Renal Erythropoietin Production Research Articles

Hypoxia sensing through β-adrenergic receptors.

Life-sustaining responses to low oxygen, or hypoxia, depend on signal transduction by HIFs, but the underlying mechanisms by which cells sense hypoxia are not completely understood. Based on prior studies suggesting a link between the β-adrenergic receptor (β-AR) and hypoxia responses, we hypothesized that the β-AR mediates hypoxia sensing and is necessary for HIF-1α accumulation. Beta blocker treatment of mice suppressed hypoxia induction of renal HIF-1α accumulation, erythropoietin production, and erythropoiesis in vivo. Likewise, beta blocker treatment of primary human endothelial cells in vitro decreased hypoxia-mediated HIF-1α accumulation and binding to target genes and the downstream hypoxia-inducible gene expression. In mechanistic studies, cAMP-activated PKA and/or GPCR kinases (GRK), which both participate in β-AR signal transduction, were investigated. Direct activation of cAMP/PKA pathways did not induce HIF-1α accumulation, and inhibition of PKA did not blunt HIF-1α induction by hypoxia. In contrast, pharmacological inhibition of GRK, or expression of a GRK phosphorylation-deficient β-AR mutant in cells, blocked hypoxia-mediated HIF-1α accumulation. Mass spectrometry-based quantitative analyses revealed a hypoxia-mediated β-AR phosphorylation barcode that was different from the classical agonist phosphorylation barcode. These findings indicate that the β-AR is fundamental to the molecular and physiological responses to hypoxia.

Human CD133+ Renal Progenitor Cells Induce Erythropoietin Production and Limit Fibrosis After Acute Tubular Injury.

Persistent alterations of the renal tissue due to maladaptive repair characterize the outcome of acute kidney injury (AKI), despite a clinical recovery. Acute damage may also limit the renal production of erythropoietin, with impairment of the hemopoietic response to ischemia and possible lack of its reno-protective action. We aimed to evaluate the effect of a cell therapy using human CD133+ renal progenitor cells on maladaptive repair and fibrosis following AKI in a model of glycerol-induced rhabdomyolysis. In parallel, we evaluated the effect of CD133+ cells on erythropoietin production. Administration of CD133+ cells promoted the restoration of the renal tissue, limiting the presence of markers of injury and pro-inflammatory molecules. In addition, it promoted angiogenesis and protected against fibrosis up to day 60. No effect of dermal fibroblasts was observed. Treatment with CD133+ cells, but not with PBS or fibroblasts, limited anemia and increased erythropoietin levels both in renal tissue and in circulation. Finally, CD133+ cells contributed to the local production of erythropoietin, as observed by detection of circulating human erythropoietin. CD133+ cells appear therefore an effective source for cell repair, able to restore renal functions, including erythropoietin release, and to limit long term maldifferentiation and fibrosis.

Unexplained Anemia in the Elderly: Potential Role of Arterial Stiffness.

Anemia, as defined by hemoglobin concentration < 12.0 and < 13.0 g/dl in women and men, respectively, affects more than 150 million elderly people worldwide and even when mild is associated with increased disability, morbidity, and mortality (Ezekowitz et al., 2003; Penninx et al., 2004; De Benoist et al., 2008). The causes of anemia remain unresolved in approximately one-third of anemic older individuals, commonly referred as unexplained anemia in the elderly (UAE; Guralnik et al., 2004). As most types of anemia, UAE is normocytic and its prevalence increases with advancing age (Guralnik et al., 2004). UAE is uniquely characterized by low plasma erythropoietin (EPO) concentration compared to the other forms of anemia (Ferrucci et al., 2007; Artz and Thirman, 2011). Thus, provided that EPO is mainly synthesized in the kidneys and its clearance/degradation is not enhanced, UAE may be primarily determined by factors affecting renal EPO production and/or hemodilution (Lundby et al., 2014; de Seigneux et al., 2016). These factors are yet to be elucidated. Of note, while hemoglobin concentration is typically employed to diagnose anemia, true (non-hemodilutional) anemia is defined as a decrease in the total volume of red blood cells (RBCV) and/or hemoglobin mass. Herein, we present arguments to support the contention that a fundamental hallmark of vascular aging, arterial stiffness (AS), might be a primary etiological determinant of low EPO concentration and RBCV in UAE via the impairment of mechanisms regulating kidney perfusion, EPO production as well as blood volume. This viewpoint postulates that AS is augmented in UAE patients compared with healthy non-anemic elderly individuals. While direct proof is not available at present, independent lines of evidence demonstrate that UAE is characterized by alterations in biochemical, hematological, and physiological parameters consistently associated with AS (Ferrucci et al., 2007; Robinson et al., 2007; Artz et al., 2014; Malahfji et al., 2014), whereof some are described in detail below.

Erythropoietin corrects anaemia and reduces the risk of blood transfusion in people with chronic kidney disease, but has uncertain effects on other patient-level outcomes.

Commentary on: Cody JD, Hodson EM. Recombinant human erythropoietin versus placebo or no treatment for the anaemia of chronic kidney disease in people not requiring dialysis. Cochrane Database Syst Rev 2016;(1):CD003266 Anaemia frequency and severity worsen with advancing chronic kidney disease (CKD) and are associated with quality-of-life (QOL) impairment, morbidity and mortality.1 Deficient renal erythropoietin production is a major cause and can be corrected by recombinant human erythropoietin (rhEPO) administration.1 This may improve clinical outcomes, including delaying dialysis. Conversely, rhEPO therapy causes hypertension,2 thereby potentially accelerating CKD progression. This systematic review and meta-analysis examined rhEPO effects on clinical outcomes in anaemic, pre-dialysis CKD patients. Randomised controlled trials (RCTs) comparing rhEPO treatment with either placebo …

Erythropoietin production by PDGFR-β+ cells

PDGFR-β-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-β-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-β(+) cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70%. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-β. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-β(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2α, but not HIF-1α, was deleted either alone or in combination with Vhl in PDGFR-β(+) cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1α in PDGFR-β(+) cells but exerted no effect in mice lacking HIF-2α in PDGFR-β(+) cells. These findings suggest that PDGFR-β(+) cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-β(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest.

The Mitochondrial Respiratory Chain Is Required for Organismal Adaptation to Hypoxia.

Hypoxia-inducible factors (HIFs) are crucial for cellular and organismal adaptation to hypoxia. The mitochondrial respiratory chain is the largest consumer of oxygen in most mammalian cells; however, it is unknown whether the respiratory chain is necessary for in vivo activation of HIFs and organismal adaptation to hypoxia. HIF-1 activation in the epidermis has been shown to be a key regulator of the organismal response to hypoxic conditions, including renal production of erythropoietin (Epo). Therefore, we conditionally deleted expression of TFAM in mouse epidermal keratinocytes. TFAM is required for maintenance of the mitochondrial genome, and TFAM-null cells are respiratory deficient. TFAM loss in epidermal keratinocytes reduced epidermal levels of HIF-1α protein and diminished the hypoxic induction of HIF-dependent transcription in epidermis. Furthermore, epidermal TFAM deficiency impaired hypoxic induction of renal Epo expression. Our results demonstrate that the mitochondrial respiratory chain is essential for in vivo HIF activation and organismal adaptation to hypoxia.

Renal epithelium regulates erythropoiesis via HIF-dependent suppression of erythropoietin.

The adult kidney plays a central role in erythropoiesis and is the main source of erythropoietin (EPO), an oxygen-sensitive glycoprotein that is essential for red blood cell production. Decreases of renal pO2 promote hypoxia-inducible factor 2-mediated (HIF-2-mediated) induction of EPO in peritubular interstitial fibroblast-like cells, which serve as the cellular site of EPO synthesis in the kidney. It is not clear whether HIF signaling in other renal cell types also contributes to the regulation of EPO production. Here, we used a genetic approach in mice to investigate the role of renal epithelial HIF in erythropoiesis. Specifically, we found that HIF activation in the proximal nephron via induced inactivation of the von Hippel-Lindau tumor suppressor, which targets the HIF-α subunit for proteasomal degradation, led to rapid development of hypoproliferative anemia that was associated with a reduction in the number of EPO-producing renal interstitial cells. Moreover, suppression of renal EPO production was associated with increased glucose uptake, enhanced glycolysis, reduced mitochondrial mass, diminished O2 consumption, and elevated renal tissue pO2. Our genetic analysis suggests that tubulointerstitial cellular crosstalk modulates renal EPO production under conditions of epithelial HIF activation in the kidney.

Hydrogen Sulfide Induced Erythropoietin Synthesis is Regulated by HIF Proteins

Anemia of end stage renal disease affects 90% of patients on hemodialysis and it is a tremendous concern of patients and health care providers. Renal disease creates a state of renal hypoxia, which may contribute to a lack of erythropoietin production from the kidney when low oxygen levels are sensed. This necessitates the use of exogenous erythropoietin preparations. Recent evidence suggests that endogenously derived hydrogen sulfide may mediate oxygen sensing in tissues. Given the known involvement of other small molecules such as nitric oxide in erythropoietin production and the observation of decreased urinary H2S levels in patients with renal failure, we postulated that H2S may be the primary mediator of erythropoietin production during hypoxia. PK1, 786-O and Hep3B cells were incubated in hypoxia (1% O2) for 24 hours. Hypoxic cells were treated with the H2S donor GYY 4137 and the H2S inhibitor hydroxylamine. Following hypoxia erythropoietin, HIF-1α, HIF-2α and CBS expression was measured by quantitative real-time polymerase chain reaction and Western blot. Hydroxylamine administration led to a significant decrease in erythropoietin, HIF-1α, HIF-2α and CBS protein levels during hypoxia. This was rescued by administration of GYY 4137 for erythropoietin, CBS and HIF-2α. Additionally, CSE -/- mice placed in hypoxia for 72 hours showed decreased renal erythropoietin production compared to wild-type mice. These data suggest previously undocumented interplay of the production and action of H2S during hypoxia with subsequent erythropoietin production. The use of novel hydrogen sulfide donors could represent an alternative to standard therapies of anemia of renal failure.

Iron therapy in chronic kidney disease: Recent changes, benefits and risks

Anemia is a common complication in patients with chronic kidney disease (CKD), mainly due to inadequate renal production of erythropoietin. In hemodialysis (HD) patients this condition may be aggravated by iron deficiency (absolute or functional). The correction of this anemia is usually achieved by treatment with erythropoiesis stimulating agents (ESAs) and iron (oral or intravenous). Studies questioning the safety of ESAs (especially at higher doses) changed the pattern of anemia treatment in CKD patients. According to the new guidelines, when transferrin saturation is lower than 30% and ferritin lower than 500ng/mL, a trial with iron should be started, to avoid therapy with ESAs or at least to reduce the doses needed to treat the anemia. Recent reports showed increasing ferritin levels, towards values above 800ng/mL, in CKD patients treated according to the guidelines. In this review we focus on the risks of the increased iron use to treat CKD anemia, namely, iron overload and toxicity, increased risk of infections, as well as mortality.

Ankyrin is the major oxidised protein in erythrocyte membranes from end-stage renal disease patients on chronic haemodialysis and oxidation is decreased by dialysis and vitamin C supplementation

Chronically haemodialysed end-stage renal disease patients are at high risk of morbidity arising from complications of dialysis, the underlying pathology that has led to renal disease and the complex pathology of chronic kidney disease. Anaemia is commonplace and its origins are multifactorial, involving reduced renal erythropoietin production, accumulation of uremic toxins and an increase in erythrocyte fragility.Oxidative damage is a common risk factor in renal disease and its co-morbidities and is known to cause erythrocyte fragility. Therefore, we have investigated the hypothesis that specific erythrocyte membrane proteins are more oxidised in end-stage renal disease patients and that vitamin C supplementation can ameliorate membrane protein oxidation.Eleven patients and 15 control subjects were recruited to the study. Patients were supplemented with 2 × 500 mg vitamin C per day for 4 weeks. Erythrocyte membrane proteins were prepared pre- and post-vitamin C supplementation for determination of protein oxidation. Total protein carbonyls were reduced by vitamin C supplementation but not by dialysis when investigated by enzyme linked immunosorbent assay. Using a western blot to detect oxidised proteins, one protein band, later identified as containing ankyrin, was found to be oxidised in patients but not controls and was reduced significantly by 60% in all patients after dialysis and by 20% after vitamin C treatment pre-dialysis. Ankyrin oxidation analysis may be useful in a stratified medicines approach as a possible marker to identify requirements for intervention in dialysis patients.

Tubulovascular cross-talk by vascular endothelial growth factor a maintains peritubular microvasculature in kidney.

Vascular endothelial growth factor A (VEGFA) production by podocytes is critical for glomerular endothelial health. VEGFA is also expressed in tubular epithelial cells in kidney; however, its physiologic role in the tubule has not been established. Using targeted transgenic mouse models, we found that Vegfa is expressed by specific epithelial cells along the nephron, whereas expression of its receptor (Kdr/Vegfr2) is largely restricted to adjacent peritubular capillaries. Embryonic deletion of tubular Vegfa did not affect systemic Vegfa levels, whereas renal Vegfa abundance was markedly decreased. Excision of Vegfa from renal tubules resulted in the formation of a smaller kidney, with a striking reduction in the density of peritubular capillaries. Consequently, elimination of tubular Vegfa caused pronounced polycythemia because of increased renal erythropoietin (Epo) production. Reducing hematocrit to normal levels in tubular Vegfa-deficient mice resulted in a markedly augmented renal Epo production, comparable with that observed in anemic wild-type mice. Here, we show that tubulovascular cross-talk by Vegfa is essential for maintenance of peritubular capillary networks in kidney. Disruption of this communication leads to increased renal Epo production and resulting polycythemia, presumably to counterbalance microvascular losses.

Effect of ghrelin on renal erythropoietin production in chronic hypoxic rats

Ghrelin, a 28 amino acid peptide, has diverse effects in body organs. Erythropoietin is a key mediator in increasing the red blood cells during hypoxia. Previously, we have shown that ghrelin has a polycythemic effect. In the present study, we evaluated the effect of ghrelin on erythropoietin gene expression with the aim to find out the mechanism of its effect. Thirty two adult male Wistar rats were divided randomly into four groups. The hypoxic condition was induced by placing the rats into the hypoxic chamber with 11% oxygen for two weeks. Saline- and ghrelin-treated control rats remained in room with a regular air conditions. Erythropoietin gene expression was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR). Plasma erythropoietin was measured by enzyme linked immunosorbent assay (ELISA). After 2-weeks of hypoxia, erythropoietin transcripts and erythropoietin plasma levels were significantly increased in hypoxic animals compared with control animals. Ghrelin treatment decreased both plasma erythropoietin and erythropoietin gene expression only in the hypoxic rats. Our data indicate that ghrelin might induce polycythemia through an erythropoietin-independent manner. However, to confirm this hypothesis and to find out the precise mechanism of this phenomenon further investigations are needed.

Important Role of Renal Nerve-mediated Erythropoietin Production in the Cardioprotection during Remote Ischemic Preconditioning

Important Role of Renal Nerve-mediated Erythropoietin Production in the Cardioprotection during Remote Ischemic Preconditioning

Treatment of erythropoietin deficiency in mice with systemically administered siRNA

AbstractAnemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production.

Management of renal anemia in patients with chronic kidney disease: the role of the general practitioner

The prevalence of chronic kidney disease (CKD) is high and diabetic nephropathy is a leading cause of CKD. One of the most common complications of CKD is anemia, the frequency and severity of which increase as kidney failure progresses. Renal anemia is primarily caused by reduced renal erythropoietin production. It can also be associated with iron deficiency caused by reduced iron absorption, occult blood loss and impaired iron mobilization. This work provides an overview of the management of renal anemia with focus on intravenous iron therapy, which is more effective than oral iron administration in CKD due to reduced iron absorption.

Liver Specific Delivery of siRNA Targeting EGLN Prolyl Hydroxylases Activates Hepatic Erythropoietin Production and Stimulates Erythropoiesis,

Abstract 3161Anemia in chronic kidney disease patients due to impaired renal production of erythropoietin (EPO) and insufficient erythropoiesis is a significant public health problem. One approach to compensate for the low EPO levels in patients with impaired kidney function would be to stimulate the levels of EPO production from non-renal sources. It is well known that during fetal development the liver serves as the primary producer of EPO until the kidney becomes the dominant source after birth. Negative regulation of EPO production is mediated by the EGLN family of prolyl hydroxylases (PHDs1-3) that play an important role in oxygen sensing by targeting the transcription factor hypoxia inducible factor (HIF) for degradation via the proteasome. HIF stabilization and activity is required to mediate EPO gene transcription. Previously it has been shown that liver specific conditional knockout of all three PHDs is required to activate HIF and induce EPO production in liver (Minamishima et al. Science 2010). Here we show that simultaneous siRNA mediated knockdown of all 3 PHD genes in mouse liver using lipid nanoparticles (LNPs) can induce hepatic EPO mRNA activation, elevation of serum EPO levels and stimulation of erythropoiesis. We extend these data by examining siRNA knockdown of different combinations of the 3 PHD genes and demonstrate that PHD2 is the dominant PHD gene regulating hepatic EPO production. In addition, due to the specificity of the LNP delivery system we show that the HIF activation and increase in EPO mRNA occurs specifically in liver. Increases in serum EPO and hematocrit were durable for two weeks and one month after a single intravenous dose of LNP siRNA. Furthermore, PHD siRNA silencing in a 5/6 nephrectomy model successfully elevates hemoglobin levels and corrects anemia. In conclusion, targeting of EGLN prolyl hydroxylase genes with siRNA therapeutics has potential in the treatment of anemia associated with chronic kidney disease and provides liver-specific target gene regulation. Disclosures:Querbes:Alnylam Pharmaceuticals: Employment. Bogorad:Alnylam Pharmaceuticals: Research Funding. Moslehi:Alnylam Pharmaceuticals: Honoraria. Akinc:Alnylam Pharmaceuticals: Employment. Wong:Alnylam Pharmaceuticals: Employment. Zurenko:Alnylam Pharmaceuticals: Employment. Qin:Alnylam Pharmaceuticals: Employment. Hettinger:Alnylam Pharmaceuticals, Inc.: Employment. Kuchimanchi:Alnylam Pharmaceuticals: Employment. Charisse:Alnylam Pharmaceuticals: Employment. Sah:Alnylam Pharmaceuticals, Inc.: Employment. Fitzgerald:Alnylam Pharmaceuticals: Employment. Kotelianski:Alnylam Pharmaceuticals: Employment. Kaelin:Fibrogen: Consultancy, Equity Ownership.

Cadmium Induces Anemia through Interdependent Progress of Hemolysis, Body Iron Accumulation, and Insufficient Erythropoietin Production in Rats

Cadmium is a toxic heavy metal and distributed widely in the environment. In addition to damaging the liver, kidneys, and bone, cadmium causes anemia through hemolysis, iron deficiency, and insufficient erythropoietin (EPO) production (renal anemia) along with changes in iron metabolism. Here, we investigated the role of iron in the interdependent progress of three types of anemia in cadmium-injected rats fed iron-sufficient or iron-deficient diets for 1 or 3 months. Cadmium injections for 1 month induced renal anemia without renal injury. Injections for 3 months induced hemolysis, iron deficiency, and renal anemia, accompanied by hepatic and renal damage. Iron concentrations in the liver, kidney, and spleen were increased, derived from internally released iron from hemolyzed red blood cells, increased duodenal iron absorption, insufficient erythropoiesis, and hepatic ferritin overproduced by cadmium-induced interleukin-6. Therefore, the iron deficiency anemia was actually apparent. Cadmium suppressed renal EPO production through a direct effect, accumulated iron, and destruction of EPO-producing cells. Increased duodenal iron absorption could be attributed to hypertrophy of the duodenal mucosa derived from anemia. Thus, insufficient EPO production and iron accumulation are the central factors driving anemia in cadmium toxicity.

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

Background/Aims: Elevated plasma homocysteine (Hcy) levels have been identified as a pathogenic factor causing a variety of pathological changes in different cells and tissues. In vertebrates, Hcy is produced solely from S-adenosylhomocysteine (AdoHcy) through the catalysis of AdoHcy-hydrolase. The direction of AdoHcy-hydrolase activity is determined by its cytosolic substrate concentrations, thereby controlling intracellular AdoHcy levels. Most S-adenosylmethionine (AdoMet)-dependent methyltransferases are regulated in vivo by the ratio of AdoMet/AdoHcy, which is termed “methylation potential” (MP). To test whether high rates of erythropoietin (EPO) expression is reduced by a low MP in vivo we choosed the model of increased EPO production following carbon monoxide (CO) exposure in rats in which high transcriptional activity is responsible for renal EPO production. Results: To induce a sustained hyperhomocysteinemia in rats, we infused i.v. a low or high dose of Hcy resulting in Hcy plasma levels of 87.4±6.2 and 300.8±23.7 µmol/l, respectively. Renal tissue contents of AdoHcy, AdoMet, and adenosine (Ado) were measured after freeze clamp by means of HPLC. Within 4h of CO exposure EPO serum levels increased from 13.6±0.4 (control) to 2254.8±278.3 mIU/ml. Only high dose of Hcy reduces both, the MP from 40.8±2.0 to 8.2±1.0 in the kidney as well as EPO serum levels by 40% compared to control rats. Conclusion: Our data show that severe hyperhomocysteinemia (HHcy) affects the MP in the renal tissue and lowers EPO expression following CO induced intoxication. This result supports the concept that efficient EPO production requires an unimpaired MP.

Effect of Dialysis on Erythropoietin and some Hematological Parameters in Patients with Chronic Renal Failure

Background and objective: A prospective study was carried out for estimation the concentration of the erythropoietin hormone and its effects on some hematological parameters in chronic renal failure patients despite medical treatment. The object of the study was to evaluate the available evidences which support the relationship between anemia and adverse outcomes in chronic renal failure patients, to estimate the erythropoietin concentration of plasma in chronic renal failure patients and to examine the relationship between the anemia and erythropoietin concentration in patients with chronic kidney disease. Methods: One hundred and eleven (111) patients with CRF on dialysis in the Dialysis and Kidney Disease Center in Hawler Teaching Hospital and (40) control groups were studied. Haematological parameters: were performed by conventional manual methods. The quantitative measurement of erythropoietin concentration in serum was done by using the Erythropoietin ELISA kit (IBL Immuno Biological Laboratories Hamburg Erythropoietin Kit, German). Results: Hemoglobin, red blood cells, packed cell volume, and mean corpuscular hemoglobin were significantly decreased (P&lt;0.001) in all age groups of Chronic renal failure patients, while, erythrocyte sedimentation rate and mean corpuscular volume (MCV) were increased significantly (P&lt;0.001). Total white blood cells were decreased significantly (P&lt;0.01) at the ages (40-60, &gt;60) years groups, while not significantly decreased at the ages (&lt;20, 20-40) years. Plasma erythropoietin was decreased significantly at the level (P&lt;0.001) in chronic renal failure patients. Conclusion: Anemia is a common and often an early complication of chronic renal diseases and decreased renal production of erythropoietin is the major cause of anemia in these patients.

Androgens, Telomerase, and Aplastic Anemia

In patients with aplastic anemia, reduced counts of red blood cells, leukocytes, and platelets sometimes improve with androgen therapy. Androgens raise red cell mass by stimulating renal erythropoietin production, but the mechanism responsible for increased leukocyte and platelet production is not understood. Telomerase gene ( TERT ) mutations have been detected in some patients with acquired aplastic anemia, and TERT and other telomerase gene mutations cause dyskeratosis congenita, a disorder characterized by bone marrow failure and aplastic anemia. Citing evidence that androgens control telomerase activity in certain cell types, investigators from …