Ahsan Alam

Decreased survival in liver transplant patients requiring chronic dialysis: a Canadian experience.

Background. Chronic kidney disease is associated with increased mortality among nonrenal organ transplant recipients. End-stage renal disease (ESRD) is a serious complication after orthotopic liver transplantation (OLT). It is unclear if the outcomes of these individuals are different from nontransplant patients requiring dialysis or a kidney transplant. Methods. We report the incidence of ESRD in OLT recipients and compare their outcomes to matched dialysis controls. We analyzed 4186 patients who received an OLT in Canada between January 1981 and December 2002 and 228 matched, nontransplant, chronic dialysis controls. Results. The incidence of ESRD after OLT was 2.9% (n=120). The unadjusted mortality rate for those who required chronic dialysis was 49.2% compared with 26.8% in those who did not develop kidney failure (P<0.0001). The survival of OLT recipients on dialysis was lower than the matched chronic dialysis cohort (log-rank test, P=0.01). A kidney transplant was performed in 24% of the OLT recipients and 21% of the matched dialysis cohort, and their overall survival was similar. The OLT patients who remained on dialysis had a significantly lower survival when compared with matched dialysis patients who did not receive a kidney transplant (log-rank test, P=0.0002). Conclusions. Mortality was greater for OLT recipients on dialysis than would be expected from a matched, nontransplant, dialysis cohort. Kidney transplantation may abrogate some of this increased mortality risk.

Cardiovascular Death in Dialysis Patients: Lessons We Can Learn from AURORA

Cardiovascular events are the dominant cause of death in patients with ESRD. Until recently, plaque rupture due to atherogenic dyslipoproteinemias was presumed to be a major mechanism of cardiovascular events in dialysis patients. But how reasonable was that hypothesis and was it entirely discredited by the results of 4D and AURORA? This article places the conventional lipids-cholesterol and triglyceride-within the more physiologic framework of the apoB lipoproteins. Viewed from the perspective of atherogenic particle number, the failure of statins to lower cardiovascular mortality in hemodialysis patients versus the continuing potential for success in peritoneal dialysis patients becomes comprehensible. In the former, apoB is characteristically not elevated and therefore apoB-lowering therapy can have only limited effect; in the latter, apoB is characteristically high and therefore apoB-lowering therapy might have considerable clinical benefit. Nevertheless, plaque rupture is only one mechanism leading to cardiac death. In addition to those previously noted, a new mechanism is suggested for consideration-recurrent reperfusion injury. The coronaries of dialysis patients are often narrowed, the microcirculation underdeveloped, and the left ventricle hypertrophied-all of these plus transient hypotension could produce severe ischemia followed by reperfusion necrosis. The minor but common elevations of troponin that are so well known yet widely disregarded may be markers of an adverse sequence of events that could each trigger a fatal arrhythmia and tend to reduce left ventricular function. Thus sudden death due to arrhythmia and slow progressive death due to heart failure could be manifestations of reperfusion injury.

Endogenous Erythropoietin and the Association with Inflammation and Mortality in Diabetic Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Anemia and inflammation are prevalent in diabetic patients with chronic kidney disease (CKD). The role of endogenous erythropoietin (EPO) in the pathophysiology of anemia in chronic diseases and its relationship to clinical outcomes remain uncertain. In this cohort study, we aimed to identify factors associated with endogenous EPO levels and investigate their relation to all-cause mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between 2004 and 2005, 215 patients with type 2 diabetes were enrolled. Exclusion criteria included stage renal disease ESRD and any form of anemia therapy. The association of EPO levels with clinical and laboratory variables was investigated by linear regression modeling. Predictors of all-cause mortality were evaluated by Cox proportional hazards analyses. RESULTS Patients (median age, 67 years; 52% men; median duration of diabetes, 10 years; median estimated GFR, 49 ml/min per 1.73 m²) were followed for up to 7.0 years. Forty-one patients died. Elevated EPO levels were independently associated with elevated C-reactive protein, low ferritin, and hypertension, in a multivariate model that also included age, cardiovascular disease, kidney function, albumin, cholesterol, and hemoglobin. Higher EPO levels were independently predictive for mortality, as were age, low levels of albumin, and cardiovascular disease. CONCLUSIONS In diabetic patients with CKD, elevated endogenous EPO levels were predictive for mortality and were related mainly to markers of inflammation, independent of kidney function, and despite low hemoglobin levels. Understanding the phenomenon of EPO resistance and iron dysregulation caused by inflammation is crucial for effective and safe treatment of anemia in patients with CKD.

Management of ESRD in Patients With Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the leading hereditary cause of ESRD in the United States. Because of the renal and extrarenal manifestations of ADPKD, specific challenges exist caring for these patients once they reach ESRD. In this article, we report the overall outcomes of individuals with ADPKD after ESRD as compared with non-ADPKD patients. We also review the available literature concerning issues specific to dialysis or kidney transplantation. For the ADPKD patient on dialysis, we address the use of peritoneal dialysis, the management of renal cystic, and extrarenal complications, and we discuss the significance of the relative polycythemia often observed in this population. For the ADPKD patient undergoing kidney transplantation, we highlight issues of anemia management and aneurysm screening pretransplant, the indications for nephrectomy of the native ADPKD kidneys, the potential benefits of select immunosuppressive agents, the role for combined kidney-liver transplantation, and renal and extrarenal complications of ADPKD postkidney transplantation. In general, patients with ADPKD have more favorable outcomes after ESRD as compared with those with other causes of kidney failure. Most of our knowledge, however, is based on case series and observational studies. Although these reports have certainly been valuable to our understanding, there still remains considerable uncertainty and ambiguity in many aspects of ADPKD patient care as it relates to ESRD. Particular focus needs to be placed on performing clinical trials with the goal of enhancing outcomes and quality of life of patients with ADPKD.

Managing Cyst Infections in ADPKD: An Old Problem Looking for New Answers

Kidney and liver cyst complications are frequent in patients with autosomal dominant polycystic kidney disease (ADPKD). It has been estimated that 30 to 50% of patients with ADPKD experience some form of kidney infection during their lifetime (1,2). Patients may experience symptoms from cyst infections, cyst hemorrhage, or pain from ruptured or expanding cysts. The clinical determination of an infected kidney cyst may be difficult in a patient with ADPKD. The typical presentation of fever and abdominal pain carries a broad differential that includes pyelonephritis, infected kidney stones, perinephric or perihepatic abscess, cyst hemorrhage, or even intra-abdominal pathology unrelated to ADPKD. Conventional imaging with ultrasound, computed tomography, or magnetic resonance imaging scan may not be definitive in isolating the location of infection or even in differentiating cyst infection from cyst hemorrhage or pyelonephritis (3). A urine culture is often negative because kidney cysts become separated from their parent nephron, and one must rely more on blood cultures or cyst fluid aspiration when they can be obtained. The accurate diagnosis of cyst infection is of great importance, because it can influence the prompt initiation of antibiotics (particularly one that is widely known to penetrate cyst membranes), it can determine the need for extending the duration of antibiotic …

Phenylethanolamine N-methyltransferase gene polymorphisms and adverse outcomes in acute kidney injury.

Background/Aims: The catecholaminergic pathway is important in the physical stress response; however, its role is not well understood in acute kidney injury (AKI). We studied single nucleotide polymorphisms (SNPs) of phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholaminergic pathway, and their association with adverse outcomes in AKI. Methods: We performed a case-control study of 961 Caucasian subjects (194 with AKI and 767 controls). The PNMT promoter G–161A (rs876493) and coding A+1543G (rs5638) SNPs were genotyped and haplotypes generated. The outcomes of interest were the development of AKI, in-hospital mortality, dialysis requirement, oliguria, and hemodynamic shock. Urine catecholamines were measured in cases to explore genotype-phenotype correlations. Results: The PNMT +1543 G allele was associated with AKI [odds ratio (OR) 2.19, 95% confidence interval (CI): 1.04–4.60]. For AKI cases, each PNMT –161 A allele was associated with lower mortality (OR 0.58, 95% CI: 0.35–0.99) and hemodynamic shock (OR 0.63, 95% CI: 0.40–1.00). The PNMT +1543 G allele was associated with oliguria (OR 3.35, 95% CI: 1.13–9.95). Urine adrenaline was associated with increased hemodynamic shock and mortality, but was lowest in PNMT –161 A/A carriers. Conclusion: In Caucasians, PNMT SNPs are associated with the development of AKI, disease severity, and in-hospital mortality. The adrenergic pathway provides another area of focus in the study of AKI.

Preoperative hospital length of stay as a modifiable risk factor for mediastinitis after cardiac surgery

BackgroundAs high-risk cardiac patients frequently remain within hospital while waiting for surgery, the aim of the present study was to determine the role of preoperative length of hospital stay on mediastinitis, and also, to assess contemporary risk factors for this complication.MethodsThe source population consisted of 6653 consecutive patients undergoing coronary bypass surgery, valve surgery, or both between September 2000 and September 2009 at a single tertiary care hospital. A retrospective cohort analysis was used to assess the effect of 18 preoperative variables, including length of stay, on mediastinitis.ResultsMediastinitis developed in 108 patients (1.6%) resulting in an in-hospital mortality rate of 13.9%. Independent predictors of mediastinitis included obesity (2.59, CI 1.58-4.23), COPD (2.44, CI 1.55-3.84), diabetes (2.16, CI 1.44-3.24), and impaired estimated glomerular filtration rate. Preoperative hospital stay was also found to be an independent risk factor leading to a 15% increased risk of mediastinitis per week of stay. The primary wound pathogen was coagulase negative staphylococcus (82%) followed by multi-flora isolates (49%), but was unrelated to hospital stay.ConclusionsIn addition to the traditional risk factors, prolonged preoperative hospital stay is also a significant and potentially modifiable predictor for the development of mediastinitis following cardiac surgery. All efforts should be made to minimize the delay in operating on hospitalized patients awaiting heart surgery.

Lack of association of Klotho gene variants with valvular and vascular calcification in Caucasians: a candidate gene study of the Framingham Offspring Cohort

BACKGROUND Valvular and vascular calcification are important early aging phenotypes and represent risk factors for cardiovascular morbidity and mortality. Klotho is a gene primarily expressed in the kidney that has an important role in calcium-phosphate homeostasis. The functional KL-VS variant of Klotho has been associated with aging and cardiovascular disease in human studies, but its role in valvular and vascular calcification remains unknown. We performed a candidate gene study in the Framingham Offspring Cohort to evaluate the effect of KL-VS variant of the Klotho gene on valvular calcification. METHODS We analyzed the Klotho KL-VS genotype (rs9536314) from the Affymetrix 550K genome-wide dataset, distributed by dbGAP, on 1389 cases and 2139 controls from the Framingham Heart Study Offspring Cohort. Allele and genotype frequencies were compared between cases and controls. Valvular calcification was defined as presence of calcification on the mitral annulus or the aortic valve as determined by echocardiography. A sensitivity analysis of coronary artery calcification by electron beam computed tomography was performed on 1363 patients. RESULTS The frequency of the TT versus the TG allele was not different between the cases and the controls (39 versus 41%). The KL-VS variant of Klotho was not associated with valvular or vascular calcification, despite adequate power to detect association (86% for odds ratios ≥1.2). In sensitivity analyses, no association (P > 0.001) between other common variants of Klotho, β-Klotho or fibroblast growth factor-23 and the end points of valvular or vascular calcification was observed. CONCLUSIONS In our adequately powered candidate gene study, we did not observe an association with the functional KL-VS variant of Klotho and presence of valvular or vascular calcification. Future studies aimed at combining cohorts with echocardiographic phenotypes need to be conducted to identify genetic variants associated with valvular calcification.

Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease.

Background Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels. Methods 249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003–2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models. Results Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05). Conclusions We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define “high risk” populations in CKD.

Predictors of suboptimal and crash initiation of dialysis at two tertiary care centers

Many end‐stage renal disease patients do not have an optimal start to dialysis. Many patients have suboptimal initiation, while others “crash” start on dialysis without prior care from a nephrologist. We examined factors associated with suboptimal or crash starts. We conducted a retrospective cohort study of 377 incident dialysis patients at two tertiary care centers from January 2006 to April 2011. Logistic regression was used to identify factors associated with suboptimal and crash starts to dialysis. Out of 377 patients, 102 (27%) had optimal starts, 221 (59%) had suboptimal starts, and 54 (14%) had crash starts. Three hundred thirty‐four patients (89%) began with hemodialysis, while 11% started with peritoneal dialysis. Factors independently associated with a suboptimal start as opposed to an optimal start included nephrology care more than 12 months prior to initiation of dialysis (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.12–0.58), Charlson Comorbidity Index (OR, 1.25 per 1 point; 95% CI, 1.09–1.43), and age (OR, 1.02 per 1 year; 95% CI, 1.00–1.04). In comparison, diabetic nephropathy (OR, 0.25; 95% CI, 0.12–0.54), a history of pulmonary edema within 6 months prior to initiation of dialysis (OR, 3.70; 95% CI, 1.77–7.75), and a diagnosis of chronic obstructive lung disease (OR, 0.07; 95% CI, 0.01–0.52) were independently associated with a crash start. There was a low incidence of optimal dialysis starts in our tertiary care dialysis population. Our study highlights that suboptimal and crash start patients are distinct populations. Modifying factors that predict nonoptimal dialysis starts will need to consider these distinctions.