-up period at a lower level than that of the control group. The patients' lymphocytic profile throughout the study was characterized by lymphopenia and decreased B and T8 lymphocytes. During the first two years of continuous ambulatory peritoneal dialysis (CAPD), a high percentage of patients met the "adequacy" dialysis criteria as residual renal function plays an important role as regards treatment.

Effect of recombinant human erythropoietin treatment on hemodynamic parameters in continuous ambulatory peritoneal dialysis and hemodialysis patients.

We studied the hemodynamic changes and the incidence of hypertension after correction of anemia with recombinant human erythropoietin (rhEPO) in 25 hemodialysis (HD) and in 27 continuous ambulatory peritoneal dialysis (CAPD) patients with a mean age of 44.6 years and a mean time on dialysis of 43.6 months. We analyzed basal and final hemoglobin concentrations, time elapsed to reach target hemoglobin, rhEPO dosage, and the following echocardiographic parameters: left ventricular end-systolic and end-diastolic diameters and volumes, posterior wall thickness, interventricular septum, ejection fraction, fractional fiber shortening, cardiac output index, and peripheral vascular resistance index. We did not find any significant difference between HD and CAPD patients in basal and final hemoglobin, concentrations, time elapsed to reach target hemoglobin, dose of rhEPO received for response, and incidence of hypertension. Changes were more evident in HD patients, with a decrease of 15% in cardiac output index and an equal increase of peripheral vascular resistance,. In the patients on CAPD, these variations were less important, with a decrease in cardiac output index of 10% and no significant change in peripheral vascular resistance. Despite both techniques showing the occurrence of hypertension, the left ventricular mass stabilized during the study time. We conclude that CAPD seems to modulate the changes observed in hemodynamic parameters after rhEPO treatment.

Low turnover bone disease is the more common form of bone disease in CAPD patients.

CAPD is considered a risk factor for low turnover bone disease. This was previously attributed to aluminum accumulation. We evaluated by biochemical and histomorphometric parameters (including double tetracycline labelling), 26 patients maintained on CAPD for 12-14 months. Three (11.5%) showed mild hyperparathyroidism, 5 (19.2%) osteitis fibrosa, 3 (11.5%) mixed forms, 4 (15%) osteomalacia and 11 (42.3%) adynamic bone disease. Only one patient with diabetes mellitus showed an aluminum stained bone surface > 10%. Intact PTH serum levels were lower in LTBD (133.2 +/- 128 vs 468.2 +/- 451 pg/ml; p < 0.05). We also evaluated prospectively 11 patients who underwent a bone biopsy at start of dialysis and after 12 months of CAPD treatment. Bone biopsies pre CAPD demonstrated normal-high bone turnover disease in 8/11 (72.7%) and low turnover bone disease in 3/11 (27%). In the follow-up biopsies, 2 patients showed osteitis fibrosa and other two mild forms. Low turnover bone disease was found in 7 patients (3 osteomalacia and 4 adynamic bone disease). We conclude that the predominant bone lesion in our CAPD patients is low turnover bone disease, predominantly adynamic forms, and aluminum does not seem to play a role on its genesis. Low intact PTH serum levels may be a predictor of low turnover bone disease.

Could CAPD modulate the hemodynamic changes induced by rHuEPO treatment?

Hemodynamic response to treatment with erythropoietin has been analyzed on two different groups of patients. The first group of 25 patients was treated with hemodialysis. The second group of 27 was treated with peritoneal dialysis. Both groups were studied before starting the treatment with erythropoietin, after reaching the hemoglobin target point, and after one year of treatment. The following parameters were recorded: basal and hemoglobin target point, time and dosage of response, incidence of arterial hypertension, diastolic and systolic left ventricular diameters, interventricular septum and posterior wall thickness, ejection fraction, fractional fiber shortening, left ventricular mass index, cardiac output index and peripheral resistance index. The incidence of hypertension was 28.8% and, in both techniques, stabilization of left ventricular mass index occurred a year later. When the hemoglobin target point was reached, a decrease in cardiac output and an increase in peripheral resistance was found. These changes were more evident in the group of patients treated with HD. After a year of treatment, both peripheral resistance and cardiac output were similar to basal values in both groups of patients.

Peritoneal dialysis efficiency in CAPD patients in treatment with rHuEPO.

Possible modifications in peritoneal behaviour that can be caused by erythropoietin (EPO) treatment and/or correction of anemia in the ultrafiltration and peritoneal diffusion were studied in 24 CAPD patients. The evolution of the patients on the medium run was also studied. The dialysate to plasma ratio, the peritoneal clearance and the mass transfer coefficient of urea and creatinine and the ultrafiltration volume were studied, baseline, after reaching the hemoglobin target, and after eight months of treatment. The group of patients developed a decrease in the dialysate to plasma ratio and in the peritoneal clearance of creatinine. After evaluating the effects of the hemoglobin and the hematocrit, we found a decrease in the dialysate to plasma ratio of urea and creatinine, and in the peritoneal clearance of creatinine. A decrease was also found in the mass transfer coefficients of urea and creatinine. An increase in the ultrafiltration was also found in the patients with hemoglobin levels higher or equal to 11 g/dl. Those changes are reversible after turning the hemoglobin levels back to levels lower than 11 g/dl.

Anemia in dialysis: its relation to acquired cystic kidney disease and serum levels of erythropoietin.

Acquired cystic kidney disease has been related to improvement of anemia in dialysis patients. It has been suggested that this could be due to erythropoietin production by the cysts. We studied 110 patients, 58 on hemodialysis and 52 on continuous ambulatory peritoneal dialysis, with an age of 48.6 +/- 14.78 years and a time on dialysis of 44.5 +/- 35.53 months. A renal echography was performed in every patient, evaluating presence and number of cysts. These findings were related to the blood levels of hemoglobin, ferritin, and erythropoietin as well as to the number of transfusions prescribed during the year of the study. The serum erythropoietin level was 18.23 +/- 12.14 U/l in hemodialysis patients, 15.04 +/- 12.35 in patients on continuous ambulatory peritoneal dialysis, and 12.4 +/- 4.7 U/l in the control group. Hemoglobin and erythropoietin were significantly higher in patients with polycystic kidney disease. Patients without cysts had the lowest levels of hemoglobin and erythropoietin, although no significant difference was found in those with multiple bilateral cysts or in those with 1-3 isolated cysts.

[Complications in diabetic patients on dialysis: experiences in 10 years of treatment using 3 technics]. / Complicaciones de los pacientes diabéticos en diálisis: experiencia en diez años de tratamiento con tres técnicas.

In treated diabetic patients with terminal renal failure we have examined the complications arising from the dialysis technique used. 55 patients were followed up for 1.279 months. Out of the latter, 24 were on hemodialysis (HD) 33 on continuous ambulatory peritoneal dialysis (CAPD) and 9 on intermittent peritoneal dialysis (IPD). Intraperitoneal insulin in patients on CAPD best controlled glycemia. Antihypertensive therapy was not necessary in 86%, 66%, and 46% of the patients on CAPD, IPD and HD respectively (CAPD vs HD, p less than 0.001). Acute myocardial infarction was more common in patients on HD (33%) (p less than 0.05). 22% of the patients on IPD had limb amputation (IPD vs CAPD-HD, p less than 0.05). The type of dialysis method used does not seem to influence the course of the retinopathy. The neuropathy behaved in a similar manner in those on CAPD and on HD when followed up for two years. Vascular complications were frequent in those on HD with one thrombotic event every 9.7 months/patient and a new vascular access every 7.4 months/patient. Peritonitis was the main complication of CAPD and IPD which was found more frequent in the former and longer hospitalization in the latter. The election of the dialysis technique in diabetic patients can directly influence the glycemia levels and blood pressure reading, as well as heart complications and those due to the method used. However they seem to influence less the neuropathy, retinopathy and peripheral vasculopathy.