Hepatitis C virus infection in end‐stage renal disease and kidney transplantation

Liver disease secondary to chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients with end‐stage renal disease (ESRD) on renal replacement therapy and after kidney transplantation (KT). Hemodialytic treatment (HD) for ESRD constitutes a risk factor for bloodborne infections because of prolonged vascular access and the potential for exposure to infected patients and contaminated equipment. Evaluation of HCV‐positive/ESRD and HCV‐positive/KT patients is warranted to determine the stage of disease and the appropriateness of antiviral therapy, despite such treatment is challenging especially due to tolerability issues. Antiviral treatment with interferon (IFN) is contraindicated after transplantation due to the risk of rejection, and therefore, treatment is recommended before KT. Newer treatment strategies of direct‐acting antiviral agents in combination are revolutionizing HCV therapy, as a result of encouraging outcomes streaming from recent studies which report increased sustained viral response, low or no resistance, and good safety profiles, including preservation of renal function. KT has been demonstrated to yield better outcomes with respect to remaining on HD although survival after KT is penalized by the presence of HCV infection with respect to HCV‐negative transplant recipients. Therefore, an appropriate, comprehensive, easily applicable set of clinical practice management guidelines is necessary in both ESRD and KT patients with HCV infection and HCV‐related liver disease.     

Renal cell carcinoma in patients with end‐stage renal disease has favorable overall prognosis

Patients with end‐stage renal disease (ESRD) demonstrate a greater risk for renal cell carcinoma (RCC) than the general population. This study compared pathological and clinical outcomes in patients with RCC with and without ESRD. Patients with ESRD who underwent nephrectomy and were found to have RCC at our institution since 1999 were identified. The control group was composed of patients from the general population with RCC. The primary outcome was risk of cancer recurrence. The study included 338 RCC patients: 84 with ESRD and 243 without ESRD. In the ESRD group, mean tumor size was smaller, there was decreased prevalence of advanced T category (>3) , and the average Karakiewicz nomogram score was lower. ESRD was associated with decreased tumor recurrence and clear cell pathology. No patients with ESRD had metastatic disease. There was no difference in overall or cancer‐specific mortality between the ESRD and control groups. Patients with ESRD who develop RCC have a better prognosis compared to RCC in patients without ESRD, which is likely secondary to favorable histopathologic phenotype as well as the likelihood of early diagnosis. Thus, the delay between nephrectomy and renal transplantation may not be necessary, especially in patients with asymptomatic, low grade tumors.     

Gut bacterial translocation is associated with microinflammation in end‐stage renal disease patients

Aim: To investigate whether gut bacteria translocation occurs in end‐stage renal disease patients and contributes to microinflammation in end‐stage renal disease (ESRD). Methods: The subjects were divided into two groups: nondialysed ESRD patients (n = 30) and healthy controls (n = 10). Blood samples from all participants were subjected to bacterial 16S ribosomal DNA amplification and DNA pyrosequencing to determine the presence of bacteria, and the alteration of gut microbiomes were examined with the same methods. High‐sensitive C‐reactive protein and interleukin‐6 were detected. Plasma D‐lactate was tested for gut permeability. Results: Bacterial DNAs were detected in the blood of 20% (6/30) of the ESRD patients. All the observed genera in blood (Klebsiella spp, Proteus spp, Escherichia spp, Enterobacter spp, and Pseudomonas spp) were overgrown in the guts of the ESRD patients. Plasma D‐lactate, High‐sensitive C‐reactive protein, and interleukin‐6 levels were significantly higher in patients with bacterial DNA than those without. The control group showed the same results as that of patients without bacterial DNA. Conclusion: Bacterial translocation occurs in ESRD patients and is associated with microinflammation in end stage renal disease.     

Follow-up after renal transplantation with organs from donors after cardiac death

Kidneys obtained from donors after cardiac death (DCD) are known to have higher rates of primary nonfunction and delayed graft function (DGF) than heart beating cadaveric donor (CAD) kidneys, but little is known about long-term function of DCD grafts that survive to 1 year. To investigate the outcomes of renal transplant recipients whose DCD graft functioned for at least 1 year, this study analyzed data collected from 326 DCD graft recipients and 340 CAD-matched controls enrolled in a prospective, multinational, observational study--Neoral-MOST (Multinational Observational Study in Transplantation) (Novartis, Basel, Switzerland). No differences were found in the demographics or immunosuppression between the two groups. All patients received a Neoral-based immunosuppressive regimen. Donors after cardiac death graft recipients had a higher incidence of DGF (40% vs. 27% CAD; P < 0.001). One year glomerular filtration rate (GFR) and GFR-decline after 1 year were similar in DCD and CAD recipients (GFR 56 ml/min DCD vs. 59 ml/min CAD; GFR-decline -1.3 ml/min DCD vs. -1.4 ml/min CAD; P = not significant). Multifactorial analyses confirmed that GFR at 1 year was significantly influenced by donor age and gender, DGF, and acute rejection; however, DCD status was not an independent risk factor in cyclosporine-treated patients with grafts that had functioned for at least 1 year.     

Chronic renal outcome after living donor liver transplantation

Chronic kidney disease (CKD) is one of the common complications after deceased donor liver transplantation. Although the worldwide pressing shortage in deceased donors has directed attention to living donor liver transplantation (LDLT), LDLT cohort data focusing on chronic renal dysfunction is limited. A total of 280 adult LDLT recipients (median 49 yr, 156 men) at the University of Tokyo hospital between 1996 and 2006 were reviewed. A total of 224 pre‐transplant liver failure patients (80.0%) showed an estimated glomerular filtration rate (eGFR) of more than 60 mL/min/1.73 m². However, during follow‐up at a mean of 1222 d after transplantation, eGFR declined to 60 mL/min/1.73 m² and 30 mL/min/1.73 m² in 150 (53.2%) and 21 (7.5%), respectively, and four patients (1.4%) required maintenance renal replacement therapy. Multivariate Cox proportional hazard model regression analysis revealed that recipient age (HR, 3.42 per 10‐yr increment; p < 0.001) and pre‐transplant eGFR (HR, 0.85 per 10‐mL/min/1.73 m² increment; p = 0.04) were associated independently with a post‐transplant decrease in eGFR to less than 30 mL/min/1.73 m². We conclude that higher age and lower pre‐transplant eGFR of an LDLT recipient indicate a high likelihood of subsequent development of advanced CKD. Preventive or therapeutic intervention should be optimized for these high‐risk patients.     

Impact of MELD-based allocation on end-stage renal disease after liver transplantation

The proportion of patients undergoing liver transplantation (LT), with concomitant renal dysfunction, markedly increased after allocation by the model for end-stage liver disease (MELD) score was introduced. We examined the incidence of subsequent post-LT end-stage renal disease (ESRD) before and after the policy was implemented. Data on all adult deceased donor LT recipients between April 27, 1995 and December 31, 2008 (n = 59 242), from the Scientific Registry of Transplant Recipients, were linked with Centers for Medicare & Medicaid Services' ESRD data. Cox regression was used to (i) compare pre-MELD and MELD eras with respect to post-LT ESRD incidence, (ii) determine the risk factors for post-LT ESRD and (iii) quantify the association between ESRD incidence and mortality. Crude rates of post-LT ESRD were 12.8 and 14.5 per 1000 patient-years in the pre-MELD and MELD eras, respectively. Covariate-adjusted post-LT ESRD risk was higher in the MELD era (hazard ratio [HR]= 1.15; p = 0.0049). African American race, hepatitis C, pre-LT diabetes, higher creatinine, lower albumin, lower bilirubin and sodium >141 mmol/L at LT were also significant predictors of post-LT ESRD. Post-LT ESRD was associated with higher post-LT mortality (HR = 3.32; p < 0.0001). The risk of post-LT ESRD, a strong predictor of post-LT mortality, is 15% higher in the MELD era. This study identified potentially modifiable risk factors of post-LT ESRD. Early intervention and modification of these risk factors may reduce the burden of post-LT ESRD.     

Bladder function of end‐stage renal disease patients

Objectives: To evaluate the bladder function of end‐stage renal disease (ESRD) patients by using video H₂O cystometry (CM) before renal transplantation (RTx). Methods: A total of 92 patients (57 men and 35 women; mean age 45.4 years; mean period of renal replacement therapy (RRT) 60.2 months) were divided in two groups based on the presence of detrusor overactivity (DO). In each group the following parameters were recorded during CM: first sensation (FS), maximum cystometric capacity (MC) and compliance. The effect of the duration of RRT on the H₂O cystometric results was also assessed. Results: There were 25 patients (27.2%) who had DO before their operation, this ratio being higher than the general Japanese population. Subjects with DO were observed independently for the duration of RRT and there was no difference in the prevalence of DO based on this variable. In contrast, 50 patients kept their bladder compliance in the normal range. The numerical value of FS, MC and compliance decreased proportionally for the duration of RRT. Conclusions: Patients undergoing RTx frequently present with bladder dysfunction in terms of low capacity, low compliance and also DO. This bladder dysfunction has a negative impact on patients' quality of life. Thus, bladder function and its related symptoms require specific attention during the management of transplant patients.     

Calciphylaxis in end‐stage liver and renal disease patients before and after transplant

Calciphylaxis is a rare vascular disorder characterized by calcification of arterioles which causes tissue inflammation and necrosis. It is associated with the metabolic disturbances seen in end‐stage renal disease (ESRD) and has also been described in patients with cirrhosis with preserved kidney function. Characteristic calciphylaxis lesions are black eschars surrounded by retiform purpura, and the gold standard for diagnosis is skin biopsy. Reported 1‐year mortality rates range between 45% and 80%. No treatment modality has been evaluated in a prospective randomized trial, and reports of treatment efficacy vary. Kidney transplant has been reported as a successful therapy for calciphylaxis; however, cases exist of the initial onset of calciphylaxis following kidney transplant as well as simultaneous liver‐kidney (SLK) transplant. The decision to maintain a patient with end‐stage renal and liver disease on the waiting list for SLK transplant following the onset of calciphylaxis must consider the high 1‐year mortality associated with this condition. More research is necessary to understand how to allocate donor allografts to manage patients with calciphylaxis and ESRD and/or cirrhosis effectively.     

Predictors of diabetic end‐stage renal disease in Japan

SUMMARY: Diabetes mellitus (DM) has been the leading cause of incident dialysis in Japan since 1998, according to the Japanese Society for Dialysis Therapy (JSDT). In particular, the number of male DM dialysis patients is increasing. DM is becoming a worldwide epidemic in both developed and developing countries. Strategies to detect individuals at high‐risk of developing CKD and end‐stage renal disease (ESRD) are needed that can be implemented on a population‐basis. Among the commonly measured variables, dipstick urinalysis (proteinuria, haematuria), blood pressure, serum creatinine, body mass index (BMI), and serum uric acid are significant predictors of ESRD. Recently, we evaluated the effect of DM as a risk factor of developing ESRD. DM was diagnosed when the fasting plasma glucose (FPG) was 126 mg/dL or more in participants (n = 78529) of the 1993 screening program in Okinawa. The prevalence of DM was 5.2%. The odds ratio (95% CI) of DM for developing ESRD was 3.098 (1.738–5.525, P = 0.0001) after adjusting for possible confounding variables. Early detection and treatment of DM might prevent DM‐related ESRD. We examined 7125 non‐DM screenees who underwent a 1‐day health check between April 1997 and March 1998. They were followed‐up until March 2000 to determine whether they developed DM. Over the 2 years, the cumulative incidence of DM was 2.3%, 2.9% in men and 1.3% in women. Proteinuria was the most robust predictor of the development of DM; the adjusted relative risk (95% CI) was 1.90 (1.14–3.17). Obesity, per se, is also recognized as a risk factor for developing proteinuria. The higher the BMI, the higher the risk of developing ESRD; the adjusted odds ratio (95% CI) was 1.273 (1.121–1.446, P = 0.0002) for men. Other than being overweight (BMI = 25.0 kg/m²), a smoking habit was a significant predictor of developing proteinuria. The prevalence of obesity and DM is increasing in Japan. It is possible that the impact of obesity and complications of DM are different among races and ethnicities. Public relations regarding the risk of DM and its complications are especially important in Asian countries. Asians have more fat than non‐Asians, even at the same BMI levels. Knowledge of the predictors of DM‐ESRD is crucial as a first step toward prevention. Consistent with this notion, initiatives on the management of CKD and ESRD were recently organized in Japan and internationally.     

Model for end‐stage liver disease‐sodium and survival benefit in liver transplantation

There are currently no studies calculating the survival benefit of liver transplantation (LT) according to model for end‐stage liver disease‐sodium (MELD‐Na) and based on the competing risk (CR) method. We enrolled consecutive adult patients with chronic end‐stage liver disease entering the waiting list (WL) for primary LT (WL group = 337) and undergoing LT (LT group = 220) in the period 2006–2009. Two independent multivariable regressions (WL and LT models) were created to measure the prognostic power of MELD‐Na with respect to MELD. For the WL model, both Cox and CR multivariable analyses were performed. Estimates were finally included in a Markov model to calculate 3‐year survival benefit. WL Cox model: MELD‐Na (P < 0.0001) and MELD (P < 0.0001) significantly predicted survival. WL CR model: MELD‐Na (P = 0.0045) and MELD (P = 0.0109) significantly predicted survival. LT Cox model: MELD‐Na (P = 0.7608) and MELD score (P = 0.9413) had not correlation with survival. Benefit model: MELD and MELD‐Na had an overlapping significant impact on 3‐year survival benefit; CR method determined a significant decrease in 3‐year life expectancy (LE) estimations. MELD‐Na and MELD scores similarly predicted 3‐year LT survival benefit, but the gain in LE is significantly lower when a CR method is adopted.     

Renal tumors in end‐stage renal disease: A comprehensive review

The incidence of end‐stage renal disease has increased owing to the greater prevalence of patients with chronic kidney disease and diabetes mellitus. End‐stage renal disease is usually accompanied by acquired cystic disease and is a risk factor for renal cell carcinoma. The present review discusses the etiology of renal cell carcinoma in end‐stage renal disease patients, focusing on two unique renal cell carcinoma histological subtypes: acquired cystic disease‐associated renal cell carcinoma and clear cell papillary renal cell carcinoma. Acquired cystic disease‐associated renal cell carcinoma occurs almost exclusively in patients who underwent hemodialysis, especially long‐term (>10 years) hemodialysis. Its histology is distinctive: a cribriform or sieve‐like architecture with intra‐ or intracystic lumina; tumor cells containing abundant eosinophilic cytoplasm and large nuclei with prominent nucleoli; and most notably, calcium oxalate crystal deposition. Recognition of the crystals is critical for diagnosing acquired cystic disease‐associated renal cell carcinoma. Acquired cystic disease‐associated renal cell carcinoma typically has an indolent clinical course, except in cases with sarcomatoid components. Clear cell papillary renal cell carcinoma also has an indolent course (no cases involving metastasis have been reported to date), and its features resemble those of both clear cell renal cell carcinoma and papillary renal cell carcinoma. Unlike acquired cystic disease‐associated renal cell carcinoma, which occurs only in end‐stage renal disease patients, clear cell papillary renal cell carcinoma occurs in non‐end‐stage renal disease patients as well. Additional renal tumors in end‐stage renal disease patients include anastomosing hemangiomas. Long‐term hemodialysis worsens the prognosis of end‐stage renal disease patients with renal cell carcinoma, regardless of its original histological subtype, presumably by inducing oxidative stress and sarcomatoid transformation.     

Pulmonary vascular resistance determines mortality in end‐stage renal disease patients with pulmonary hypertension

The multifactorial etiology of pulmonary hypertension (PH) in end‐stage renal disease (ESRD) includes patients with and without elevated pulmonary vascular resistance (PVR). We explored the prognostic implication of this distinction by evaluating pretransplant ESRD patients who underwent right heart catheterization and echocardiography. Demographics, clinical data, and test results were analyzed. All‐cause mortality data were obtained. Median follow‐up was 4 years. Of the 150 patients evaluated, echocardiography identified 99 patients (66%) with estimated pulmonary artery (PA) systolic pressure > 36 mm Hg, which correlated poorly with mortality (HR = 1.28, 95% CI 0.72‐2.27, P = .387). Right heart catheterization identified 88 (59%) patients with mean PA pressure ≥ 25 mm Hg. Of these, 70 had PVR ≤ 3 Wood units and 18 had PVR > 3 Wood units. Survival analysis demonstrated a significant prognostic effect of an elevated PVR in patients with high mean PA pressures (HR = 2.26, 95% CI 1.07‐4.77, P = .03), while patients with high mean PA pressure and normal PVR had equivalent survival to those with normal PA pressure. Despite the high prevalence of PH in ESRD patients, elevated PVR is uncommon and is a determinant of prognosis in patients with PH. Patients with normal PVR had survival equivalent to those with normal PA pressures.     

Preformed donor‐specific HLA antibodies are associated with increased risk of early mortality after liver transplantation

There is limited evidence for a negative impact of preformed, donor‐specific HLA antibodies (DSA) identified by cross‐matching on outcomes after liver transplantation. Three recent studies have suggested an association between preformed DSA detected by Luminex and reduced graft or recipient survival in liver transplant cohorts with a high prevalence of hepatitis C. This study investigated the impact of preformed DSA identified by Luminex in the Scottish liver transplant population. All recipients of liver transplants in Scotland between 2007 and 2015 with samples available for day of transplant antibody testing and donor HLA typing were included (n=459); 96% of the cohort were white and 19% had a primary diagnosis of hepatitis C. The median follow‐up time was 36 months. Preformed DSA were detected in 88 recipients. In multivariate analysis, preformed DSA with a median fluorescent intensity ≥10 000 were associated with recipient mortality at 1 year. There was no association between DSA and overall graft or recipient survival. This study adds to the growing body of evidence supporting a detrimental impact of preformed, high‐level DSA in a subset of liver transplant recipients by identifying an association in an ethnically and demographically distinct liver transplant population.