L. E Ianhez

Screening for significant coronary artery disease in high-risk renal transplant candidates.

BackgroundRenal transplant candidates are at an increased risk for coronary artery disease (CAD), a strong predictor of cardiovascular events [major adverse coronary events (MACE)]. Coronary angiography is a costly, risky, invasive procedure. We sought to determine clinical predictors of significant CAD (stenosis ≥70%) in high-risk renal transplant candidates. MethodsClinical evaluation and coronary angiography were performed in 301 patients (57±8 years, 73% men) on hemodialysis for 32 months (median). Patients were followed-up for 22 months (median). Inclusion criteria were diabetes (type 1 or 2), evidence of cardiovascular disease, or age ≥50 years. Risk factors included hypertension (93.7%), overweight/obesity (54.3%), dyslipidemia (44.9%), diabetes (42.1%), and smoking (24.3%). Cardiovascular disease was found as follows: peripheral arterial disease (PAD) (31.2%), angina (28.1%), stroke (12.9%), myocardial infarction (MI) (10.3%), and heart failure (9.3%). ResultsSignificant CAD was found in 136 individuals (45.2%). Diabetes [odds ratio (OR)=1.82; 95% confidence interval (CI)=1.08–3.07], PAD (OR=2.50; 95% CI=1.44–4.37), and previous MI (OR=7.75; 95% CI=3.03–23.98) were associated with significant CAD. The prevalence of significant CAD increased with the number of clinical predictors from 26% (none) to 100% (all present) (P<0.0001). The incidence of fatal/nonfatal MACE increased two, four, and sixfold in those with diabetes, PAD, or previous MI, respectively (P<0.0001). ConclusionsIn high-risk patients with end-stage renal disease, the prevalence of CAD and the incidence of MACE were high. Significant CAD or cardiovascular complications were not related to the majority of classic risk factors. Patients with diabetes, PAD, or previous MI are at higher risk of CAD, MACE, or both and, thus, must be referred for invasive diagnostic procedures.

Cardiac Effects of Persistent Hemodialysis Arteriovenous Access in Recipients of Renal Allograft

In hemodialysis patients, large arteriovenous (AV) fistulas for vascular access may cause ventricular hypertrophy and high-output cardiac failure. The long-term cardiac consequences of functional AV fistulas in renal transplant patients are unclear. A precise knowledge of these consequences is important to decide if and when such fistulas should be closed in successfully transplanted patients. In this retrospective study including 61 stable renal transplant patients with adequate renal function (serum creatinine <2.0 mg/100 ml), echocardiography was performed in 39 patients with a functional AV fistula (group 1) and in 22 whose fistulas had been closed, for esthetic reasons, within 2 months postoperatively (group 2). The volume flow of the fistulas, measured in 22 randomly selected individuals of group 1, was 900 ± 350 ml/min (range 500–1,600). Patients of group 1 were older (40 ± 12 vs. 33 ± 12 years, p < 0.05), had longer duration of the fistula (62 ± 31 vs. 36 ± 30 months, p < 0.05), higher body mass index (24 ± 4 vs. 22 ± 3 kg/m2, p < 0.05), systolic (154 ± 24 vs. 138 ± 18 mm Hg, p < 0.05) and diastolic (96 ± 12 vs. 89 ± 11 mm Hg, p < 0.05) blood pressure and increased left ventricular (LV) end-diastolic dimension (53 ± 5 vs. 49 ± 5 mm, p < 0.01). LV mass, cardiac index, ejection fraction and the proportion of patients with LV hypertrophy were comparable in the two groups. LV end-diastolic dimension was positively and independently influenced only by the presence of the AV fistula (p < 0.01) after adjusting for age, duration of the fistula, body mass index, systolic and diastolic blood pressure and the nature of the antihypertensive drugs used. In conclusion, the persistence of large, high-flow AV fistulas for prolonged periods of time had little impact on cardiac morphology and function of stable renal transplant patients with adequate renal function. The data do not support routine closure of these fistulas in all renal transplant patients.

Protective Effect of N-acetylcysteine on Early Outcomes of Deceased Renal Transplantation

We investigated the effects of the antioxidant N-acetylcysteine (NAC) on early outcomes of deceased donor renal transplantation. Between April 2005 and June 2008, adult primary graft recipients of deceased renal donors were assigned to treatment (n = 38) or control (n = 36) groups and evaluated for 90 days and one year after renal transplantation. The treatment group received NAC orally (600 mg twice daily) from day 0 to 7 postoperatively. Renal function was determined by serum creatinine, MDRD and Cockcroft-Gault estimated GFR (eGFR), delayed graft function (DGF) and dialysis free Kaplan-Meier estimate curve. Serum levels of thiobarbituric acid reactive substances (TBARS), were employed as markers of oxidative stress. The NAC group displayed a lower mean serum creatinine during the first 90 days (P = .026) and at 1 year after transplantation (P = .005). Furthermore, the NAC group showed a higher mean eGFR throughout the first 90 days and at 1 year. DGF was lower among the NAC group (P = .017) and these recipients required fewer days of dialysis (P = .012). Oxidative stress was significantly attenuated with NAC (P < .001). Our results suggested that NAC enhanced early outcomes of deceased donor renal transplantation by attenuating oxidative stress.

C4d-Positive Chronic Rejection : A Frequent Entity With a Poor Outcome

Background. Chronic rejection (CR) is an important cause of kidney graft loss. Some studies have suggested the role of antibodies mediating chronic graft dysfunction. In this context, C4d identification is an important tool to evaluate antibody-mediated rejection. Method. This is a retrospective study that analyzed 80 patients with histological diagnosis of chronic allograft nephropathy (CAN) according Banff 97 and no evidence of transplant glomerulopathy. These patients had renal biopsies available for C4d immunoperoxidase staining at the time of diagnosis. Cases were reclassified by the presence of C4d in peritubular capillaries. Results. C4d was negative in 30 cases (37.5%) and positive in 50 (62.5%). C4d+ group had more female and highly sensitized patients (PRA) at transplant. All variables were similar between C4d- and C4d+ cases at diagnosis time, but more C4d+ patients presented proteinuria (>0.3 g/L). Patients were submitted to various immunosuppression regimens after the CAN diagnosis. Four years after the diagnosis, death-censored graft survival was 87% for C4d- and 50% for C4d+ (P=0.002). In the multivariate Cox regression analysis, C4d+, PRA>10%, and vascular intimal proliferation were the variables that present higher relative risk for graft loss. Conclusion. These data indicate that C4d positive chronic rejection is very common, associated with proteinuria, and has a poor outcome. A larger study is warranted to identify which immunosuppressive regimen may modify the poor course of this entity.

Non–Human Leukocyte Antigen Antibodies Reactive with Endothelial Cells Could Be Involved in Early Loss of Renal Allografts

Preformed donor-specific human leukocyte antigen (HLA) antibodies have been associated with allograft dysfunction and failure. However, recipients of HLA-identical kidneys can develop acute humoral rejection, implicating putative pathogenic antibodies that are directed against non-HLA antigens. We investigated the presence of endothelial cell-reactive antibodies in 11 patients who experienced early loss of their transplanted kidneys owing to humoral rejection and 1 loss from renal venal thrombosis. We examined the potential efficacy of intravenous immunoglobulin to block the binding of these antibodies, as previously suggested for anti-HLA antibodies.

Does low-dose allopurinol, with azathioprine, cyclosporin and prednisolone, improve renal transplant immunosuppression?

This communication reports the results of two studies aimed at improving the immunosuppressive efficacy of azathioprine in renal transplant patients. Although azathioprine has been used in transplantation for over 30 years, the mechanism of its cytotoxicity is not yet completely defined. It is generally accepted that its principal mode of action involves rapid conversion in vivo to 6-mercaptopurine (6MP), which is further metabolised via 6-thioinosinic acid to cytotoxic thioguanine nucleotides (1). The efficacy of 6MP is reduced by catabolic pathways, one of them being via xanthine oxidase (XO), which oxidises 6MP to thiouric acid. Thus the therapeutic combination of azathioprine with allopurinol, which inhibits the XO path, is usually contra-indicated, having been associated with bone marrow toxicity (2). The importance of this catabolic route is illustrated by the severe myelotoxicity reported in an XO-deficient patient treated with azathioprine (3). Azathioprine and 6MP catabolism may also occur via aldehyde oxidase (AO) and thiopurine methyltransferase (TPMT) (Figure 1).

Hyperhomocyst(e)inemia in chronic stable renal transplant patients

PURPOSE Hyperhomocyst(e)inaemia is an important risk factor for atherosclerosis, which is currently a major cause of death in renal transplant patients. The aim of this study was to assess the influence of immunosuppressive therapy on homocyst(e)inemia in renal transplant recipients. METHODS Total serum homocysteine (by high performance liquid chromatography), creatinine, lipid profile, folic acid (by radioimmunoassay-RIA) and vitamin B12 (by RIA) concentrations were measured in 3 groups. Group I patients (n=20) were under treatment with cyclosporine, azathioprine, and prednisone; group II (n=9) were under treatment with azathioprine and prednisone; and group III (n=7) were composed of renal graft donors for groups I and II. Creatinine, estimated creatinine clearance, cyclosporine trough level, lipid profile, folic acid, and vitamin B12 concentrations and clinical characteristics of patients were assessed with the aim of ascertaining determinants of hyperhomocyst(e)inemia. RESULTS Patient ages were 48.8 +/- 15.1 yr (group I), 43.3 +/- 11.3 yr (group II); and 46.5 +/- 14.8 yr (group III). Mean serum homocyst(e)ine (tHcy) concentrations were 18.07 +/- 8.29 mmol/l in renal transplant recipients; 16.55 +/- 5.6 mmol/l and 21.44 +/- 12.1 mmol/l respectively for group I (with cyclosporine) and group II (without cyclosporine) (NS). In renal donors, tHcy was significantly lower (9.07 +/- 3.06 mmol/l; group I + group II vs. group III, p<0.008). There was an unadjusted correlation (p<0.10) between age (r=0.427; p<0.005) body weight (r=0.412; p<0.05), serum creatinine (r=0.427; p<0.05), estimated creatinine clearance (r=0.316; p<0.10), and tHcy in renal recipients (group I +II). Independent regressors (r2=0.46) identified in the multiple regression model were age (coefficient= 0.253; p=0.009) and serum creatinine (coefficient=8.07; p=0.045). We found no cases of hyperhomocyst(e)inemia in the control group. In contrast, 38% of renal recipients had hyperhomocyst(e)inemia: 7 cases (35%) on cyclosporine and 4 (45%) without cyclosporine, based on serum normal levels. CONCLUSIONS Renal transplant recipients frequently have hyperhomocyst(e)inemia. Hyperhomocyst(e)inemia in renal transplant patients is independent of the scheme of immunosuppression they are taking. The older the patients are and the higher are their serum creatinine levels, the more susceptible they are to hyperhomocyst(e)inemia following renal transplantation.

Acute vascular rejection: a clinical and morphological study

Abstract We analyzed one special type of acute vascular rejection (AVR), defined as fibrous thickening of the arterial intimal layer that leads to early renal failure. Twenty‐one patients who presented this histological pattern were studied among 339 transplanted over 4 years. Patients were separated into two groups. Thirteen patients have restained their kidneys (Group A, 61.9 %) and 8 have lost their grafts (Group B, 38 %). Diagnosis was made on average 430. POD in GA and at 49° POD in GB on the 43rd postoperative day in group A and on the 49th postoperative day in group B (NS). In group A, mean serum creatinine is 2.2 mg/dl and follow‐up time is 29 months. Oliguria was much more frequent in group B (75% versus 15.3%, P= 0.01). These patients were submitted to 91 renal biopsies always because of non‐function. Typical vascular lesions began at arcuate arteries and progressed, as seen in sequential biopsies, to interlobular arteries and arterioles. When only arcuate arteries were affected, 22.5 % of renal losses were seen, but when arcuate plus interlobular arteries were compromised, 72.2 % of patients lost their kidneys (P= 0.006). We did not identify any difference in immunofluorescent staining from biopsies with or without vascular rejection, or between groups A and B. We concluded that about 2.3 % of our patients lost their kidneys because of this kind of AVR, diagnosed near the 43rd postoperative day. The only clinical predictive sign of poor reversibility was oliguria. The attack on arcuate plus interlobular arteries meant a poor prognosis. Immunofluorescent staining did not have a prognostic value.

Hemorrhagic Cystitis Secondary to Adenovirus or Herpes Simplex Virus Infection Following Renal Transplantation: Four Case Reports

Viral infections are common complications following renal transplantation. However, there have been few reported cases of viral cystitis secondary to herpes simplex virus or adenovirus infection. Herein, we have reported four cases of hemorrhagic cystitis secondary to infections with herpes simplex virus and adenovirus following renal transplantation. The etiology was adenovirus in three cases and herpes simplex virus in the remaining case. In all four cases, the primary cause of the renal dysfunction was diabetic nephropathy. All four patients presented with a clinical profile characterized by dysuria, pollakiuria, macroscopic hematuria, and graft dysfunction. Three of the four patients developed these symptoms within the first 3 months after renal transplantation. In all four cases, there was an increase, albeit slight, in creatinine levels, which returned to normal or near-normal values upon resolution of the symptoms. Acute cellular rejection was observed in only one case. Although rare, hemorrhagic cystitis secondary to infection, which typically occurs early in the posttransplant period, causes pronounced symptoms. The infection appears to be self-limiting, resolving completely within 4 weeks.

Is azathioprine harmful to chronic viral hepatitis in renal transplantation? A long-term study on azathioprine withdrawal

CHRONIC viral hepatitis represents one major morbidity factor in renal transplantation because the incidence of hepatitis C reaches 30% of the patients. Azathioprine (AZA) has been a major immunosuppressive agent for decades. Among the AZA side effects, AZA hepatitis is one of the most common, presenting with an increase in the serum liver enzymes due to hepatocellular necrosis and sometimes increased bilirubin serum levels due to intrahepatic cholestasis. The AZA side effects are now recognized as occurring almost exclusively in patients with viral liver disease, either hepatitis C or B. There is a concern that the use of AZA can precipitate the progression of liver disease and patient morbidity and mortality. We report here the results of a single-center retrospective study comparing AZA withdrawal with dose reduction only, on the progression of liver disease and patient survival.