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![Chronic Renal Failure
Pharmacotherapy
ANEMIA
• Before the introduction of recombinant human
erythropoietin (epoetin alfa [EPO]) in the late 1980s,
anabolic steroids and red cell transfusions were the
primary modalities by which anemia was treated in
the CRD population
• The synthesis of epoetin revolutionized anemia
management in the ESRD population, but despite
more than a decade of clinical use, opinions are still
evolving regarding the most appropriate manner of
EPO use, optimal therapeutic hemoglobin (or
hematocrit) goals, and their associated risk-benefit
ratios](https://image.slidesharecdn.com/chronicrenalfailure-230208035926-27854bcb/75/Chronic-Renal-Failure-pdf-38-2048.jpg)
![Chronic Renal Failure
• Epoetin alfa, a recombinant molecule with the
same structure as endogenous erythropoietin, is
manufactured under two name brands (Procrit,
Epogen)
• This modification gives darbepoetin [also known as a
novel erythropoiesis-stimulating protein (NESP)], an
increased half-life compared with epoetin alfa.
• This characteristic allows it to be dosed less
frequently than epoetin was traditionally dosed](https://image.slidesharecdn.com/chronicrenalfailure-230208035926-27854bcb/75/Chronic-Renal-Failure-pdf-39-2048.jpg)
Chronic Renal Failure.pdf
- 1.
- 2. Chronic Renal Failure DEFINITION •CKD is defined as either of the following conditions for a minimum of 3 months: glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2, or old damage to the kidney(s) with or without a decrease in GFR • This damage may be evidenced by abnormalities in the composition of blood or urine, or by changes seen in imaging studies
- 3. Chronic Renal Failure •The K/DOQI2 Working Group further categorizes the extent of kidney disease according to the presence of kidney damage and the GFR • Stage 1 CKD is defined as the presence of kidney damage even though GFR may be normal or even increased (≥90 mL/min/1.73 m2) • Stage 2 CKD is evidenced by a GFR between 60 and 89 mL/min/1.73 m2 • Patients with stage 3 CKD may or may not have kidney damage, while their GFR is reduced to between 30 and 59 mL/min/1.73 m2
- 4. Chronic Renal Failure •CKD patients with stage 4 disease also may not have intrinsic kidney damage, but their GFR is severely reduced to between 15 and 29 mL/min/1.73 m2 • The last stage, stage 5, is also known as end-stage kidney disease (ESKD) • End-stage renal disease (ESRD) is defined as a GFR less than 15 mL/min/1.73 m2 or the need for renal replacement therapy (RRT) for survival
- 5. Chronic Renal Failure Pathophysiology GLOMERULARHYPERFILTRATION AND INTRAGLOMERULAR HYPERTENSION • The nephron, the functional unit of the kidney, comprises the glomerulus and the tubules • Approximately 1 million nephrons are located in each kidney • When the number of functioning nephrons is reduced because of insult or disease, the remaining nephrons compensate by enlarging (hypertrophy) and by increasing their individual GFRs
- 6. Chronic Renal Failure Pathophysiology •Sustained elevations of blood flow and pressure within the glomeruli cause damage to remaining nephrons, ultimately leading to their demise • Glomerular injury is also believed to result from increased capillary permeability (reduced permselectivity), which allows proteins and other macromolecules to leak through capillaries into the renal tubules
- 7. Chronic Renal Failure Pathophysiology •Microalbuminuria is one of the earliest clinical manifestations of glomerular damage • This process in turn may promote the secretion of proinflammatory mediators and induce renal mesangial cells to deposit an extracellular glycoprotein matrix, leading to a type of renal fibrosis and scarring called sclerosis • Sclerosis may involve the entire nephron (nephrosclerosis), extending from the glomerulus (glomerulosclerosis) to the tubules and interstitium
- 8. Chronic Renal Failure Pathophysiology PROTEINURIA •Because protein (mostly albumin) is a relatively large molecule, it generally is not filtered in the glomerulus but is returned to systemic circulation via the efferent arteriole • The presence of small amounts of protein in the urine (microalbuminuria) or larger amounts (proteinuria) is due to damage within the glomerulus • Although this may be the result of a self-limiting situation (e.g., acute muscle breakdown), it occurs more often as a result of injury caused by a disease process such as diabetes or hypertension
- 9. Chronic Renal Failure Pathophysiology •Both of these disease states may lead to intraglomerular hypertension and altered glomerular permeability • Filtering of protein in the glomerulus causes direct damage, and protein deposition evokes an inflammatory response that may cause more damage in the glomerulus or the tubules • The association of proteinuria with direct kidney damage is so strong that clinicians often use the degree of albuminuria as a measure of nephropathy
- 10. Chronic Renal Failure Pathophysiology DIABETICNEPHROPATHY • DM is the single most important disease leading to ESKD • The incidence of diabetic nephropathy peaks after 10 to 15 years of diabetes; however, functional renal abnormalities are often present within 2 years of the onset of type 1 DM • Tthe diagnosis of type 2 DM is often delayed by actual onset, renal changes are usually present at diagnosis in this population • Aside from hyperglycemia, comorbidities such as hypertension and hyperlipidemia are common in patients with diabetes and are believed to contribute to progression of nephropathy in most cases
- 11. Chronic Renal Failure Pathophysiology HYPERTENSION •Moderate to severe hypertension is strongly correlated with the risk of developing ESKD, consistent with observations that systemic hypertension may both cause and result from renal disease • Assuming that an elevated systemic blood pressure is transmitted to the glomerulus, systemic hypertension may be anticipated to exacerbate CKD progression by contributing to intraglomerular hypertension and hyperfiltration
- 12. Chronic Renal Failure Pathophysiology •Antihypertensive therapies have been postulated to protect against glomerulopathy by several mechanisms, including reduction in blood pressure or blood flow reaching the glomerulus, attenuation of intraglomerular hypertension via reductions in afferent or efferent arteriolar tone, alteration of nonhemodynamic factors such as membrane permselectivity, inflammation, and oxidative stress, or possibly some combination of these mechanisms
- 13. Chronic Renal Failure Pathophysiology HYPERLIPIDEMIA •Dyslipidemia is more prevalent in patients with CKD than in the general population (30% vs. 20%).4 In patients with nephrotic range proteinuria (>3 g/24 hours), the incidence may be as high as 70% to 100% because of increased hepatic lipoprotein synthesis • In these patients, the degree of proteinuria is directly proportionate to the increase in total cholesterol • Dyslipidemia may lead to the progression of CKD caused by oxidation and deposition of lipoproteins in the glomerulus and the mesangial cells
- 14. Chronic Renal Failure Pathophysiology •Oxidized low-density lipoprotein (LDL) may cause synthesis of inflammatory cytokines, vasoactive substances, and macrophage chemotactic factors • These changes eventually lead to glomerular scarring • Common abnormalities seen in patients with CKD include increased LDL, decreased HDL, and elevated triglycerides
- 15. Chronic Renal Failure Pathophysiology METABOLICAND SYSTEMIC CONSEQUENCES OF CHRONIC KIDNEY DISEASE • The extent to which renal dysfunction reduces urinary solute excretion has been found to vary for different substances • For example, rises in urea and creatinine are observed early in CKD and inversely correlate with GFR, whereas the renal excretion of potassium, urate (uric acid), phosphorus, and hydrogen ion is generally preserved until GFR falls to below 25% of normal.
- 16. Chronic Renal Failure Pathophysiology •Excretion of these solutes may be enhanced by increased tubular secretion or reduced reabsorption until GFR is 25 to 30 mL per minute or less, at which point accumulation becomes unavoidable and plasma levels of these solutes begin to rise • Finally, the renal handling of other solutes (e.g NaCl) may be well preserved late into CKD but differs substantially among the various types of renal disease
- 17. Chronic Renal Failure Pathophysiology VOLUME,SODIUM, AND WATER BALANCE • Because daily sodium intake usually exceeds requirements, the kidneys are able to maintain sodium balance by simply reducing urinary Na reabsorption . • Conversely, if sodium intake is below output, the kidney is usually able to increase its conservation of sodium, except in certain salt-wasting nephropathies.
- 18. Chronic Renal Failure Pathophysiology •At creatinine clearances below 25 mL per minute, however, renal adaptation to wide fluctuations in sodium or water intake is sluggish and incomplete • The kidney becomes unable to concentrate or dilute urine efficiently, and urinary excretion of water and salt tends to become fixed at nearly iso- osmotic concentrations, in volumes of about 2 L per day
- 19. Chronic Renal Failure Pathophysiology ELECTROLYTEBALANCE: POTASSIUM AND MAGNESIUM • Potassium is carefully regulated in the body. Only a small amount—approximately 2%—is extracellular. Potassium is moved into and out of cells via sodium, potassium adenosine triphosphatase pumps • Various factors may upregulate or downregulate the number of pumps on the cell membrane, causing a shift in potassium to other mechanisms. • Insulin and β2-agonists increase the movement of potassium intracellularly, and hyperparathyroidism and hypertonicity may cause potassium to shift to the extracellular compartment
- 20. Chronic Renal Failure Pathophysiology •As the degree of kidney failure progresses, an adaptive increase in colonic elimination of potassium occurs; in patients with ESKD • This increase may be up to two fold to threefold greater than that in subjects with normal kidney function • This increased gastrointestinal secretion and an increase in distal tubular secretion prevent hyperkalemia until kidney function declines to 10 to 15 mL per minute • Factors that increase the risk of hyperkalemia include an increase in potassium intake and use of drugs that impair potassium excretion (ACE-Is, potassium-sparing diuretics), or drugs or conditions that shift potassium to the extracellular fluid from the intracellular fluid
- 21. Chronic Renal Failure Pathophysiology ACID-BASEREGULATION • A normal adult who consumes a mixed diet generates approximately 1 mEq per kg of metabolic acid daily • This hydrogen ion is rapidly buffered by circulating bicarbonate and is excreted by the lungs as respiratory acid (CO2) • Bicarbonate lost during this process is regenerated by the kidney through the excretion of acid which must be buffered by ammonia or other urinary buffers
- 22. Chronic Renal Failure Pathophysiology •In kidney disease, renal ammonia formation (ammoniagenesis) is generally impaired as a consequence of reduced nephron mass • Because urinary acid secretion and renal regeneration of bicarbonate are coupled with the availability of ammonia, these associated processes become impaired in CKD • Bicarbonate is also filtered into the urine and must be reclaimed by reabsorption; however, this tends to remain intact until CKD is far advanced
- 23. Chronic Renal Failure Pathophysiology ANEMIAOF CHRONIC KIDNEY DISEASE • Erythropoietin (EPO) is a hormone that is produced and secreted by the granular cells of the kidney in response to hypoxia or ischemia. • When secreted, EPO travels to the bone marrow and causes the proliferation and differentiation of committed erythroid progenitor cells • Additionally, EPO prevents apoptosis of these cells, allowing them to mature
- 24. Chronic Renal Failure Pathophysiology •The primary cause of anemia in CKD is the diminished production of EPO by the failing kidneys • Other causes include frequent phlebotomy, malnutrition, iron or vitamin deficiencies, and, for those patients on hemodialysis, blood loss in the dialytic circuit • Another contributing factor to anemia is the shortened life cycle of red blood cells in uremia
- 25. Chronic Renal Failure Pathophysiology CALCIUM,PHOSPHORUS, AND BONE HOMEOSTASIS • As GFR decreases, excretion of solutes is impaired. Phosphorus may begin to accumulate in the early stages of CKD—stages 3 and 4 • Hyperphosphatemia causes a decrease in serum calcium brought about through a physiochemical interaction and complexation • Reduction in serum calcium triggers the parathyroid gland to synthesize and secrete more parathyroid hormone (PTH)
- 26. Chronic Renal Failure Pathophysiology •PTH in turn causes an increase in osteoclast activity in the bone, breaking down bone to release calcium and restore serum levels. These abnormalities are compounded by a relative deficiency of vitamin D • The failing kidneys are not able to convert vitamin D to the active form—1,25-dihydroxycholecalciferol (vitamin D3)
- 27. Chronic Renal Failure Pathophysiology ENDOCRINEAND HORMONAL ABNORMALITIES • Abnormalities in female and male gonadal hormones are common in ESKD and result in high incidences of infertility and sexual dysfunction • Hyperprolactinemia is common, and gonadotropin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels may be low in both men and women. Women may cease to ovulate or menstruate, or they may do so irregularly
- 28. Chronic Renal Failure Pathophysiology •Although pregnancy is still possible, these are considered high-risk cases and only 40% result in successful deliveries • Decreased libido and erectile dysfunction are common among men with ESKD, which may be related not only to reduced testosterone levels but also to concurrent malaise, anemia, and vascular and neurologic abnormalities
- 29. Summary • Chronic kidneydisease (CKD), also known as chronic renal disease, is progressive loss in kidney functionover a period of months or years. • The symptoms of worsening kidney function are not specific, and might include feeling generally unwell and experiencing a reduced appetite. • This disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia, pericarditis orrenal osteodystrophy (the latter included in the novel term CKD-MBD). • CKD is a long-term form of kidney disease; thus, it is differentiated from acute kidney disease (acute kidney injury) in that the reduction in kidney function must be present for over 3 months.
- 30. Chronic Renal Failure SIGNSAND SYMPTOMS • Most patients experience few symptoms of CKD until less than 25% of normal renal function remains • CKD can therefore progress insidiously over months to years, evident only through abnormal biochemical parameters, such as gradually rising levels of BUN and serum creatinine values • Nonspecific complaints such as malaise, fatigue, and nocturia may be noted
- 31. Chronic Renal Failure •Urine output may or may not be diminished. Hypertension may develop and, if discovered, presents a critical opportunity for investigation of renal implications • Unless patients are recognized to be at risk of and are monitored for kidney disease, they usually do not seek medical attention until the onset of uremic symptoms • At this point, interventions to forestall progression to ESKD are largely unfruitful
- 32. Chronic Renal Failure Pharmacotherapy TREATMENTOF DIABETIC NEPHROPATHY • Diabetic nephropathy is caused mainly by the presence of hyperglycemia, as has been previously discussed • In this situation, the best way to prevent or slow renal damage is to prevent hyperglycemia • Several trials have shown that minimizing hyperglycemia can delay the onset and slow the progression of the microvascular and macrovascular complications of diabetes
- 33. Chronic Renal Failure •The Diabetes Control and Complications Trial Research Group (DCCT trial) demonstrated that patients with type 1 diabetes who maintain hemoglobin A1C levels at approximately 7% (vs. 9%) delayed the onset and progression of retinopathy, nephropathy, and neuropathy
- 34. Chronic Renal Failure Pharmacotherapy TREATMENTOF DYSLIPIDEMIA • The benefits of treating dyslipidemia in patients with CKD have been demonstrated through many studies. • Specifically, studies suggest that hydroxymethylglutaryl coenzyme A reductase inhibitors (HMG-CoA, statins) are particularly beneficial • Statins may decrease proliferation of mesangial and proximal tubular cells, reducing glomerulosclerosis • They may also decrease the inflammatory response stimulated by endothelin-1
- 35. Chronic Renal Failure •They have been shown to have an antiproteinuric effect, as well as the ability to slow progression of renal dysfunction. Studies have shown decreases in carotid intimal thickening (a marker of total body atherosclerosis) • Statins have also been shown to decrease plasma homocysteine levels; fibrates may have the opposite effect
- 36. Chronic Renal Failure Pharmacotherapy TREATMENTOF METABOLIC AND SYSTEMIC CONSEQUENCES OF CHRONIC KIDNEY DISEASE- DIURETICS AND VOLUME MANAGEMENT • Until patients become dialysis dependent, diuretic therapy is a mainstay of fluid and volume management. • When used as single agents, thiazides lose much of their diuretic efficacy after GFR falls to below 20 to 30 mL per minute. • At this point, loop diuretics such as furosemide, bumetanide, and torsemide become drugs of choice in maintaining volume balance.
- 37. Chronic Renal Failure •These agents enter the urine through tubular secretion, producing dose-dependent diuretic responses that require a “threshold” urinary concentration to be present • In patients with CKD, drug entry into urine and at the site of action is impaired • Administration of doses two to ten times higher than those given to patients with normal renal function may be required to produce a comparable diuretic response
- 38. Chronic Renal Failure Pharmacotherapy ANEMIA •Before the introduction of recombinant human erythropoietin (epoetin alfa [EPO]) in the late 1980s, anabolic steroids and red cell transfusions were the primary modalities by which anemia was treated in the CRD population • The synthesis of epoetin revolutionized anemia management in the ESRD population, but despite more than a decade of clinical use, opinions are still evolving regarding the most appropriate manner of EPO use, optimal therapeutic hemoglobin (or hematocrit) goals, and their associated risk-benefit ratios
- 39. Chronic Renal Failure •Epoetin alfa, a recombinant molecule with the same structure as endogenous erythropoietin, is manufactured under two name brands (Procrit, Epogen) • This modification gives darbepoetin [also known as a novel erythropoiesis-stimulating protein (NESP)], an increased half-life compared with epoetin alfa. • This characteristic allows it to be dosed less frequently than epoetin was traditionally dosed
- 40. Chronic Renal Failure •All three products have the same mechanism of action—stimulation of the production and differentiation of erythrocytes. • Procrit and Epogen are the same molecule but with different FDA-approved indications. • Only Epogen and Aranesp are approved for the treatment of patients with anemia of chronic kidney disease
- 41. Chronic Renal Failure Pharmacotherapy BLEEDINGAND HEMOSTATIC DEFECTS • In the absence of clinical bleeding or in situations of increased risk for bleeding (e.g., invasive or surgical procedures), no specific therapy is required • Bleeding diathesis may be reduced by adequate treatment of patients in the uremic state through hemodialysis or peritoneal dialysis, and by avoidance of unnecessary agents with antiplatelet effects • Through EPO therapy (or transfusion), correction of hematocrit to levels to above 30% may help enhance platelet–endothelium interactions. • Although the benefit has largely been attributed to improved intravascular dispersion of platelets by red blood cell (RBC) mass, EPO has been proposed to increase the expression of platelet membrane GPIIb-IIIa receptors.
- 42. Chronic Renal Failure Pharmacotherapy •Acute treatment for severe bleeding necessitates RBC transfusion and, in life-threatening circumstances, administration of cryoprecipitate • The role of platelet transfusion is more controversial, given that repeated platelet transfusions are likely to promote the development of antiplatelet antibodies • Moreover, platelets transfused into uremic environment are thought to become deficient in function, in the manner described in earlier sections for native platelets • Relatively rapid improvements in bleeding time can be produced in most uremic patients through the administration of desmopressin (DDAVP) 0.3 µg per kg by IV infusion
- 43. Chronic Renal Failure Pharmacotherapy GASTROINTESTINALCOMPLICATIONS • Antacids were once used heavily in patients with CKD for relief of dyspepsia or gastrointestinal irritation. In the setting of renal insufficiency, many of these agents present potential problems. Bicarbonate-based products may cause the inadvertent administration of large sodium loads, but they may be useful in controlling metabolic acidosis • When magnesium-containing antacids or cathartics are given on a long-term basis to patients with renal failure, accumulation of magnesium becomes a concern, as creatinine clearance falls to below 30 mL per minute
- 44. Chronic Renal Failure Pharmacotherapy •Serum magnesium levels may rise to above 6 mEq per L (3 mmol/L), leading to central nervous system depression, lethargy, somnolence, and loss of deep tendon reflexes • Dialysis removes magnesium effectively and may be indicated in cases of severe toxicity. • long-term use of aluminum-based antacids or phosphate binders may lead to aluminum intoxication syndromes
- 45. Chronic Renal Failure Pharmacotherapy UREMICPRURITUS • The uremic milieu and the use of dialyzer membranes that are less biocompatible have been implicated in the pathogenesis of uremic pruritus (UP) • This appears to be true, and with the improvements in hemodialysis adequacy and more compatible dialyzer membranes, a decrease in the incidence of pruritus has been reported
- 46. Chronic Renal Failure Pharmacotherapy •Still, UP is a significant issue, especially in the dialysis population. • A variety of topical and systemic therapies have been reported as beneficial in reducing or relieving uremic pruritus • Unfortunately, none of these has proved uniformly effective, often necessitating a trial-and-error approach
- 47. Chronic Renal Failure Pharmacotherapy MUSCULOSKELETALCOMPLAINTS • Control of acute gouty attacks is often achieved through cautious use of traditional agents such as NSAIDs (e.g., indomethacin) and colchicine. • Upon initiation of an NSAID, patients should be monitored closely for bleeding, worsened renal function, and loss of diuretic efficacy • Allopurinol, which decreases uric acid production, is the preferred prophylactic agent because it possesses an active metabolite (oxypurinol) that is renally eliminated; doses are usually reduced to 100 to 200 mg daily in advanced CKD
- 48. Chronic Renal Failure PATIENTEDUCATION • Patients with advanced renal disease are expected to understand and follow complex dietary, medication, and physical care regimens • Data indicate that intense educational effort in ESKD is associated with increased patient autonomy, improved quality of life, increased compliance with therapies, and clinician ability to delay initiation of dialysis • The need for renal replacement therapy (RRT) can often be predicted more than 1 year in advance, providing ample opportunity for early education of patients who face ESKD (and their caregivers)
- 49. Chronic Renal Failure PATIENTEDUCATION • Educational programs generally emphasize patient comprehension of: – The most common complications of kidney disease (anemia, bone disease, hypertension), – Measures to slow progression of renal disease (if still feasible), – Dietary management (protein, phosphorus, potassium, sodium, and fluid restrictions), – Medication management (reason for use, manner of use, and precautions), – Choice of rrt modality and physical preparation for this (e.G., Catheter or fistula placement, transplantation referral), – Options for medical care and prescription coverage, and – Possibilities for vocational support
- 50. Chronic Renal Failure PATIENTEDUCATION • Patient referral to a renal care specialty team may help ensure that the patient gains an adequate understanding of kidney disease and participates in decisions regarding options for renal replacement modality
- 51. Summary • The presenceof CKD confers a markedly increased risk of cardiovascular disease, and people with CKD often have other risk factors for heart disease, such as high blood lipids. • The most common cause of death in people with CKD is cardiovascular disease rather than kidney failure. • Aggressive treatment of hyperlipidemia is warranted. • Apart from controlling other risk factors, the goal of therapy is to slow down or halt the progression of CKD to stage 5. • Control of blood pressure and treatment of the original disease, whenever feasible, are the broad principles of management. Generally, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are used, as they have been found to slow the progression of CKD to kidney failure