Natavudh Townamchai

Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies

Recombinant human erythropoietin (r-HuEpo) has been used for the treatment of renal anemia. With the loss of its patent protection, there has been an upsurge of more affordable biosimilar agents, increasing patient access to treatment for these conditions. The complexity of the manufacturing process for these recombinant proteins, however, can result in altered properties that may significantly affect patient safety. As it is not known whether various r-HuEpo products can be safely interchanged, we studied 30 patients with chronic kidney disease treated by subcutaneous injection with biosimilar r-HuEpo and who developed a sudden loss of efficacy. Sera from 23 of these patients were positive for r-HuEpo-neutralizing antibodies, and their bone marrow biopsies indicated pure red-cell aplasia, indicating the loss of erythroblasts. Sera and bone marrow biopsies from the remaining seven patients were negative for anti-r-HuEpo antibodies and red-cell aplasia, respectively. The cause for r-HuEpo hyporesponsiveness was occult gastrointestinal bleeding. Thus, subcutaneous injection of biosimilar r-HuEpo can cause adverse immunological effects. A large, long-term, pharmacovigilance study is necessary to monitor and ensure patient safety for these agents.

The need for robust validation for MDRD-based glomerular filtration rate estimation in various CKD populations

BACKGROUND Currently, estimated glomerular filtration rate (eGFR) equations have been validated only in Caucasians and African-Americans and is not applicable to people of other races/ethnicities as shown in studies conducted in two Asian populations: Chinese and Japanese. Because of this, it is important that eGFR equations are validated in its prospective population before applying it in the clinical setting and in epidemiologic studies. Therefore, we examined all eGFR equations available: reexpressed isotope dilution mass spectroscopy (IDMS)-traceable Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, Chinese equation and Japanese equation. METHODS A total of 350 adult Thai CKD patients were studied. The (99m)Tc-DTPA plasma clearance was used as a reference for glomerular filtration rate (GFR). The serum creatinine was determined by IDMS reference enzymatic methods (Cr(Enz)) and Jaffes kinetic assay (Cr(Jaffe)) as indicated in each equation. RESULTS The disagreement between the reference GFR and eGFR (reference GFR minus eGFR) was 9.6 mL/min/1.73 m(2) for the reexpressed IDMS-traceable MDRD equation, 8.0 mL/min/1.73 m(2) for CKD-EPI equation, 1.9 mL/min/1.73 m(2) for eGFR equation from the Chinese study and 20.9 mL/min/1.73 m(2) for the eGFR equation from the Japanese study. The Thai coefficient for the reexpressed MDRD was 1.129. The reexpressed MDRD equation for Thais is as follows: 175 × Cr(Enz) ((-1.154)) × Age ((-0.203)) × 0.742 (if female) × 1.129 (if Thai). When stepwise multiple regression analysis was used, the Thai eGFR formula is: 375.5 × Cr(Enz) ((-0.848)) × Age ((-0.364)) × 0.712 (if female). CONCLUSIONS Differences in race/ethnicity can significantly affect the results obtained from MDRD-based eGFR equation. It is highly recommended that each population should validate eGFR equations before applying the equation in epidemiologic studies or clinical use.

The Outcomes of Kidney Transplantation in Hepatitis B Surface Antigen (HBsAg)–Negative Recipients Receiving Graft From HBsAg-Positive Donors: A Retrospective, Propensity Score-Matched Study

The outcomes of kidney transplantation (KT) from hepatitis B surface antigen–positive [HBsAg(+)] donors to HBsAg(−) recipients remain inconclusive, possibly due to substantial differences in methodological and statistical models, number of patients, follow‐up duration, hepatitis B virus (HBV) prophylactic regimens and hepatitis B surface antibody (anti‐HBs) levels. The present retrospective, longitudinal study (clinicaltrial.gov NCT02044588) using propensity score matching technique was conducted to compare outcomes of KT between HBsAg(−) recipients with anti‐HBs titer above 100 mIU/mL undergoing KT from HBsAg(+) donors (n = 43) and HBsAg(−) donors (n = 86). During the median follow‐up duration of 58.2 months (range 16.7–158.3 months), there were no significant differences in graft and patient survivals. No HBV‐infective markers, including HBsAg, hepatitis B core antibody, hepatitis B extracellular antigen and HBV DNA quantitative test were detected in HBsAg(+) donor group. Renal pathology outcomes revealed comparable incidences of kidney allograft rejection while there were no incidences of HBV‐associated glomerulonephritis and viral antigen staining. Recipients undergoing KT from HBsAg(+) donors with no HBV prophylaxis (n = 20) provided comparable outcomes with those treated with lamivudine alone (n = 21) or lamivudine in combination with HBV immunoglobulin (n = 2). In conclusion, KT without HBV prophylaxis from HBsAg(+) donors without hepatitis B viremia to HBsAg(−) recipients with anti‐HBs titer above 100 mIU/mL provides excellent graft and patient survivals without evidence of HBV transmission.

Rituximab for recurrent IgA nephropathy in kidney transplantation: A report of three cases and proposed mechanisms.

Recurrent IgA nephropathy (IgAN) is a common recurrent glomerular disease after kidney transplantation. Recurrent IgAN, in particular, with crescent formation or endocapillary proliferation might result in kidney allograft loss. However, the current treatment options of recurrent IgAN are conflicting.

The validation of estimated glomerular filtration rate (eGFR) equation for renal transplant recipients.

BACKGROUND The re-expressed Modification of Diet in the Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology (CKD-EPI) equation were developed to estimate glomerular filtration rate in non-transplant chronic kidney disease (CKD) patients. The Nankivell equation was created to estimate GFR in transplant recipients. However, none of these formulas have been validated in Asian renal transplant patients. Several recently published studies have highlighted the need to adapt estimated glomerular filtration rate (eGFR) equations to the race of their patients. Although the eGFR equation for Thai CKD has been derived, it has not been validated for transplant recipients. Our study aimed validating the Nankivell equation, re-expressed MDRD equation, CKD-EPI, re-expressed MDRD equation with Thai racial factor correction, as well as the Thai eGFR equation in Thai renal transplant recipients. METHODS A total of 97 adult Thai renal transplant recipients were studied. The 99mTc-DTPA plasma clearance was used as a reference GFR. The serum creatinine was determined by IDMS reference enzymatic methods (CrEnz). RESULTS The mean reference GFR and CrEnz were 67.86 ± 20.72 ml/min/1.73 m2 and 1.23 ± 0.59 mg/dl. The bias estimated by Bland-Altman analysis can be expressed as -12.11 ± 15.87 ml/ min/1.73 m2 for the Nankivell equation, 2.72 ± 13.90 ml/min/1.73 m2 for the re-expressed IDMS-traceable MDRD equation, -2.59 ± 14.16 ml/min/1.73 m2 for the CKD-EPI equation, -7.05 ± 17.34 ml/min/1.73 m2 for the Thai re-expressed MDRD with Thai racial factor, and -8.62 ± 16.00 ml/min/1.73 m2 for the Thai eGFR equation. The CKD-EPI equation provided the best accuracy and precision in terms of Pearson correlation coefficient, mean difference, error, and accuracy within 10%, 20%, and 30%. CONCLUSIONS The equations derived mainly from Caucasian and/or non-transplant status can be applied to Thai transplantation recipients with some bias. The CKD-EPI had the least bias compared with other eGFR equations.

Urinary type IV collagen excretion predicts subsequent declining renal function in type 2 diabetic patients with proteinuria

Baseline urinary type IV collagen excretion was negatively correlated with the subsequent GFR change (r(s)=-0.39, p=0.04) in our cohort of 30 type 2 diabetic patients with proteinuria. Therefore, it could be used to predict subsequent declining renal function in type 2 diabetic patients with proteinuria.

Neutrophil Gelatinase Associated Lipocalin (NGAL) in Leptospirosis Acute Kidney Injury: A Multicenter Study in Thailand

AKI is one of the most serious complications of leptospirosis, an important zoonosis in the tropics. Recently, NGAL, one of the novel AKI biomarkers, is extensively studied in various specific settings such as sepsis, cardiac surgery, and radiocontrast nephropathy. In this multicenter study, we aimed to study the role of NGAL as an early marker and an outcome predictor of leptospirosis associated AKI. Patients who presented with clinical suspiciousness of leptospirosis were prospectively enrolled in 9 centers from August 2012 to November 2014. The first day of enrollment was the first day of clinical suspicious leptospirosis. Blood and urine samples were serially collected on the first three days and day 7 after enrollment. We used three standard techniques (microscopic agglutination test, direct culture, and PCR technique) to confirm the diagnosis of leptospirosis. KDIGO criteria were used for AKI diagnosis. Recovery was defined as alive and not requiring dialysis during hospitalization or maintaining maximum KDIGO stage at hospital discharge. Of the 221 recruited cases, 113 cases were leptospirosis confirmed cases. Thirty seven percent developed AKI. Median uNGAL and pNGAL levels in those developing AKI were significantly higher than in patients not developing AKI [253.8 (631.4) vs 24.1 (49.6) ng/ml, p < 0.001] and [1,030 (802.5) vs 192.0 (209.0) ng/ml, p < 0.001], respectively. uNGAL and pNGAL levels associated with AKI had AUC-ROC of 0.91, and 0.92, respectively. Both of urine NGAL and pNGAL level between AKI-recovery group and AKI-non recovery were comparable. From this multicenter study, uNGAL and pNGAL provided the promising result to be a marker for leptospirosis associated AKI. However, both of them did not show the potential role to be the predictor of renal recovery in this specific setting.

Biomarkers for Refractory Lupus Nephritis: A Microarray Study of Kidney Tissue.

The prognosis of severe lupus nephritis (LN) is very different among individual patients. None of the current biomarkers can be used to predict the development of refractory LN. Because kidney histology is the gold standard for diagnosing LN, the authors hypothesize that molecular signatures detected in kidney biopsy tissue may have predictive value in determining the therapeutic response. Sixty-seven patients with biopsy-proven severely active LN by International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification III/IV were recruited. Twenty-three kidney tissue samples were used for RNA microarray analysis, while the remaining 44 samples were used for validation by real-time polymerase chain reaction (PCR) gene expression analysis. From hundreds of differential gene expressions in refractory LN, 12 candidates were selected for validation based on gene expression levels as well as relevant functions. The candidate biomarkers were members of the innate immune response molecules, adhesion molecules, calcium-binding receptors, and paracellular tight junction proteins. S100A8, ANXA13, CLDN19 and FAM46B were identified as the best kidney biomarkers for refractory LN, and COL8A1 was identified as the best marker for early loss of kidney function. These new molecular markers can be used to predict refractory LN and may eventually lead to novel molecular targets for therapy.

Endothelial Progenitor Cells in Asian Kidney Transplant Patients

BACKGROUND Endothelial progenitor cells (EPC) involved in endothelial repair and maintenance are restored following renal transplantation. There are scarce data regarding EPC in Asian kidney allograft patients. AIM We determined the EPC numbers in Thai renal allograft patients to compare with various other parameters. PATIENTS AND METHODS The EPC numbers which were verified as CD 133+/VEGFR-2 cells in peripheral blood of 38 renal transplant recipients were measured by flow cytometry, and by a cell culture assay using acetylated low-density lipoprotein and Ulex europaeus agglutinin-1 immunofluorescence. Renal function calculated as estimated glomerular filtration rate (eGFR) was obtained by the abbreviated Modification of Diet in Renal Disease (MDRD) formula. RESULTS Renal allograft patients had lower EPC numbers than normal controls (P < .05). The EPC numbers showed a significant correlation with renal allograft function (P < .05). Recipients with stable eGFR at 12 months of follow-up displayed significantly greater EPC numbers at baseline compared with those subjects who experienced a decline in eGFR (P < .05). Recipients using angiotensin receptor blockers had greater EPC numbers at baseline and better 12-month renal allograft function (P < .05). CONCLUSION EPC numbers may influence the fate of renal allograft function. Enhancing EPC numbers may be a new strategy to improve long term renal allograft function.

Biomarkers in kidney transplantation: From bench to bedside.

Immunosuppressive drug level monitoring and serum creatinine are widely used for kidney transplantation (KT) monitoring. Monitoring of drug level is not the direct measurement of the immune response while the rising of creatinine is too late for detection of allograft injury. Kidney biopsy, the gold standard for KT monitoring, is invasive and may lead to complications. Many biomarkers have been discovered for direct monitoring of the immune system in KT and the benefit of some biomarkers has reached clinical level. In order to use biomarkers for KT monitoring, physicians have to understand the biology including kinetics of each marker. This can guide biomarker selection for specific condition. Herein, we summarize the recent findings of donor specific anti-human leukocyte antigen antibody, B lymphocyte stimulator, interferon-gamma induced protein of 10 kDa, and intracellular adenosine triphosphate monitoring, all of which have very strong evidence support for the clinical use in KT.