Pisut Katavetin

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.

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.

A Girl with a Novel Splice Site Mutation in VDR Supports the Role of a Ligand-Independent VDR Function on Hair Cycling

Mutations in vitamin D receptor (VDR) cause hereditary vitamin D resistant rickets (HVDRR). We reported a Thai girl with HVDRR, presenting with an early onset of rickets and partial alopecia. She was a product of a consanguineous couple. Mutation analysis showed that she was homozygous for a novel splice site mutation of the VDR gene, 462 + 1 G → C, resulting in incorporation of the whole 254 bp of the intron 4 into its mRNA. The mutated protein is expected to contain no ligand-binding domain. The fact that she did not develop total alopecia despite of no VDR ligand-binding domain supports that VDR function on hair cycling is ligand independent.

Comparison of middle-molecule clearance between convective control double high-flux hemodiafiltration and on-line hemodiafiltration.

Hemodiafiltration (HDF) is now a well-recognized treatment modality for end-stage renal disease (ESRD) patients. It provides superior characteristics over conventional hemodialysis in many respects. On-line HDF, however, which has been mainly used in clinical practice, requires a special machine. Interestingly, the recently innovated convective-control double high-flux hemodiafiltration (CC-DHF) machine can provide HDF treatment with an adjustable convection rate by using the conventional volume-controlled dialysate flow hemodialysis machine in a modified way. The present study was conducted to compare the efficacy of CC-DHF compared to on-line HDF in terms of middle and small solute clearances in 12 stable, chronic hemodialysis patients who underwent hemodialysis three times a week for at least 6 months. The results showed that the β2-microglobulin (β2M) removal represented by the β2M clearance in CC-DHF was comparable to that in on-line HDF (112.4±17.0 vs. 119.4±15.5 ml/min respectively, NS). Also, the β2M reduction ratio in the CC-DHF group did not differ from the on-line HDF group (85.5±4.2% vs. 86.1±6.7%, NS). With regard to small solute clearances, the values of single-pool Kt/V and phosphate clearance did not differ between CC-DHF and on-line HDF groups. In conclusion, CC-DHF provides removal of β2M and small molecule uremic toxins that is comparable to on-line HDF. An on-line HDF machine may not be available in all hemodialysis centers, whereas CC-DHF can be easily set up, with proper precautions regarding the fluid quality. Therefore, CC-DHF can provide the benefits of convective therapy to patients in situations where use of an on-line HDF machine is limited.

Efficacy Comparison Between Simple Mixed-Dilution and Simple Mid-Dilution On-Line Hemodiafiltration Techniques: A Crossover Study

Mid-dilution and mixed-dilution on-line hemodiafiltration (OL-HDF) techniques are innovated to overcome the limitations of two standard techniques including predilution and postdilution. Unfortunately, the head-to-head comparisons between these two novel techniques in the same study are still limited. Moreover, the original mid-dilution and mixed-dilution OL-HDF need special dialyzers and special machines. In the present study, simple mid-dilution and simple mixed-dilution OL-HDF were settled with the aim for clinical use in general hemodialysis (HD) centers. The efficacies of uremic toxins removal between both modalities were measured and compared. This prospective randomized crossover study was conducted on 12 stable HD patients undergoing simple mixed-dilution and simple mid-dilution OL-HDF techniques. HD prescriptions were similar in both techniques. The dialysis efficacies were determined by calculating small- (urea, creatinine, and phosphate) and middle-molecule (beta-2 microglobulin [β2M]) removal. Moreover, potential complications such as high transmembrane pressure (TMP) and protein loss were also observed. Simple mixed-dilution OL-HDF provided significantly greater clearances of urea, creatinine, and β2M when compared with the simple mid-dilution OL-HDF techniques. Phosphate clearances in both techniques were comparable. In addition, TMP and dialysate albumin loss were not different. There were no intradialytic complications in both techniques. Simple mixed-dilution OL-HDF could provide greater efficacy for small- and middle-molecule clearances and acceptable potential risks, while phosphate removal is comparable.

Correlations of Plasma Desphosphorylated Uncarboxylated Matrix Gla Protein with Vascular Calcification and Vascular Stiffness in Chronic Kidney Disease.

Background: Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification and needs vitamin K-dependent carboxylation for its activity. High levels of desphosphorylated uncarboxylated MGP (dp-ucMGP) were significantly associated with vitamin K deficiency and vascular calcification. This study was conducted to explore the correlations of plasma dp-ucMGP with vascular calcification and vascular stiffness in chronic kidney disease (CKD) patients. Methods: This cross-sectional study enrolled 83 CKD stages 3-5 patients. Vascular calcification score was determined by calcific lesions in the abdominal aorta (AAC) shown by lateral lumbar film; vascular stiffness was assessed by cardio-ankle vascular index (CAVI) and pulse wave velocity, while plasma dp-ucMGP levels were measured using ELISA method. Multivariate regression analyses were used to select factors that were independently associated with vascular calcification and vascular stiffness. Results: The mean age was 62.9 ± 13.9 years. CKD stages 3, 4, and 5 constituted 51.8, 13.3, and 34.9%, respectively. The median of plasma dp-ucMGP levels in CKD stages 3, 4, and 5 were 586 (452-888), 870 (594-1,591), and 1,050 (518-1,298) pmol/L, respectively. The prevalence of vascular calcification (AAC score ≥1) was 63.4% and that of vascular stiffness (CAVI ≥9) was 46.3%. Vascular calcification was correlated with vascular stiffness (r2 = 0.50, p < 0.001). Multivariate logistic regression analysis models to predict vascular calcification showed that age and plasma dp-ucMGP levels were significantly correlated with vascular calcification (OR 1.21; 95% CI 1.09-1.33; p < 0.001 and OR 1.002; 95% CI 1.001-1.004; p = 0.004, respectively). In contrast, there was no association between plasma dp-ucMGP levels and vascular stiffness. Conclusions: Plasma dp-ucMGP levels increase according to the severity of CKD. Plasma dp-ucMGP was positively associated with vascular calcification and might be utilized as an early marker for vascular calcification in CKD patients.

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.

A novel simple hemoglobin dilution technique to measure hemodialysis vascular access flow

Measurement of the vascular access flow rate (Q(a)) is a widely accepted method for surveillance and predicting access failure. Among current practical methods, the ultrasound dilution technique is standard, but this requires a costly device available in few hemodialysis (HD) centers. Here, we devised a simple hemoglobin dilution technique to accurately measure Q(a) without the need for any special machines. Before HD, values of Q(a) were determined in each of 30 patients by hemoglobin dilution and then, in the same session, by ultrasound dilution. There was a significant correlation between the two techniques using automated hemoglobin and hematocrit or centrifuge-measured hematocrit levels to calculate HD fluid-derived Q(a) values. Our study shows that the HD dilution technique, using no special device, is economical, highly accurate, and easy to perform, and can be used as an alternative to standard ultrasound dilution for vascular access surveillance.

Efficacy of separated system continuous venovenous hemofiltration in critical acute kidney injury.

Integrated system continuous venovenous hemofiltration (CVVH), the most popularly utilized mode for continuous renal replacement therapy (CRRT), needs a sophisticated and expensive machine that is available only in limited critical care units. Separated system CVVH, which can be simply set up, might be an effectively alternative to CRRT. A one‐year prospective observational study regarding the efficacy of separated system CVVH was conducted with 192 critically ill patients with acute kidney injury. All patients underwent separated system CVVH with the pre‐dilution mode and a mean CVVH dose of 34.9 ± 2.7 mL/kg/h. The APACHE II score was 23.2 ± 8.4 and the Sequential Organ Failure Assessment score was 12.0 ± 4.3. No complications, including air‐embolism or circuit clotting, were observed and the survival rate was 32.3%. Separated system CVVH is simple, safe, and efficient and could provide cheaper treatments than the integrated system. It could thus be an effective, alternative treatment for critical acute kidney injury patients when the integrated mode is unavailable.