Somchai Eiam-Ong

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.

Regulation of collecting tubule adenosine triphosphatases by aldosterone and potassium.

To examine the precise role of potassium and aldosterone on acid-base composition and on collecting tubule ATPases, glucocorticoid-replete adrenalectomized rats were replaced with zero, physiological, or pharmacological doses of aldosterone and were fed varying potassium diets to produce hypokalemia, normokalemia, or hyperkalemia. Radiochemical measurement of ATPase activities showed that collecting tubule H/K-ATPase changed inversely with potassium and not with aldosterone whereas H-ATPase changed directly with aldosterone but not with potassium. When both enzymes changed in the same direction, alterations in acid-base composition were profound; however, when these two acidifying enzymes changed in opposite directions or when only one enzyme changed, the effect on acid-base balance was modest. Serum bicarbonate was approximately 45 meq/liter when aldosterone was high and potassium was low; it was only 29 meq/liter when aldosterone was high but potassium was normal or when aldosterone was normal and potassium was low. Our observations may help explain the metabolic alkalosis of primary aldosteronism in which aldosterone excess and hypokalemia are combined and the metabolic acidosis of aldosterone deficiency in which hypoaldosteronism and hyperkalemia are paired. The present study also demonstrated that aldosterone plays the major role in controlling Na/K-ATPase activity in cortical collecting tubule. Hypokalemia stimulates Na/K-ATPase activity in the medullary collecting tubule; this stimulatory effect of hypokalemia supports the hypothesis that the enzyme is present on the apical membrane at this site.

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.

An update on acute postinfectious glomerulonephritis worldwide.

Postinfectious glomerulonephritis is an immunologic response of the kidney to infection, commonly triggered by streptococci, although many other organisms can cause the condition. In recent decades, the prevalence of postinfectious glomerulonephritis has tended to decline in most industrialized countries, but high rates persist in some developing communities. Nowadays, patients in developed countries are usually adult and male, and those with comorbidities such as diabetes and alcoholism are at increased risk of developing the disease. The acute presentation ranges from nephritic syndrome to asymptomatic glomerulonephritis. The exact pathophysiology of postinfectious glomerulonephritis is still unknown; however, several possible pathologic antigens are under investigation. The majority of children and patients with the epidemic form of postinfectious glomerulonephritis have an excellent prognosis, which contrasts with the poor long-term outcome of sporadic cases. Therapy is largely supportive unless renal function fails to recover after eradication of the causative organism. This Review focuses on acute postinfectious glomerulonephritis, and covers its epidemiology, presentation, pathology, pathogenesis, treatment and outcomes.

Efficacy and Safety of Combined vs. Single Renin–Angiotensin–Aldosterone System Blockade in Chronic Kidney Disease: A Meta-Analysis

BACKGROUND Although dual blockade of the renin-angiotensin-aldosterone system (RAAS) has gained popularity for the treatment of kidney disease, its benefits and potential risks have not been fully elucidated. We conducted a meta-analysis of all randomized controlled trials comparing the efficacy and safety of combined vs. single RAAS blockade therapy in chronic kidney disease (CKD). METHODS We performed a literature search using MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, scientific abstracts from meetings, and bibliographies of retrieved articles. We used random-effects models to compute net changes and rate differences in variables. RESULTS Fifty-nine (25 crossover and 34 parallel-arm) randomized controlled trials (RCTs) comparing the efficacy and safety of combined vs. single RAAS blockade therapy in CKD were identified (4,975 patients). Combined RAAS blockade therapy was associated with a significant net decrease in glomerular filtration rate (GFR) (-1.8ml/min or ml/min/1.73 m(2); P = 0.005), albuminuria (-90mg/g of creatinine; P = 0.001 or -32mg/day; P = 0.03), and proteinuria (-291mg/g; P = 0.003 or -363mg/day; P < 0.001). Combined RAAS blockade therapy was associated with a 9.4% higher rate of regression to normoalbuminuria and a 5% higher rate of achieving the blood pressure (BP) goal (as defined in individual trials). However, combined RAAS blockade therapy was associated with a significant net increase in serum potassium level, a 3.4% higher rate of hyperkalemia, and a 4.6% higher rate of hypotension. There was no effect on doubling of the serum creatinine level, hospitalization, or mortality. CONCLUSIONS Although combined RAAS blockade therapy in CKD is associated with a decrease in albuminuria and proteinuria, it is associated with a decrease in GFR and a higher incidence of hyperkalemia and hypotension relative to monotherapy. The potential long-term kidney benefits of combined RAAS blockade therapy require further study.

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.

APRIL, a proliferation-inducing ligand, as a potential marker of lupus nephritis.

IntroductionBLyS and APRIL are cytokines from the tumor necrosis factor family which play an important role in systemic lupus erythematosus (SLE). Previous works suggested an association between both molecules and SLE disease activity although their correlation with lupus nephritis is not known. We therefore assessed serum BLyS and APRIL in active lupus nephritis patients.MethodsSerum samples from active lupus nephritis and at 6 months post-treatment were obtained. Serum levels of BLyS and APRIL (n = 47) as well as renal mRNA expression were measured. Serum levels of both molecules and clinical data (n = 27) were available at 6 months follow-up. All biopsy-proven lupus nephritis patients were treated with similar immunosuppressive drugs.ResultsSerum levels of APRIL were associated with proteinuria (Rs = 0.44, P value < 0.01) and degree of histological activity (Rs = 0.34; P value < 0.05) whereas BLyS levels were associated with complement levels (Rs = 0.46; P value < 0.01) and dosage of immunosuppressant. Interestingly, serum APRIL as well as its intrarenal mRNA levels were associated with resistance to treatment. From the receiver operating characteristic (ROC) analysis, high levels (> 4 ng/mL) of serum APRIL predicted treatment failure with a positive predictive value of 93 percent.ConclusionAPRIL could be a potential biomarker for predicting difficult-to-treat cases of lupus nephritis.

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.