Sirolimus is associated with new-onset diabetes in kidney transplant recipients

New-onset diabetes (NOD) is associated with transplant failure. A few single-center studies have suggested that sirolimus is associated with NOD, but this is not well established. With the use of data from the United States Renal Data System, this study evaluated the association between sirolimus use at the time of transplantation and NOD among 20,124 adult recipients of a first kidney transplant without diabetes. Compared with patients treated with cyclosporine and either mycophenolate mofetil orazathioprine, sirolimus-treated patients were at increased risk for NOD, whether it was used in combination with cyclosporine (adjusted hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.36 to 1.90),tacrolimus (adjusted HR 1.66; 95% CI 1.42 to 1.93), or an antimetabolite (mycophenolate mofetil orazathioprine; adjusted HR 1.36; 95% CI 1.09 to 1.69). Similar results were obtained in a subgroup analysis that included the 16,861 patients who did not have their immunosuppressive regimen changed throughout the first posttransplantation year. In conclusion, sirolimus is independently associated with NOD. Given the negative impact of NOD on posttransplantation outcomes, these findings should be confirmed in prospective studies or in meta-analyses of existing trials that involved sirolimus.     

Predictors of cardiovascular events and associated mortality of kidney transplant recipients

BACKGROUND: Cardiovascular disease is the most common cause of death after renal transplantation. Furthermore, acute coronary syndrome (ACS) attributable to coronary artery disease (CAD) accounts for the majority of deaths due to cardiovascular disease posttransplant. Although renal transplantation is the treatment of choice for end-stage renal disease, understanding the causes of graft and patient loss is exceedingly important to improve outcomes. METHODS: This observational study included 1200 patients who underwent a kidney transplant between 1988 and 2003. The outcome was the occurrence of an ACS event within a maximum of 15 years after renal transplantation. RESULTS: Of all 215 deaths, 28.3% were caused by complications of CAD, the most common cause of death at our center. On multivariate analysis, diabetes (P = .005), prior transplant (P = .047), body mass index (BMI) at the time of transplant (P = .01), cholesterol level (P = .012), and low-density lipoprotein (LDL) level (P = .007) during 3 years after transplant were associated with early ACS. In conclusion, diabetes, prior transplant, BMI, cholesterol, and LDL were significantly associated with early ACS highlighting the importance of improved screening and perioperative management.     

Factors associated with erectile dysfunction in male kidney transplant recipients

A transversal study was carried out in order to evaluate the prevalence of erectile dysfunction (ED) in adult kidney transplant patients of our region (N=243), and to investigate the sociodemographic, analytic, and clinical factors associated with it. To evaluate ED, the Spanish five items version of the International Index of Erectile Function (IIEF-5) was employed. Sociodemographic, analytic, and clinical data, including 12 cardiovascular risk factors, were also collected. A total of 199 patients (82%) were included. The median age was 52 y (43-62 y); 106 patients (54.9%) presented with ED. Variables associated with ED were: higher age; longer time on dialysis prior to transplantation; higher comorbidity; presence of diabetes mellitus; had undergone prostatic surgery or peripheric artheriopathy; lower diastolic pressure; and some anti hypertensive drugs. Logistic Regression Model performed step by step showed (R(2)=0.52) that factors independently associated with ED were: age, time on dialysis previous to transplant, and peripheric artheriopathy.     

Preemptive deceased donor kidney transplant not associated with patient survival benefit in minority kidney transplant recipients

Previous studies have shown an inverse association between pre-transplant dialysis exposure and post-kidney transplant outcomes. Socioeconomic and allocation factors, in contrast to medical factors, play a greater role in dialysis exposure among minorities, and medical causes for delay may impact post-transplant outcomes. This study sought to test whether minorities behaved similarly to Caucasians with regard to the effect of duration of dialysis on post-transplant outcomes. All primary deceased donor kidney transplants between 1997 and 2004 (n = 54,162) were analyzed from the Organ Procurement and Transplant Network database and were categorized as either Caucasian or minority. Adjusted patient and graft survivals were determined in each subgroup based on the duration of pre-transplant dialysis. Caucasians recipients show a clear stepwise increase in risk of graft failure and death with increasing duration of dialysis. The risk of graft failure among minorities increased less without a clear stepwise pattern. The risk of death, however, showed a U-shaped risk profile with the highest risk of death among preemptive transplants and recipients with more than five yr of dialysis. The disparate effect of dialysis on minorities suggests that a selection bias and not a biologic effect may explain the association between dialysis duration and outcomes after kidney transplantation previously reported.     

Cytomegalovirus infection in renal transplant recipients is associated with impaired survival irrespective of expected mortality risk

Cytomegalovirus (CMV) infection and CMV disease are associated with increased mortality post-transplantation. We have thus retrospectively examined whether this association is found both in patients with high and low mortality risk. Between 1994 and 1997, 471 kidney transplant recipients were monitored once weekly for CMV pp65 antigenemia and CMV disease the first 100 d after tx and followed prospectively for median 66.6 months. Patients with nephrosclerosis, diabetic nephropathy and amyloidosis were selected as high mortality risk groups (HRG). Overall and cardiovascular mortality beyond 100 d in the low-risk group (n = 372) was 14% and 3.5%, and in the HRG (n = 99) 31% and 16%, respectively. The effects of CMV infection and disease, recipient age and gender, panel-reactive cytotoxic antibodies, acute rejection, HRG, and graft loss in the whole study period were tested on overall mortality beyond 100 d in multiple analysis. HRG was independently associated with overall mortality, RR = 2.03, and still both CMV infection and disease were significant risk factors for mortality, independent of HRG. The same analysis was repeated for HRG (n = 99). Even in this small group CMV disease was independently associated with overall mortality. These data indicate that CMV increase mortality independently both in patients with otherwise high- or low-risk for long-term mortality.     

Low-density lipoprotein oxidation is increased in kidney transplant recipients

Abstract  Oxidative modification of low-density lipoproteins (LDL) plays an important role in the pathogenesis of atherosclerosis. In addition, there is evidence that chronic vascular allograft rejection may be mediated by oxidised LDL. Plasma lipoprotein concentrations and parameters of LDL oxidation were determined in 19 kidney transplant recipients and 19 healthy controls. Plasma triglycerides and total cholesterol was significantly higher in patients than in the controls. The mean LDL diameter was smaller in patients than in the controls (23.6 ± 0.71 nm vs 27.78 ± 1.16 nm, P < 0.002). Furthermore, the lag time of copper-induced in vitro LDL oxidation was shorter in patients than in the controls (101 ± 23 min vs 148 ± 81 min, P = 0.02). The titre and concentration of both IgG and IgM autoantibodies against mal-ondialdehyde-modified LDL (MDA-LDL) were higher in the patients. We conclude that there is in vitro and in vivo evidence of increased LDL oxidation in renal transplant recipients. This might facilitate the progression of atherosclerosis and enhance the process of chronic vascular rejection.     

Acute kidney injury in pediatric stem cell transplant recipients

Because respiratory dysfunction after hematopoietic stem cell transplantation is a manifestation of a continuum of dysfunction temporarily induced by the transplant process, a proactive rather than reactive approach might prevent or attenuate its progression to acute respiratory distress syndrome. Organ dysfunction in this population results from cytokine-driven processes, of which the first manifestation includes fluid accumulation. We describe a multistep protocol that first targets fluid balance control, both through restriction of intake and through augmentation of output using dopamine and furosemide infusions. If these steps fail to stem the tide of water accumulation, we advocate the relatively early use of continuous renal replacement therapy, its use triggered by a continued increase in body weight (>10% above baseline), an increasing c-reactive protein level, and an increasing oxygen need. Renal function parameters do not figure in this protocol. We recommend continuous renal replacement therapy at 35 mL/kg/h (2,000 mL/1.73 m(2)/h), a dose that allows adequate flexibility in fluid management and that may provide effective clearance of proinflammatory (and anti-inflammatory) mediators that drive the evolving dysfunction. Proactive intervention improves the clinical status such that the transition to mechanical ventilation may proceed smoothly or in some cases even may be avoided altogether.     

Anti-B cell lymphocytotoxic antibodies in kidney transplant recipients.

Serial serum samples from 47 renal allotransplant recipients were screened for antiperipheral blood lymphocyte, anti-B cell, and anti-Daudi cell line antibodies. Various associations of these antibodies were observed in 28 patients. Anti-Daudi did not correlate with graft survival, whereas anti-B, although they were often associated with anti-peripheral blood lymphocyte antibodies, showed the strongest correlation with chronic rejection (P = 0.00002). However anti-B cytotoxicity preceded or was concurrent with the onset of chronic rejection in only 53% of the cases. Antibodies were absent in six of nine patients with irreversible acute rejection, but they usually appeared after transplant nephrectomy. These findings suggest that anti-B cell antibodies may play a role in the rejection process. In 15 of 17 recipients (88%), anti-B cell antibodies occurred during the first trimester after transplantation. These patients showed 20% 1-year graft survival compared with 68% in those without antibodies at that time (P less than 0.005).     

Characterization of B cell antibodies in kidney transplant recipients

Antibodies against B lymphocytes were found in the serum of the majority of 59 kidney transplant recipients and of 22 eluates obtained from kidney allografts undergoing rejection. To characterize these B cell lymphocytotoxins we have used a mouse monoclonal anti-DR antibody (L227) that inhibits cytotoxicity of antibodies against HLA-DR antigens and a chicken serum against human Ia-like antigens that also inhibits antibodies against DR-related supertypic determinants and other Class II histocompatibility antigens. Three types of B cell cytotoxins were defined: antibodies against HLA-DR, antibodies against Ia-like antigens other than DR, and antibodies against non-Ia-related B cell antigens. Before transplantation, B cell antibodies were detected in about a third of the patients studied. They were inhibited by monoclonal anti-DR more often in recipients who ultimately rejected a kidney allograft (67%) than in those in whom the graft was successful (44%, P less than 0.03). After transplantation, antibodies inhibited by L227 were found in 56% of the patients with functioning grafts and in 94% of the recipients whose grafts had been removed because of rejection (P less than 0.001). B cell antibodies inhibited by monoclonal anti-DR were found in the majority of kidney eluates. However, although 85% of the B cell reactions of kidney eluates were blocked by this antibody, only 55% of the B cell reactions of sera obtained from the same recipients after nephrectomy were similarly inhibited. Thus it appears that antibodies against HLA-DR were bound and concentrated in the transplanted organ and other B cell antibodies were not. These results indicate that anti-DR antibodies blocked by the monoclonal antibody L227 are the most common type of B cell lymphocytotoxins formed in kidney transplant recipients. Their role in kidney allografts undergoing rejection, where they are bound in high concentration, needs to be determined.     

Pregnancy in kidney transplant recipients

PURPOSE: Our aim was to investigate kidney allograft, obstetric, and maternal outcomes in pregnant women undergoing kidney transplantation in our center. METHODS: Retrospective data on 74 pregnancies in 60 patients were reviewed and completed through phone interviews were compared with information on a control group of female kidney recipients. RESULTS: Mean age of patients at transplantation was 26.55 +/- 4.72 years and the median interval between transplantation and pregnancy was 27.5 months. Gestational period was 8 months. Live birth was the outcome in 43.2% of pregnancies; 9.5% led to still birth, 24.3% were aborted, and obstetrical data of the remaining were unavailable. Among the 11 patients who became pregnant within 12 months after transplantation, we observed seven live births and four abortions. None of pregnancies that were accompanied by acute rejection episodes (ARE) were successful. Twenty-six patients experienced at least one ARE versus 23 patients of the control group (P = NS). However, the first ARE occurred later in the pregnant group (P = .028). Chronic rejection and graft loss were seen in 24 and 18 study group cases and 17 and 17 control cases, respectively (P = NS). One-, 3-, 5-, and 10-year graft survivals were 100%, 96.5%, 94.5%, and 77.1% in the pregnant group versus 93.2%, 85.7%, 81%, and 64.7% in the control group, respectively (P = .07). CONCLUSION: Pregnancy in kidney recipients seems to be safe for kidney allograft recipients even within the first year posttransplant. Nonetheless, the outcomes of pregnancy in this group of patients is not always favorable, especially when rejection occurs simultaneously.     

Hypertension in kidney transplant recipients

Arterial hypertension is frequently observed in renal transplant recipients. Its pathogenesis is multifactorial in most cases. Calcineurin inhibitors (CNI) can increase peripheral vascular resistance by inducing arteriolar vasoconstriction and can cause extracellular fluid expansion by reducing the glomerular filtration rate (GFR), activating the renin–angiotensin system (RAS), and by inactivating the atrial natriuretic peptide. Glucocorticoids can impair urinary water and salt excretion. Poor graft function can lead to increased extracellular volume and inappropriate production of renin. Native kidneys, older age of the donor and transplant renal artery stenosis (TRAS) may also contribute to the development of hypertension. Arterial hypertension not only can increases the risk for cardiovascular events but can also deteriorate renal allograft function. A number of studies have shown that the higher the levels of blood pressure are, the higher is the risk of graft failure. On the other hand, a good control of blood pressure may prevent many cardiovascular and renal complications. Appropriate lifestyle modification is the first step for treating hypertension. Calcium channel blockers (CCB) and renin–angiotensin system (RAS) inhibitors are the most frequently used antihypertensive agents, but in many cases, a combination of these and other drugs is required to obtain good control of hypertension.     

Cryoglobulinemia in kidney transplant recipients

The aim of this study was to assess the presence of cryoglobulins, the constitution of the cryoprecipitate, as well as the possible etiology and clinical features in kidney transplant recipients. We excluded patients with clinical or laboratory evidence of autoimmune, liver or neoplasm disease, infections, blood transfusions or immunizations in the previous 3 months. Detection of cryoglobulins was obtained from the peripheral venous blood. In cases of cryoprecipitate formation it was analyzed using anti-IgG, anti-IgM, anti-IgA, anti-C3, and anti-C4 antibodies. The hepatitis C virus (HCV) was detected by the polymerase chain reaction. Thirty-nine patients were selected, of whom 23 were men and the overall mean age was 40.6 +/- 12.7 years. Cryoprecipitate was detected in 74.4% (29/39) patients. Among patients with or without cryoprecipitate formation, the serum creatinine values, the percentage of patients with proteinuria, and the posttransplantation times were similar. In patients with cryoglobulins, 37.9% (11/29) were HCV positive. The etiology was not determined for the other patients. The IgG, IgM, and IgA immunoglobulins and the complement fractions C3 and C4 were found in the cryoprecipitate. Their compositions were similar among patients with or without HCV. Few clinical features were associated with the presence of cryoglobulins, including deep venous thrombosis, cutaneous purpura and peripheral neuropathy. In conclusion, cryoglobulinemia was prevalent in kidney transplant recipients, but appeared to not affect graft function. HCV infection was the most frequently associated etiology and clinical features were infrequent.     

Renal Doppler resistance indices are associated with systemic atherosclerosis in kidney transplant recipients

BACKGROUND: In kidney transplant recipients, increased intrarenal resistance indices measured by duplex ultrasound are associated with poor subsequent allograft performance. It remains unclear whether high resistance indices rather reflect local renal damage or systemic vessel disease. We hypothesized that resistance indices are associated with cardiovascular risk factors and with subclinical systemic atherosclerosis in transplant recipients. METHODS: In 105 renal transplant recipients, categories of risk for coronary heart disease were determined by Framingham risk scoring. Intrarenal resistive index (RI) and pulsatility index (PI) were measured in segmental arteries at five representative locations. For assessment of subclinical atherosclerosis, common carotid intima-media thickness, and ankle-brachial blood pressure index (ABI) were determined. RESULTS: Transplant recipients with high coronary risk had higher intrarenal resistance indices than low-risk patients. Higher age, female gender, and lower body mass index were independently associated with increased resistance indices. Renal resistance indices were correlated with common carotid intima-media thickness [RI: r= 0.270 (P= 0.005); PI: r= 0.355 (P < 0.001)]. This association remained significant after adjusting for renal function. Renal resistance indices were increased in patients with pathologic ankle-brachial-indices compared to patients with physiologic ankle-brachial-indices [RI: 73.3 +/- 7.1 vs. 70.2 +/- 6.9 (P= 0.03); PI: 146.4 +/- 29.9 vs. 131.4 +/- 25.9 (P= 0.01)]. Renal resistance indices were neither significantly correlated with glomerular filtration rate (GFR), nor with donor age. CONCLUSION: Intrarenal resistance indices are a complex integration of arterial compliance, pulsatility, and peripheral resistance. They are associated with traditional cardiovascular risk factors as well as with subclinical atherosclerotic vessel damage and should thus not be considered specific markers of renal damage.