Symptomatic BK Virus Infection Is Associated With Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

Comparison of longer-term outcomes after kidney transplantation between Hispanic and non-Hispanic whites in the United States.

Little is known about the longer-term kidney transplant outcomes in the rapidly growing Hispanic population. Using the United States Renal Data System, we identified 105 250 Caucasian patients who received a first kidney transplant between January 1, 1996 and December 31, 2010. We tested for differences between Hispanic and non-Hispanic patients in the outcomes of (1) mortality, (2) all-cause graft failure, and (3) graft failure excluding death with a functioning graft. We used Cox regression to estimate (with 95% confidence intervals) multivariable-adjusted cause-specific hazard ratios (aHRCS ) for mortality and all-cause graft failure and subdistribution hazard ratios (aHRSD ) accounting for death as a competing risk for graft failure excluding death with a functioning graft. Both mortality [aHRCS = 0.69 (0.65-0.73)] and all-cause graft failure [aHRCS = 0.79 (0.75-0.83)] were lower in Hispanics. The association between Hispanic ethnicity and graft failure excluding death was modified by age (p < 0.003). Compared with non-Hispanic whites, graft failure excluding death with a functioning graft did not differ in Hispanics aged 18-39 years [aHRSD = 0.96 (0.89-1.05)] or aged 40-59 years [aHRSD = 1.08 (1.00-1.16)], but was 13% lower in those aged ≥60 years [aHRSD = 0.87 (0.78-0.98)]. In conclusion, once accounting for differences in overall survival, better graft survival was found in older Hispanic patients, but among not those aged <60 years.

Coronary artery bypass graft type and outcomes in maintenance dialysis.

AIM: Patients with end-stage renal disease (ESRD) on maintenance dialysis have a high burden of coronary disease. Prior studies in non-dialysis patients show better outcomes in coronary artery bypass surgery using the internal mammary artery (IMA) compared with the saphenous vein graft (SVG), but less is known about outcomes in ESRD. We sought to compare the effectiveness of multivessel bypass grafting using IMA versus SVG in patients on maintenance dialysis in the United States. METHODS: Cohort study using data from the United States Renal Data System to examine IMA versus SVG in patients on maintenance dialysis undergoing multivessel coronary revascularization. We used Cox proportional hazards regression with multivariable adjustment in the full cohort and in a propensity-score matched cohort. The primary outcome was death from any cause; the secondary outcome was a composite of non-fatal myocardial infarction or death. RESULTS: Overall survival rates were low in this patient population (5-year survival in the matched cohort 25.3%). Use of the IMA compared to SVG was associated with lower risk of death (adjusted hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.84-0.92) and lower risk of the composite outcome (adjusted HR 0.89; CI 0.85-0.93). Results did not materially change in analyses using the propensity-score matched cohort. We found similar results irrespective of patient sex, age, race, or the presence of diabetes, peripheral vascular disease or heart failure. CONCLUSION: Although overall survival rates were low, IMA was associated with lower risk of mortality and cardiovascular morbidity compared to SVG in patients on dialysis.

Temporal trends in the incidence, treatment and outcomes of hip fracture after first kidney transplantation in the United States.

It is currently unknown whether any secular trends exist in the incidence and outcomes of hip fracture in kidney transplant recipients (KTR). We identified first-time KTR (1997-2010) who had >1 year of Medicare coverage and no recorded history of hip fracture. New hip fractures were identified from corresponding diagnosis and surgical procedure codes. Outcomes studied included time to hip fracture, type of surgery received and 30-day mortality. Of 69,740 KTR transplanted in 1997-2010, 597 experienced a hip fracture event during 155,341 person-years of follow-up for an incidence rate of 3.8 per 1000 person-years. While unadjusted hip fracture incidence did not change, strong confounding by case mix was present. Using year of transplantation as a continuous variable, the hazard ratio (HR) for hip fracture in 2010 compared with 1997, adjusted for demographic, dialysis, comorbid and most transplant-related factors, was 0.56 (95% confidence interval [CI]: 0.41-0.77). Adjusting for baseline immunosuppression modestly attenuated the HR (0.68; 95% CI: 0.47-0.99). The 30-day mortality was 2.2 (95% CI: 1.3-3.7) per 100 events. In summary, hip fractures remain an important complication after kidney transplantation. Since 1997, case-mix adjusted posttransplant hip fracture rates have declined substantially. Changes in immunosuppressive therapy appear to be partly responsible for these favorable findings.

Outcomes after kidney transplantation of patients previously diagnosed with atrial fibrillation.

Little is known about the prevalence and outcomes of patients with atrial fibrillation/flutter (AF) who receive a kidney transplant. We identified all patients who had >1 year of uninterrupted Medicare A+B coverage before receiving their first kidney transplant (1997-2009). The presence of pretransplant AF was ascertained from diagnosis codes in Medicare physician claims. We studied the posttransplant outcomes of death, all-cause graft failure, death-censored graft failure and stroke using multivariable Cox regression. Of 62 706 eligible first kidney transplant recipients studied, 3794 (6.4%) were diagnosed with AF prior to kidney transplant. Over a mean follow up of 4.9 years, 40.6% of AF patients and 24.9% without AF died. All-cause and death-censored graft failure were 46.8% and 16.5%, respectively, in the AF group and 36.4% and 19.5%, respectively, in those without AF. Ischemic stroke occurred in 2.8% of patients with and 1.6% of patients without AF. In patients with AF, multivariable-adjusted hazard ratios (95% confidence intervals) for death, graft failure, death-censored graft failure and ischemic stroke were 1.46 (1.38-1.54), 1.41 (1.34-1.48), 1.26 (1.15-1.37) and 1.36 (1.10-1.68), respectively. Pre-existing AF is associated with poor posttransplant outcomes. Special attention should be paid to AF in pretransplant evaluation, counseling and risk stratification of kidney transplant candidates.

Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors: challenges in comparative effectiveness using Medicare data.

An evidence gap exists in comparing the effectiveness of angiotensin receptor II blockers (ARBs) for hypertension with that of angiotensin-converting enzyme inhibitors (ACEIs). We identified elderly hypertensive patients in whom ACEI/ARB therapy had been initiated after hospitalization for coronary artery disease (CAD), heart failure (HF), or stroke and who were eligible for Medicare and state pharmacy assistance programs. Of 18,801 initiators of ACEIs and 2,641 initiators of ARBs, 2,535 died during the follow-up. We observed substantial differences in characteristics between ARB and ACEI initiators, suggesting that ARB users were more health seeking. The incidence of death and sudden cardiac death (SCD) in ACEI initiators was 77 and 22 per 1,000 person-years, respectively. The relative risk for SCD comparing ARB initiators to ACEI initiators was 0.69 (95% confidence interval (CI) 0.50-0.96); when the analysis was restricted to patients with low ejection fraction (EF), the relative risk was 1.1. The reduced risk of SCD can be explained, at least partly, by (i) residual confounding because ARB users were healthier on unobserved domains and (ii) lack of data on EF.

Temporal trends in adherence to cardiovascular medications in elderly patients after hospitalization for heart failure.

Although the complexity of treatment regimens for patients with heart failure (HF) has increased over time because of the increased availability of efficacious medications, little is known about temporal trends in adherence to treatment regimens in these patients. We assessed trends in adherence to angiotensin-system blockers (ABs), ß-blockers (BBs), and spironolactone (SL) for HF in Medicare beneficiaries enrolled in two statewide pharmacy benefit programs from 1995 to 2004. The proportion of days covered (PDC) (%) was assessed after the first dispensing among users of an AB, BB, or SL. Proportions of full adherence (PDC >80%) did not change over time for ABs (54% in both 1996 and 2003) but increased slightly for BBs (from 47% in 1996 to 57% in 2003) and SL (from 31% in 1996 to 42% in 2003). Black race and dialysis treatment predicted poor adherence to any medications. Adherence to BBs and SL increased modestly over time, but overall nonadherence remained high.

Late referral to paediatric renal failure service impairs access to pre-emptive kidney transplantation in children.

BACKGROUND: Timing of referral to subspecialists may be a major determinant for access to adequate treatment. Kidney transplantation is the preferred modality of renal replacement therapy (RRT) in children. In adults, delayed referral from general physicians to nephrologists reduced access to kidney transplantation. This study investigated the association between timing of referral and the likelihood of pre-emptive kidney transplantation in children. METHODS: In this retrospective study, all patients in a tertiary paediatric nephrology centre were grouped according to first paediatric nephrologist visit (< or = 3 months prior to RRT was defined as 'late referral (LR)') and modality of first RRT. Descriptive, correlation and contingency statistics, Pearson's chi(2) test and logistic regression techniques were used for analysis. RESULTS: The median duration of nephrologists pre-RRT care of 111 children (50 girls and 61 boys; aged 8.0 years at first referral) was 1.5 (range 0-17.5) years. Thirty-two of 84 children who had their first visit >3 months prior to RRT were pre-emptively transplanted (38%), but only three of the 27 children with LR (11%; OR 4.9; 95% CI 1.37 to 17.7). Using a threshold of 12 months, the likelihood of pre-emptive kidney transplantation was still significantly influenced by timing of referral (OR 2.5; 95% CI 1.06 to 5.91). CONCLUSIONS: LR of children with chronic kidney disease to paediatric nephrology centre impairs the likelihood of receiving a pre-emptive kidney transplant. Specialised care of at least 12 months before the need for RRT arises is needed to allow for identification of and completion of the medical investigation of the living donor. Further studies using larger multicentre registries are needed to validate these single centre data.

Benzodiazepine use and mortality of incident dialysis patients in the United States.

Benzodiazepines and other omega-receptor agonists are frequently used for sleep and anxiety disorders. We studied the rates, correlates, and safety of individual benzodiazepines and zolpidem use from the records of 3690 patients in a national cohort of Dialysis Morbidity and Mortality Study Wave 2 data. We assessed drug utilization and an association between drug use and all-cause mortality. Overall, 14% of incident dialysis patients used a benzodiazepine or zolpidem. Women, Caucasians, current smokers, and patients with chronic obstructive pulmonary disease were more likely to use these drugs, whereas patients with cerebrovascular disease were less likely to use these drugs. In adjusted analyses, benzodiazepine or zolpidem use was associated with a 15% higher mortality rate. Chronic obstructive pulmonary disease significantly modified this association, suggesting that these patients were at higher risk. No association was found between benzodiazepine use and greater risk for hip fracture. We conclude that benzodiazepine or zolpidem use is common in incident dialysis patients and may be associated with greater mortality. Further studies are needed to elucidate the safety of these drugs in the dialysis population, which may lead to cautious and restrictive utilization of omega-receptor agonists in dialysis patients.

Clinical presentation of myocardial infarction contributes to lower use of coronary angiography in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) have high mortality following myocardial infarction (MI), but are less likely to undergo coronary angiography than those without CKD. Whether this phenomenon is explained by differences in the presentation of MI or by bias against performing coronary angiography in patients with CKD is unclear. We examined the clinical presentation of 1876 elderly patients who presented with MI and categorized them by estimated glomerular filtration rate: >60 ml/min (no/mild CKD), 30-60 ml/min (CKD Stage 3) or <30 ml/min (CKD Stage 4/5). Compared with patients with no/mild CKD, patients with CKD Stage 3 or Stage 4/5 had more comorbidity, greater prior nursing home use, and higher frequency of conduction abnormalities or anterior infarction. By contrast, peak creatinine kinase-MB fraction (CK-MB) concentrations were lower and ST-elevation MI was less common in patients with CKD Stage 3 or Stage 4/5. In univariate analyses, patients with CKD Stage 4/5 (odds ratio (OR)=0.34, 95% confidence interval (CI): 0.23-0.50) or Stage 3 (OR=0.57, 95% CI: 0.45-0.73) were markedly less likely to undergo angiography than subjects with no/mild CKD. After multivariable adjustment, the association of CKD Stage 3 with the use of coronary angiography was attenuated (OR=0.78, 95% CI: 0.60-1.03), but CKD Stage 4/5 remained strongly associated with lower use (OR=0.52, 95% CI: 0.34-0.80). Clinical features of MI are different in patients with and without CKD and may partly explain the low use of angiography in patients with CKD Stage 3. However, the clinical features of MI do not account for its underuse in MI patients with CKD Stages 4/5. Whether reduced use of angiography in patients with advanced CKD is justified must be evaluated in formal risk-benefit analyses.

Predialysis nephrologist care and access to kidney transplantation in the United States.

Predialysis nephrologist care is associated with morbidity and mortality in incident dialysis patients, but the relationship with access to kidney transplantation (KT) is unclear. From a national study of incident US dialysis patients, we identified 2253 patients with detailed information about predialysis care, sociodemographic characteristics and comorbidities. We used multivariate Cox proportional hazards models to study associations between predialysis nephrology care and two outcomes: time from first dialysis to the first day on the KT wait-list, and time to first KT. Two-thirds of patients first encountered a nephrologist >3 months prior to dialysis and one-third

Comparison of hemodialysis and peritoneal dialysis survival in The Netherlands.

Considerable geographic variation exists in the relative use of hemodialysis (HD) vs peritoneal dialysis (PD). Studies comparing survival between these modalities have yielded conflicting results. Our aim was to compare the survival of Dutch HD and PD patients. We developed Cox regression models using 16 643 patients from the Dutch End-Stage Renal Disease Registry (RENINE) adjusting for age, gender, primary renal disease, center of dialysis, year of start of renal replacement therapy, and included several interaction terms. We assumed definite treatment assignment at day 91 and performed an intention-to-treat analysis, censoring for transplantation. To account for time dependency, we stratified the analysis into three time periods, >3-6, >6-15, and >15 months. For the first period, the mortality hazard ratio (HR) of PD compared with HD patients was 0.26 (95% confidence interval (CI) 0.17-0.41) for 40-year-old non-diabetics, which increased with age and presence of diabetes to 0.95 (95% CI 0.64-1.39) for 70-year-old patients with diabetes as primary renal disease. The HRs of the second period were generally higher. After 15 months, the HR was 0.86 (95% CI 0.74-1.00) for 40-year-old non-diabetics and 1.42 (95% CI 1.23-1.65) for 70-year-old patients with diabetes as primary renal disease. We conclude that the survival advantage for Dutch PD compared with HD patients decreases over time, with age and in the presence of diabetes as primary disease.

Anaemia after renal transplantation.

Anaemia is a frequent complication among long-term renal transplant recipients. A prevalence of approximately 40% has been reported in several studies. If renal function declines to stage 5 kidney disease, the prevalence of anaemia in kidney transplants is even higher. A positive correlation between haemoglobin concentration and creatinine clearance has been reported, which is a function of endogenous erythropoietin production by the functioning graft. Inflammation related to a retained kidney graft may cause hypo-responsiveness to erythropoietic agents once kidney transplant recipients return to dialysis. Furthermore, the use of azathioprine, mycophenolate mofetil and sirolimus may be associated with post-transplant anaemia. Along with erythropoietin deficiency, depletion of iron stores is one of the major reasons for anaemia in the kidney transplant population. The proportion of hypochromic red blood cells appears to be a useful parameter to measure iron supply and utilization as well as to estimate mortality risks in kidney transplant recipients. While anaemia is an important cardiovascular risk-factor after transplantation, our data suggest that anaemia is not associated with mortality and graft loss. Nevertheless, inadequate attention is paid so far to the management of anaemia after renal transplantation. A promising future aspect for risk reduction of cardiovascular disease includes the effect of erythropoietic agents on endothelial progenitor cells.

A cost minimization model for the treatment of minor bleeding episodes in patients with haemophilia A and high-titre inhibitors.

Treatment of acute bleeding episodes in patients with haemophilia A and inhibitory antibodies to factor VIII (FVIII) most often involves the use of bypassing haemostatic agents, such as activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa). We constructed a cost minimization model to compare the costs of initial treatment with aPCC vs. rFVIIa in the home treatment of minor bleeding episodes. We developed a clinical scenario describing such a case and presented it to a panel of US haemophilia specialists. For each product class, we asked panellists to provide dosing regimens required to achieve complete resolution of a minor haemarthrosis in a child with high-titre inhibitors, and for the probabilities of success at two time points (8-12 and 24 h). Consensus among the panellists was refined by a second round of the process, and the median values resulting were used as inputs to a decision analysis model. Sensitivity analyses were conducted to determine threshold values for key variables. The base case model found that initial treatment with aPCC would result in a mean cost per episode of 21 000 dollars, compared with 33 400 dollars for initial treatment with rFVIIa. Sensitivity analyses over a range of clinically plausible values for cost, dosing, and efficacy did not change the selection of aPCC as the dominant strategy.

Patterns of co-occurrence of three single nucleotide polymorphisms of the 5,10-methylenetetrahydrofolate reductase gene in kidney transplant recipients.

BACKGROUND: Recently, a new mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) encoding gene was first described (1793G > A). Only few reports have studied the prevalence of this polymorphism, especially in combination with other MTHFR mutations (677C > T, 1298A > C). METHODS: We cross-sectionally identified the novel MTHFR 1793G > A polymorphism in 730 kidney transplant recipients. MTHFR 677C > T and 1298A > C were also assessed and the frequency of each was described individually as well as in cross-tabulation with the other MTHFR genotypes. The expected number of patients for each MTHFR genotype combination was calculated and contrasted with the observed numbers. Fisher's exact test was used for statistical inference. RESULTS: The allelic frequency of MTHFR 1793G > A was 0.052. Seventy-two patients (9.9%) were heterozygous and two patients (0.3%) were homozygous. From the cross-tabulations, we identified 53 patients (expected: 33.6) with the MTHFR 1298AC/1793GA genotype and 17 patients (expected: 6.7) with the MTHFR 1298CC/1793GA genotype. Furthermore, we found two patients with double homozygosity for MTHFR 1793G > A and MTHFR 1298A > C (MTHFR 1793AA/1298CC genotype). The frequencies of these genotype combinations were substantially larger than could be expected (P < 0.001). CONCLUSIONS: These findings suggest a selection or survival advantage for individuals with combined MTHFR 1793G > A and MTHFR 1298A > C genotypes, possibly owing to a mutually stabilizing effect on MTHFR enzyme activity.

Determinants of delayed nephrologist referral in patients with chronic kidney disease.

Late referral to nephrologists of patients with chronic kidney disease (CKD) is a major public health problem because it is prevalent and associated with increased morbidity, mortality, and greater healthcare costs. To identify factors associated with delayed nephrologist referral (first nephrologist visit < 90 days before the onset of renal replacement therapy), we identified a cohort of patients with preexisting CKD that progressed to end-stage renal failure. We developed a logistic regression model to measure the association of specific demographic and clinical covariates with delayed nephrologist referral. Delayed referral was highly associated with older age (P < 0.001), race other than white or black (P = 0.002), and the absence of certain comorbidities: hypertension (P < 0.001), coronary artery disease (P < 0.001), malignancy (P = 0.005), and diabetes (P = 0.02). Associations of late referral with male sex (P = 0.07) and lower socioeconomic status (P = 0.09) were of borderline significance. Patients who were predominantly cared for by a general internist were more likely to be referred late to a nephrologist compared with those cared for by a family or primary care practitioner (P = 0.002) or another subspecialist (P = 0.019). These findings suggest that several factors increase the risk that patients with CKD will have the first nephrologist consultation excessively late in the course of their disease. Although timely access to nephrologist services is important for all patients with advanced CKD, this is of particular concern in older patients, those in certain minority populations, and those in whom the absence of comorbidity may provide a false sense of true risk status.

Late referral and modality choice in end-stage renal disease.

BACKGROUND: We sought to determine whether late versus early referral to a nephrologist in patients with chronic kidney disease influences the initial choice of hemodialysis (HD) versus peritoneal dialysis (PD) or the likelihood of switching treatment modalities in the first six months of therapy. METHODS: Using New Jersey Medicare/Medicaid claims, all patients who started RRT between January 1991 and June 1996 and were diagnosed with renal disease more than one year prior to RRT were identified. In the resulting cohort of 3014 patients, 35% had their first nephrologist consultation < or =90 days prior to initiation of dialysis. RESULTS: After controlling for demographic characteristics, socioeconomic status and underlying renal disease, age, black race [Odds ratio (OR) = 0.56], race other than black or white (OR = 0.56), and socioeconomic status (OR = 0.68) influenced the choice of initial treatment modality, but timing of the referral did not. However, patients starting on PD who were referred late were 50% more likely to switch to HD than were patients who saw a nephrologist earlier [Hazard's ratio (HR) = 1.47]. In patients originally on HD, diabetic nephropathy (HR = 1.49) and black race (HR = 0.69) influenced the likelihood of switching to PD, but the timing of referral did not. CONCLUSIONS: These results refute earlier findings that late referral may limit access to PD. We found that modality choice depends on factors such as age, race, or socioeconomic status, rather than on than timing of nephrologist referral. Late referral does not influence the likelihood to switch modality in patients starting on HD, but does so in patients starting on PD.

Optic neuropathy in uremia: an interdisciplinary emergency.

Optic neuropathy in uremia is rare. Although the consequences of optic neuropathy-blindness or substantial loss of vision-are devastating, only a few cases have been reported by way of single case reports and case series studies. The reported patients are heterogeneous with regard to the cause of neuropathy. We report the case of a patient with uremic optic neuropathy and summarize the other cases reported in the literature so far. Based on the data available from these reports, we propose a classification system, which includes nonischemic neurotoxic uremic optic neuropathy; ischemic optic neuropathy, more specifically anterior ischemic optic neuropathy; and optic neuropathy as a result of drug side effects, benign intracranial hypertension, and optic neuritis. The immediate institution of dialysis and corticosteroid therapy and correction of anemia and relative hypotension can optimize the chances of visual recovery for these patients. Close collaboration among nephrologists, ophthalmologists, and neurologists is important in this interdisciplinary emergency.

Therapeutic potential of total homocysteine-lowering drugs on cardiovascular disease.

An elevated total homocysteine (tHcy) plasma concentration is associated with increased morbidity and mortality due to cardiovascular disease in the general population and in patients with impaired renal function. The prevalence of hyperhomocysteinaemia (plasma levels above 15 micromol/l) in the general population is less than 5% and can be as high as 50% in patients with vascular disease. In patients with renal insufficiency, elevated tHcy plasma levels are detected in 50 - 100% of the patients. Total homocysteine plasma levels can be lowered or normalised by folic acid and/or vitamin B(6) and vitamin B(12) supplementation. In patients with advanced chronic renal insufficiency or end-stage renal disease, hyperhomocysteinaemia is partially resistant to folic acid or vitamin therapy. However, higher tHcy plasma levels may also reflect tissue damage and the increase in Hcy after an acute incident such as stroke or myocardial infarction may be necessary for tissue repair mechanisms. This implies, that lowering tHcy may even be harmful to some patients. Currently, prospective studies are underway to clarify whether folate supplementation, with or without additional other vitamins, improves cardiovascular disease morbidity and mortality in the general population, as well as in renal failure patients. While population-wide screening for and treatment of hyperhomocysteinaemia is generally not recommended, treatment of high risk patients may be considered.