Chronic kidney diseases affect people worldwide with its adverse consequences on almost all other systems of the body. Anemia due to deficient erythropoietin production is a prevalent complication with further deleterious effects on cardiovascular system particularly increased workload on heart leading to left ventricular hypertrophy. Increased level of procoagulant biomarkers causes enhanced thrombotic activity which promotes atherosclerostic lesions development and greater risk for ischemic cardiac events. Small dense low- density lipoprotein and its ratio with low density lipoprotein (sd-LDL: LDL) was also found to be increased in patients with CKD, which is also a traditional risk factor for CVDs. Erythropoietin and iron therapy is the main treatment employed for the treatment of anemia. Whereas, Low molecular weight heparins (LMWHs) are preferably used in the cases of thrombotic events in CKD. Dyslipoproteinemia has been treated with statins but have not shown as promising results as it does in general population with absent CKD.
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Keywords: anemia, chronic kidney disease, renal insufficiency, venous thromboembolism, dyslipoproteinemia.
Chronic Kidney diseases affects people worldwide with its consequences such as end stage renal disease, cardiovascular complications and haematological manifestations such as anemia and coagulation dysfunctions1. Anemia due to deficient erythropoietin or iron deficiency are commonly seen in patients with chronic kidney diseases for which a routinely Haemoglobin monitoring is advised. Anemia when managed in early stages could prevent further deteriorating complications of other systems of the body most likely cardiovascular diseases and death2. Anemia is defined, according to World Health Organization (WHO) criteria, to be that level of hemoglobin below age- and gender-determined normal ranges. Thus, for males and non-menstruating females, anemia is defined as Hb <13.5 g/dl, while in premenopausal women, anemia is defined as a Hb <11.5 g/dl. It's evident that patients on dialysis have low Hb throughout because of deficient kidney function which results in bulk of anemic chronic kidney disease cases 3. Haemostatic dysfunctions involve platelet abnormalities with initial prothrombotic state and later increased tendency for bleeding4. C-reactive protein, factor VIIc, fibrinogen, interleukin-6, factor VIIIc, D- dimer & plasmin-antiplasmin complex are increased in patients with renal insufficiency5. Inflammation which occurs in CKD is the reason for the decreased erythropoietin formation, it harms the development of erythroblasts and encourages the immature erythroblast to die. Hepatic production of Hepcidin is also induced by this inflammatory process which hinders iron absorption from the GI tract51. Hepcidin- a peptide hormone produced by liver is expected to be elevated in obese patients thus resulting in further destructing inflammatory process and iron deficiency but no excess risk of anemia was found in obes patients infact higher EPO levels were seen in conjugation with higher BMI levels52. Treatment of anemia is planned keeping in consideration the causes which can lead to anemia such as correction of iron deficiency or replacement of decreased erythropoietin production by recombinant human erythropoietin. Dyslipoproteinemia- a common precursor for cardiovascular complications, is also quite prevalent in CKD.
Chronic kidney diseases compromises the renal function which evidently results in misbalanced homeostasis inside the human body and ultimately affecting multiple organ system. Kidney itself does not function only as an excretory organ but has diverse functions in the body such as its participation in normal erythropoiesis, normal bone mineral deposition, blood pressure regulation etc.
CAUSES OF ANEMIA IN CKD:
Anemia in chronic kidney diseases was considered to be because of three causes mainly, reduction in Red blood cell life span, uraemic solutes inhibiting erythropoiesis and deficiency of erythropoietin which is essential for RBC formation30.The anemia of chronic renal failure is usually normochromic and normocytic characteristically. When GFR falls below 20-25 ml/ min the deficient erythropoietin function is evident6. Using WHO definitions of anemia, 87% of patients with GFR below 25 ml/min, but not yet on dialysis have anemia7. In normal subjects, plasma EPO levels range from 0.01 to 0.03 Units/ml and increase up to 100-to 1000- folds during hypoxia or anemia. In .patients with chronic renal failure, production of EPO is impaired, and this EPO deficiency is the primary cause of the anemia8. Other causes of anemia could be iron, B12 or folic acid deficiency, reduced red cells life or blood loss3. Low oxygen carrying capacity of blood leads to increased blood volume and increased cardiac output resulting in left ventricular hypertrophy (LVH) . LVH is more prevalent even in early stages of Kidney diseases when compared to general population14. In a study by Levin the prevalence of LVH in patients with a creatinine clearance less than 25ml/min was found to be 45% which reaches to 75% till the initiation of the dialysis14-15. Modifiable risk factors for the prevention of LVH are anemia and systolic blood pressure which gets even more deleterious as the kidney functions decline. Some studies suggests that even the correction of anemia does not reduces the risk for cardiovascular events in patients with CKD31. Anemia is a cause of end stage renal disease (ESRD) and pre-dialysis mortality in patients with stages 3,4-5 of CKD prior to dialysis32. Likewise in patients with already existing CVS diseases CKD and resulting anemia act as an additive factor. In post-transplant patients if the graft is well functioning it is able to sustain adequate levels of erythropoietin but in under functioning grafts decreased erythropoietin production can lead to post-transplant anemia (PTA) at any stage leading to hypoxia and even the damage to the graft56.
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A case report was presented in which a patient exhibited post-transplant pancytopenia for which the suggested reason was either the uremia or the hyperparathyroidism leading to bone marrow fibrosis which is another complication of renal dysunction57. Protein energy malnutrition and inflammation are quite prevalent in patients undergoing hemodialysis and as these two conditions are associated with atherosclerosis, this syndrome is collectively known as malnutrition -inflammation- atherosclerosis (MIA syndrome)58 .
Haemodialysis, excessive RBC production due to erythropoiesis stimulating agents or blood losses due to GI bleeding could lead to co-existing iron deficient anemia. Initial preliminary line of action would be to evaluate the iron levels, RBC counts, reticulocyte count, blood smears, assessments for haemolytic anemia and existence of GI bleeding sites. GI assessment becomes even more necessary if even after replacing the iron deficiency through effective iron supplementation, the iron stores remain depleted or if there is rapid decrease in Haemoglobin levels35.
ELEVATION OF PROCOAGULANT BIOMARKERS IN CKD:
Fibrinogen levels are higher in CKD whereas Antithrombin III levels are lower, coagulation is marked but the fibrinolysis is not enhanced in proportion comparable to the level of elevated coagulation which leads to increased cardiac complications9. Additionally a patient with CKD most probably dies due to cardiovascular disease10. Preponderance of atherosclerosis is high in CKD. Atherosclerotic plaques are calcified in kidney failure with increased media thickness compared with the controls with atherosclerosis but absent CKD. Atherosclerosis results in ischemia of cardiac tissue which causes angina pectoris, myocardial infarction, sudden cardiac death & heart failure11. Venous thromboembolism has also been associated with the elevated fibrinogen, factorVII, factor VIII, Von Willebrand factor, D-dimer and plasminogen activator inhibitor, all of which indicates the presence of altered levels of these procoagulant biomarkers responsible for the Cardiovascular diseases12. 11% of men with creatinine levels > 1.5mg/dl and women with levels > 1.3mg/dl had Chronic renal insufficiency (CRI). The prevalence of clinical and subclinical Cardiovascular diseases was 64% in participants with CRI. The possible mediators were again found to be increased levels of C- reactive protein, Fibrinogen, IL-6, factor VII, factor VIII, plasma-antiplasma complex13 . TNFÎ± is increased in inflammatory processes and it has an inverse relation with the GFR. As GFR decreases TNFÎ± increases whereas TNFÎ±is directly related with the vWF antigen levels that is as due to decreased GFR, TNFÎ± increases as well as the vWF antigen also increases59.
PLATELET DYSFUNCTION IN CKD:
In contrast to the higher incidences of prothrombotic events, platelet dysfunction and abnormal interaction between the platelets and the vessel wall also leads to bleeding diathesis in patients with CKD33. Platelets dysfunctions are responsible for the bleeding tendencies in advanced stages of kidney disorders which results in haemorrhages at different sites over the body. Intracranial and GI bleedings are therefore quite prevalent in these patients. Use of anticoagulants and its retention in patients undergoing dialysis due to ESRD is a probable cause of bleeding complications34-35. A defect in glycoprotein GPIb which serves as a receptor for vWF was also found in these patients and an inverse relation was observed between serum creatinine levels and the expression of glycoprotein GPIb36. Additionally the patients with chronic kidney disease exhibits decreased platelet activity in vitro in response to ADP, TRAP (tartrate resistant acid phosphatase) and CRP (C-reactive protein) as compared to the healthy individuals37.Previously few studies suggested elevated levels of protein Z (PZ) a vitamin K dependent serine protease inhibitor which blocks factor Xa activity in ESRD but only in patients who are on dialysis but later the studies contraindicated the elevated levels of PZ in patients on hemodialysis 39 .Despite the decrease in platelet functions still the thrombotic and cardiovascular diseases are prevalent among these patients33..
DYSLIPOPROTEINEMIA IN CKD:
Dyslipoproteinemia, a common metabolic disorder in CKD and also a risk factor for Cardiovascular disorder. Lower levels of serum total cholesterol (TC), low density lipoprotein-cholestrol (LDL-C), normal size LDL and high density LP- cholesterol (HDL-C) were found but the triglyceride levels and very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and small dense low- density lipoprotein (sd-LDL) levels were found to be elevated, which also results in increased sd-LDL:LDL ratio in CKD patients26. HMG- CoA reductase inhibitors (statins) reduce cardiovascular events and mortality in general population with CVDs but similar results have not been yet confirmed in patients with CKD27. Fibrates usage have also shown reduced plasma triglyceride concentrations and increasing HDL cholesterol concentrations in the general population. The use of gemfibrozil in those with creatinine clearances of 30 to 75 ml/min arw associated with 20% decrease in CV events28.
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MANAGEMENT OF ANEMIA OF CHRONIC KIDNEY DISEASES:
In the study of anemia prevalence in CKD it was found to be 47.7% in pre-dialysis patients16. Periodic evaluation and monitoring of Hb is required for timely interventions. In early stages of kidney disease an annual follow up would be adequate. In moderate or severe stages of disease more often monitoring would be necessary due to increased risk to this group, whereas monthly evaluation has to be done for those under the treatment of erythropoiesis stimulants17. After excluding other causes of anemia, it is managed as anemia of CKD. Before treating anemia with ESR complete evaluation of Hb levels, CBC, reticulocyte count, serum iron, serum ferritin, transferrin saturation (TSAT), serum vitamin B12 should be well evaluated and other causes of anemia to be excluded. TSAT is beneficial pointer for determination of anemia in patients not yet on dialysis whereas patients on stage 5 of CKD are prone to bleeding disorders so the risk of TSAT should be avoided38. 20% of non -dialysis CKD patients who had anemia get transfused with their mean Hb levels 8.8g/dl before transfusion43. In 1989 US FDA approved recombinant human erythropoietin (epoetin alfa), which along with similar agents now collectively known as erythropoietin stimulating agents (ESA) are being used for the treatment in erythropoietin deficient anemia of CKD19.
ADAPTED FROM GUIDELINES OF THE NATIONAL KIDNEY FOUNDATION. K/DOQI CLINICAL PRACTICE GUIDELINES FOR CHRONIC KIDNEY DISEASE: EVALUATION,CLASSIFICATION & STRATIFICATION18.
ESAs have revolutionized the treatment of anemia in CKD and improved life quality and reduced hospitalization and mortality. Iron therapy in conjugation with ESA is the main stream for treatment. ESA therapy diminishes the transfusion requirements, improves health status and regress the cardiovascular complication of LVH44. Epoetin alfa and beta are the two forms of recombinant DNA-derived erythropoietin (rEPO), which are produced in ovary cells of Chinese hamster41. ESA is available in two forms in USA namely Epoetin alpha and darbepoetin alfa. They could be self -administered at home but intravenous three times a week dose is administered to the patients on haemodialysis. Darbepoetin having longer half-life is administered once weekly but patients not yet being on dialysis have reduced dosage of once in 4 weeks20. Darbepoetin has equal efficacy when administered either by subcutaneous or intravenous route but in all ESA's administration intravenous route is preferred due to adverse outcome of pure red cell aplasia through subcutaneous route. After ESA therapy initiation the Hb levels should be monitored weekly in the beginning then afterwards managed by monthly evaluation. Anti-erythropoietin antibodies which neutralize erythropoietin and pure red-cell aplasia can develop during treatment with the ESA. Immediate screening for anti-eythropoietin antibodies is advised and if they are found instant discontinuation of the drug is recommended. Replacing the drug with other erythropoietin protein are also not advised as a cross reaction is expected among the different commercially available recombinant erythropoietin products. A decrease in the titre of antibody was observed after epoetin administration was halted; immunosuppressive drugs fasten the vanishing of the antibodies . Pure red cell aplasia has also been observed in these patients who have developed antibodies against epoetin42. Excessive usage of ESAs can be prevented by targeting the Hb levels no more than 10-12g/dl with additional consideration to the CVS complications and aiming the rightful cause of anemia in each patient44. Regardless the prevalent usage of recombinant EPO several cases of rHuEPO resistance or hyporesponsiveness have been reported30.Iron deficiency is the most common cause of rHuEPO hyporesponsiveness, however other causes such as neoplasms, infections, aluminium toxicity and rised PTH levels should also be evaluated to rule out the other causes resulting in deficient response to ESAs (rHuEPO)45. ESA would not be sufficient without competent iron stores available20. Continuous erythropoietin Receptor activator (C.E.R.A) is a newly developed drug which is under surveillance for its effect on anemia in CKD patients49. In ND-CKD patients CERA once every four week and darbepoetin alfa one weekly or evry 2 weeks have been proved to maintain a stable Hb level within the required targeted range50. Patients with CKD could be iron deficient due to various causes like platelet abnormalities due to uremia leading to occult blood loss from GI, frequent phlebotomies and punctures for dialysis. Therefore iron stores and serum levels are to be assessed frequently. In dialysis independent patient iron deficiency is treated at <100ng/ml serum ferritin concentration whereas in dialysis dependent patients levels <200ng/ml as iron stores are rapidly depleted due to increased consumption during enhanced erythropoiesis20. Patients given oral iron supplements may not respond adequately due to several reasons. Reduced iron absorption due to few newly available formulations or increased utilization in comparison to the absorptive capacity of iron by oral route21. In non-dialysis CKD patients iron therapy through intravenous route is preferred over oral route that is 1000 mg iron sucrose in divided doses for those with lower iron levels. There are several factors which aid in increased efficacy and early replenishment of depleted iron stores in patients who are administered iron through IV route40. Evidence based medicine have suggested increased incidences of mortality and morbidity in patients with higher Hb targets. Adverse effects of ESAs have already been addressed but the adverse outcomes of higher doses of IV iron therapy have not been considered yet as iron overdoses could be hazardous. Catalytically active iron can lead to inflammatory condition, immune disorders and further progression of renal disease but these studies have been conducted for short term period47.
MANAGEMENT OF THROMBOTIC STATE IN CKD:
In thromboembolic disorders of the chronic kidney disease patients, anticoagulant therapy is required22. Newer anticoagulants with FDA approval for venous thromboembolism (VTE) prophylaxis and treatment are low molecular wight heparin (LMWHs) and factor Xa inhibitors (fondaparinux). Whereas some of the LMWHs are also indicated in Acute coronary syndrome (ACS). All of the newer drugs approved for VTE and ACS are slso being used in mild to moderate renal insufficiency. LMWHs, factor Xa inhibitors and direct thrombin inhibitors use renal route for excretion so the dosage needs to be adjusted with the increasing grade of renal insufficiency.
The most approved and favoured anticoagulant for use in most of the patients with renal insufficiency was unfractioned heparin (UFH)23 but LMWHs have replaced UFH due to manageable administration and less need for continuous monitoring .Decreased clearance (below 30ml/min) and accumulation of drug may leads to increased bleeding tendency 24. In moderate or severe cases anti Xa activity should be evaluated for avoiding bleeding25.The bleeding tendency was found to be increased in patients who were on combination of antiplatelet drugs whereas the results for a single anti platelet drug was diversed. These drugs were found to be more effective in averting shunt and catheter thrombosis, but not for avoiding the thrombosis of arteriovenous grafts55.
Strong associations have been evident in the above discussion among anemia, increased procoagulant biomarkers, CVDs and CKDs. In addition to the increasing complexity of maintaining Hb levels within narrower margins, the options for treatments are also increasing. Newly available ESAs and the discovery and entry into the market of epoetin biosimilars as well as recently identified iron regulatory protein hepcidin are expected to exhibit profound results for the improvement and the management of complications in CKD29-30. Renal progression means further deterioration in renal functions. In adults the major risk factors for renal progression are diabetic nephropathy and hypertension whereas in children with CKD are found to have an existing history of congenital kidney disorders53-54. Health related quality of life could be improved by treating anemia and other modifiable risk factors of patients with CKD46. Despite the increased prevalence of CKD worldwide, the number of studies do not match the due and required attention and work needed for such a global health challenge. Prospective studies with clinical trials for the management of the disease and improvement of the life quality of the patients are essential48.