Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation

KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD+ generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.

Clinical and genetic markers of erythropoietin deficiency anemia in chronic kidney disease (predialysis) patients

Aim: To determine the clinical and genetic markers associated with erythropoietin deficiency anemia in predialysis individuals. Materials & methods: Patients were categorized into cases and control group. Demographic characteristics and clinical parameters were obtained from medical record review and serum EPO and ferritin were obtained with ELISA. HIF-1α (rs2057482), IL-1β (rs1143627) and EPO (rs1617640) gene polymorphism were genotyped. Results: Female gender, glomerular filtration rate, treatment with hematinics, anticoagulant and diuretic were strong predictors of EPO-deficient anemia in predialysis chronic kidney disease patients. Genetic polymorphism in the HIF-1α recessive model was associated with non-EPO-deficiency, followed by EPO recessive allele associated with low-serum erythropoietin and IL-1β recessive model with low hemoglobin level. Conclusion: EPO-deficiency anemia can be diagnosed more conveniently in the presence of biomarkers.

Low erythropoietin levels predict faster renal function decline in diabetic patients with anemia: a prospective cohort study

Elevated erythropoietin (EPO) levels have been reported to predict poor survival in various populations including diabetic patients. However, data regarding its impact on renal outcomes are scarce. We conducted a single-center, prospective cohort study of 339 type 2 diabetic patients with anemia. The primary outcome was the estimated glomerular filtration rate (eGFR) slope for two years. We performed multiple linear regression and restricted cubic spline analyses to assess the association of serum EPO levels with the renal outcome. Chronic kidney disease (CKD) was defined as eGFR <60 mL/min/1.73 m2 or urine albumin-to-creatinine ratio >30 mg/g creatinine. Median baseline EPO and eGFR level were 14.4 IU/L and 53 mL/min/1.73 m2, respectively. Inappropriately low EPO levels were observed in 73% of anemic patients and 59% of anemic patients even without CKD, suggesting that EPO deficiency precedes the onset of CKD in diabetes mellitus. Multivariable analysis revealed that iron status and hemoglobin levels were major determinants of EPO levels. Median eGFR slope was −1.3 mL/min/1.73 m2/year. We found that low EPO levels, but not low hemoglobin levels, were associated with a faster decline in eGFR, independent of clinically relevant factors. The eGFR decline was steeper, particularly when the EPO level was below the upper limit of normal. Lower EPO concentrations were associated with rapid eGFR decline, especially in patients with iron deficiency (P for interaction = 0.01). Relative EPO deficiency should be considered as a culprit in anemia of unknown etiology in diabetic patients, even those without CKD. Low EPO levels, especially when accompanied by poor iron status, are predictive of rapid loss of renal function.

STATUS BESI PADA PASIEN PENYAKIT GINJAL KRONIK YANG SEDANG MENJALANI HEMODIALISIS DI BLU RSU.Prof.Dr.R.D KANDOU MANADO

ABSTRACTBackground: Chronic Kidney Disease (CKD) is kidney damage that occurred during the three months or more with a glomerular filtration rate less than 60 ml/men./1, 73 m2. One complication that often occurs in patients with CKD is anemia. Anemia in CKD can be caused by several factors such as EPO deficiency, Iron Deficiency, etc. and one of the parameters commonly examined in patients with CKD who are undergoing hemodialysis is composed of iron status Serum Iron(SI), TIBC, Transferrin Saturation, Ferritin.Objective: Looking iron status in CKD patientsMethods: The study design was a descriptive look at the medical records of the patients who are undergoing hemodialysis with purposive sampling technique.Results: In patients with CKD undergoing hemodialysis anemia. Anemia all experienced that often caused by the presence of erythropoietin deficiency. But there are also caused by iron deficiency from a status marked where the iron transferrin saturation <20%. There was also found an increase in ferritin> 400 ng / ml caused by the presence of an infection such as anemia or chronic disease can also be caused due to frequent blood transfusions. Treatment for iron overload in patients with CKD, especially regular hemodialysis patients who undergo repeated blood transfusions can be re-utilization by the use of ESA, anemia in CKD caused by deficiency erythropoietin.ESA therapy may also be given.Conclusion: Based on the results of research in the department of hemodialysis room Prof.Dr.RD Kandou obtained all patients with chronic kidney disease decreased hemoglobin, and Serum Iron which fell by 40%, the normal 60%, and ferritin were increased by 46.7% , that no data 53.3% and TIBC were decreased by 80%, as much as 20% of normal and Transferrin Saturation fell by 6.7%, which increased by 3.3% and as much as 90% of normal.Keywords: CKD, iron statusABSTRAKLatar Belakang : Penyakit Ginjal Kronik (PGK) adalah kerusakan ginjal yang terjadi selama atau lebih tiga bulan dengan laju filtrasi glomerulus kurang dari 60 ml/men./1,73 m2. Salah satu komplikasi yang sering terjadi pada pasien PGK adalah anemia. Anemia pada PGK dapat disebabkan oleh beberapa faktor seperti: Defisiensi EPO, Defisiensi Besi, dll dan salah satu parameter yang biasa diperiksa pada pasien PGK yang sedang menjalani hemodialisis adalah status besi yang terdiri dari Serum Iron (SI), TIBC, Saturasi Transferin, Feritin.Tujuan : Melihat Status besi pada pasien PGKMetode : Desain penelitian adalah deskriptif dengan melihat data rekam medik para pasien yang sedang menjalani hemodialisis dengan teknik purposive sampling.Hasil : Pada pasien PGK yang menjalani hemodialisis semuanya mengalami anemia.Anemia yang sering terjadi disebabkan oleh karena adanya defisiensi eritropoetin. Namun ada juga yang disebabkan oleh defisiensi besi yang ditandai dari pemeriksaan status besi dimana saturasi transferin < 20%. Ada juga didapatkan peningkatan Feritin > 400 ng/ml yang disebabkan oleh karena adanya infeksi seperti pada anemia penyakit kronis atau juga bisa disebabkan karena seringnya transfusi darah. Penatalaksanaan untuk kelebihan zat besi pada pasien PGK terutama pasien hemodialisis reguler yang mengalami transfusi darah berulang dapat dire-utilisasi dengan pemakaian ESA, anemia pada PGK yang disebabkan oleh dekfisiensi eritopoetin juga dapat diberikan terapi ESA.Kesimpulan : Berdasarkan hasil penelitian di ruangan hemodialisis di RSUP Prof.Dr.R.D Kandou didapatkan semua pasien penyakit ginjal kronik mengalami penurunan Hb,dan Serum Iron yang menurun sebanyak 40%, yang normal sebanyak 60%, dan Feritin yang meningkat sebanyak 46,7%, yang tidak ada data sebanyak 53,3% dan TIBC yang menurun sebanyak 80%, yang normal sebanyak 20% dan Saturasi Transferin yang menurun sebanyak 6,7% yang meningkat sebanyak 3,3% dan yang normal sebanyak 90%.Kata Kunci: PGK, Status Besi

Epo Is Relevant Neither for Microvascular Formation Nor for the New Formation and Maintenance of Mice Skeletal Muscle Fibres in Both Normoxia and Hypoxia

Erythropoietin (Epo) and vascular growth factor (VEGF) are known to be involved in the regulation of cellular activity when oxygen transport is reduced as in anaemia or hypoxic conditions. Because it has been suggested that Epo could play a role in skeletal muscle development, regeneration, and angiogenesis, we aimed to assess Epo deficiency in both normoxia and hypoxia by using an Epo-deficient transgenic mouse model (). Histoimmunology, ELISA and real time RT-PCR did not show any muscle fiber atrophy or accumulation of active HIF-1 but an improvement of microvessel network and an upregulation of VEGFR2 mRNA in Epo-deficient gastrocnemius compared with Wild-Type one. In hypoxia, both models exhibit an upregulation of VEGF120 and VEGFR2 mRNA but no accumulation of Epo protein. EpoR mRNA is not up-regulated in both Epo-deficient and hypoxic gastrocnemius. These results suggest that muscle deconditioning observed in patients suffering from renal failure is not due to Epo deficiency.

Usual Clinical Parameters Underestimate the Incidence and Significance of Erythropoietin Deficiency as a Risk Factor for Death in Sickle Cell Disease.

A robust reticulocytosis is necessary to maintain hemoglobin levels compatible with life in patients with sickle cell disease. Relative reticulocytopenia, defined as a absolute reticulocyte count less than 250 x 109/L despite hemoglobin &lt;9g/dl, has been identified as a risk factor for early death. RR could result from chronic bone marrow vaso-occlusive insult or a renal endocrine defect leading to erythropoietin (EPO) deficiency. In non-SCD patients, EPO levels and creatinine clearance are clinical parameters that are used to define patients with anemia from EPO deficiency. The normal ranges for these parameters may not apply to SCD, and therefore the incidence and significance of EPO deficiency in SCD may have been underestimated, compromising rational EPO replacement therapy. In a retrospective analysis of 417 patients with HbSS or S-β-thalassemia, confirming previous findings, RR was a risk factor for early death. There was a significant association between RR and proteinuria. Usually, there is an inverse correlation between hemoglobin and EPO levels (negative feed-back), this was seen in patients without RR. However, in patients with proteinuria, the correlation between hemoglobin and EPO levels was a positive one, suggesting hemoglobin dependence on EPO levels. Proteinuria or increased creatinine levels were a risk factor for early death but not if RR was included in the model, suggesting the increased risk of death associated with proteinuria and creatinine was mediated by RR. RR was also associated with decreased platelet and WBC counts, suggesting a contribution by cumulative vaso-occlusive bone marrow damage to RR. However, platelet and WBC counts were not risk factors for early death within the cohort. Damage to renal endocrine function/EPO deficiency should be added to the list of clinically significant chronic organ damage in SCD. EPO deficiency may precede and be causative of other end-organ damage, such as cardiac diastolic dysfunction and renal exocrine failure. Proteinuria should be recognized as a clinical parameter that should prompt consideration of EPO deficiency. Since EPO replacement is clinically feasible, renal endocrine dysfunctiton is a cause of symptoms, clinical deterioration and death that could be rationally addressed.

Correlation between Fractional Reabsorption of Sodium and Erythropoietin dose in Peritoneal Dialysis Patients

Background Erythropoietin (EPO) deficiency of chronic renal failure (CRF) may be a functional consequence of decreased glomerular filtration rate and fractional reabsorption of sodium (FRNa). Decreased FRNa reduces renal oxygen consumption and increases tissue oxygen pressure, resulting in less EPO production. We hypothesized that, in CRF patients, there is a positive relationship between EPO production and FRNa and that, in such patients receiving EPO, a negative correlation is expected between FRNa and EPO dose. Methods Creatinine clearance, FRNa, serum iron, transferrin, transferrin saturation, ferritin, and intact parathyroid hormone (iPTH) levels were measured in 91 peritoneal dialysis patients. The correlation between EPO dose and FRNa was studied. Results Mean EPO dose was 7076 ± 4821 units/week and mean FRNa was 93.40% ± 6.14%. A negative correlation was found between EPO dose and FRNa ( r = -0.28, p < 0.01), and a positive correlation was found between both ferritin and iPTH and EPO dose ( r = 0.39, p < 0.001 and r = 0.35, p < 0.002 respectively). After adjusting for the effect of creatinine clearance, ferritin, and iPTH, there was still a significant correlation between EPO dose and FRNa ( p < 0.05). Conclusion In CRF patients there is a negative correlation between FRNa and EPO dose, which supports the hypothesis that EPO deficiency may be related to the decreased renal oxygen-consuming work of sodium reabsorption.