Dose equivalency and efficacy of biosimilar erythropoietin stimulating agents: Data from real clinical practice.

Recently, biosimilar erythropoietin stimulating agents become available in Kazakhstan. Important properties of the biosimilar such as dose equivalency to the original medicine (originator) and the ability to maintain hemoglobin target levels remain insufficiently described in many clinical settings. Thus, the current study aims to determine dose equivalency and hemoglobin target levels in a cohort of dialysis patients who were switched from the originator to biosimilar. Retrospective data of 74 patients from different dialysis centers who received at least 6 months of originator and switched to biosimilar and had at least 6 months follow-up were analyzed. The clinical data of 32 male and 42 female patients were collected. The mean age was 52.5 ± 13.5 years. There is no significant difference in mean levels of hemoglobin during pre-switching from originator to biosimilar (6 months prior) and post switching period (9 months after). Additionally, a subgroup analysis of 59 patients who received originator (epoetin beta), 6 months before the switch, showed similar level of hemoglobin (110.7 ± 14 vs 113.2 ± 10 g/L, P = .05) 6 months after the switch to biosimilar (epoetin zeta) at the equivalent dose regimen (69.5 ± 29 vs 68.1 ± 30 IU/kg/wk, P = .55). However, after 9 months of switching, patients using lower doses of biosimilar (69.5 ± 29 vs 63.3 ± 30 IU/kg/wk, P < .01), showed significantly higher levels of hemoglobin (110.7 ± 14 vs 114.7 ± 8 g/L, P = .01) compared to preswitching period. In conclusion, long-term use of lower doses of biosimilar managed to maintain hemoglobin within the target levels.

Infusion of autologous bone marrow derived mononuclear stem cells potentially reduces urinary markers in diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Previous studies demonstrated safety and efficacy of autologous bone marrow-derived mononuclear cells (ABM-MNCs) in induced type-1 diabetes mellitus (T1DM) rats. However, the effect of ABM-MNCs on urinary markers of DN in humans is not well studied. We evaluated the therapeutic effect of ABM-MNCs on the urinary markers microalbuminuria (MAU), urinary type-IV collagen and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in T1DM patients with and without nephropathy. METHODS: This prospective open-label pilot study included 15 patients with T1DM, who had completed 2 visits within 6 months. Patients were divided into two groups according to the presence (DN, n = 7) and absence of nephropathy (T1DM, n = 8). ABM-MNCs were injected at each visit as per study protocol. Routine laboratory data, diabetes tests (fasting serum C-peptide and insulin, glycated hemoglobin, fasting and postprandial glucose), 24-h MAU and urinary type-IV collagen were measured at each visit. uNGAL levels were studied before and after 3 days of ABM-MNCs infusion at each visit. RESULTS: Mean age of patients was 29.2 ± 10.4 years, 33% were male, and 27% of the overall group had hypertension. MAU was significantly reduced in the overall group (- 26.0%, p = 0.037), including in DN (- 83.2%, p = 0.021). A short-term significant reduction of uNGAL levels was observed 3 days after ABM-MNCs administration during the both the 1st visit (median 13.4 vs. 9.5 ng/ml, p = 0.027) and 2nd visit (median 8.8 vs. 6.4 ng/ml, p = 0.042) in both groups. However this reduction did not remain significant at the 6-month follow-up. Urinary type-IV collagen did not respond significantly to ABM-MNCs infusion. CONCLUSION: Infusion of autologous bone marrow-derived mononuclear cells significantly reduced levels of MAU in DN patients. Further studies with larger sample size are needed to confirm these observations.

Leptin Levels in Patients with Type 1 Diabetes Mellitus After Fetal Pancreatic Stem Cell Transplant.

OBJECTIVES: Our objective was to determine leptin levels in patients with type 1 diabetes mellitus after fetal pancreatic stem cell transplant. MATERIALS AND METHODS: Seven patients, aged 20 to 42 years, with type 1 diabetes mellitus received a fetal pancreatic stem cell transplant by intravenous infusion. The quantity of fetal stem cells infused was ≥ 5 × 106, and the cells were of 12 to 14 weeks of gestation. We analyzed the levels of leptin, C-peptide, and antibodies to the islets of Langerhans before and 3 months after the transplant procedure. RESULTS: Fetal pancreatic stem cell transplant led to significant increases in leptin and C-peptide levels, from 4.63 ± 1.17 ng/mL and 0.09 ± 0.02 ng/mL to 7.71 ± 1.45 ng/mL (P < .05) and 0.22 ± 0.05 ng/mL (P < .005), respectively, without an increase in antibodies to the islets of Langerhans, which measured 0.64 ± 0.13 U/mL before transplant and 0.57 ± 0.18 U/mL 3 months later (P > .05). CONCLUSIONS: Leptin levels increase significantly within 3 months of fetal pancreatic stem cell transplant in patients with type 1 diabetes mellitus.

Leptin Level in Patients with Type 2 Diabetes Mellitus after Fetal Pancreatic Stem Cell Transplant.

OBJECTIVES: We aimed to determine leptin level in patients with type 2 diabetes mellitus after fetal pancreatic stem cell transplant. MATERIALS AND METHODS: We examined 14 patients (aged 43-63 years old) with type 2 diabetes mellitus, which we subsequently divided into 2 groups and examined. Group 1 comprised 8 patients who received fetal pancreatic stem cell transplant (cells were 16-18 wk gestation) performed by intravenous infusion; group 2 comprised 6 patients in the control group who were on hypoglycemic tablet therapy or insulin therapy. The quantity of fetal stem cells infused was 5 to 6 × 106. We analyzed leptin and C-peptide levels in patients both before and 3 months after the fetal pancreatic stem cell transplant procedure. RESULTS: In patients with type 2 diabetes mellitus, fetal pancreatic stem cell transplant led to a significant increase in leptin levels, from 11.01 ng/mL to 16.29 ng/mL, after 3 months (P < .05). CONCLUSIONS: Leptin level increase significantly within 3 months after fetal pancreatic stem cell transplant in patients with type 2 diabetes mellitus.

Renal functional reserve and renal hemodynamics in hypertensive patients.

The renal functional reserve (RFR) is the ability of the kidneys to increase renal plasma flow and glomerular filtration rate (GFR) in response to protein intake. It is a measure of functional and anatomic integrity of nephrons. It is not known what relation between RFR and kidney Doppler parameters. We aimed to study the relation between the RFR and renal hemodynamic parameters in hypertensive patients with and without nephropathy who had normal kidney function. Twenty-four hypertensive subjects with nephropathy (HTN-n, n = 10) and hypertension without nephropathy (HTN, n = 14) were included in the study. Control group included 11 healthy subjects. Baseline GFR (GFR1) and GFR after intake of egg protein 1 mg/kg of body weight were determined (GFR2). RFR was calculated by the following formula: (GFR2-GFR1)/GFR1 × 100%. Doppler ultrasonography was performed. Arterial blood pressure (BP), body mass index (BMI), and estimated GFR were also recorded. HTN and HTN-n groups had impaired levels of RFR compared with controls (p < 0.05), significantly decreased value of flow velocity parameters (Vmax, Vmin), and increased RRI compared with controls. There was significant negative correlation of RFR with blood pressure levels (sBP, r = -0.435, p = 0.009; dBP, r = -0.504, p = 0.002), RRI (r = -0.456, p = 0.008), micro albuminuria (MAU, r = -0.366, p = 0.031) and positive correlation with Vmax and Vmin (r = 0.556, p = 0.001 and r = 0.643, respectively, p < 0.001). Linear regression showed that RRI and MAU were independent predictors of decreased RFR. RFR is lower in hypertensive patients despite near-normal level of kidney function and is related to particular level of BP. RRI and MAU were independent predictors of decreased RFR.

Multinational observational study on clinical practices and therapeutic management of mineral and bone disorders in patients with chronic kidney disease stages 4, 5, and 5D: The OCEANOS study.

Our aim is to assess the current clinical practices in monitoring and treatment patterns of chronic kidney disease (CKD)-mineral bone disorder and the degree to which these practices met the kidney disease improving global outcome (KDIGO) guidelines. This was an international, multi-center, cross-sectional, observational study in adult patients diagnosed with CKD Stages 4, 5, and 5D. Patients were enrolled from Middle East, South Asia, Eurasia, and Africa; patients with estimated glomerular filtration rate ≥30 mL/min/1.73 m(2) or with any medical/surgical conditions precluding their participation were excluded. Frequency of measurements, levels of serum calcium (Ca), phosphorus and parathormone (parathyroid hormone [PTH], and presence vascular/valvular calcification were recorded. Of the 2250 patients enrolled, data on 2247 patients were evaluated. Overall, only a small percentage of patients met all three target KDIGO ranges of serum Ca, phosphorus, and PTH (13.7% [95% confidence interval: 12.0; 15.4], with a higher proportion among CKD Stage 5D patients (14.8%) than CKD Stage 4 and 5 (5.6%) patients. Majority (84.3%) of the patients received treatment with phosphorous binders, of whom 85.5% received Ca-based phosphate binders. Overall, 57.0% of patients received Vitamin D treatment with a similar frequency among patients with CKD Stages 4, 5, and 5D. Over half (65.7%) of the patients were screened for vascular/valvular calcification; of these, 58.8% had ≥1 calcification. Diabetes status, P, PTH, and low density lipoprotein-cholesterol had significant impact on the prescription pattern of phosphorous binders. The current practices for the management of bone and mineral metabolism in CKD patients in the study region fall far short of meeting the KDIGO target range.

Organ Transplants in Kazakhstan.

The Republic of Kazakhstan is one of the fastest developing countries in the world and has a health care system that is unique in Central Asia. Its organ transplant services are also developing rapidly. We aimed to analyze and briefly report on the current status of organ transplant in the Republic of Kazakhstan. We analyzed organ transplant activities in that country for the period 2012 to 2014. All data were collected from the official database of the National Transplant Coordinating Center of the Republic of Kazakhstan. At the end of 2014, the number of transplant centers had increased to 10, three of which could perform multiorgan transplants; during the same period, the number of deceased-donor organ-donating hospitals increased up to 37. By 2013, the transplant activity rate for all centers had reached 9.22 per million population. During the previous 3 years (2012-2014), there was a 3-fold increase in the number of living donors and an 18-fold increase in the number of kidney transplants. Between 2012 and 2014, the number of living-donor liver transplants increased from 17 to 25, and the number of deceased-donor transplants increased from 3 to 7. During the last 3 years (2012-2014), the number of heart transplants increased to 7 cases. During the last 3 years (2012-2014), Kazakhstan achieved a significant improvement in the organization of its transplant services, and a noticeable upward trend in the system continues.

Fetal Renal Stem Cell Transplant in Nephrotic and Nonnephrotic Glomerulonephritis with Stage 2-4 Chronic Kidney Disease: Potential Effect on Proteinuria and Glomerular Filtration Rate.

OBJECTIVES: Proteinuria is a major cause of glomerulosclerosis progression in glomerular diseases, and the development of end-stage renal disease is more rapid in nephrotic patients than in nonnephrotic ones. The renal parenchyma is less regenerable because it is a tissue consisting of renal cells. Thus, stem cells obtained from fetal kidney tissue might be effective for reducing proteinuria and delaying glomerulosclerosis in these patients. MATERIALS AND METHODS: This report presents preliminary data from a prospective cohort study that included 17 patients with chronic glomerulonephritis in stage 2 to 4 chronic kidney disease who completed 3 visits during 1 year of follow-up. Fetal renal stem cells (multiple cells in suspension) were injected into the patient every 6 months. Patients were divided into 2 groups according to their nephrotic status, and 24-hour maximal proteinuria was recorded for at least 6 months (first group with proteinuria < 3.5 g/24 h, and second group with proteinuria > 3.5 g/24 h). RESULTS: During follow-up, group 1 was observed to have stable hemoglobin and total protein levels but significantly decreased albumin levels and glomerular filtration rates. In group 2, total protein with serum albumin significantly increased, and proteinuria and glomerular filtration rates significantly decreased. There was no significant difference in glomerular filtration rate decline between groups. CONCLUSIONS: Treatment with fetal renal stem cells significantly decreased proteinuria in nephrotic patients. However, this outcome also might have resulted from a reduction in glomerular filtration rate. Further studies with a larger number of patients and a control group would help to achieve better results that measure the efficacy of this treatment.

Fetal Pancreatic Stem-Cell Transplant in Patients With Diabetes Mellitus.

OBJECTIVES: To determine the efficacy of fetal stem cell transplant for treating patients with diabetes mellitus types 1 and 2. MATERIALS AND METHODS: Five patients with diabetes mellitus type 1 and 5 patients with diabetes mellitus type 2 (aged 18-56 years) received a fetal pancreatic stem-cell transplant (cells were 16-18 wk gestation) performed by intravenous infusion at 50 mL/hour. The quantity of fetal stem cells infused was ≥ 5-8*106. We analyzed the patients' C-peptide and glycated hemoglobin levels both before and 3 months after fetal stem cell transplant. RESULTS: In patients with diabetes mellitus type 1, fetal stem-cell transplant led to a significant increase in C-peptide levels, from 0.09 ± 0.01 ng/mL to 0.20 ± 0.07 ng/mL, after 3 months (P < .008). CONCLUSIONS: Treatment with fetal pancreatic stem cells may be beneficial for treating patients with type 1 or type 2 diabetes.

The Results of Fetal Chondrocytes Transplantation in Patients with Rheumatoid Arthritis.

INTRODUCTION: Nowadays anti-inflammatory and immunosuppressive therapy has significantly improved the quality of life and prognosis of rheumatoid arthritis (RA). Nevertheless, there are still many patients with progressive rheumatoid inflammation, resulting in the destruction of joints. Cell therapy seems like a promising direction in rheumatology. The aim of our research was to evaluate the efficacy of fetal chondrocyte transplantation in patients with RA. METHODS: We examined 60 patients with rheumatoid arthritis (I - III stages) between 20 and 63 years of age. They were divided into 2 groups: the first group underwent the fetal chondrocytes transplantation (n = 40), and the second was a control group who got conservative therapy (n = 20). Donor cells were taken from the chondrogenic layer of the humerus or femur heads and hip condyles of human embryos in gestation for 17-20 weeks. A suspension of fetal chondrocytes injected into affected areas of the articular surfaces under X-ray control. Cell viability was determined before the injection. Efficacy of the therapy was assessed by clinical, instrumental, and laboratory tests. This clinical trial was allowed by The Ministry of Public Health and Ethics Committee. All of our patients gave informed consent for the fetal chondrocytes transplantation. RESULTS: Evaluation of the clinical manifestations of RA in the first group of patients showed 3.7 times decrease in pain and 1.6 times relief of synovitis. Complete reduction of contracture was observed in 82% of patients in the first group. Morphometric changes in X-ray demonstrated inhibition of the destruction in articular cartilage and surfaces of bones after transplantation of fetal chondrocytes. The dynamics of morphological changes in synovium showed 2.5 times reduction of the inflammatory reaction. Transplantation of fetal chondrocytes led to a significant reduction in ESR, CRP, fibrinogen, γ-globulin after a period of 12 months (p < 0.03). Furthermore, patients in the second group had 2.7 times higher risk of ankylosis compared to the first group. We did not observe any complications of fetal chondrocytes transplantation. CONCLUSIONS: Application of fetal chondrocytes therapy had the desired clinical effect, which was confirmed by reduction of the RA activity and decrease of cartilage and bone destruction.