Blood And Bone Marrow Disorders
Serious blood disorders, such as some cancers, can lead to low hemoglobin levels. These disorders leave bone marrow unable to produce red blood cells fast enough, leading to a severe shortage. In addition to the conditions and diseases themselves, the treatment of those diseases often causes low levels, as well. Chemotherapy and radiation are two such treatments.
Pathophysiology Of Iron Metabolism In Chronic Kidney Disease
Iron is a vital element in human metabolism. Due to its unique ability to act both as an electron donor and as an electron acceptor , iron plays an imperative part in cellular respiration as well as oxygen transport and storage. However, due to its ability to receive and transfer electrons, iron can cause severe oxidative stress and tissue damage . As iron has an essential role in both energy metabolism and damaging potential, its absorption, transfer, and metabolism are tightly regulated. The regulation of iron is done mainly by adjusting absorption . This is due to the fact that the ability of the body to secrete iron is negligible .
In addition, CKD patients have an absolute iron deficiency. This can arise from an increased rate of blood loss during dialysis . The frequent phlebotomies, and blood remaining in the dialysis tubing, contribute to iron loss . The high rate of iron loss is also due to gastrointestinal bleeding from the combination of gastritis and platelet dysfunction . This is common in both dialysis- and non-dialysis -dependent CKD . Decreased gastrointestinal iron absorption and malnutrition contribute as well.
Due to the combination of reduced iron absorption and increased iron losses, iron deficiency is common among CKD patients who are both ND and dialysis dependent.
How Does Chronic Kidney Disease Cause Anemia
Anybody can develop anemia, but it is very common in people with CKD. People with CKD may start to have anemia in the early stages of CKD, but it is most common in stages 3-5. Anemia usually gets worse as CKD gets worse. If your kidneys are not working as well as they should, you are more likely to get anemia.
Anemia in CKD is more common if you:
Are older than 75 years
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What Drugs Interact With Lasix
Lasix may increase the ototoxic potential ofaminoglycoside antibiotics, especially in the presence of impaired renalfunction. Except in life-threatening situations, avoid this combination.
Lasix should not be used concomitantly with ethacrynicacid because of the possibility of ototoxicity. Patients receiving high dosesof salicylates concomitantly with Lasix, as in rheumatic disease, mayexperience salicylate toxicity at lower doses because of competitive renalexcretory sites.
There is a risk of ototoxic effects if cisplatin andLasix are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugssuch as cisplatin may be enhanced if Lasix is not given in lower doses and withpositive fluid balance when used to achieve forced diuresis during cisplatintreatment.
Lasix has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action ofsuccinylcholine.
Lithium generally should not be given with diureticsbecause they reduce lithium’s renal clearance and add a high risk of lithiumtoxicity.
Lasix combined with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers may lead to severe hypotensionand deterioration in renal function, including renal failure. An interruptionor reduction in the dosage of Lasix, angiotensin converting enzyme inhibitors,or angiotensin receptor blockers may be necessary.
Potentiation occurs with ganglionic or peripheraladrenergic blocking drugs.
How Do Health Care Professionals Treat Anemia In Ckd
Health care professionals first treat any underlying conditions that may be causing the anemia, such as an iron or vitamin deficiency. If your anemia is mild and you have few symptoms, you may not need treatment at first.
Treatments for anemia may ease your symptoms and improve your quality of life.
Your health care professional may refer you to a hematologist or a nephrologist, a health care professional who treats people with kidney problems or related conditions.
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How Common Is Anemia In Ckd
Anemia is common in people with CKD, especially among people with more advanced kidney disease. More than 37 million American adults may have CKD,1 and it is estimated that more than 1 out of every 7 people with kidney disease have anemia.2
Most people who have kidney failurewhen kidney damage is so advanced that less than 15 percent of the kidney is working normallyalso have anemia.3
Symptoms And Physical Findings
Although the diseases that lead to anemia, such as malignancy or chronic kidney disease , may cause obvious symptoms, the anemia itself tends to cause quite nonspecific symptoms. Clinicians must be wary of the tendency to dismiss these symptoms as insignificantâfor example, as being due to old ageâwhen in fact they should serve as alarming signals of disease or pathology.
Patients with anemia of chronic disease or CKD may present with the following symptoms:
- Generalized weakness or malaise, easy fatigability
- Generalized body aches, or myalgias
- Orthostatic symptoms
- Syncope or near-syncope
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Possible Causes Of Anemia
Usually, it happens because you donât have enough red blood cells. That can make you more likely to get certain diabetes complications, like eye and nerve damage. And it can worsen kidney, heart, and artery disease, which are more common in people with diabetes.
Diabetes often leads to kidney damage, and failing kidneys can cause anemia. Healthy kidneys know when your body needs new red blood cells. They release a hormone called erythropoietin , which signals your bone marrow to make more. Damaged kidneys donât send out enough EPO to keep up with your needs.
Often, people donât realize they have kidney disease until itâs very far along. But if you test positive for anemia, it can be an early sign of a problem with your kidneys.
People with diabetes are more likely to have inflamed blood vessels. This can keep bone marrow from getting the signal they need to make more red blood cells.
And some medications used to treat diabetes can drop your levels of the protein hemoglobin, which you need to carry oxygen through your blood. These drugs include ACE inhibitors, fibrates, metformin, and thiazolidinediones. If you take one of these, talk to your doctor about your risk for anemia.
If you have kidney dialysis, you may have blood loss, and that can also cause anemia.
What Are The Complications Of Anemia In Someone With Ckd
In people with CKD, severe anemia can increase the chance of developing heart problems;because the heart is getting less oxygen than normal and is working harder to pump enough red blood cells to organs and tissues. People with CKD and anemia may also be at an increased risk for complications due to strokes.
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What Clinical Studies For Anemia In Ckd Are Looking For Participants
You can view a filtered list of clinical studies on anemia in CKD that are open and recruiting at www.ClinicalTrials.gov. You can expand or narrow the list to include clinical studies from industry, universities, and individuals; however, the NIH does not review these studies and cannot ensure they are safe. Always talk with your health care professional before you participate in a clinical study.
When To Talk With Your Doctor
Anemia doesnât always cause symptoms. It also tends to come on slowly and get worse over time.
Untreated anemia can make it hard to think clearly or go about your daily tasks. It also makes your heart work harder and can lead to serious heart problems.
Tell your doctor right away if you:
- Feel tired and weak
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Hypoxia Inducible Factor System
EPO is a glycoprotein that binds to its receptor on the surface of erythroid progenitor cells mainly in the bone marrow, and serves as a key stimulus for red cell survival, proliferation and differentiation. EPO is produced predominantly by the fibroblast-like interstitial peritubular cells of the kidneys, and in a much lesser proportion, by the perisinusoidal cells in the liver, in response to changes in tissue oxygen tension . The production of EPO is controlled at the level of the EPO gene transcription. One of the most important factors that regulate its expression is the hypoxia-inducible factor system, whose activity depends on the tissue oxygen levels.
Under normoxic conditions, HIF1 is degraded. For this purpose, HIF1 is hydroxylated at two proline residues. This hydroxylation is performed by specific HIF prolyl-hydroxylase enzymes called prolyl hydroxylase domain enzymes that need the presence of oxygen, iron, and 2-oxoglutarate as co-factors. Three forms have been described: PHD1, PHD2, PHD3. PHD2 is the main isoform regulating HIF activity . Once HIF1 is hydroxylated, the E3 ubiquitin ligase von Hippel-Lindau binds HIF1, and is targeted for proteasomal degradation. In contrast, under low oxygen tension the action of PHDs is prevented, allowing for HIF1 stabilization and translocation to the nucleus . This pathway is the target of the new so-called hypoxia-inducible factor prolyl hydroxylase inhibitors .
Treatment For Low Hemoglobin In Stage 4 Ckd
Many patients with stage 4 CKD notice that their hemoglobin levels are lower than the normal level, and we can call it anemia. Anemia will make patients feel weak and have poor appetite. While severe anemia may cause heart failure and result in a series of obvious symptoms. Then, what is the efficient treatment for anemia in stage 4 CKD.
Cause for anemia in stage 4 CKD
Red blood cell is the important mean of transportation for human body, it carries oxygen and nutrition to every organ and cell in the body, and then takes the metabolic products to liver and then kidneys to remove them out of body finally, which plays an important role maintaining life. Red blood cell is created by marrow, while Erythropoietin stimulates marrows hematopoietic function and promotes the generation of red blood cell.
We can call stage 4 CKD the kidney failure stage, which means the severe reduction in kidney function. Once kidneys are unable to work normally, the secretion of EPO will be reduced. What is more, the accumulation of toxins and other harmful substances leads to the decline in both the amount and quality of red blood cells, thus causing low hemoglobin and anemia.
Treatment for anemia in stage 4 CKD
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Efficacy Of Hif Prolyl Hydroxylase Inhibitors
Roxadustat is the most advanced HIF-PHI under clinical development, which has already been approved in China and Japan. Two phase 3 studies were published in 2019 comparing roxadustat with placebo in NDD, and with epoetin alfa in DD-CKD patients in China. These studies had a relative small sample size a study population and of short duration. The former compared roxadustat with placebo, without adjuvant iron supplements, and demonstrated its efficacy in rising hemoglobin levels after 9 weeks . The latter compared roxadustat with epoetin alfa, with iron supplement only as a rescue therapy. After 26 weeks of follow up, the attained hemoglobin levels in the roxadustat group were non-inferior to those in the epoetin alfa-arm, and both groups had a similar safety profile . These results were similar to those found by a phase 3 study comparing roxadustat to ESAs in hemodialysis and peritoneal dialysis patients in Japan .
The OLYMPUS, ALPS, and ANDES trials evaluated roxadustat vs. placebo in NDD-CKD patients . An integrated analysis showed that roxadustat was efficacious in achieving and maintaining Hb levels, with lower risk of rescue therapy. Regarding adverse events, both arms of treatment had comparable safety profiles regarding cardiovascular events and all-cause mortality .
Has published the protocol for a systematic review on HIF-PHIs for the treatment of anemia of chronic kidney disease .
Management Of Anemia Of Ckd
The US Food and Drug Administration advises clinicians to consider starting ESA treatment for patients with CKD when the hemoglobin level is less than 10 g/dL, but does not define how far below 10 g/dL would be an appropriate threshold for initiating ESA treatment in an individual patient. Kidney Disease: Improving Global Outcomes guidelines suggest basing the decision whether to initiate ESA therapy in nonâdialysis-dependent CKD patients with a hemoglobin concentration < 10.0 g/dL on the following:
- Rate of fall of the hemoglobin concentration
- Prior response to iron therapy
- Risk of needing a transfusion
- Risks related to ESA therapy
- Presence of symptoms attributable to anemia
To evaluate response to ESA treatment, the KDIGO guidelines recommend measuring hemoglobin at least monthly during the initiation phase. During the maintenance phase, measurement is recommended at least every 3 months in patients with nonâdialysis-dependent CKD patients, and at least monthly in CKD 5D patients.
In 2011, the FDA abandoned the concept of a target range for the hemoglobin level in ESA treatment. Instead, the FDA recommended using the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions for each patient, and adjusting the dose as appropriate.
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What Causes Low Hemoglobin And Hematocrit
If the lifespan of the RBC is disrupted, it may result in low hemoglobin and hematocrit. The normal lifespan of an RBC is only about 120 days, and this is created in the bone marrow.
There are two main causes of anemia
- A decrease in RBC or hemoglobin production
- An increase in RBC loss or destruction.
Anemia may also be classified based on the mean corpuscular volume
- MCV less than 80 means that you have microcytic anemia;
- MCV within 80 to 100 means that you have normocytic anemia; and
- MCV is higher than 80 means that you have macrocytic anemia.
One of the most common causes of anemia is iron deficiency. This is because one of the major components of hemoglobin is iron, and it is also crucial for it to function properly. If you are experiencing chronic blood loss, your iron level will become low.
Who Is Most Likely To Develop Iron
Anyone can develop iron-deficiency anemia, although the following groups have a higher risk:
- Women, because of blood loss during monthly periods and childbirth
- People over 65, who are more likely to have diets that are low in iron
- People who are on blood thinners such as aspirin, Plavix®, Coumadin®, or heparin
- People who have kidney failure , because they have trouble making red blood cells
- People who have trouble absorbing iron
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Treatment Of Renal Anemia
Androgens started to be used to treat anemia of end-stage renal disease in 1970, and before the advent of recombinant human erythropoietin, they were a mainstay of nontransfusional therapy for anemic patients on dialysis.
The approval of recombinant human erythropoietin in 1989 drastically shifted the treatment of renal anemia. While the initial goal of treating anemia of chronic kidney disease with erythropoietin was to prevent blood transfusions, subsequent studies showed that the benefits might be far greater. Indeed, an initial observational trial showed that erythropoiesis- stimulating agents were associated with improved quality of life, improved neurocognitive function, and even cost savings. The benefits also extended to major outcomes such as regression of left ventricular hypertrophy, improvement in New York Heart Association class and cardiac function, fewer hospitalizations and even reduction of cardiovascular mortality rates.
As a result, ESA use gained popularity, and by 2006 an estimated 90 percent of dialysis patients were receiving these agents. The target and achieved hemoglobin levels also increased, with mean hemoglobin levels in hemodialysis patients being raised from 9.7 to 12 g/dL.
Disappointing results in clinical trials of ESAs to normalize hemoglobin
To prospectively study the effects of normalized hemoglobin targets, four randomized controlled trials were conducted :
General approach to therapy
Two ESA preparations
Target iron levels
Iron Supplementation For Anemia In Ckd
Guidelines acknowledge that the optimal strategy to manage iron metabolism remains unclear, and advocate for balancing the potential benefits and risks of iron supplementation . Table 1 summarizes the principles and targets of the management of iron supplements of the KDIGO ERBP NICE guidelines. In recent years some good quality pre-clinical studies, clinical trials and epidemiological studies have shed some light on the therapeutic approach regarding iron deficiency in CKD and will surely change clinical practice.
Intravenous iron has shown benefits both in DD-CKD and more recently in NDD-CKD, as it has proved to be more efficacious in rising ferritin and Hb levels, while reducing ESA and transfusion requirements. Specifically, in hemodialysis patients, oral preparations seem to be useless, maybe except for the phosphate binder ferric citrate . In addition, gastrointestinal intolerance and constipation reduce tolerance and compliance of oral iron formulations .
However, some concerns raised about IV iron formulation such as enhanced oxidative stress, endothelial dysfunction or the potential role in favoring infection. Further, IV iron administration has been associated with an increased risk of hypotension, headaches or hypersensitivity reactions. Labile iron, which is the iron that is freed into the circulation after administration and non-bound to transferrin, is an important cause of such adverse reactions.
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Shortness Of Breath After Very Little Effort
Why this happens:
Being short of breath can be related to the kidneys in two ways. First, extra fluid in the body can build up in the lungs. And second, anemia can leave your body oxygen-starved and short of breath.
What patients said:
At the times when I get the shortness of breath, it’s alarming to me. It just fears me. I think maybe I might fall or something so I usually go sit down for awhile.
I couldn’t sleep at night. I couldn’t catch my breath, like I was drowning or something. And, the bloating, can’t breathe, can’t walk anywhere. It was bad.