Kearkiat Praditpornsilpa

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.

Renal pathology and HIV infection in Thailand.

The existence of a human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) as a distinct disease entity characterized by glomerulosclerosis is well established in North America and Western Europe. Although the large number of HIV-infected cases overwhelm the Asian countries, no cases of HIVAN are documented in the literature. We studied 26 cases of HIV-infected Thai patients with proteinuria greater than 1.5 g/d of protein during 1995 and 1996. None of the patients were treated with antiretroviral drugs at the time of renal biopsy. Intravenous drug addiction and sexual transmission were risk factors in 11 and 15 patients, respectively. Pathological examinations were performed by light microscopic and immunoperoxidase study. Mesangial proliferative glomerulonephritis was found in 17 cases, immunoglobulin A (IgA) nephropathy in 2 cases, and diffuse proliferative glomerulonephritis and interstitial nephritis secondary to cryptococcal infection in 2 cases each. One case each had membranous glomerulopathy, membranoproliferative glomerulonephritis, and granulomatous interstitial nephritis secondary to tuberculosis. The renal pathological findings of HIVAN with the unique features described in previous literature were not evident in these patients. Although the data in this study are limited to 26 HIV-infected Thai patients, we believe that HIVAN is uncommon in the Asian HIV-infected population.

Prevalence of herbal and dietary supplement usage in Thai outpatients with chronic kidney disease: a cross-sectional survey

BackgroundThere are few studies of the prevalence and patterns of herbal and dietary supplement (HDS) use in patients with chronic kidney disease (CKD), although many researchers and health professionals worldwide have raised concern about the potential effects of HDS on patients with renal insufficiency. A survey was conducted to determine: the prevalence and patterns of HDS use in Thai patients with CKD; the demographic factors related to HDS use; the reasons why Thai patients with CKD use HDS; respondent experiences of benefits and adverse effects from HDS; and the association between conventional medication adherence and HDS use.MethodsThis cross-sectional survey recruited patients with CKD attending two teaching hospitals in Thailand. Data were collected via an interview using a semi-structured interview schedule regarding demographics, HDS usage, reasons for HDS use, and respondent experiences of effects from HDS. Conventional medication adherence was measured using the Thai version of 8-Item Morisky Medication Adherence Scale. Descriptive statistics were used to analyse the prevalence and the patterns of HDS use. Chi-square tests and multiple logistic regression were used to determine any associations between HDS use, demographics and conventional medication adherence.ResultsFour hundred and twenty-one eligible patients were recruited. The prevalence of HDS use in the previous 12 months was 45%. There were no demographic differences between HDS users and non-users, except former drinkers were less likely to use HDS, compared with non-drinkers (OR 0.43, 95% CI 0.25-0.75). Those with a medium level of adherence to conventional medication were less likely to use HDS compared with those with a low level of adherence (OR 0.53, 95% CI 0.32-0.87). Maintaining well-being was most common purpose for using HDS (36%). Nearly 18% used HDS, such as holy mushroom, river spiderwort and boesenbergia, to treat kidney disease. The top three most often reported reasons why respondents used HDS were family and friend’s recommendation, followed by expecting to gain benefit from HDS and wanting to try them. Perceived beneficial effects on renal function from HDS were reported by around 10% of HDS users. Among HDS users, seven patients perceived worsening CKD from HDS, such as river spiderwort, kariyat and wheatgrass. Additionally, 72% of respondents did not inform their doctor about their HDS use mainly because their doctor did not ask (46%) or would disapprove of their HDS use (15%).ConclusionsAround half of the Thai patients with CKD used HDS. Health professionals should be aware of HDS use amongst such patients and enquire about HDS use as a part of standard practice in order to prevent any detrimental effects on kidney function.

Regional Citrate Anticoagulation Reduces Polymorphonuclear Cell Degranulation in Critically Ill Patients Treated With Continuous Venovenous Hemofiltration

Citrate which chelates ionized calcium can be used as regional anticoagulation in continuous venovenous hemofiltration (CVVH). This is the first study conducted to examine the potentially additive benefit effect of regional citrate anticoagulation (RCA) on polymorphonuclear (PMN) cell degranulation of myeloperoxidase (MPO) and cytokines production in patients with critically acute kidney injury (AKI) undergoing CVVH treatment. This prospective randomized controlled trial was conducted in 20 critically ill patients with AKI who underwent CVVH. The patients were randomized into regional citrate group (n = 10) and heparin group (n = 10). The pre‐dilution CVVH with polyethersulfone dialyzers were utilized in both groups. The levels of pre‐filter and post‐filter MPO as well as inflammatory and anti‐inflammatory cytokines were measured at baseline, 6 h, and 24 h after initiating CVVH. In the heparin group, the post‐filter serum MPO levels were significantly higher than the pre‐filter (median 49.0 vs. 60.5 ng/mL, P < 0.05) at 6 h. There were no significant differences between pre‐ and post‐dialyzer MPO levels in the citrate group. Citrate could significantly decrease systemic pre‐filter serum MPO levels from baseline at 6 h (median 43.5 vs. 17.3 ng/mL, P < 0.01) as well as IL‐8 levels (P < 0.05) whereas heparin provided only significant TNF‐α reduction (P < 0.05). The CVVH circuit survival in the citrate group was longer than the heparin group. In conclusion, citrate, utilized as a regional anticoagulant in CVVH, can reduce both membrane bioincompatibility‐induced and systemic oxidative stress and inflammation, and can prolong CVVH circuit survival time.

Comparisons between validated estimated glomerular filtration rate equations and isotopic glomerular filtration rate in HIV patients

Objective:Understanding how best to measure renal function in HIV-infected patients is critical because estimated glomerular filtration rate (eGFR) in HIV-infected patients can be affected by ethnicity and body composition. We validated the available eGFR equations and compared them to the plasma 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) clearance in HIV-infected patients. Design:Test of diagnostic accuracy. Methods:One hundred and ninety-six HIV-infected patients underwent measuring of 99mTc-DTPA plasma clearance, five creatinine-based eGFR equations, cystatin-C GFR, and 24-h urine creatinine clearance (CrCl). Results:Mean (SD) 99mTc-DTPA GFR was 117.7 ± 29.2 ml/min per 1.73 m2. The re-expressed Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), re-expressed MDRD formula with Thai racial correction factor, Thai eGFR equation, Cockcroft–Gault equation, cystatin-C GFR, and 24-h urine CrCl underestimated the reference GFR. The bias estimated by the mean of differences (SD) for the re-expressed MDRD equation, CKD-EPI, re-expressed MDRD formula with Thai racial correction factor, Thai eGFR, Cockcroft–Gault equation, cystatin-C, and 24-h urine CrCl can be expressed as 18.9 ± 27.3, 11.1 ± 25.5, 6.2 ± 28.8, 15.4 ± 27.0, 30.4 ± 28.0, 3.2 + 36.1, and 5.0 ± 12.1 ml/min per 1.73 m2, respectively. Conclusion:The available eGFR equations underestimated GFR in HIV-infected adults. However, the eGFR by cystatin-C GFR was the most precise and accurate. Among creatinine-based eGFR equations, re-expressed MDRD formula with Thai racial correction factor was the most precise and accurate. The racial factor for each ethnicity is important and the existing eGFR equation should be validated before using it in the HIV population.

The association of anti-r-HuEpo-associated pure red cell aplasia with HLA-DRB1*09-DQB1*0309

BACKGROUND Anti-r-HuEpo associated PRCA developed in patients received subcutaneous injection of r-HuEpo for treatment of renal anemia in chronic kidney disease. This adverse immunological effect of r-HuEpo causes sudden loss of r-HuEpo efficacy, low circulating reticulocyte count and bone marrow biopsy shows an absence of erythroid precursor cells with normal cell population of non-erythroid lineage. There are postulation cause of anti-r-HuEpo associated PRCA including genetic factor, immunogenicity factor, storage and handlings factor and formulation of r-HuEpo product. Previous observation of our report showed an aggregation of HLA-DRB1*09 in four anti-r-HuEpo associated PRCA cases. This allele is rare in Caucasian (<1%) but more common in Thai population (8.4-12.5%). This study was aimed to investigate the possible association between HLA-DRB1*09 or other specific HLA and anti-r-HuEpo associated PRCA. METHODS Twenty two cases of proven anti-r-HuEpo associated PRCA were recruited and studied retrospectively based on the incidence report of serious adverse drug reaction. The EDTA bloods were drawn for HLA typing using sequence specific primer polymerase chain reaction (SSP-PCR). The HLA data of 1,800 potential cadaveric kidney transplantation recipients in the waiting list as chronic kidney disease control and 1,500 potential bone marrow stem cell donors in national stem cell registry as healthy population control were retrieved from the database of Thai Red Cross for comparison. RESULTS The distribution of gene frequency of HLA-A, -B, -DR and -DQ alleles in anti-r-HuEpo associated PRCA cases showed high gene frequency of HLA-A*02, HLA-A*11 and HLA-A*24 for HLA-A loci, HLA-B*18, HLA-B*46, HLA-B*60 and HLA-B*62 for HLA-B loci, and HLA-DRB1*09, HLA-DRB1*12 and HLA-DRB1*15 for HLA-DR loci. There was a significant difference of HLA-DRB1*09 gene frequency (P < 0.001) which associated with HLA-DQB1*0309 between anti-r-HuEpo associated PRCA cases, and potential cadaveric kidney transplantation in the waiting list or potential national stem cell registry donor. The odd ratio of HLA-DRB1*09 allele for anti-r-HuEpo associated PRCA was 2.89 (95% CI: 1.88-4.46; p-value: <0.001). CONCLUSIONS Our data demonstrated the association of HLA-DRB1*09-DQB1*0309 and anti-r-HuEpo associated PRCA cases. This association may be used in identifying the risk of the patients.

Erythropoietin and its non‐erythropoietic derivative: Do they ameliorate renal tubulointerstitial injury in ureteral obstruction?

Objectives:  Pleiotropic effects of recombinant human erythropoietin (EPO) have recently been discovered in many non‐renal animal models. The renoprotective effects of EPO and carbamylated‐erythropoietin (CEPO), a novel EPO which has a small stimulatory effect on hemoglobin, have never been explored in unilateral ureteral obstruction (UUO), a chronic tubulointerstitial (TI) disease model which is independent of systemic factors.

Effective bilirubin reduction by single-pass albumin dialysis in liver failure.

Albumin dialysis is widely accepted as a liver-support technique for patients with liver failure. The Molecular Adsorbent Recirculating System, the widely accepted albumin dialysis technique, has limited use in developing countries because of its technical difficulties and high cost. Therefore, we assessed the efficacy of the more practical modality, the single-pass albumin dialysis (SPAD), in terms of bilirubin reduction, as a marker of albumin-bound toxins removal, as well as the patient outcomes. Twelve acute or acute-on-chronic patients with liver failure who had hyperbilirubinemia (total bilirubin > 20 mg/dL) were treated with SPAD by using 2% human serum albumin dialysate for 6 h. SPAD treatment significantly improved the levels of total bilirubin, conjugated bilirubin, urea, and creatinine (P < 0.001 for all parameters). The reduction ratios of these four parameters were 22.9 +/- 3.8%, 20.9 +/- 5%, 19.0 +/- 4.1%, and 27.7 +/- 3.2%, respectively. No significant difference was observed between serum ammonia before and after treatment. No significant changes in mean arterial pressures were noted during the maneuver, representing cardiovascular tolerability. No treatment-related complications were found. The 15-day in-hospital survival was 16.7%. However, a subgroup of the patients who had moderate severity showed 100% 15-day-survival rate (2 of 2 patients). In conclusion, SPAD is salutarily effective in reducing bilirubin in patients with liver failure. The procedure is safe and simply set up.

Understanding kidney care needs and implementation strategies in low- and middle-income countries: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Evidence-based cinical practice guidelines improve delivery of uniform care to patients with and at risk of developing kidney disease, thereby reducing disease burden and improving outcomes. These guidelines are not well-integrated into care delivery systems in most low- and middle-income countries (LMICs). The KDIGO Controversies Conference on Implementation Strategies in LMIC reviewed the current state of knowledge in order to define a road map to improve the implementation of guideline-based kidney care in LMICs. An international group of multidisciplinary experts in nephrology, epidemiology, health economics, implementation science, health systems, policy, and research identified key issues related to guideline implementation. The issues examined included the current kidney disease burden in the context of health systems in LMIC, arguments for developing policies to implement guideline-based care, innovations to improve kidney care, and the process of guideline adaptation to suit local needs. This executive summary serves as a resource to guide future work, including a pathway for adapting existing guidelines in different geographical regions.