The paradigm shift from polycythemia to anemia in COPD: the critical role of the renin–angiotensin system inhibitors

ABSTRACT

Introduction

Although polycythemia has been considered a common adverse event in COPD, anemia is reported more often and has gained more importance than polycythemia over the last thirty years.

Areas covered

Factors considered to be associated with the development of anemia in COPD have included: Aging and kidney dysfunction with erythropoietin deficiency and bone marrow suppression due to uremic toxins; heart failure (HF), often encountered in COPD and accompanied by anemia in one-third of the cases; Low-grade chronic inflammation, directly suppressing bone marrow and diminishing iron absorption and utilization via increased hepcidin levels; long-term oxygen therapy (LTOT), ameliorating chronic hypoxia, and most important, RAS inhibitors, which are widely used for the comorbidities associated with COPD (hypertension, HF, CKD, diabetes) and have previously been shown to lower hematocrit values or cause anemia in various clinical conditions.

Expert opinion

Introduction of LTOT in COPD and especially the established use of RAS inhibitors form the basis for the shift from polycythemia to anemia in COPD. Interestingly, when the SGLT2 inhibitors are introduced for cardiorenal protection in COPD, one could anticipate correction of anemia or even reemergence of polycythemia, since this new class of drugs can augment erythropoietin secretion and increase hematocrit values.

KEYWORDS:

• COPD
• polycythemia
• anemia
• renin-angiotensin system
• long-term oxygen therapy
• SGLT2 inhibitors

Article highlights

• Although polycythemia has been conventionally considered a common adverse event in COPD, anemia has been reported more often and gained more importance over the last thirty years.

• Aging of COPD population, renal dysfunction, HF, low-grate inflammation, absolute or relative iron deficiency, LTOT and most important the wide use of ACEi and ARB for the treatment of co-morbidities in patients with COPD, all play an important role in increasing the prevalence of anemia in COPD.

• Angiotensin II, the active octapeptide of RAS, is involved with the regulation of erythropoiesis, since it increases the endogenous erythropoietin secretion, acts as a direct growth factor on erythroid progenitors and facilitates iron absorption and utilization. Consequently, inactivation of RAS has often been associated with a dose-dependent decrease in hematocrit values and even the development of anemia in various clinical conditions.

• Anemia has been recognized, as a significant and independent risk factor for increased morbidity and mortality in COPD. Anemia work-up will be required with laboratory examinations and various procedures (gastroscopy, colonoscopy, bone marrow aspiration etc), which further escalate the morbidity and the cost in debilitated patients with COPD.

• RAS inhibition should always be considered in the differential diagnosis of hematocrit lowering and anemia in patients with COPD. Since the beneficial effect of RAS inhibitors requires their administration at the maximum tolerated dose, the decision to decrease the dose or even stop these drugs should rest on the severity of patient’s clinical condition and the availability of alternative therapeutic modalities. At any rate, all potential causes of anemia (including iron deficiency and inflammatory states) should be addressed and corrected.

• As a final point, the case of the SGLT2i in relation to COPD should be addressed. These medications have initially been developed for the treatment of diabetes, but they confer impressive cardiorenal protection and are expected to become increasingly used in real-world practice. Their use is associated with a significant rise in the hemoglobin and the hematocrit values, a phenomenon originally attributed to their diuretic action and hemoconcentration, but subsequently found to emanate from their ability to augment erythropoietin secretion. Future studies should evaluate the benefits and implications of initiation of SGLT2i in patients with COPD and comorbidities and reveal whether SGLT2i can counterbalance the hematocrit lowering effect of RAS inhibitors or play a role in the reemergence of polycythemia in vulnerable patients with COPD and chronic hypoxia.

List of abbreviations

COPD, Chronic Obstructive Pulmonary Disease; HF, Heart Failure; CKD, Chronic Kidney Disease; LTOT, Long Term Oxygen Therapy; RAS, Renin Angiotensin System; ACEi, Angiotensing Converting Enzyme Inhibitor; ARB, Angiotensin Receptor Blocker

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.