Time Of Renal Transplantation Research Articles

Clinical Course of Hepatitis B Virus Infection in Renal Allograft Recipients

The outcome of renal transplantation is adversely affected by hepatitis B virus infection. We retrospectively analyzed data of 1,251 renal transplant recipients, 20 of whom were hepatitis B surface antigen positive and hepatitis B virus DNA negative at the time of renal transplantation. Hepatitis B virus reactivation was seen in 14 of the 20 patients at a mean time of 16.3+/-7.1 months after transplantation. All patients with hepatitis B virus reactivation after transplantation were treated with lamivudine, biochemical, and serologic response was achieved in 13 of 14 patients at a mean time of 7.0+/-1.1 months. Seven of 13 patients experienced a breakthrough at a mean time of 9.2+/-6.2 months. Three of the 20 patients died at a mean time of 57.0+/-38.5 months after transplantation. Our data demonstrated that chronic immunosuppression is associated with a significantly high risk of hepatitis B virus reactivation in renal transplant recipients and hepatitis B reactivation does not increase the likelihood of graft rejection or patient mortality after renal transplantation.

Demand for evaluation of vaccination antibody titers in children considered for renal transplantation

Vaccinations are recommended for achieving protection against vaccine-preventable infections in solid-organ transplant recipients. In order to evaluate the protection at the time of renal transplantation, the antibody titers against measles, mumps, rubella, varicella, hepatitis B, diphtheria, and tetanus were determined in 35 children one month prior to transplantation. Only 26% of patients on dialysis listed for transplantation showed protective antibodies against all tested pathogens. Particularly, low protection was found for hepatitis B. Children younger than four yr showed significantly lower protective antibody titers compared with older children for almost all vaccines. Children who completed vaccination in the last six months to six yr prior to renal transplantation showed higher rates of protective antibody titers against all pathogens compared with children who had vaccination more than six yr before transplantation. Preventive strategies in children with chronic renal failure include repeated measurements of serum antibodies and appropriate revaccination if titers decline. Our results underline the demand for continuous surveillance of specific antibody titers against vaccine-preventable diseases in the risk group of renal transplant recipients.

Cardiovascular Complications After Renal Transplantation and Their Prevention

By the time of renal transplantation, end-stage renal disease patients have a huge burden of cardiovascular disease (CVD) and are heavily saturated with atherosclerotic risk factors. Worsening of preexisting risk factors or new CVD risk factors may develop in the posttransplant period consequent in part to the diabetogenic and atherogenic potential of immunosuppressive drugs. The annual risk of a fatal or non-fatal CVD event of 3.5 to 5% in kidney transplant recipients is 50-fold higher than the general population. Renal allograft dysfunction, proteinuria, anemia, moderate hyperhomocysteinemia and elevated serum C-reactive protein concentrations, each dependently confer greater risk of CVD morbidity and mortality in the posttransplant period. Long-term care of renal transplant recipients should programmatically incorporate the recommendations of the National Kidney Foundation Working Groups and European Best Practice Guidelines Expert Group on Renal Transplantations into the management of hypertension, dyslipidemia, smoking, and posttransplant diabetes mellitus. Timely utilization of coronary revascularization procedures should be undertaken as these treatments are equally effective in the kidney transplant population.

Carotid Plaques and Their Predictive Value for Cardiovascular Disease and All-Cause Mortality in Hemodialysis Patients Considering Renal Transplantation: A Decade Follow-Up

Carotid plaque formation is very common in dialysis patients. The prognostic value of plaques, both calcified and noncalcified, rarely was investigated prospectively in these patients. By using a carotid plaque score, this study aims to determine the risk for combined cardiovascular disease (CVD) events and all-cause mortality in 165 hemodialysis patients in a long-term follow-up considering phases of renal transplantation. Baseline carotid ultrasonography was performed in 165 hemodialysis patients to screen for carotid plaques. Patients subsequently were followed up for a period up to 13 years (average, 86 months). Because of biases associated with renal transplantation, 3 methods of multivariate analysis were compared by using Cox proportional hazards regression models. Plaques were present in 107 of 165 patients (65%). During the observation period, 50 patients (30%) experienced a combined CVD event, 95 patients (58%) died, and 79 patients (48%) underwent at least 1 renal transplantation. Mean plaque score differed significantly between patients who reached an end point and those who did not (CVD events, 3.1 +/- 2.7 versus 2.0 +/- 2.4; P = 0.01; all-cause mortality, 3.5 +/- 2.6 versus 0.9 +/- 1.3; P < 0.001). Plaque score entered all 3 tested Cox regression models for CVD events and all-cause mortality. The lowest statistical power was associated with censoring at the time of renal transplantation. Not considering transplantation at all neglected a major change in risk. We identified carotid plaque score and treatment modality as highly significant predictors for CVD events and all-cause mortality.

Risk Factors for Development of Posttransplant Diabetes Mellitus in Renal Transplant Recipients

Diabetes mellitus appearing after kidney transplantation—posttransplant diabetes mellitus (PTDM)—is a common complication associated with poor graft and patient survival. The purpose of the current study was to determine the risk factors for developing PTDM in 204 renal transplant recipients who had been followed for at least 30 months. Posttransplant diabetes mellitus was diagnosed according to the American Diabetic Association/WHO criteria, or a requirement for insulin, an oral hypoglycemic agent, or both. Analyses of possible risk factors for PTDM included demographic features, dialysis and posttransplantation duration, smoking, body mass index, medications, co-morbid diseases, HLA mismatches, as well as laboratory metrics of serum creatinine, albumin, calcium, phosphorus, C-reactive protein, parathyroid hormone, and lipid profiles. Twenty-six patients displayed PTDM. Univariate analysis showed that older age, greater body mass index, presence of hepatitis C virus (HCV) infection, and smoking at the time of renal transplantation were associated with PTDM development. In a multivariate analysis, HCV infection, smoking, and patient age at the time of transplantation were independent risk factors for PTDM. In conclusion, the presence of HCV infection or a smoking habit in addition to older age at the time of transplantation were the main predictors for developing PTDM. Patients should be closely followed regarding their smoking habit and weight gain as modifiable risk factors for PTDM.

Lamivudine Therapy in Kidney Allograft Recipients Who Are Seropositive for Hepatitis B Surface Antigen

Background There are numerous recent reports on the use of lamivudine for hepatitis B virus (HBV) infection after renal transplantation. However, the optimal strategy (prophylactic, preemptive, or salvage approach) for starting lamivudine treatment in this patient group has not been determined. The aim of this study was to assess how the timing of lamivudine therapy affected the HBV serological status and the transaminase levels in renal allograft recipients with chronic HBV infection. Methods We investigated outcomes for patients who were seropositive for hepatitis B surface antigen (HBsAg) and underwent transplantation before or after October 2004 (the date our institution implemented a prophylactic lamivudine treatment strategy against HBV). The data included serum liver enzyme levels and polymerase chain reaction (PCR) screening results for HBV-DNA in serum. Results Fifteen patients (11 before October 2004, four after October 2004) were included in the study. Preoperatively all patients had normal transaminases levels and 2 of 15 patients had detectable HBV-DNA on PCR. Eight of the 15 total HBsAg-positive patients in our series were not placed on lamivudine at the time of renal transplantation. Half of those who were not treated initially showed transaminase elevations in the first year of follow-up requiring lamivudine therapy at that time. In contrast, all seven individuals who received lamivudine at the time of transplantation were negative for HBV-DNA throughout the follow-up. Conclusion To prevent viral replication in HBsAg-positive patients who are scheduled for renal transplantation, it is best to initiate lamivudine therapy before or immediately after transplantation.

The Granule Exocytosis and Fas/FasLigand Pathways at the Time of Transplantation and During Borderline and Acute Rejection of Human Renal Allografts

Cytotoxic lymphocytes induce target cell death by the granule exocytosis mechanism in which perforin and granzyme B induce target cell lysis, and ligation of the Fas-FasLigand, which results in apoptosis. The purpose was to detect the level of activation of cytolytic pathways at the time of renal transplantation and during acute rejection. We investigated 119 biopsies obtained at transplantation from 100 deceased donor allografts and 19 living donor allografts as well as 45 allograft biopsy specimens collected from recipients because of a clinical suspicion of an acute rejection episode. Total RNA was isolated and transcribed to cDNA. To measure mRNA encoding perforin, granzyme B, and FasLigand by real-time quantitative, polymerase chain reaction we used oligonucleotide primers in a LightCycler equipment with cyclophilin B as the housekeeping gene. At the time of transplantation, the transcript expression levels of perforin and granzyme B were the same in the biopsies from deceased and living donors. During acute rejection episodes ( n = 10), perforin ( P < .01), and granzyme B levels ( P < .05) were significantly up-regulated. In cases of suspected rejection ( n = 12), both the clinical picture and the effector gene responses were heterogeneous. The FasLigand expression was up-regulated during acute rejection episodes ( n = 8) compared with the time of transplantation, but the change was not significant. In conclusion, brain death did not seem to influence the granule exocytosis pathway in the kidney. The cytolytic effector pathways are up-regulated in renal allograft tissue in acute rejection episodes.

Concomitant Nephrectomy of Massively Enlarged Kidneys and Renal Transplantation in Autosomal Dominant Polycystic Kidney Disease

Objectives We compared perioperative and intraoperative data of patients with end-stage renal disease (ESRD) due to autosomal dominant polycystic kidney disease (ADPKD) who received a renal allograft without native nephrectomy with ADPKD patients who underwent concomitant native nephrectomy of massively enlarged kidneys and renal transplantation to determine whether the latter approach is reasonable and safe. Patients and methods From January 1987 to December 2003, 13 patients with ESRD due to ADPKD were stratified as 6 patients who underwent bilateral and 7 patients who underwent unilateral native nephrectomy in conjunction with renal transplantation (group A), versus 20 patients with ESRD due to ADPKD underwent renal transplantation without native nephrectomy (group B). Operative time, need for intraoperative transfusion, time to oral intake, duration of hospital stay, serum creatinine level on the day of discharge, readmission rate, and postoperative complications were compared for both groups. Results Mean intraoperative duration was significantly longer for patients in group A, but there was no statistically significant difference in the findings between both groups. Conclusions Concomitant native nephrectomy of massively enlarged kidneys at the time of renal transplantation is reasonable and safe for patients with ESRD due to ADPKD.

Urothelial differentiation in chronically urine-deprived bladders of patients with end-stage renal disease

It is unknown whether normal bladder voiding function, or soluble factors present in urine, contribute to the maturation and maintenance of the differentiated state of the uroepithelial cell lining of the lower urinary tract. We used the urothelium of anuric patients on long-term hemodialysis, sampled at the time of renal transplantation, to investigate the expression of urothelial differentiation-associated antigens, including uroplakins (UPIa, UPIb, UPII, and UPIIIa), cytokeratin isotypes (CK7, CK8, CK13, CK14, CK17, CK18, and CK20), nuclear hormone receptors [peroxisome proliferators activated receptor-gamma (PPAR-gamma) and retinoid X receptor-alpha (RXR-alpha)], and a cell cycle marker (Ki-67). To determine whether urinary metabolites of the arachidonic pathway could induce urothelial differentiation, cultured normal human urothelial (NHU) cells were treated with 15-deoxy-delta12, 14-prostaglandin J2 (15d-PGJ2) and prostaglandin J2 (PGJ2). The expression levels of the markers of differentiation, the uroplakins, were assessed by ribonuclease protection assay. Results. When compared in a blinded analysis against control normal urothelium, no significant changes were found in the expression or localization patterns of any of the antigens studied in the anuric patients. Furthermore, neither 15d-PGJ2 nor PGJ2 were able to induce expression of the UPII gene in NHU cells, in contrast to cultures exposed to the pharmacologic PPAR-gamma agonist, troglitazone. Conclusion. These data provide prima facie evidence that exogenous urine-derived factors do not modulate the differentiation program in urothelium, suggesting that other urothelial- or serum-derived factors are likely to be involved. These findings are important in understanding post-developmental maturation and functional relationships in urologic tissues of the adult organism.

Coronary Artery Calcification in Renal Transplant Recipients

Cardiovascular disease is the leading cause of mortality in renal transplant recipients. Although renal transplant recipients frequently undergo cardiac functional tests prior to surgery, coronary atherosclerosis can remain undetected. Coronary artery calcification (CAC), an early marker of atherosclerosis can be quantified using EBCT. The purpose of this study was to determine the extent and characteristics of CAC at the time of renal transplantation. We evaluated 79 consecutive incident asymptomatic renal transplant recipients. Patients were mostly White (62%), male (54%) and had a deceased donor renal transplant (61%). The mean age was 47 (12.1) years. Sixty-five percentage of subjects had CAC. The mean CAC score was 331.5 (562.4) with a median of 43.3. Older age, presence of diabetes, not having a preemptive transplant, deceased donor transplantation and hypercholesterolemia were significantly associated with presence of CAC univariately. Median CAC scores were significantly increased in subjects with diabetes (127.8 vs. 28.9, p=0.05), exposed to dialysis (102.9 vs. 3.7, p<0.001) and deceased donor recipients (169.7 vs. 7.5, p=0.02). Using multiple logistic regression, age and time on dialysis were significantly associated with the presence of CAC at the time of transplant. In summary, CAC is prevalent in patients undergoing kidney transplant. CAC may be a method to identify renal transplant recipients at increased risk for future cardiovascular events.

Cyst fluid composition in human autosomal recessive polycystic kidney disease

Sirs, Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic renal disorder and frequently progresses to renal failure [1]. Because of its relative prevalence, it is the most well-characterized of the genetic cystic renal diseases. Histopathologically, the cysts are derived from all segments of the nephron, yet they “bud off” and separate from the tubule from which they are derived [1]. Cystic expansion is thought to be related to multiple biological processes including Na, Cl, and fluid secretion into cysts, processes that would tend to enlarge a discrete cyst and compress surrounding normal renal tissue [1]. Autosomal recessive polycystic kidney disease (ARPKD) is less common than ADPKD with an incidence of ~1 in 20,000 live births [1, 2]. Phenotypically, infants and children with ARPKD frequently present with hypertension, which generally appears well in advance of renal insufficiency [3]. Histologically, ARPKD is associated with ectasia and dilatation of renal collecting ducts and intra-hepatic bile ducts, and therefore does not retain the classic ADPKD “blind loop” sac-like cystic pattern [1]. We have previously examined the transepithelial Na transport properties of human ARPKD cystic epithelial cells in culture and reported that these cells absorb Na, as did normal age-matched counterparts. However, we showed, unexpectedly, that ARPKD cyst-lining cells reabsorbed Na at a rate ~50% greater than that of controls [4]. The Na absorptive flux in ARPKD cells was only modestly inhibited by high doses (100 mM) of amiloride, an inhibitor of the epithelial Na channel (ENaC) and Na-H antiporter [4]. Similar investigations of collecting duct epithelial cells derived from orpk mice, a murine model of ARPKD, suggested that these cells, like their human ARPKD counterparts, absorb Na at a higher rate than controls [5]. Based on these laboratory investigations, we were interested to determine if the in vitro studies could be validated in vivo. With institutional review board approval, we sought to characterize cyst fluid composition from ARPKD nephrectomy specimens at the time of renal transplantation. Cyst fluid (~0.1–0.3 ml samples, 8–11 samples per kidney) was collected in the operating room from freshly harvested pediatric ARPKD kidneys. Analysis of fluid aspirated from cysts within the renal parenchyma from three separate end-stage ARPKD kidney specimens revealed a low Na concentration and an osmolality similar to that of serum (Table 1). We speculate that the urine osmolality of ~300 mosmol/kg is due to the presence of urea, which was not measured. The cyst fluid R. Rohatgi Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA

Long-term survival of human skin allografts in patients with immunosuppression.

Severe burn patients lack adequate skin donor sites to resurface their burn wounds. Patients with severe burn injuries to areas such as an entire face are presently reconstructed with skin grafts that are inferior to normal facial skin. This study was designed in part to determine whether human skin allografts would survive, repopulate, and persist on patients with immunosuppression and after discontinuation of immunosuppression. Small split-thickness skin grafts were synchronously transplanted at the time of renal transplantation from six renal transplant donors to recipients. All six patients were immunosuppressed with the usual doses of renal transplant immunosuppressants (methylprednisolone, cyclosporine, prednisone, and azathioprine). The skin allografts were biopsied when rejection was suspected and at various intervals. Special histologic studies were performed on skin biopsy specimens. Class II DNA tissue typing was performed on transplanted and autogenous skin biopsy specimens of four patients. Fluorescent in situ hybridization was performed successfully on skin biopsies of four patients' transplanted skin and on two of these four patients' autogenous skin. All six human skin allografts sustained a 100 percent take and long-term clinical survival. DNA tissue typing performed on skin allograft biopsy specimens from patients taking immunosuppressants all revealed donor and recipient cells. DNA tissue typing performed on autogenous skin biopsies from the same patients all revealed only recipient cells. Fluorescent in situ hybridization performed on allograft and autogenous specimens from patients taking immunosuppressants revealed transplanted donor cells with rare recipient cells in the allograft and only recipient cells in the autogenous skin. This study of six patients proves that it is possible for human skin allografts to survive indefinitely on patients taking the usual dosages of immunosuppressants used for renal transplantation. There was minimal repopulation of skin allografts by autogenous keratinocytes and fibroblast while patients were taking immunosuppressants. Immunosuppression was discontinued in two patients after renal transplant rejection after 6 weeks and 5 years. When immunosuppression was discontinued after 5 years in one patient, the skin allograft cells were destroyed and replaced with autogenous cells, but the skin graft did not reject acutely and persisted clinically. It is hypothesized that the acellular portion of the skin allograft was not rejected acutely because of relatively low antigenicity and because it acted as a lattice for autogenous cells to migrate into and replace rejected allograft skin cells. No chimerism was seen in autogenous skin in the skin-renal transplant patients in this study.

Response to Dr. Dai D. Nghiem

Response to Dr. Dai D. Nghiem

Alemtuzumab and tolerance: the university of wisconsin experience

H istorically, the transplantation program at the University of Wisconsin, Madison, WI, has used induction agents followed by steroid-based maintenance therapy in solid organ transplantation. Nonhuman primate experiments showed the usefulness of an antibody that could effectively deplete 2 to 3 logs of lymphocytes from the recipient at the time of renal transplantation.1 Experience in humans has accumulated with virtually all of the commonly used antibodies including Minnesota antilymphocyte globulin, OKT3 (muromonab-CD3), Thymoglobulin (rabbit antithymocyte globulin; SangStat Medical Corporation, Fremont, CA), Simulect (basiliximab; Novartis AG, Basel, Switzerland), Zenapax (daclizumab; Hoffmann-La Roche Inc, Nutley, NJ), and, most recently, alemtuzumab (CAMPATH 1H; ILEXTM Oncology, Inc [ILEX], San Antonio, TX). Our protocol is modified on the basis of results and clinical experience in one of the largest renal transplant programs in the United States. Because of the published results observed in renal transplant recipients treated with alemtuzumab as an induction agent followed by cyclosporine maintenance therapy,2,3 physicians at Wisconsin designed an immunosuppressive protocol in which 29 low-risk patients were treated with alemtuzumab 20 mg intravenously and methylprednisolone 500 mg intravenously on days 0 and 1 and maintenance therapy with rapamycin (sirolimus) 2 mg/d orally starting on day 1 (Fig 1). Rapamycin was substituted for cyclosporine because it predisposes alloreactive cells to apoptosis whereas cyclosporine inhibits their apoptosis and because rapamycin is antifibrogenic and is not nephrotoxic. The dose of rapamycin was adjusted to achieve target levels in blood of 8 to 12 ng/dL.4 Eight of the 29 patients (28%) experienced a rejection episode, with all but 2 occurring within 30 days after transplantation, and most of which (5/8) were shown histologically to include humoral responses. These 5 patients had evidence of C4d deposition in the peritubular capillaries. Results from flow cytometry studies performed retrospectively on patients who experienced rejection episodes confirmed that the episodes were humoral responses directed at major histocompatibility complex class I antigen, but these responses were not because of pretransplant recipient sensitization. Treatment of rejection with steroids, Thymoglobulin, plasmapheresis, and rituximab was well tolerated, indicating that the treatment regimen did not induce overimmunosuppression. Interestingly, the occurrence of early rejection was clustered around younger patients, with 7 of 13 patients younger than 45 years experiencing rejection compared with 1 of 16 patients older than 45 years. To date, no incidents of biopsy-proven chronic rejection have been detected. Other notable complications included 2 operations for lymphoceles and 1 case of hepatotoxicity with anemia, all of which were considered as secondary effects of the rapamycin therapy. There were no systemic or opportunistic infections. The treatment regimen was modified as a result of the unexpected increased incidence of aggressive humoral rejection and because flow cytometry results showed that patients who experienced these rejection episodes had CD52-negative cells in the blood within 1 month after transplantation. Physicians theorized that CD52-negative cells may be involved in the rejection process. Therefore Thymoglobulin was added to the treatment to target the CD52-negative cells, and steroids were included to deter nonspecific activation of the immune response (Table 1). Five patients were treated with the modified treatment regimen of alemtuzumab 20 mg intravenously on days 1 and 0 followed by Thymoglobulin 1.5 mg/kg on day 1, maintenance therapy with sirolimus 2 mg/d starting on day 1, and steroid therapy 500 mg starting on day 1 tapered to 30 mg and discontinued on day 14. Three of the patients have From the Division of Organ Transplantation, University of Wisconsin, Madison, WI. Address reprint requests to Stuart Knechtle, MD, Division of Organ Transplantation, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792-7375. © 2003 Elsevier Inc. All rights reserved. 0955-470X/03/1704-0000$30.00/0 doi:10.1016/S0955-470X(03)00079-X

Long-term effects on bone mineral density of pamidronate given at the time of renal transplantation

Fracture rate after renal transplantation is substantially increased, is a source of morbidity and mortality, and correlates with osteopenia. The rate of bone loss after transplantation is time dependent. While we recorded marked bone loss during the first year after renal transplantation, bone loss in long-term recipients (>24 months) was found to be similar to expected age-related decline. We have previously shown that treatment with pamidronate at the time of transplantation protected the skeleton over a 1-year study period. We have reexamined patients who participated in our original study, all of whom had been randomized to receive either placebo or pamidronate (0.5 mg/kg) at the time of transplantation and 1 month later. We now report 4-year data from 17 of the 26 original cohort. All patients received immunosuppression, comprising prednisolone, cyclosporine, and azathioprine. We found that without prophylaxis bone loss at 4 years was substantial and significant at the femoral neck (mean loss was -12.3%) but was not significant at the lumbar spine (mean loss was -4.64%). Patients who received two doses of pamidronate experienced no statistically significant bone loss at either the femoral neck or the lumbar spine. Patient characteristics of the placebo and treatment groups were similar with the exception of serum parathyroid hormone concentrations, which remained higher at 4 years in the pamidronate-treated patients (15.8 +/- 3.7 pmol/L vs. 9.8 +/- 1.8 pmol/L, P < 0.05). Without prophylaxis, most patients who continue to receive low dose glucocorticoids as part of maintenance immunosuppression manifest a substantial deficit in bone mineral density (BMD) at the femoral neck. In contrast, two doses of pamidronate given at the time of transplantation and 1 month later protected the skeleton from significant bone loss over the 4 years after transplantation.

Evolution of hepatitis C virus quasispecies in renal transplant patients with de novo glomerulonephritis.

Long-term renal allograft survival in kidney transplant recipients infected by hepatitis C virus (HCV) may be influenced by the occurrence of de novo glomerulopathy associated with this virus. Therefore, we studied the evolution of HCV quasispecies in kidney transplant recipients infected by HCV with or without de novo glomerulopathy. The hypervariable region 1 (HVR-1) of the virus envelope was analyzed by cloning and sequencing 20 clones per sample to assess complexity and diversity from six kidney transplant patients who developed de novo glomerulopathy (group I) matched to six kidney transplant recipients without glomerular disease (group II), according to age, time since renal transplantation, and HCV genotype. Two sera were analyzed for each patient: one at the time of renal transplantation and the other at the time of appearance of de novo glomerulopathy, or after a similar duration since transplantation in group II. Overall, there was a significant increase of HCV viremia after the transplantation. This increase did not differ significantly between group I (+0.5 log copies/ml) and group II patients (+1 log copies/ml). The intersample diversity of HCV was similar in the two groups. Complexity and viral diversity were also similar at the time of transplantation. By contrast, complexity, diversity, and the proportion of nonsynonymous substitutions per nonsynonymous site were significantly higher after transplantation in group I patients. Our findings suggest a higher immune response and/or a particular cytokine production in patients developing de novo glomerulopathy rather than a direct effect of HCV on renal cells.

Atrial fibrillation in chronic dialysis patients in the United States: risk factors for hospitalization and mortality.

BackgroundThe incidence and risk factors for hospitalized atrial fibrillation have not been previously assessed in a national population of dialysis patients.MethodsWe analyzed the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave II in a historical cohort study of hospitalized atrial fibrillation. Data from 3374 patients who started dialysis in 1996 with valid follow-up times were available for analysis, censored at the time of renal transplantation and followed until November 2000. Cox Regression analysis was used to model factors associated with time to first hospitalization for atrial fibrillation (ICD9 code 427.31x) adjusted for comorbidities, demographic factors, baseline laboratory values, blood pressures, dialysis modality, and cardioprotective medications.ResultsThe incidence density of atrial fibrillation was 12.5/1000 person years. Factors associated with atrial fibrillation were older age (> = 71 years vs. <48 years), extremes (both high and low) of pre-dialysis systolic blood pressure, dialysis modality (hemodialysis vs. peritoneal dialysis), and digoxin use. Baseline use of coumadin was associated with reduced mortality in patients later hospitalized for atrial fibrillation.ConclusionsDialysis patients had a high incidence of atrial fibrillation. This risk was largely segregated among those with established risk factors for atrial fibrillation, and hemodialysis patients. Use of coumadin was associated with improved survival among patients later hospitalized for atrial fibrillation.

Incident acute coronary syndromes in chronic dialysis patients in the United States

Patients on dialysis have a disproportionately high rate of cardiovascular disease (CVD). However, the incidence and risk factors for incident acute coronary syndromes (ACS) have not been previously assessed in dialysis patients. We analyzed the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave II in a historical cohort study of ACS. Data from 3374 patients who started dialysis in 1996 with valid follow-up times were available for analysis, censored at the time of renal transplantation and followed until March 2000. Cox regression analysis was used to model factors associated with time to first hospitalization for ACS (ICD9 code 410.x or 411.x) adjusted for comorbidities, demographic factors, baseline laboratory values, blood pressures and cholesterol levels, type of vascular access, dialysis adequacy, and cardioprotective medications (angiotensin-converting enzyme inhibitors, calcium channel blockers, HMG-CoA reductase inhibitors (statins), beta blockers, and aspirin). Follow-up was 2.19 +/- 1.14 years. The incidence of ACS was 29/1000 person-years. Factors associated with ACS were older age, the extreme high and low ranges of serum cholesterol level, history of coronary heart disease (CHD), male gender, and diabetes. No cardioprotective medications including statins had a significant association with ACS in this study. However, medications known to reduce mortality after ACS were used in less than 50% of patients with known CHD at the start of the study, and statins were used in less than 10% of patients with CHD. Dialysis patients had similar risk factors for ACS compared to the general population. Cardioprotective medications were not associated with a significant benefit, possibly due to their striking underutilization in this at-risk population.

Impact of HIV seropositivity on graft and patient survival after cadaveric renal transplantation in the United States in the pre highly active antiretroviral therapy (HAART) era: an historical cohort analysis of the United States Renal Data System.

National statistics are presented for patient survival and graft survival in patients seropositive for the human immunodeficiency virus (HIV+) at the time of renal transplantation in the era prior to highly active antiretroviral therapy (HAART). Historical cohort analysis of 63, 210 cadaveric solitary renal transplant recipients with valid HIV serology entries in the United States Renal Data System (USRDS) from 1 January 1987 to 30 June 1997. The medical evidence form was also used for additional variables but, because of fewer available values, was analyzed in a separate model. Outcomes were patient characteristics and survival associated with HIV+ status. Thirty-two patients (0.05%) in the study period were HIV+ at transplant. HIV+ patients were comparable to the national renal transplant population in terms of gender and ethnic distribution but were younger and had younger donors and better HLA matching than the USRDS population. Patient and graft three-year survival were significantly reduced in HIV+ recipients (53% graft, 83% patient survival) relative to the USRDS population (73% and 88%, respectively). In multivariate analysis, HIV+ status was independently associated with patient mortality and decreased graft survival in recipients of cadaveric kidney transplants. This analysis was retrospective and may underestimate the number of HIV+ patients transplanted in the United States. Although the clinical details of patient selection for transplant were unknown, these results show HIV+ patients can have successful outcomes after cadaveric renal transplantation, although outcomes are significantly different from HIV- recipients.

Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins

In non-ESRD patients, recent studies have demonstrated that the process of vascular calcification resembles developmental osteogenesis. Patients with ESRD are known to have excessive vascular calcification, but this has previously been attributed to the non-cell-mediated process of metastatic calcification. To determine if the calcification observed in patients with ESRD is related to a cell-mediated process, we removed a piece of inferior epigastric artery at the time of renal transplant. Calcium content of the entire vessel was quantified with spiral computed tomography (CT). The vessel was then examined histologically for calcification and the presence of bone matrix proteins by immunohistochemistry, and medial and intimal thickness quantified by histomorphometry. These findings were correlated with demographic, clinical and laboratory values. The proximal inferior epigastric artery was obtained from 41 patients undergoing renal transplantation, but two were inadequate for histologic examination. Twenty-seven of the remaining vessels had no evidence of calcification by MacNeal's or Alizarin red pH 4.2 staining, five vessels had mild/moderate calcification, and seven had severe calcification, all in the medial layer. Calcification assessed histologically was closely correlated with calcification score as assessed by spiral CT, normalized for vessel weight (P=0.027). Positive immunostaining for the bone matrix proteins osteopontin, type I collagen, bone sialoprotein, and alkaline phosphatase was strongly correlated with calcification (all P < or = 0.001), as was a history of coronary artery disease (P < 0.001), and diabetes (P=0.034). The calcification score by spiral CT correlated with these same factors and the serum phosphorus and calcium x phosphorus product (P=0.032 and 0.037). The location of immunostaining for the bone proteins was strongly associated with the presence of calcification. However, positive immunostaining also was observed in association with disorganization of the vascular smooth muscle cells in the medial layer due to deposition of a matrix-like substance, prior to overt calcification. In patients with ESRD undergoing renal transplantation, vascular calcification of the medial layer of the inferior epigastric artery is common (44%), can be detected by spiral CT, and is associated with deposition of bone matrix proteins. This implies an active cell-mediated process, raising hope that directed intervention can arrest this process.