Shang-Feng Tsai

Reduced Variability of Tacrolimus Trough Level in Once-Daily Tacrolimus-Based Taiwanese Kidney Transplant Recipients With High-Expressive Genotype of Cytochrome P450 3A5

BACKGROUND Our previous study results indicated that conversion from twice-daily Prograf to once-daily Advagraf associated with lower variability of tacrolimus blood trough level. Some factors, such as frequency of interaction by food exposure, expression of cytochrome P450 3A5 genetic polymorphism, and other interactions of unknown factors, could be the reasons for the change of variability. We aimed to clarify the impact of cytochrome P450 3A5 genetic polymorphism on the variability of tacrolimus blood trough level in Taiwanese kidney transplant recipients. METHODS We collected blood samples from kidney transplant recipients to prepare DNA and then performed single-nucleotide polymorphism genotyping by using the restriction fragment length polymorphism. RESULTS We found that 79 (52.7%) of 150 kidney transplant recipients had the low-expressive genotype (CYP3A5*3/*3), whereas the other 71 (47.3%) kidney transplant recipients had high-expressive genotype (CYP3A5*1/*1 and CYP3A5*1/*3). The prevalence of high-expressive genotype is higher than previous reports from western countries. Compared with the patients with high-expressive genotype, the average dose-normalized trough level of tacrolimus was significantly higher in patients with low-expressive genotype. Interestingly, when patients converted from twice-daily Prograf to once-daily Advagraf, the percent coefficient of variation of tacrolimus trough level was significantly decreased in patients with high-expressive genotype. CONCLUSION This study suggested that there is a potential benefit for kidney transplant recipients with cytochrome P450 3A5 high-expressive genotype (*1/*1 or *1/*3) to convert from Prograf to once-daily Advagraf.

Urinary Cyclophilin A as a New Marker for Diabetic Nephropathy: A Cross-Sectional Analysis of Diabetes Mellitus.

Abstract Type 2 diabetes mellitus (DM) is the most common single cause of end-stage renal disease. Albuminuria is the most commonly used marker to predict onset of diabetic nephropathy (DN) without enough sensitivity and specificity to detect early DN. This is the first study to identify urinary cyclophilin A (CypA) as a new biomarker for early DN. We recruited DM outpatients and healthy control subjects from January 2014 to December 2014. In this cross-sectional study, patients’ urine samples were collected to determine the expression of urinary CypA. We also treated mesangial (MES-13) and tubular (HK-2) cells with glucose or free radicals to observe the expression of secreted CypA in Western blot analysis. A total of 100 DN patients and 20 healthy control subjects were enrolled. All variables were matched. In univariate analysis, the concentration of urinary CypA correlated well with the progression of renal function. A significant increase in urinary CypA was noted in stage 2 DN and persisted in later stages. We could diagnose stage 2 DN using urinary CypA with a sensitivity of 90.0% and specificity of 72.7%. The area under curve was up to 0.85, indicating a good discriminatory power. In cellular models, MES-13 and HK-2 cells can both release CypA. Urinary CypA is a good biomarker for early DN detection in humans and it can be released from either mesangial or tubular cells. The underlying molecular mechanisms still need further clarification in cellular and animal studies.

Current Safety of Renal Allograft Biopsy With Indication in Adult Recipients: An Observational Study.

AbstractRenal biopsy remains the golden standard diagnosis of renal function deterioration. The safety in native kidney biopsy is well defined. However, it is a different story in allograft kidney biopsy. We conduct this retrospective study to clarify the safety of allograft kidney biopsy with indication.All variables were grouped by the year of biopsy and they were compared by Mann–Whitney U test (for continuous variables) or Chi-square test (for categorical variables). We collected possible factors associated with complications, including age, gender, body weight, renal function, cause of uremia, status of coagulation, hepatitis, size of needle, and immunosuppressants.We recruited all renal transplant recipients undergoing allograft biopsy between January of 2009 and December of 2014. This is the largest database for allograft kidney biopsy with indication. Of all the 269 biopsies, there was no difference in occurrence among the total 14 complications (5.2%) over these 6 years. There were only 3 cases of hematomas (1.11%), 6 gross hematuria (2.23%), 1 hydronephrosis (0.37%), and 2 hemoglobin decline (0.74%). The outcome of this cohort is the best compared to all other studies, and it is even better than the allograft protocol kidney biopsy. Among all possible factors, patients with pathological report containing “medullary tissue only” were susceptible to complications (P < 0.001, 1.8 of relative risk).In modern era, this study demonstrates the safety of allograft kidney biopsy with indication. Identifying the renal capsule before biopsy to avoid puncture into medulla is the most important element to prevent complications.

Trend of Outcomes in Renal Transplant Recipients With Hepatitis B Virus: A Longitudinal Analysis Using a National Database

INTRODUCTION Manifestations of hepatitis B virus (HBV) infection in renal transplant (RTx) recipients tend to be worse because of the higher viral load. RTx recipients with Asian heritage have a higher HBV infection rate and have unique characteristics. To date, no large-scale study on the outcomes of Asian RTx recipients has been conducted. Furthermore, there are few longitudinal studies comparing outcomes before and after availability of anti-HBV drugs. MATERIAL AND METHODS We conducted a nationwide, population-based study to elucidate patient survival, graft survival, and hepatic outcome (incidence of hepatoma) in Asian RTx recipients. The study includes all RTx recipients in Taiwan from 1997 to 2006. Patients were divided into 2 groups according to HBV infection status to examine the effect of antiviral drug therapy. RESULTS In all, 3826 RTx recipients were followed for a mean of 7.4 years, with a mean age of 43.7 years. There were no differences between the HBV and non-HBV groups in patient or graft survival rates. At 5 years after RTx, 89.2% of the patients were still alive and 84.5% RTx recipients were still dialysis free. In the era before anti-HBV drugs were available (1997-2001), patient survival in the HBV and non-HBV groups were similar (P = .614). This result can also be seen in the anti-HBV drug era, from 2002 to 2006 (P = .148). The unusual lack of a significant effect of drug anti-HBV administration on HBV-related mortality in RTx patients may be explained by the short duration of follow-up in the 2 eras. Another explanation may be the confounding effect of the different health status of RTx patients in the pre-anti-HBV drug era, when cardiovascular and infection-related mortality rates were considerably greater than HBV-related mortality rates. CONCLUSION These results demonstrate that HBV is not a contraindication for RTx. Asian recipients with HBV can still achieve a similar graft outcome and survival rate compared with those of patients without HBV.

Paraquat Poisoning in Patients With HIV Infection: A Case Report and Literature Review.

AbstractParaquat poisoning is very severe. Most victims, including those who have ingested a small amount, will die from Paraquat poisoning. The cause of death in the majority of such cases is lung fibrosis. Paraquat poisoning in patients with positive human immunodeficiency virus (HIV) infection status has seldom been reported. Herein, we report a case of an HIV patient with Paraquat poisoning who had an excellent outcome even without standard treatment. Currently, only 3 such cases have been reported in the literature and in each case there was a good outcome, which was not expected according to predictive models. A possible mechanism may involve the relative lack of functional macrophages in HIV patients, which would tend to result in much less severe lung injury. None of the available predictive models of Paraquat poisoning appear to be appropriate for HIV patients.Paraquat poisoning in HIV patients may have better survival due to less lung injury.

Long-Term Follow-Up of a Homozygous Familial Hypercholesterolemic Patient Receiving Regular Double Filtration Plasmapheresis - Case Report and Literature Review

Homozygous familial hypercholesterolemia (HoFH) is a very rare condition (1 case per 1 million people) with a dismal outcome due to inevitable coronary artery disease that occurs when left untreated. Lipoprotein apheresis (LA), previously known as low-density lipoprotein (LDL) apheresis, is very effective in reducing LDL-cholesterol (LDL-C) if HoFH is refractory to aggressive drug therapy and diet control. In this study, we report a case with HoFH, who presented with xanthomata over the 4 limbs when she was 3 years old. When she was 11 years old, she began treatment with semi-selective LA with double filtration plasmapheresis (DFPP) once per week because HoFH was refractory to high-dose statin and diet control. LDL-C was reduced from 8.2 ± 0.9 to 2.69 ± 0.75 mmol/l (reduction rate = 67.3 ± 6.1%). The xanthomata over the 4 limbs were nearly completely resolved after 2 years of DFPP. Two years later, after the initiation of DFPP, we performed coronary angiography and echocardiography for regular checkup in the absence of chest pain, and the result was negative. To date (11 years after initiation of DFPP), she has not complained of any chest pain, shown intolerance to exercise, or exhibited ST-T change on electrocardiography. At the age of 20, multidetector computed tomography showed no significant stenosis over the coronary arteries. At the most recent follow-up visit, she was found to have good heart function and no xanthomata. LA is effective in the treatment of HoFH when drug therapy and diet control fail. With this treatment, pre-existing xanthomata can regress and coronary artery disease can be prevented.

Universal Valganciclovir Prophylaxis Significantly Reduces Episodes of First-Year Cytomegalovirus Disease and Biopsy-Proven Acute Rejection in Kidney Transplant Recipients

BACKGROUND Cytomegalovirus (CMV) remains the most critical viral pathogen after kidney transplantation (KTx). The universal prophylaxis, but not pre-emptive therapy, could avoid the wide range of indirect effects induced by CMV infection. This study aims to examine the effect of universal prophylaxis with oral valganciclovir for the first year of CMV disease after KTx. METHODS The universal prophylaxis therapy was started in May 2008. Patients who received KTx between January 2006 and September 2010 were included in the study. Oral valganciclovir (Valcyte) was used for 3 months with dosage adjusted by eGFR. CMV disease was defined by typical CMV syndrome with positive viremia or tissue proven. The study end points are episode of CMV disease and first-year biopsy-proven acute rejection. RESULTS In total, 68 KTx patients who received universal prophylaxis for 3 months (study group) and another 50 KTx recipients without universal prophylaxis (control group) were enrolled. The incidence of CMV disease was 8.0% (4 of 50) in the control group. The universal prophylaxis significantly reduced the first-year episodes of CMV disease to 0% (0 of 68). There were 8 episodes of biopsy-proven acute rejection (8 of 50, 16%) within 1 year after KTx in the control group, but only 2 episodes of biopsy-proven acute rejection (2 of 68, 2.9%) in the treatment group (P < .05). CONCLUSIONS Universal prophylaxis with oral valganciclovir for 3 months significantly reduced episodes of first-year CMV disease and biopsy-proven acute rejection in kidney transplant recipients.

High Prevalence of Anemia in Kidney Transplant Recipients with Stage 3B Chronic Kidney Disease

BACKGROUND: Anemia is one of the most common complications of chronic kidney disease (CKD), The aim of this study was to assess the prevalence of anemia in kidney transplant (KTx) recipients with CKD. METHODS: A total of 439 KTx recipients were enrolled in this cross-sectional study. Anemia was defined as hemoglobin (Hgb) ≤11 g/dL. RESULTS: The prevalence of CKD stages 3 to 5 in KTx recipients was 55.6%. The mean Hgb level was 12.7 ± 2.0 g/dL. Among KTx recipients, 22.1% had anemia, but the percentage was significantly higher in females, and increased with severity of CKD. Moreover, moderately severe anemia occurred significantly earlier in KTx recipients (i.e., with better preserved renal function). The overall rate of treatment with erythropoiesis-stimulating agents (ESAs) in KTx recipients with anemia was 21.6%. CONCLUSION: Anemia is common in KTx patients with CKD. It appears to be associated with female gender and renal dysfunction. Moreover, moderately severe anemia can develop as early as CKD stage 38. The ESA treatment for anemia in KTx recipients was inadequate. Early diagnosis and treatment of anemia in KTx recipients is mandatory.

Effect of different hemodialyzers on serum levels of interleukin-6, interleukin-10 and interleukin-18.

Background: The blood and membrane contact during dialysis may elicit an immune reaction. The current study looked at the impact of different dialyzers on blood levels of cytokines. Methods: During the first month, randomly selected patients were treated with one dialyzer (PF-170H) and then crossed over to another dialyzer (FLX-18GW) during the next month. Pre- and postdialysis blood samples were assayed for interleukin (IL)-6, IL-10 and IL-18. Results: A significant drop of postdialysis systolic blood pressure (pre vs. post 156.4 ± 31.8 vs. 143.1 ± 24.8 mm Hg, p = 0.014) and diastolic pressure (80.7 ± 12.7 vs. 73.4 ± 10.9 mm Hg, p = 0.002) were found when patients were dialyzed with PF-170H. A significant increase of postdialysis IL-18 levels was found in both groups (pre vs. post 605.5 ± 278.6 vs. 690.6 ± 315.3 pg/ml, p = 0.016, for PF-170H and 556.4 ± 231.0 vs. 647.3 ± 282.6 pg/ml, p = 0.067, for FLX-18GW). There was a positive correlation between IL-6 and IL-10 levels (p < 0.0001). Conclusion: We demonstrated a significant increase of postdialysis serum IL-18 level when either dialyzer was used. There is a strong correlation between serum levels of IL-6 and IL-10.

Impact of Abnormal Liver Enzymes on Long-term Renal Outcome in Patients with Hepatitis B Virus Infection and IgA Nephropathy

BACKGROUND: IgA nephropathy (IgAN) is the most common form of glomerulonephritis among patients undergoing renal biopsy. Several conditions are associated with IgAN. Hepatitis B virus (HBV) infection has been reported to be a common secondary cause of IgAN. The aim of this study was to delineate whether abnormal liver enzymes or the presence of cirrhosis is associated with unfavorable renal outcome in patients with HBV infection and IgAN (HBV+IgAN). METHODS: We retrospectively reviewed our renal biopsy database covering the past 28 years. Sixty-seven cases with both HBs antigenemia and biopsy-proven IgAN were identified and all relevant medical records were reviewed. We excluded patients with incomplete medical records, those whose serum aminotransferase levels were not obtained, hepatitis C virus (HCV) carriers and patients with less than 3 months of post-biopsy follow-up. A total of 45 patients were recruited for this study. RESULTS: Patients had been followed up for an average of 138.9 ± 130.9 months after the confirmation of diagnosis. The mean age at the time of renal biopsy was 35.1 ± 11.0 years. They were divided into two groups according to the final renal outcomes. The ”progressive” group included patients with deterioration to end-stage renal disease (ESRD) or doubled values of serum creatinine (Cr). All the other patients were included in the ”stable” group. Compared with the stable group, the progressive group had a significantly higher baseline serum Cr, a lower baseline estimated glomerular filtration rate (eGFR), higher urine protein, lower hematocrit, higher incidence of hypertension (HTN), higher grade of Haass sub-classification, and higher incidence of liver abnormality detected during follow-up (defined as ＞ 2-fold the upper normal limits of liver transaminase levels or the presence of cirrhosis). Multivariate Cox regression analysis demonstrated that higher maximal liver transaminase during follow-up periods or presence of cirrhosis was independently associated with unfavorable renal outcome (Hazard ratio [HR] in Model B: 4.24, 95% CI: 1.17-15.34, P=0.03). Median renal survival was 7.9 years in 13 patients with liver dysfunction compared with 28.2 years in patients without liver dysfunction (P=0.0009). Kaplan-Meier analysis revealed that the 1-year (HR: 0.22, 95% CI: 0.07-0.68, P=0.0086), 5-year (HR: 0.18, 95% CI: 0.06-0.55, P=0.0023) and 10-year (HR: 0.18, 95% CI: 0.54, P=0.0022) renal survival rates were significantly decreased in patients with liver abnormality. CONCLUSION: Abnormal liver enzymes or the presence of cirrhosis was associated with an increased rate of progression to ESRD in our patients with chronic HBV infection and IgAN. Close monitoring of liver function and prompt treatment are mandatory in such patient groups.