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This document discusses the pharmacotherapy of chronic renal failure. It begins by defining chronic renal failure and classifying the stages of chronic kidney disease. It then discusses the epidemiology, risk factors, pathophysiology, clinical manifestations, complications, and investigations of chronic renal failure. Management of chronic renal failure focuses on slowing progression of the disease.

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PHARMACOTHERAPY OF CHRONIC RENAL FAILURE 1 4/12/2022 By Belayneh K. Belayneh K.(B.Pharm., M.Pharm., RPh.) Clinical Pharmacy Course Team Department of Pharmacy, CMHS, Bahir Dar University Email: bkefale5@gmail.com
Outline of presentation • Definition CRF • Classifications • Epidemiology • Risk factors • Pathophysiology • Clinical manifestations • Complications • Investigations • Management 2 4/12/2022 By Belayneh K.
Chronic Renal failure • The kidney is made up of approximately 2 million nephrons that are responsible for filtering, reabsorbing & excreting solutes & water • As the number of functioning nephrons declines, the primary functions of the kidney are affected 3 4/12/2022 By Belayneh K.
Primary functions of the kidney • Production & secretion of erythropoietin • Activation of vitamin D • Regulation of fluid and electrolyte balance • Regulation of acid-base balance 4 4/12/2022 By Belayneh K.
Chronic kidney diseases/Chronic renal failure • Defined as the presence of kidney damage –Usually detected as urinary albumin excretion of 30 mg/day or more or • Decreased kidney function – GFR <60 mL/min for three or more months, irrespective of the cause • Is a progressive decline in kidney function that occurs over a period of several months to years • Also known as chronic renal insufficiency, progressive kidney disease 5 4/12/2022 By Belayneh K.
Chronic kidney diseases • The persistence of the damage or • Decreased function • Is necessary to distinguish CKD from acute kidney disease 6 for at least 3 months 4/12/2022 By Belayneh K.
Estimation of GFR • GFR can be estimated using equation from the modification of diet in renal disease study 7 4/12/2022 By Belayneh K.
Estimating creatinine clearance: Cockcroft-Gault formula • Creatinine clearance (ml/min) = [(140-age) x (weight in kg)] x 0.85 (if female) [(72) x (serum creatinine in mg/dL)] • Creatinine clearance (ml/min)= [(140-age) x (weight in kg)] x1.23)x 0.85 (if female) (serum creatinine in micromol/L) 8 4/12/2022 By Belayneh K.
Chronic kidney disease (CKD) • According to the NKF, normal GFR results range from 90-120 mL/min/1.73 m2 • Older people will have lower than normal GFR levels, because GFR decreases with age • Levels <60 mL/min for 3 or more months are a sign of chronic kidney disease • A GFR <15 mL/min is a sign of kidney failure & requires immediate medical attention 9 4/12/2022 By Belayneh K.
10 Classification of chronic renal failure 4/12/2022 By Belayneh K.
Chronic kidney disease (CKD) • The decline in kidney function is often irreversible –Therefore, measures to treat CKD are aimed at slowing the progression to end-stage renal disease 11 4/12/2022 By Belayneh K.
Epidemiology • A worldwide public health problem • The prevalence increases with age • Greater in females 12 4/12/2022 By Belayneh K.
Risk factors for CKD • Because of the progressive nature of CKD, determination of risk factors for CKD is difficult • Susceptibility factors –Associated with an increased risk of developing CKD, but are not directly proven to cause CKD –are generally not modifiable by pharmacologic therapy or lifestyle modifications 13 4/12/2022 By Belayneh K.
Risk factors for CKD • Initiation factors – directly cause CKD – are modifiable by pharmacologic therapy • Progression factors – which result in a faster decline in kidney function & cause worsening of CKD – may also be modified by pharmacologic therapy or lifestyle modifications to slow the progression of CKD 14 4/12/2022 By Belayneh K.
15 4/12/2022 By Belayneh K.
Susceptibility Factors • Can be readily used to develop screening programs for CKD • Advanced age • Reduced kidney mass • Family history of kidney disease • Systemic inflammation • Dyslipidemia 16 4/12/2022 By Belayneh K.
Susceptibility Factors • Hyperlipidemia – Patients with CKD have a higher prevalence of dyslipidemia compared to the general population – Manifested as an elevation in total cholesterol, LDL-C & triglycerides levels – Decreases in high HDL-C levels – Mounting evidence suggests that hyperlipidemia can promote renal injury & subsequent progression of CKD. 17 4/12/2022 By Belayneh K.
Susceptibility Factors • Hyperlipidemia can promote renal injury & subsequent progression of CKD – Lipid deposition causes activation of macrophages & monocytes – Secrete growth factors that stimulate cell proliferation and oxidation of lipoproteins. – Endothelial dysfunction, cellular injury & fibrosis in the kidney 18 4/12/2022 By Belayneh K.
Initiation Factors • Diabetes mellitus • Hypertension • Glomerulonephritis • Account for about 75% of the cases of CKD –(37% for diabetes, 24% for HTN & 14% for glomerulonephritis) most common causes of CKD 19 4/12/2022 By Belayneh K.
Initiation Factors • Autoimmune disease • Polycystic kidney disease • Drug toxicity • Urinary tract abnormalities (infections, obstruction, stones) 20 4/12/2022 By Belayneh K.
Initiation Factors • Diabetes mellitus –The most common cause of CKD –The risk of developing nephropathy associated with DM is closely linked to hyperglycemia –Risk of nephropathy is slightly higher in patients with type II DM 21 4/12/2022 By Belayneh K.
Initiation Factors • Hypertension –The second most common cause of CKD –More difficult to determine the true risk of developing CKD in patients with hypertension because the two are so closely linked, with CKD also being a cause of hypertension –Risk of developing ESRD is linked to both systolic & diastolic blood pressure 22 4/12/2022 By Belayneh K.
Initiation Factors • Hypertension • The prevalence of HTN is correlated with the degree of renal dysfunction With 40% of patients with CKD stage I 55% of patients with CKD stage II >75% of patients with CKD stage III presenting with HTN 23 4/12/2022 By Belayneh K.
Progression Factors • Can be used as predictors of CKD • Hyperglycemia: Poor blood glucose control (in patients with DM) • Hypertension • Proteinuria • Tobacco smoking 24 4/12/2022 By Belayneh K.
Progression Factors • Proteinuria –The presence of protein in the urine is a marker of glomerular & tubular dysfunction and is recognized as an independent risk factor for the progression of CKD –The degree of proteinuria correlates with the risk for progression 25 4/12/2022 By Belayneh K.
Progression Factors • Elevated Blood Pressure –Contribute to glomerular damage –Decline in GFR 26 4/12/2022 By Belayneh K.
Progression Factors • Elevated Blood Glucose – The rxn b/n glucose & protein in the blood produces advanced glycosylation end-products (AGEs), which are metabolized in the proximal tubules – Hyperglycemia increases the synthesis of AGEs in patients with diabetes & the corresponding increase in metabolism is suspected to be a cause of nephropathy associated with diabetes 27 4/12/2022 By Belayneh K.
Progression Factors • Tobacco Smoking –Induces glomerular hyperfiltration, produces an antidiuretic action that increases blood pressure –Can damage the proximal tubule –Increase platelet activity & thromboxane A2 production –These effects are related to the amount of cigarettes smoked, in terms of pack years 28 4/12/2022 By Belayneh K.
Pathophysiology of CKD • A number of factors can cause initial damage to the kidney • Damage results in loss of nephron mass. • Hypertrophy of the remaining nephrons to compensate for the loss of renal function & nephron mass • Adaptive changes result in an increase in glomerular filtration & tubular function in the remaining nephrons 29 4/12/2022 By Belayneh K.
Pathophysiology of CKD • Initially, these adaptive changes preserve many of the clinical parameters of renal function • As time progresses, glomerular capillary pressure is increased, mediated by AG II • Angiotensin II is a potent vasoconstrictor of both the afferent & efferent arterioles, but has a preferential effect to constrict the efferent arteriole, thereby increasing the pressure in the glomerular capillaries 30 4/12/2022 By Belayneh K.
Pathophysiology of CKD • Increased glomerular capillary pressure expands the pores in the glomerular basement membrane allowing proteins to be filtered through the glomerulus • Filtered proteins are reabsorbed in the renal tubules, which activates the tubular cells to produce inflammatory & vasoactive cytokines & triggers complement activation 31 4/12/2022 By Belayneh K.
Pathophysiology of CKD • These in turn cause interstitial damage & scarring within the renal tubules, leading to damage and loss of more nephrons • Ultimately, the process leads to progressive loss of nephron mass to the point where the remaining nephrons are no longer able to maintain clinical stability & renal function declines 32 4/12/2022 By Belayneh K.
Figure: Proposed mechanisms for progression of renal disease 33 4/12/2022 By Belayneh K.
Clinical manifestations • Stages 1 and 2 CKD are generally asymptomatic. • Stages 3 and 4 CKD may be associated with minimal symptoms. 34 4/12/2022 By Belayneh K.
Clinical manifestations 35 4/12/2022 By Belayneh K.
Clinical manifestations • Polyuria & nocturia – Patient frequently voids high volumes of urine, is often seen in CKD and results from medullary damage & the osmotic effect of a high serum urea level (>40 mmol/L) – The ability to concentrate urine is also lost in CKD which together with failure of physiological nocturnal antidiuresis results in nocturia – “foaming” of urine (indicative of proteinuria) 36 4/12/2022 By Belayneh K.
Clinical manifestations • Proteinuria – the prevalence of proteinuria increases with the severity of CKD – Pronounced proteinuria (>1 g of protein in a 24-h collection) usually indicates a glomerular etiology. • Hematuria – likely to result from lower urinary tract pathology (such as bladder lesions) & glomerular origin 37 4/12/2022 By Belayneh K.
Clinical manifestations • Hypertension & fluid overload –Severe renal impairment leads to sodium retention, which in turn produces circulatory volume expansion with consequent hypertension 38 4/12/2022 By Belayneh K.
Clinical manifestations • Uraemia – Many substances including urea, creatinine are normally excreted by the kidney & accumulate as renal function decreases – There are a wide range of uraemic toxins but it is the blood level of urea that is often used to estimate the degree of toxin accumulation in uraemia. – True symptomatic uraemia only occurs in very advanced CKD. 39 4/12/2022 By Belayneh K.
Clinical manifestations • Uraemia –The symptoms include anorexia, nausea, vomiting, constipation, foul taste –Pruritus without an underlying rash –In extremely severe cases, crystalline urea is deposited on the skin (uraemic frost) 40 4/12/2022 By Belayneh K.
Uremic frost 41 4/12/2022 By Belayneh K.
• Anaemia –A common consequence of CKD and affects most people with CKD stages 4 and 5 –The fall in haemoglobin level is a slow, insidious process accompanying the decline in renal function 42 4/12/2022 By Belayneh K.
Factors contribute to the pathogenesis of anemia in CKD • Shortened red cell survival, marrow suppression by uraemic toxins • Iron or folate deficiency associated with poor dietary intake or increased loss, for example, from gastro - intestinal bleeding • Principal cause results from damage of peritubular cells leading to inadequate secretion of erythropoietin • Hyperparathyroidism also reduces erythropoiesis by damaging bone marrow & therefore exacerbates anaemia associated with CKD 43 4/12/2022 By Belayneh K.
• Bone disease (renal osteodystrophy) –Secondary hyperparathyroidism –Osteomalacia (reduced mineralisation) –Mixed renal osteodystrophy (both hyperparathyroidism & osteomalacia) –Adynamic bone disease (reduced bone formation & resorption) 44 4/12/2022 By Belayneh K.
Fig. Disturbance of Phosphate & calcium balance in chronic renal failure 45 4/12/2022 By Belayneh K.
• Neurological changes • Probably caused by uraemic toxins –Inability to concentrate –Memory impairment –Irritability stupor 46 4/12/2022 By Belayneh K.
• Muscle function –Muscle symptoms are probably caused by general nutritional deficiencies and electrolyte disturbances, notably of divalent cations and especially by hypocalcaemia –Muscle cramps & restless legs 47 4/12/2022 By Belayneh K.
Electrolyte disturbances • Potassium –Can be elevated in CKD –Hyperkalaemia is a potentially dangerous condition as the first indication of elevated potassium levels may be life-threatening cardiac arrest –Potassium levels of over 7.0 mmol/L are life-threatening & should be treated as an emergency 48 4/12/2022 By Belayneh K.
Electrolyte disturbances • Hydrogen ions –A common end-product of many metabolic processes –In renal failure, H+ is retained, causing acidosis 49 4/12/2022 By Belayneh K.
Complications of CKD • Fluid and electrolyte disorders • Anemia • Metabolic bone disease 50 4/12/2022 By Belayneh K.
Investigations • Physical examination – Signs of anaemia – Whitening of the skin with crystalline urea („uraemic frost‟) – Ankle oedema & a raised jugular venous pressure suggest fluid retention – Fishy smell on the breath known as „uraemic fetor – In some patients, the kidneys may be palpable – Change of urine color (froth excessively in proteinuria) 51 4/12/2022 By Belayneh K.
Investigations • The primary marker of structural kidney damage is proteinuria, even in patients with normal GFR • Clinically significant proteinuria is defined as urinary protein excretion >300 mg/day • Microalbuminuria is defined as 30-300 mg of albumin excreted in the urine per day 52 4/12/2022 By Belayneh K.
Investigations • Laboratory Tests –Stages 1 and 2 CKD: Increased blood urea nitrogen (BUN) & serum creatinine (SCr) and decreased GFR –Stages 3, 4, and 5 CKD: Increased BUN & SCr; decreased GFR. 53 4/12/2022 By Belayneh K.
Laboratory Tests • Advanced stages: –Hyperkalaemia –Hypocalcaemia –Hyperphosphataemia –Decreased bicarbonate (metabolic acidosis) –Decreased albumin, if inadequate nutrition intake 54 4/12/2022 By Belayneh K.
Laboratory Tests • Decreased RBC count, hemoglobin & hematocrit (Hct) • Erythropoietin levels are not routinely monitored & are generally normal to low • Urine positive for albumin or protein. • Increased parathyroid hormone (PTH) level • Decreased vitamin D levels (stages 4 or 5 CKD) 55 4/12/2022 By Belayneh K.
Management of CKD • Non-pharmacologic Therapy • Pharmacologic Therapy 56 4/12/2022 By Belayneh K.
Goals of therapy in CKD • To slow & prevent the progression of CKD • To treat the secondary complications of CKD • To relieve symptoms 57 4/12/2022 By Belayneh K.
Non-pharmacological treatment • Potassium restriction –Dietary K+ restriction = 50–80mEq/d –Advise patient to limit intake of high K+ containing foods (e.g., bananas, avocados, tomatoes, orange juice, oranges) –K+ sparing diuretics (e.g., spironolactone, eplerenone), ACEI, ARB, β-blocking agents may ↑K+ 58 4/12/2022 By Belayneh K.
Non-Pharmacological treatment • Sodium restriction –<2.0 g/d if on HD: <2.4g/d in adult patients with CKD & HTN, further restriction may be necessary if significant fluid overload, cardiac problems, or concurrent liver disease • Phosphate restriction –Restrict dietary phosphorus to 800– 1000mg/d –Milk, meat, beans 59 4/12/2022 By Belayneh K.
Non-pharmacological treatment • Reduction in dietary protein intake –Slow the progression of kidney disease –Must be balanced with the risk of malnutrition in patients with CKD –Patients with a GFR <25 mL/minute received the most benefit from protein restriction –Patients with a GFR >25 mL/minute should not restrict protein intake 60 4/12/2022 By Belayneh K.
Non-pharmacological treatment • The NKF recommends that patients who are not receiving dialysis, should restrict protein intake to 0.6 g/kg per day • If patients are not able to maintain adequate dietary energy intake, protein intake may be increased up to 0.75 g/kg/day • Patients receiving dialysis should maintain protein intake of 1.2-1.3 g/kg/day 61 4/12/2022 By Belayneh K.
Non-pharmacological treatment • Smoking Cessation • May be a practical approach to slow the progression of CKD • Does not reverse existing renal dysfunction in former smokers. 62 4/12/2022 By Belayneh K.
Pharmacological management of CKD • Intensive Blood Glucose Control (for Patients with Diabetes) –Administration of insulin three or more times daily • to maintain preprandial blood glucose levels b/n 70-120 g/dL • postprandial blood glucose levels <180 g/dL • decrease the incidence of proteinuria & albuminuria in patients with diabetes, both with & without documented nephropathy 63 4/12/2022 By Belayneh K.
Pharmacological management of CKD • Optimal Blood Pressure Control • Goal BP in CKD –Stages 1-4 CKD <130/80 mmHg –Stage 5 CKD • Patients who are receiving hemodialysis <140/90 mmHg before hemodialysis & <130/80 after hemodialysis NKF recommendation 64 4/12/2022 By Belayneh K.
Optimal Blood Pressure Control • Reductions in BP are associated with a decrease in proteinuria • A decrease in the rate of progression of kidney disease • Three or more agents are generally required to achieve the blood pressure goal of <130/80 mm Hg in CKD patients 4/12/2022 By Belayneh K.
Reduction in Proteinuria • ACEIs & ARBs –Decrease glomerular capillary pressure & volume because of their effects on angiotensin II –This, in turn, reduces the amount of protein filtered through the glomerulus, which ultimately decreases the progression of CKD –Greater reduction in proteinuria (35-40%) as compared to other anti-hypertensive agents • Hence, the antihypertensive agents of choice for all patients with CKD 66 4/12/2022 By Belayneh K.
Reduction in Proteinuria • ACEIs & ARBs – All patients with documented proteinuria should receive regardless of BP –B/C diabetes is associated with an early onset of microalbuminuria, all patients with diabetes should also receive an ACE-I or ARB, regardless of BP 67 4/12/2022 By Belayneh K.
ACEIs & ARBs • Enalapril – Initial: 2.5-5 mg PO qDay – Maintenance: 10-40 mg/day PO qDay or divided q12hr – 1.25 mg/dose IV over 5 minutes q6hr; doses up to 5 mg/dose IV q6hr have been administered – CrCl <30 mL/min: (IV) Initiate 0.625 mg q6hr; titrate based on response – CrCl <30 mL/min: (PO) Initiate 2.5 mg; titrate to response; not to exceed 40 mg • Losartan: 50-100 mg PO qDay 68 4/12/2022 By Belayneh K.
Outcome Evaluation • Monitor serum Cr, K+ levels & BP within 1 week after initiating ACEI or ARBs therapy • Discontinue the medication & switch to another agent if – A sudden increase in Serum Cr>30% occurs – Hyperkalemia develops – The patient becomes hypotensive • Titrate the dose of the ACE-I or ARB every 1-3 months to the maximum tolerable dose • If BP is not reduced to <130/80 mm Hg, add another agent to the regimen 69 4/12/2022 By Belayneh K.
Figure: Hypertension management algorithm for patients with CKD 70 4/12/2022 By Belayneh K.
Figure: Hypertension management algorithm for patients with CKD 71 4/12/2022 By Belayneh K.
Management of complications of CKD • Mgt of impaired Na+& Water Homeostasis • Impaired K+ Homeostasis • Anemia of CKD • Secondary Hyperparathyroidism & Renal Osteodystrophy • Metabolic Acidosis • Uremic Bleeding • Pruritus 72 4/12/2022 By Belayneh K.
Impaired Na+& Water Homeostasis • Sodium & water balance are primarily regulated by the kidney • Reductions in nephron mass decrease glomerular filtration & subsequent reabsorption of sodium and water, leading to edema • The inability of the kidney to concentrate the urine results in nocturia in patients with CKD, usually presenting as early as stage 3 CKD. 73 4/12/2022 By Belayneh K.
Clinical Presentation of impaired Na+& Water Homeostasis • Symptoms – Nocturia can present in stage 3 CKD. – Edema generally presents in stage 4 CKD or later • Signs – Cardiovascular: Worsening hypertension, edema. – Genitourinary: Change in urine volume and consistency. • Laboratory Tests – Increased blood pressure – Sodium levels remain within the normal range 74 4/12/2022 By Belayneh K.
Mgt of impaired Na+& Water Homeostasis • Pharmacologic Therapy • Diuretic therapy – Is often necessary to prevent volume overload in patients with CKD – Loop diuretics (lasix 20-80 mg PO/day) are most frequently used to increase sodium & water excretion – Thiazide diuretics are ineffective when used alone in patients with a GFR <30 mL/minute – dose: Hydrochlorothiazide 25-100mg Po/day – As CKD progresses, higher doses or continuous infusion of loop diuretics may be needed, or combination therapy with loop and thiazide diuretics to increase sodium and water excretion. 75 4/12/2022 By Belayneh K.
Mgt of impaired Na+& Water Homeostasis Outcome Evaluation • Monitor edema after initiation of diuretic therapy • Monitor fluid intake to ensure obligatory losses are being met and avoid dehydration • If adequate diuresis is not attained with a single agent, consider combination therapy with another diuretic 76 4/12/2022 By Belayneh K.
Impaired K+ Homeostasis • K+ balance is primarily regulated by the kidney via the distal tubular cells –It secrete 90-95% of the daily dietary intake of K+ • Reduction in nephron mass decreases tubular secretion of K+, leading to hyperkalemia. • Hyperkalemia is estimated to affect > 50% of patients with stage 5 CKD 77 4/12/2022 By Belayneh K.
Impaired K+ Homeostasis • As nephron mass decreases, both the distal tubular secretion & GI excretion are increased b/c of aldosterone stimulation • This maintins serum K+ concentrations within the normal range through stages 1-4 CKD • Hyperkalemia begins to develop when – GFR falls <20% of normal – When nephron mass & renal K+ secretion is so low that the capacity of the GI tract to excrete potassium has been exceeded 78 4/12/2022 By Belayneh K.
Medications that can increase the risk of hyperkalemia in patients with CKD • ACEI • ARBS • K+ sparing diuretics, used for the treatment of edema and chronic heart failure • should be used with caution in patients with stage 3 CKD or higher used for the treatment of proteinuria and hypertension. 79 4/12/2022 By Belayneh K.
Impaired K+ Homeostasis • Symptoms –Mild hyperkalemia is generally not associated with overt symptoms. • Signs –Cardiovascular: ECG changes • Laboratory Tests –Increased serum K+ levels (>5.5 mEq/L) 80 4/12/2022 By Belayneh K.
Impaired K+ Homeostasis • Non-Pharmacological therapy –Patients should avoid abrupt increases in dietary intake of K+ –Severe hyperkalemia is most effectively managed by hemodialysis 81 4/12/2022 By Belayneh K.
Impaired Potassium Homeostasis • Pharmacologic Therapy – Patients who present with cardiac abnormalities caused by hyperkalemia should receive calcium gluconate or chloride (1gm IV) to reverse the cardiac effects • Temporary shift of EC K+ into the IC compartment to stabilize cellular membrane – regular insulin (5-10 units IV) – 50ml of 50% dextrose (IV) – nebulized albuterol (10-20 mg) • These measures will decrease serum K+ levels within 30-60 minutes after treatment 82 4/12/2022 By Belayneh K.
Impaired K+ Homeostasis • Pharmacologic Therapy • Sodium polystyrene sulfonate – 15-30 gm/day PO – A sodium-potassium exchange resin – Promotes potassium excretion from the GI tract. – The onset of action is within 2 hours – Maximum effect on K+ levels may not be seen for up to 6 hours which limits the utility in patients with severe hyperkalemia. 83 4/12/2022 By Belayneh K.
Impaired K+ Homeostasis • Pharmacologic Therapy • loop diuretics (lasix 40-80mg IV) – often used to decrease K+ levels in patients with normal or mildly decreased kidney function, but are not useful in patients with stage 5 CKD to decrease K+ concentrations • Fludrocortisone – increases K+ excretion in the distal tubules & through the GI tract – However, it causes significant Na+ & water retention, which exacerbates edema & hypertension, and may not be tolerated by many CKD patients 84 4/12/2022 By Belayneh K.
Outcome Evaluation • Monitor ECG continuously in patients with cardiac abnormalities until serum K+ levels drop <5 mEq/L or cardiac abnormalities resolve • Evaluate serum K+ & glucose levels within 1hr in patients who receive insulin & dextrose therapy • Evaluate serum K+ levels within 2-4 hrs after treatment with SPS or diuretics • Repeat doses of diuretics or SPS if necessary until serum potassium levels fall < 5 mEq/L • Monitor BP & serum K+ levels in 1 week in patients who receive fludrocortisone 85 4/12/2022 By Belayneh K.
Anemia in CKD • Kidney produce 90% of the hormone erythropoietin (EPO), which stimulates RBC production • Patients with CKD should be evaluated for anemia when the GFR falls below 60 mL/min • Reduction in nephron mass decreases renal production of EPO, which is the primary cause of anemia in patients with CKD • Anemia decreases oxygen delivery to the renal tubules, promoting the release of inflammatory & vasoactive cytokines, which contribute to the progression of CKD 86 4/12/2022 By Belayneh K.
Anemia in CKD • The development of anemia of CKD results in –decreased oxygen delivery & utilization –increased cardiac output & left ventricular hypertrophy –increase the cardiovascular risk & mortality in patients with CKD. 87 4/12/2022 By Belayneh K.
Anemia in CKD • The prevalence is correlated with the degree of renal dysfunction • The risk of developing anemia increases as GFR declines –doubling for patients with stage 3 CKD –increasing to 3.8-fold in patients with stage 4 CKD –to 10.5-fold for patients with stage 5 CKD 88 4/12/2022 By Belayneh K.
Causes Anemia in CKD • Decrease in EPO production – The primary cause of anemia in patients with CKD • Uremia – A result of declining renal function, decreases the lifespan of RBCs from a normal of 120 days to as low as 60 days in patients with stage 5 CKD • Iron deficiency & blood loss from regular laboratory testing & hemodialysis 89 4/12/2022 By Belayneh K.
Clinical Presentation of Anemia of CKD • General – presents with fatigue & decreased quality of life. • Symptoms – cold intolerance, shortness of breath, and decreased exercise capacity. • Signs – Cardiovascular: Left ventricular hypertrophy, ECG changes, congestive heart failure – Neurologic: Impaired mental cognition – Genitourinary: Sexual dysfunction • Laboratory Tests – Decreased RBC count, Hgb (<11 g/dL) and Hct – Decreased erythropoietin levels 90 4/12/2022 By Belayneh K.
Management of anemia in CKD • Goal of treatment –to increase Hgb levels >11 g/dL 91 4/12/2022 By Belayneh K.
Management of anemia in CKD • Iron Supplementation – The first-line treatment for anemia of CKD involves replacement of iron stores with iron supplements – When iron supplementation alone is not sufficient to increase Hgb levels, ESAs are necessary to replace erythropoietin – May be indicated if Hgb levels are below the goal level, but avoided if the patient is infected. 92 4/12/2022 By Belayneh K.
Management of anemia in CKD • Iron supplementation • Use of ESAs increases the iron demand for RBC production & iron deficiency is common – Requiring iron supplementation to correct & maintain adequate iron stores to promote RBC production • Oral iron supplements are the 1st line treatment for iron supplementation for patients with CKD not receiving hemodialysis • When administering iron by the oral route, 200 mg of elemental iron should be delivered daily to maintain adequate iron stores 93 4/12/2022 By Belayneh K.
Management of anemia in CKD • Oral iron supplementation is generally not effective in maintaining adequate iron stores in patients receiving ESAs because of: –poor absorption –an increased need for iron with ESA therapy, making the IV route necessary for iron supplementation • give a total of 1g of IV iron, divided doses 94 4/12/2022 By Belayneh K.
Management of anemia in CKD • Maintenance doses are often used in patients receiving hemodialysis • Maintenance doses consist of smaller doses of iron administered weekly or with each dialysis session (e.g., iron dextran or iron sucrose 20-100 mg/week; sodium ferric gluconate 62.5-125 mg/week) • IV iron preparations are equally effective in increasing iron stores 95 4/12/2022 By Belayneh K.
Management of anemia in CKD • Anaphylaxis may occur with all IV preparations, but most notably with iron dextran • A test dose of 25 mg iron dextran should be administered 30 minutes before the full dose to monitor for potential anaphylactic reactions • After administering a 1-g course of IV iron, iron status should be monitored to determine the effectiveness of the treatment. • Serum ferritin and TSat should be monitored no sooner than 1 week after the last dose of IV iron • If Hgb does not increase after a course of IV iron, an additional 1 g of IV iron may be administered 96 4/12/2022 By Belayneh K.
Management of anemia in CKD • Erythropoiesis stimulating agents (ESAs) –Abnormalities found during the anemia workup should be corrected before initiating ESAs, particularly iron deficiency –If Hgb is <10 when all other causes of anemia have been corrected, EPO deficiency should be assumed. –May be considered if Hgb levels remain persistently low to improve symptoms of anemia 97 4/12/2022 By Belayneh K.
Management of anemia in CKD • Erythropoiesis stimulating agents (ESAs) – Epoetin alfa (SC preferred): • 50-100 units/kg SC 2-3x per week – Darbepoetin alfa (IV or SC): • 0.45 mcg/kg once weekly – Use of this agents beyond 12 g/dL Hgb levels is associated with increased mortality – SC administration of ESA produces a more predictable & sustained response than IV administration – The maximum target Hgb should not exceed 11 g/dL 98 4/12/2022 By Belayneh K.
Erythropoiesis stimulating agents (ESAs): adverse effects • Increased blood pressure –May require antihypertensive agents to control BP • Seizures & pure red cell aplasia • Increased blood viscosity & hemoconcentration, which occurs when large amounts of fluid are removed during hemodialysis 99 4/12/2022 By Belayneh K.
100 Algorithm for management of anemia of CKD 4/12/2022 By Belayneh K.
101 4/12/2022 By Belayneh K.
Outcome Evaluation • Evaluate Hgb monthly when ESA therapy is initiated or the dose is adjusted to ensure Hgb does not exceed 11.5 g/dL • The ESA dose can increase monthly if Hgb is below goal. • Once a stable Hgb is attained, evaluate Hgb every 3 months thereafter. • While the patient is receiving ESA therapy, monitor iron stores at least every 3 months 102 4/12/2022 By Belayneh K.
Secondary Hyperparathyroidism & Renal Osteodystrophy • Increases in parathyroid hormone (PTH) occur early as renal function begins to decline • As many as 75-100% of patients with stage 3 CKD have renal osteodystrophy • High bone turnover is the most common cause of bone abnormalities in patients with CKD • As renal function declines in patients with CKD, decreased phosphorus excretion disrupts the balance of calcium & phosphorus homeostasis 103 4/12/2022 By Belayneh K.
Pathogenesis of Secondary Hyperparathyroidism & Renal Osteodystrophy in patients with CKD 104 FGF: Fibroblast growth factor 4/12/2022 By Belayneh K.
Clinical Presentation of secondary Hyperparathyroidism & Renal Osteodystrophy • Symptoms –Usually asymptomatic in early disease –Calcification in the joints can be associated with decreased range of motion –Conjunctival calcifications are associated with a gritty sensation in the eyes, redness, and inflammation 105 4/12/2022 By Belayneh K.
Clinical Presentation of secondary Hyperparathyroidism & Renal Osteodystrophy Signs • Cardiovascular: Increased HR, DBP & MAP • Musculoskeletal: Bone pain, muscle weakness • Dermatologic: Pruritus 106 4/12/2022 By Belayneh K.
Laboratory investigations • Increased serum phosphorus levels • Low to normal serum calcium levels • Increased Ca-P product • Increased PTH levels • Decreased vitamin D levels • Radiographic studies show calcium-phosphate deposits in joints and/or cardiovascular system 107 4/12/2022 By Belayneh K.
Management of secondary Hyperparathyroidism & Renal Osteodystrophy • Management of bone disease in CKD is based on –Corrected serum levels of calcium & phosphorus –The Ca-P –Intact PTH levels • The target levels of each vary with the stage of CKD 108 4/12/2022 By Belayneh K.
109 4/12/2022 By Belayneh K.
Management of secondary Hyperparathyroidism & Renal Osteodystrophy • Non-pharmacologic Therapy • Pharmacological therapy 110 4/12/2022 By Belayneh K.
Non-pharmacologic Therapy • Dietary phosphorus restriction to 800-1000 mg/day in patients with stage 3 CKD or higher who have phosphorus levels at the upper limit of the normal range or elevated iPTH levels • Foods high in phosphorus are also high in protein (meat, milk, legumes, carbonated beverages) –Which can make it difficult to restrict phosphorus intake while maintaining adequate protein intake to avoid malnutrition 111 4/12/2022 By Belayneh K.
Non-pharmacologic Therapy • Hemodialysis & peritoneal dialysis can remove up to 2-3 g of phosphorus per week – Insufficient to control hyperphosphatemia & pharmacologic therapy is necessary • Restriction of aluminum exposure – Ingestion of aluminum containing antacids & other aluminum-containing products should be avoided in patients with stage 4 CKD or higher b/c of the risk of Al toxicity & potential uptake into the bone 112 4/12/2022 By Belayneh K.
Non-pharmacologic Therapy • Parathyroidectomy –A portion or all of the parathyroid tissue may be removed –a treatment of last resort for sHPT –but should be considered in patients with persistently elevated PTH levels >800 pg/mL (800 ng/L) that is refractory to medical therapy 113 4/12/2022 By Belayneh K.
Pharmacological therapy • Phosphate-Binding Agents –used when serum phosphorus levels cannot be controlled by restriction of dietary intake –used to bind dietary phosphate in the GI tract to form an insoluble complex that is excreted in the feces –Phosphorus absorption is decreased, thereby decreasing serum phosphorus levels 114 4/12/2022 By Belayneh K.
Phosphate-Binding Agents • Calcium-based phosphate binders – calcium carbonate & calcium acetate, are effective in decreasing serum phosphate levels, as well as increasing serum calcium levels – Calcium citrate is usually not used as a phosphate binding agent because the citrate salt can increase Al absorption – Doses should not be >1500 mg of elemental calcium/ day – Total elemental calcium intake per day should not exceed 2000 mg, including medication and dietary intake – Adverse effects: constipation & hypercalcemia 115 4/12/2022 By Belayneh K.
116 4/12/2022 By Belayneh K.
sevelamer hydrochloride & lanthanum carbonate • Phosphate-binding agents that do not contain calcium, magnesium, or aluminum • Particularly useful in patients with hyperphosphatemia who have elevated serum calcium levels or who have vascular or soft tissue calcifications 117 4/12/2022 By Belayneh K.
Sevelamer • A cationic polymer that is not systemically absorbed and binds to phosphate in the GI tract, and prevents absorption and promotes excretion of phosphate through the GI tract via the feces • Has an added benefit of reducing LDL-C by up to 30% and increasing HDL-C levels • Adverse effects: nausea, constipation & diarrhea 118 4/12/2022 By Belayneh K.
119 4/12/2022 By Belayneh K.
120 4/12/2022 By Belayneh K.
Vitamin D Therapy • Exogenous vitamin D compounds that mimic the activity of calcitriol act directly on the parathyroid gland to decrease PTH secretion • Particularly useful when reduction of serum phosphorus levels does not sufficiently reduce PTH levels 121 4/12/2022 By Belayneh K.
Calcitriol • The active form of vitamin D • Effects are mediated by upregulation of the vitamin D receptor in the parathyroid gland – Which decreases parathyroid gland hyperplasia and PTH synthesis and secretion • Vitamin D receptor upregulation also occurs in the intestines – increases calcium & phosphorus absorption – increasing the risk of hypercalcemia & hyperphosphatemia 122 4/12/2022 By Belayneh K.
Calcitriol • Serum calcium & phosphorus levels should be within the normal range for the stage of CKD and the Ca-P product <55 mg2/dL2 prior to starting calcitriol therapy 123 4/12/2022 By Belayneh K.
Paricalcitol • Less effect on vitamin D receptors in the intestines –decreasing the effects on intestinal calcium & phosphorus absorption –more useful in patients with an elevated Ca-P product • Retaining the effects on parathyroid gland hyperplasia and PTH synthesis and secretion 124 4/12/2022 By Belayneh K.
Doxercalciferol • Has similar effects as calcitriol on vitamin D receptors in the parathyroid glands and intestines • Like calcitriol, calcium & phosphorus levels and the Ca-P product should be within the normal range for the stage of CKD prior to starting 125 4/12/2022 By Belayneh K.
126 4/12/2022 By Belayneh K.
Calcimimetics • Cinacalcet –a calcimimetic that increases the sensitivity of receptors on the parathyroid gland to serum calcium levels to reduce PTH secretion –may be beneficial in patients with an increased Ca-P product who have elevated PTH levels & cannot use vitamin D therapy 127 4/12/2022 By Belayneh K.
Cinacalcet • Should not be used if serum calcium levels are below normal – b/c of the effects on PTH can reduce serum calcium levels and result in hypocalcemia • dose: 30mg PO/day 128 4/12/2022 By Belayneh K.
Patient monitoring • phosphate-binding agents –Monitor serum calcium & phosphorus levels regularly –Monitor serum levels every 1-4 weeks depending on the severity of hyperphosphatemia –Once target levels are achieved, monitor serum calcium & phosphorus levels every 1-3 months 129 4/12/2022 By Belayneh K.
Patient monitoring • vitamin D therapy – Monitor intact PTH levels monthly while initiating, then every 3 months once stable iPTH levels are achieved. • cinacalcet – When starting or increasing the dose monitor serum Ca++& phosphorus levels within 1 week and iPTH levels should be monitored within 1-4 weeks – Once target levels are achieved, then monitor every 3 months 130 4/12/2022 By Belayneh K.
Metabolic Acidosis • The kidneys play a key role in acid-base homeostasis in the body by regulating excretion of H+ ions • With normal kidney function, HCO3- is freely filtered through the glomerulus & completely reabsorbed via the renal tubules • H+ ions generated during metabolism of ingested food are excreted at the same rate by the kidney 131 4/12/2022 By Belayneh K.
Metabolic Acidosis • As kidney function declines – Reduced HCO3- reabsorption – H+ ion excretion is decreased • The positive hydrogen balance leads to metabolic acidosis • As nephron function declines, production of NH3 is increased to compensate for a decrease in secretion of H+ions • Once the maximal capacity for NH3 production is reached, acidosis develops 132 4/12/2022 By Belayneh K.
Metabolic Acidosis • Approximately 80% of patients with a GFR <20- 30 mL/minute can develop metabolic acidosis • Can increase protein catabolism & decrease albumin synthesis • Can contribute to bone disease by promoting bone resorption 133 4/12/2022 By Belayneh K.
Management of Metabolic Acidosis • Treatment goal – normalizing the plasma bicarbonate concentration or at least achieving bicarbonate levels near ≥ 22 mEq/L • Pharmacologic therapy – use of preparations containing sodium bicarbonate or sodium citrate • Once dialysis starts, PO or IV bicarbonate is not required since the dialysate baths contain sodium bicarbonate 134 4/12/2022 By Belayneh K.
Management of Metabolic Acidosis • Each 650-mg tablet NaHCO3 provides 8 mEq of Na+ & 8 mEq of HCO3- • The use of two to four 650-mg NaHCO3 tablets per day, usually divided into 2-3 doses (0.5-1 meq/kg /day) • When determining the dose of bicarbonate replacement, the dose is usually determined by calculating the base deficit: =[0.5 L/kg × body weight] × [(normal value of 24 mEq/L) – (patient‟s serum bicarbonate value )]. 135 4/12/2022 By Belayneh K.
Management of Metabolic Acidosis • Because of the risk of volume overload resulting from the Na load administered with HCO3 replacement, the total base deficit should be administered over several days • After normalization, a maintenance regimen of HCO3- of 12-20 mEq/day in divided doses may be required • Titrate doses to maintain normal plasma bicarbonate concentrations thereafter 136 4/12/2022 By Belayneh K.
Management of Metabolic Acidosis • Sodium citrate – Citrate is rapidly metabolized to bicarbonate – May be used in patients who are unable to tolerate NaHCO3, since it does not produce the bloating associated with NaHCO3 therapy – Citrate also promotes Al absorption & should not be used in patients taking Al-containing agents 137 4/12/2022 By Belayneh K.
Patient monitoring • Monitor serum electrolytes & arterial blood gases regularly • Correct metabolic acidosis slowly to prevent the development of metabolic alkalosis or other electrolyte abnormalities 138 4/12/2022 By Belayneh K.
Uremic Bleeding • Urea is probably not the major platelet toxin • no predictable correlation b/n the BUN & the bleeding time in patients with renal failure • Studies in uremic patients have shown that platelet NO synthesis is increased & that uremic plasma stimulates NO production – NO is an inhibitor of platelet aggregation • The increase in NO synthesis may be due to elevated levels of guanidinosuccinic acid, a uremic toxin that may be a precursor for NO 139 4/12/2022 By Belayneh K.
Uremic Bleeding • Uremia can lead to a number of alterations in clotting ability, resulting in hemorrhage • Bleeding complications associated with CKD: –Ecchymoses –Prolonged bleeding from mucous membranes –GI bleeding, intramuscular bleeding 140 4/12/2022 By Belayneh K.
Uremic Bleeding • Uremia alters a number of mechanisms that contribute to bleeding • Platelet function & aggregation is altered through decreased production of thromboxane • Platelet–vessel wall interactions are also altered in patients with uremia b/c of decreased activity of von Willebrand factor 141 4/12/2022 By Belayneh K.
Management of Uremic Bleeding • Non-pharmacologic Therapy – Dialysis initiation improves platelet function & reduces bleeding time – hemodialysis or peritoneal dialysis can partially correct the bleeding time in approximately two- thirds of uremic patients • Pharmacologic Therapy – Cryoprecipitate – Desmopressin – Conjugtaed Estrogen 142 4/12/2022 By Belayneh K.
Cryoprecipitate • Contains various components important in platelet aggregation & clotting, such as von Willebrand factor & fibrinogen • Decreases bleeding time within 1hr in 50% of patients • Dose: 10 units IV every 12-24hrs • cost & the risk of infection have limited the use of cryoprecipitate 143 4/12/2022 By Belayneh K.
Desmopressin The vasopressin V2 receptor agonist causes release of von Willebrand factor (vWF) & factor VIII from endogenous storage sites Bleeding time is promptly reduced, within 1hr of administration & sustained for 4-8 hrs • Doses used for uremic bleeding – 0.3 - 0.4 mcg/kg IV over 20 - 30 minutes – 0.3 mcg/kg SC or – 2-3 mcg/kg intranasally 144 4/12/2022 By Belayneh K.
Conjugated Estrogens • Used to decrease bleeding time • Onset of action is slower than Desmopressin • Dose – 0.6 mg/kg IV daily for five days – 2.5-25 mg Po/ day for five days or – 50-100 microgram of transdermal patches twice weekly • IV administration – decreases bleeding time within 6 hours of administration & produces an effect that lasts up to 2 weeks after stopping therapy 145 4/12/2022 By Belayneh K.
Conjugated Estrogens • MOA –Not well understood –Preliminary studies suggest an increase in platelet reactivity may be important perhaps due to decreased generation of NO –estrogens act by reducing the production of L- arginine, the precursor of NO 146 4/12/2022 By Belayneh K.
Pruritus • Can affect 25-86% of patients with advanced stages of CKD • Not related to the cause of renal failure • Can be significant & has been linked to mortality in patients receiving hemodialysis 147 4/12/2022 By Belayneh K.
Pathophysiology of Pruritus in CKD • Cause is unknown, although several mechanisms have been proposed • Vitamin A is known to accumulate in the skin & serum of patients with CKD, but a definite correlation with pruritus has not been established • Histamine may also play a role in the development of pruritus, which may be linked to mast cell proliferation in patients receiving hemodialysis • Hyperparathyroidism has also been suggested as a contributor to pruritus, although serum PTH levels do not correlate with itching 148 4/12/2022 By Belayneh K.
Management of Pruritus in CKD • Non-Pharmacological therapy –Adequate dialysis (1st line of treatment) –Maintaining proper nutritional intake, especially with regard to dietary phosphorus and protein intake –Warming or cooling the skin using baths, three times weekly 149 4/12/2022 By Belayneh K.
Pharmacologic Therapy • Pharmacologic Therapy • Antihistamines (first line therapy) –hydroxyzine 25-50 mg or –diphenhydramine 25-50 mg Po • Cholestyramine –at doses of 5 g twice daily 150 4/12/2022 By Belayneh K.
Renal replacement therapy • Patients who progress to ESRD require renal replacement therapy • The modalities that are used for RRT are: –Dialysis: Heamodialysis (HD) & peritoneal dialysis (PD) –Kidney transplantation • The most common form of RRT is dialysis, accounting for 72% of all patients with ESRD 151 4/12/2022 By Belayneh K.
Indications for Dialysis • Dialysis is initiated in most patients when the GFR falls <15 mL/minute • Symptoms that may indicate the need for dialysis – persistent anorexia, nausea, vomiting, fatigue & pruritus • Other criteria that indicate the need for dialysis – declining nutritional status – declining serum albumin levels – uncontrolled hypertension – volume overload which may manifest as chronic heart failure – hyperkalemia – BUN & SCr 152 4/12/2022 By Belayneh K.
Haemodialysis 153 •a process that uses a man-made membrane (dialyzer) to: Remove wastes, such as urea, from the blood. 4/12/2022 By Belayneh K.
Haemodialysis • Involves the exposure of blood to a semipermeable membrane (dialyzer) against which a physiologic solution (dialysate) is flowing • The dialysate is composed of purified water & electrolytes • usually carried out for 3–5 hrs 3x weekly • Allows for the removal of several substances from the bloodstream, including water, urea, creatinine, uremic toxins & drugs 154 4/12/2022 By Belayneh K.
Haemodialysis • Although the dialysate is not sterilized, the membrane prevents bacteria from entering into the bloodstream. • If the membrane ruptures during hemodialysis, infection becomes a major concern for the patient 155 4/12/2022 By Belayneh K.
Concentrations of dialysate components used in hemodialysis Sodium (meq/L) 135 to 155 Potassium (meq/L) 0-4 Calcium (mmol/L) 1.25 to 1.75 (2.5 to 3.5 meq/L) Magnesium (mmol/L) 0 to 0.75 (0 to 1.5 meq/L) Chloride (meq/L) 87 to 120 Bicarbonate (meq/L) 25 to 40 Glucose (g/dL) 0 to 0.20 156 4/12/2022 By Belayneh K.
Advantages Hemodialysis • Higher solute clearance allows intermittent treatment • Efficient; 4 hrs three times per wk is usually adequate • The technique‟s failure rate is low 157 4/12/2022 By Belayneh K.
Disadvantages of Hemodialysis • Requires multiple visits each week to the hemodialysis center • May require months before patient adjusts to hemodialysis • Vascular access is frequently associated with infection & thrombosis • Decline of residual renal function is more rapid compared to peritoneal dialysis 158 4/12/2022 By Belayneh K.
Complications of Hemodialysis • Hypotension – due to fluid removal from the bloodstream. – Management • placing the patient in the Trendelenburg position (with the head lower than the feet) • administration of normal saline (100 to 200 mL) to restore intravascular volume • Myalgia – due to hypoperfusion of the muscles • Thrombosis • Infection – usually related to organisms found on the skin, namely Staphylococcus epidermidis & S. aureus 159 4/12/2022 By Belayneh K.
Vitamin Replacement • Water-soluble vitamins removed by hemodialysis (HD) contribute to malnutrition & vitamin deficiency syndromes • Patients receiving HD often require replacement of water soluble vitamins to prevent adverse effects • The vitamins that may require replacement are ascorbic acid, thiamine, biotin, folic acid, riboflavin, and pyridoxine 160 4/12/2022 By Belayneh K.
Vitamin Replacement • Patients receiving HD should receive a multivitamin B complex with vitamin C supplement • but should not take supplements that include fat- soluble vitamins, such as vitamins A, E, or K, which can accumulate in patients with renal failure 161 4/12/2022 By Belayneh K.
Renal transplantation • Offers the best chance of long-term survival in ESRD • Can restore normal kidney function and correct all the metabolic abnormalities of CKD • Compatibility of ABO blood group b/n donor and recipient is usually required • All patients with ESRD should be considered for transplantation, unless there are contraindications • Will continue to function, on average, >15 years 162 4/12/2022 By Belayneh K.
Renal transplantation • Transplant patient is less likely to be hospitalized & has a better quality of life than a dialysis patient • Secondary complications of CKD such as anaemia and bone disease resolve in many patients who are successfully transplanted • Less expensive treatment than dialysis 163 4/12/2022 By Belayneh K.
164

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2. Chronic renal failure.pdf

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    PHARMACOTHERAPY OF CHRONIC RENALFAILURE 1 4/12/2022 By Belayneh K. Belayneh K.(B.Pharm., M.Pharm., RPh.) Clinical Pharmacy Course Team Department of Pharmacy, CMHS, Bahir Dar University Email: [email protected]
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    Outline of presentation •Definition CRF • Classifications • Epidemiology • Risk factors • Pathophysiology • Clinical manifestations • Complications • Investigations • Management 2 4/12/2022 By Belayneh K.
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    Chronic Renal failure •The kidney is made up of approximately 2 million nephrons that are responsible for filtering, reabsorbing & excreting solutes & water • As the number of functioning nephrons declines, the primary functions of the kidney are affected 3 4/12/2022 By Belayneh K.
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    Primary functions ofthe kidney • Production & secretion of erythropoietin • Activation of vitamin D • Regulation of fluid and electrolyte balance • Regulation of acid-base balance 4 4/12/2022 By Belayneh K.
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    Chronic kidney diseases/Chronicrenal failure • Defined as the presence of kidney damage –Usually detected as urinary albumin excretion of 30 mg/day or more or • Decreased kidney function – GFR <60 mL/min for three or more months, irrespective of the cause • Is a progressive decline in kidney function that occurs over a period of several months to years • Also known as chronic renal insufficiency, progressive kidney disease 5 4/12/2022 By Belayneh K.
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    Chronic kidney diseases •The persistence of the damage or • Decreased function • Is necessary to distinguish CKD from acute kidney disease 6 for at least 3 months 4/12/2022 By Belayneh K.
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    Estimation of GFR •GFR can be estimated using equation from the modification of diet in renal disease study 7 4/12/2022 By Belayneh K.
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    Estimating creatinine clearance: Cockcroft-Gaultformula • Creatinine clearance (ml/min) = [(140-age) x (weight in kg)] x 0.85 (if female) [(72) x (serum creatinine in mg/dL)] • Creatinine clearance (ml/min)= [(140-age) x (weight in kg)] x1.23)x 0.85 (if female) (serum creatinine in micromol/L) 8 4/12/2022 By Belayneh K.
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    Chronic kidney disease(CKD) • According to the NKF, normal GFR results range from 90-120 mL/min/1.73 m2 • Older people will have lower than normal GFR levels, because GFR decreases with age • Levels <60 mL/min for 3 or more months are a sign of chronic kidney disease • A GFR <15 mL/min is a sign of kidney failure & requires immediate medical attention 9 4/12/2022 By Belayneh K.
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    10 Classification of chronicrenal failure 4/12/2022 By Belayneh K.
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    Chronic kidney disease(CKD) • The decline in kidney function is often irreversible –Therefore, measures to treat CKD are aimed at slowing the progression to end-stage renal disease 11 4/12/2022 By Belayneh K.
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    Epidemiology • A worldwidepublic health problem • The prevalence increases with age • Greater in females 12 4/12/2022 By Belayneh K.
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    Risk factors forCKD • Because of the progressive nature of CKD, determination of risk factors for CKD is difficult • Susceptibility factors –Associated with an increased risk of developing CKD, but are not directly proven to cause CKD –are generally not modifiable by pharmacologic therapy or lifestyle modifications 13 4/12/2022 By Belayneh K.
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    Risk factors forCKD • Initiation factors – directly cause CKD – are modifiable by pharmacologic therapy • Progression factors – which result in a faster decline in kidney function & cause worsening of CKD – may also be modified by pharmacologic therapy or lifestyle modifications to slow the progression of CKD 14 4/12/2022 By Belayneh K.
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    Susceptibility Factors • Canbe readily used to develop screening programs for CKD • Advanced age • Reduced kidney mass • Family history of kidney disease • Systemic inflammation • Dyslipidemia 16 4/12/2022 By Belayneh K.
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    Susceptibility Factors • Hyperlipidemia –Patients with CKD have a higher prevalence of dyslipidemia compared to the general population – Manifested as an elevation in total cholesterol, LDL-C & triglycerides levels – Decreases in high HDL-C levels – Mounting evidence suggests that hyperlipidemia can promote renal injury & subsequent progression of CKD. 17 4/12/2022 By Belayneh K.
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    Susceptibility Factors • Hyperlipidemiacan promote renal injury & subsequent progression of CKD – Lipid deposition causes activation of macrophages & monocytes – Secrete growth factors that stimulate cell proliferation and oxidation of lipoproteins. – Endothelial dysfunction, cellular injury & fibrosis in the kidney 18 4/12/2022 By Belayneh K.
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    Initiation Factors • Diabetesmellitus • Hypertension • Glomerulonephritis • Account for about 75% of the cases of CKD –(37% for diabetes, 24% for HTN & 14% for glomerulonephritis) most common causes of CKD 19 4/12/2022 By Belayneh K.
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    Initiation Factors • Autoimmunedisease • Polycystic kidney disease • Drug toxicity • Urinary tract abnormalities (infections, obstruction, stones) 20 4/12/2022 By Belayneh K.
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    Initiation Factors • Diabetesmellitus –The most common cause of CKD –The risk of developing nephropathy associated with DM is closely linked to hyperglycemia –Risk of nephropathy is slightly higher in patients with type II DM 21 4/12/2022 By Belayneh K.
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    Initiation Factors • Hypertension –Thesecond most common cause of CKD –More difficult to determine the true risk of developing CKD in patients with hypertension because the two are so closely linked, with CKD also being a cause of hypertension –Risk of developing ESRD is linked to both systolic & diastolic blood pressure 22 4/12/2022 By Belayneh K.
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    Initiation Factors • Hypertension •The prevalence of HTN is correlated with the degree of renal dysfunction With 40% of patients with CKD stage I 55% of patients with CKD stage II >75% of patients with CKD stage III presenting with HTN 23 4/12/2022 By Belayneh K.
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    Progression Factors • Canbe used as predictors of CKD • Hyperglycemia: Poor blood glucose control (in patients with DM) • Hypertension • Proteinuria • Tobacco smoking 24 4/12/2022 By Belayneh K.
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    Progression Factors • Proteinuria –Thepresence of protein in the urine is a marker of glomerular & tubular dysfunction and is recognized as an independent risk factor for the progression of CKD –The degree of proteinuria correlates with the risk for progression 25 4/12/2022 By Belayneh K.
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    Progression Factors • ElevatedBlood Pressure –Contribute to glomerular damage –Decline in GFR 26 4/12/2022 By Belayneh K.
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    Progression Factors • ElevatedBlood Glucose – The rxn b/n glucose & protein in the blood produces advanced glycosylation end-products (AGEs), which are metabolized in the proximal tubules – Hyperglycemia increases the synthesis of AGEs in patients with diabetes & the corresponding increase in metabolism is suspected to be a cause of nephropathy associated with diabetes 27 4/12/2022 By Belayneh K.
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    Progression Factors • TobaccoSmoking –Induces glomerular hyperfiltration, produces an antidiuretic action that increases blood pressure –Can damage the proximal tubule –Increase platelet activity & thromboxane A2 production –These effects are related to the amount of cigarettes smoked, in terms of pack years 28 4/12/2022 By Belayneh K.
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    Pathophysiology of CKD •A number of factors can cause initial damage to the kidney • Damage results in loss of nephron mass. • Hypertrophy of the remaining nephrons to compensate for the loss of renal function & nephron mass • Adaptive changes result in an increase in glomerular filtration & tubular function in the remaining nephrons 29 4/12/2022 By Belayneh K.
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    Pathophysiology of CKD •Initially, these adaptive changes preserve many of the clinical parameters of renal function • As time progresses, glomerular capillary pressure is increased, mediated by AG II • Angiotensin II is a potent vasoconstrictor of both the afferent & efferent arterioles, but has a preferential effect to constrict the efferent arteriole, thereby increasing the pressure in the glomerular capillaries 30 4/12/2022 By Belayneh K.
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    Pathophysiology of CKD •Increased glomerular capillary pressure expands the pores in the glomerular basement membrane allowing proteins to be filtered through the glomerulus • Filtered proteins are reabsorbed in the renal tubules, which activates the tubular cells to produce inflammatory & vasoactive cytokines & triggers complement activation 31 4/12/2022 By Belayneh K.
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    Pathophysiology of CKD •These in turn cause interstitial damage & scarring within the renal tubules, leading to damage and loss of more nephrons • Ultimately, the process leads to progressive loss of nephron mass to the point where the remaining nephrons are no longer able to maintain clinical stability & renal function declines 32 4/12/2022 By Belayneh K.
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    Figure: Proposed mechanismsfor progression of renal disease 33 4/12/2022 By Belayneh K.
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    Clinical manifestations • Stages1 and 2 CKD are generally asymptomatic. • Stages 3 and 4 CKD may be associated with minimal symptoms. 34 4/12/2022 By Belayneh K.
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    Clinical manifestations • Polyuria& nocturia – Patient frequently voids high volumes of urine, is often seen in CKD and results from medullary damage & the osmotic effect of a high serum urea level (>40 mmol/L) – The ability to concentrate urine is also lost in CKD which together with failure of physiological nocturnal antidiuresis results in nocturia – “foaming” of urine (indicative of proteinuria) 36 4/12/2022 By Belayneh K.
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    Clinical manifestations • Proteinuria –the prevalence of proteinuria increases with the severity of CKD – Pronounced proteinuria (>1 g of protein in a 24-h collection) usually indicates a glomerular etiology. • Hematuria – likely to result from lower urinary tract pathology (such as bladder lesions) & glomerular origin 37 4/12/2022 By Belayneh K.
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    Clinical manifestations • Hypertension& fluid overload –Severe renal impairment leads to sodium retention, which in turn produces circulatory volume expansion with consequent hypertension 38 4/12/2022 By Belayneh K.
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    Clinical manifestations • Uraemia –Many substances including urea, creatinine are normally excreted by the kidney & accumulate as renal function decreases – There are a wide range of uraemic toxins but it is the blood level of urea that is often used to estimate the degree of toxin accumulation in uraemia. – True symptomatic uraemia only occurs in very advanced CKD. 39 4/12/2022 By Belayneh K.
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    Clinical manifestations • Uraemia –Thesymptoms include anorexia, nausea, vomiting, constipation, foul taste –Pruritus without an underlying rash –In extremely severe cases, crystalline urea is deposited on the skin (uraemic frost) 40 4/12/2022 By Belayneh K.
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    • Anaemia –A commonconsequence of CKD and affects most people with CKD stages 4 and 5 –The fall in haemoglobin level is a slow, insidious process accompanying the decline in renal function 42 4/12/2022 By Belayneh K.
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    Factors contribute tothe pathogenesis of anemia in CKD • Shortened red cell survival, marrow suppression by uraemic toxins • Iron or folate deficiency associated with poor dietary intake or increased loss, for example, from gastro - intestinal bleeding • Principal cause results from damage of peritubular cells leading to inadequate secretion of erythropoietin • Hyperparathyroidism also reduces erythropoiesis by damaging bone marrow & therefore exacerbates anaemia associated with CKD 43 4/12/2022 By Belayneh K.
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    • Bone disease(renal osteodystrophy) –Secondary hyperparathyroidism –Osteomalacia (reduced mineralisation) –Mixed renal osteodystrophy (both hyperparathyroidism & osteomalacia) –Adynamic bone disease (reduced bone formation & resorption) 44 4/12/2022 By Belayneh K.
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    Fig. Disturbance ofPhosphate & calcium balance in chronic renal failure 45 4/12/2022 By Belayneh K.
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    • Neurological changes •Probably caused by uraemic toxins –Inability to concentrate –Memory impairment –Irritability stupor 46 4/12/2022 By Belayneh K.
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    • Muscle function –Musclesymptoms are probably caused by general nutritional deficiencies and electrolyte disturbances, notably of divalent cations and especially by hypocalcaemia –Muscle cramps & restless legs 47 4/12/2022 By Belayneh K.
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    Electrolyte disturbances • Potassium –Canbe elevated in CKD –Hyperkalaemia is a potentially dangerous condition as the first indication of elevated potassium levels may be life-threatening cardiac arrest –Potassium levels of over 7.0 mmol/L are life-threatening & should be treated as an emergency 48 4/12/2022 By Belayneh K.
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    Electrolyte disturbances • Hydrogenions –A common end-product of many metabolic processes –In renal failure, H+ is retained, causing acidosis 49 4/12/2022 By Belayneh K.
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    Complications of CKD •Fluid and electrolyte disorders • Anemia • Metabolic bone disease 50 4/12/2022 By Belayneh K.
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    Investigations • Physical examination –Signs of anaemia – Whitening of the skin with crystalline urea („uraemic frost‟) – Ankle oedema & a raised jugular venous pressure suggest fluid retention – Fishy smell on the breath known as „uraemic fetor – In some patients, the kidneys may be palpable – Change of urine color (froth excessively in proteinuria) 51 4/12/2022 By Belayneh K.
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    Investigations • The primarymarker of structural kidney damage is proteinuria, even in patients with normal GFR • Clinically significant proteinuria is defined as urinary protein excretion >300 mg/day • Microalbuminuria is defined as 30-300 mg of albumin excreted in the urine per day 52 4/12/2022 By Belayneh K.
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    Investigations • Laboratory Tests –Stages1 and 2 CKD: Increased blood urea nitrogen (BUN) & serum creatinine (SCr) and decreased GFR –Stages 3, 4, and 5 CKD: Increased BUN & SCr; decreased GFR. 53 4/12/2022 By Belayneh K.
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    Laboratory Tests • Advancedstages: –Hyperkalaemia –Hypocalcaemia –Hyperphosphataemia –Decreased bicarbonate (metabolic acidosis) –Decreased albumin, if inadequate nutrition intake 54 4/12/2022 By Belayneh K.
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    Laboratory Tests • DecreasedRBC count, hemoglobin & hematocrit (Hct) • Erythropoietin levels are not routinely monitored & are generally normal to low • Urine positive for albumin or protein. • Increased parathyroid hormone (PTH) level • Decreased vitamin D levels (stages 4 or 5 CKD) 55 4/12/2022 By Belayneh K.
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    Management of CKD •Non-pharmacologic Therapy • Pharmacologic Therapy 56 4/12/2022 By Belayneh K.
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    Goals of therapyin CKD • To slow & prevent the progression of CKD • To treat the secondary complications of CKD • To relieve symptoms 57 4/12/2022 By Belayneh K.
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    Non-pharmacological treatment • Potassiumrestriction –Dietary K+ restriction = 50–80mEq/d –Advise patient to limit intake of high K+ containing foods (e.g., bananas, avocados, tomatoes, orange juice, oranges) –K+ sparing diuretics (e.g., spironolactone, eplerenone), ACEI, ARB, β-blocking agents may ↑K+ 58 4/12/2022 By Belayneh K.
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    Non-Pharmacological treatment • Sodiumrestriction –<2.0 g/d if on HD: <2.4g/d in adult patients with CKD & HTN, further restriction may be necessary if significant fluid overload, cardiac problems, or concurrent liver disease • Phosphate restriction –Restrict dietary phosphorus to 800– 1000mg/d –Milk, meat, beans 59 4/12/2022 By Belayneh K.
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    Non-pharmacological treatment • Reductionin dietary protein intake –Slow the progression of kidney disease –Must be balanced with the risk of malnutrition in patients with CKD –Patients with a GFR <25 mL/minute received the most benefit from protein restriction –Patients with a GFR >25 mL/minute should not restrict protein intake 60 4/12/2022 By Belayneh K.
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    Non-pharmacological treatment • TheNKF recommends that patients who are not receiving dialysis, should restrict protein intake to 0.6 g/kg per day • If patients are not able to maintain adequate dietary energy intake, protein intake may be increased up to 0.75 g/kg/day • Patients receiving dialysis should maintain protein intake of 1.2-1.3 g/kg/day 61 4/12/2022 By Belayneh K.
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    Non-pharmacological treatment • SmokingCessation • May be a practical approach to slow the progression of CKD • Does not reverse existing renal dysfunction in former smokers. 62 4/12/2022 By Belayneh K.
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    Pharmacological management ofCKD • Intensive Blood Glucose Control (for Patients with Diabetes) –Administration of insulin three or more times daily • to maintain preprandial blood glucose levels b/n 70-120 g/dL • postprandial blood glucose levels <180 g/dL • decrease the incidence of proteinuria & albuminuria in patients with diabetes, both with & without documented nephropathy 63 4/12/2022 By Belayneh K.
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    Pharmacological management ofCKD • Optimal Blood Pressure Control • Goal BP in CKD –Stages 1-4 CKD <130/80 mmHg –Stage 5 CKD • Patients who are receiving hemodialysis <140/90 mmHg before hemodialysis & <130/80 after hemodialysis NKF recommendation 64 4/12/2022 By Belayneh K.
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    Optimal Blood PressureControl • Reductions in BP are associated with a decrease in proteinuria • A decrease in the rate of progression of kidney disease • Three or more agents are generally required to achieve the blood pressure goal of <130/80 mm Hg in CKD patients 4/12/2022 By Belayneh K.
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    Reduction in Proteinuria •ACEIs & ARBs –Decrease glomerular capillary pressure & volume because of their effects on angiotensin II –This, in turn, reduces the amount of protein filtered through the glomerulus, which ultimately decreases the progression of CKD –Greater reduction in proteinuria (35-40%) as compared to other anti-hypertensive agents • Hence, the antihypertensive agents of choice for all patients with CKD 66 4/12/2022 By Belayneh K.
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    Reduction in Proteinuria •ACEIs & ARBs – All patients with documented proteinuria should receive regardless of BP –B/C diabetes is associated with an early onset of microalbuminuria, all patients with diabetes should also receive an ACE-I or ARB, regardless of BP 67 4/12/2022 By Belayneh K.
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    ACEIs & ARBs •Enalapril – Initial: 2.5-5 mg PO qDay – Maintenance: 10-40 mg/day PO qDay or divided q12hr – 1.25 mg/dose IV over 5 minutes q6hr; doses up to 5 mg/dose IV q6hr have been administered – CrCl <30 mL/min: (IV) Initiate 0.625 mg q6hr; titrate based on response – CrCl <30 mL/min: (PO) Initiate 2.5 mg; titrate to response; not to exceed 40 mg • Losartan: 50-100 mg PO qDay 68 4/12/2022 By Belayneh K.
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    Outcome Evaluation • Monitorserum Cr, K+ levels & BP within 1 week after initiating ACEI or ARBs therapy • Discontinue the medication & switch to another agent if – A sudden increase in Serum Cr>30% occurs – Hyperkalemia develops – The patient becomes hypotensive • Titrate the dose of the ACE-I or ARB every 1-3 months to the maximum tolerable dose • If BP is not reduced to <130/80 mm Hg, add another agent to the regimen 69 4/12/2022 By Belayneh K.
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    Figure: Hypertension managementalgorithm for patients with CKD 70 4/12/2022 By Belayneh K.
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    Figure: Hypertension managementalgorithm for patients with CKD 71 4/12/2022 By Belayneh K.
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    Management of complicationsof CKD • Mgt of impaired Na+& Water Homeostasis • Impaired K+ Homeostasis • Anemia of CKD • Secondary Hyperparathyroidism & Renal Osteodystrophy • Metabolic Acidosis • Uremic Bleeding • Pruritus 72 4/12/2022 By Belayneh K.
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    Impaired Na+& WaterHomeostasis • Sodium & water balance are primarily regulated by the kidney • Reductions in nephron mass decrease glomerular filtration & subsequent reabsorption of sodium and water, leading to edema • The inability of the kidney to concentrate the urine results in nocturia in patients with CKD, usually presenting as early as stage 3 CKD. 73 4/12/2022 By Belayneh K.
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    Clinical Presentation ofimpaired Na+& Water Homeostasis • Symptoms – Nocturia can present in stage 3 CKD. – Edema generally presents in stage 4 CKD or later • Signs – Cardiovascular: Worsening hypertension, edema. – Genitourinary: Change in urine volume and consistency. • Laboratory Tests – Increased blood pressure – Sodium levels remain within the normal range 74 4/12/2022 By Belayneh K.
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    Mgt of impairedNa+& Water Homeostasis • Pharmacologic Therapy • Diuretic therapy – Is often necessary to prevent volume overload in patients with CKD – Loop diuretics (lasix 20-80 mg PO/day) are most frequently used to increase sodium & water excretion – Thiazide diuretics are ineffective when used alone in patients with a GFR <30 mL/minute – dose: Hydrochlorothiazide 25-100mg Po/day – As CKD progresses, higher doses or continuous infusion of loop diuretics may be needed, or combination therapy with loop and thiazide diuretics to increase sodium and water excretion. 75 4/12/2022 By Belayneh K.
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    Mgt of impairedNa+& Water Homeostasis Outcome Evaluation • Monitor edema after initiation of diuretic therapy • Monitor fluid intake to ensure obligatory losses are being met and avoid dehydration • If adequate diuresis is not attained with a single agent, consider combination therapy with another diuretic 76 4/12/2022 By Belayneh K.
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    Impaired K+ Homeostasis •K+ balance is primarily regulated by the kidney via the distal tubular cells –It secrete 90-95% of the daily dietary intake of K+ • Reduction in nephron mass decreases tubular secretion of K+, leading to hyperkalemia. • Hyperkalemia is estimated to affect > 50% of patients with stage 5 CKD 77 4/12/2022 By Belayneh K.
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    Impaired K+ Homeostasis •As nephron mass decreases, both the distal tubular secretion & GI excretion are increased b/c of aldosterone stimulation • This maintins serum K+ concentrations within the normal range through stages 1-4 CKD • Hyperkalemia begins to develop when – GFR falls <20% of normal – When nephron mass & renal K+ secretion is so low that the capacity of the GI tract to excrete potassium has been exceeded 78 4/12/2022 By Belayneh K.
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    Medications that canincrease the risk of hyperkalemia in patients with CKD • ACEI • ARBS • K+ sparing diuretics, used for the treatment of edema and chronic heart failure • should be used with caution in patients with stage 3 CKD or higher used for the treatment of proteinuria and hypertension. 79 4/12/2022 By Belayneh K.
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    Impaired K+ Homeostasis •Symptoms –Mild hyperkalemia is generally not associated with overt symptoms. • Signs –Cardiovascular: ECG changes • Laboratory Tests –Increased serum K+ levels (>5.5 mEq/L) 80 4/12/2022 By Belayneh K.
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    Impaired K+ Homeostasis •Non-Pharmacological therapy –Patients should avoid abrupt increases in dietary intake of K+ –Severe hyperkalemia is most effectively managed by hemodialysis 81 4/12/2022 By Belayneh K.
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    Impaired Potassium Homeostasis •Pharmacologic Therapy – Patients who present with cardiac abnormalities caused by hyperkalemia should receive calcium gluconate or chloride (1gm IV) to reverse the cardiac effects • Temporary shift of EC K+ into the IC compartment to stabilize cellular membrane – regular insulin (5-10 units IV) – 50ml of 50% dextrose (IV) – nebulized albuterol (10-20 mg) • These measures will decrease serum K+ levels within 30-60 minutes after treatment 82 4/12/2022 By Belayneh K.
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    Impaired K+ Homeostasis •Pharmacologic Therapy • Sodium polystyrene sulfonate – 15-30 gm/day PO – A sodium-potassium exchange resin – Promotes potassium excretion from the GI tract. – The onset of action is within 2 hours – Maximum effect on K+ levels may not be seen for up to 6 hours which limits the utility in patients with severe hyperkalemia. 83 4/12/2022 By Belayneh K.
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    Impaired K+ Homeostasis •Pharmacologic Therapy • loop diuretics (lasix 40-80mg IV) – often used to decrease K+ levels in patients with normal or mildly decreased kidney function, but are not useful in patients with stage 5 CKD to decrease K+ concentrations • Fludrocortisone – increases K+ excretion in the distal tubules & through the GI tract – However, it causes significant Na+ & water retention, which exacerbates edema & hypertension, and may not be tolerated by many CKD patients 84 4/12/2022 By Belayneh K.
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    Outcome Evaluation • MonitorECG continuously in patients with cardiac abnormalities until serum K+ levels drop <5 mEq/L or cardiac abnormalities resolve • Evaluate serum K+ & glucose levels within 1hr in patients who receive insulin & dextrose therapy • Evaluate serum K+ levels within 2-4 hrs after treatment with SPS or diuretics • Repeat doses of diuretics or SPS if necessary until serum potassium levels fall < 5 mEq/L • Monitor BP & serum K+ levels in 1 week in patients who receive fludrocortisone 85 4/12/2022 By Belayneh K.
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    Anemia in CKD •Kidney produce 90% of the hormone erythropoietin (EPO), which stimulates RBC production • Patients with CKD should be evaluated for anemia when the GFR falls below 60 mL/min • Reduction in nephron mass decreases renal production of EPO, which is the primary cause of anemia in patients with CKD • Anemia decreases oxygen delivery to the renal tubules, promoting the release of inflammatory & vasoactive cytokines, which contribute to the progression of CKD 86 4/12/2022 By Belayneh K.
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    Anemia in CKD •The development of anemia of CKD results in –decreased oxygen delivery & utilization –increased cardiac output & left ventricular hypertrophy –increase the cardiovascular risk & mortality in patients with CKD. 87 4/12/2022 By Belayneh K.
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    Anemia in CKD •The prevalence is correlated with the degree of renal dysfunction • The risk of developing anemia increases as GFR declines –doubling for patients with stage 3 CKD –increasing to 3.8-fold in patients with stage 4 CKD –to 10.5-fold for patients with stage 5 CKD 88 4/12/2022 By Belayneh K.
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    Causes Anemia inCKD • Decrease in EPO production – The primary cause of anemia in patients with CKD • Uremia – A result of declining renal function, decreases the lifespan of RBCs from a normal of 120 days to as low as 60 days in patients with stage 5 CKD • Iron deficiency & blood loss from regular laboratory testing & hemodialysis 89 4/12/2022 By Belayneh K.
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    Clinical Presentation ofAnemia of CKD • General – presents with fatigue & decreased quality of life. • Symptoms – cold intolerance, shortness of breath, and decreased exercise capacity. • Signs – Cardiovascular: Left ventricular hypertrophy, ECG changes, congestive heart failure – Neurologic: Impaired mental cognition – Genitourinary: Sexual dysfunction • Laboratory Tests – Decreased RBC count, Hgb (<11 g/dL) and Hct – Decreased erythropoietin levels 90 4/12/2022 By Belayneh K.
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    Management of anemiain CKD • Goal of treatment –to increase Hgb levels >11 g/dL 91 4/12/2022 By Belayneh K.
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    Management of anemiain CKD • Iron Supplementation – The first-line treatment for anemia of CKD involves replacement of iron stores with iron supplements – When iron supplementation alone is not sufficient to increase Hgb levels, ESAs are necessary to replace erythropoietin – May be indicated if Hgb levels are below the goal level, but avoided if the patient is infected. 92 4/12/2022 By Belayneh K.
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    Management of anemiain CKD • Iron supplementation • Use of ESAs increases the iron demand for RBC production & iron deficiency is common – Requiring iron supplementation to correct & maintain adequate iron stores to promote RBC production • Oral iron supplements are the 1st line treatment for iron supplementation for patients with CKD not receiving hemodialysis • When administering iron by the oral route, 200 mg of elemental iron should be delivered daily to maintain adequate iron stores 93 4/12/2022 By Belayneh K.
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    Management of anemiain CKD • Oral iron supplementation is generally not effective in maintaining adequate iron stores in patients receiving ESAs because of: –poor absorption –an increased need for iron with ESA therapy, making the IV route necessary for iron supplementation • give a total of 1g of IV iron, divided doses 94 4/12/2022 By Belayneh K.
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    Management of anemiain CKD • Maintenance doses are often used in patients receiving hemodialysis • Maintenance doses consist of smaller doses of iron administered weekly or with each dialysis session (e.g., iron dextran or iron sucrose 20-100 mg/week; sodium ferric gluconate 62.5-125 mg/week) • IV iron preparations are equally effective in increasing iron stores 95 4/12/2022 By Belayneh K.
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    Management of anemiain CKD • Anaphylaxis may occur with all IV preparations, but most notably with iron dextran • A test dose of 25 mg iron dextran should be administered 30 minutes before the full dose to monitor for potential anaphylactic reactions • After administering a 1-g course of IV iron, iron status should be monitored to determine the effectiveness of the treatment. • Serum ferritin and TSat should be monitored no sooner than 1 week after the last dose of IV iron • If Hgb does not increase after a course of IV iron, an additional 1 g of IV iron may be administered 96 4/12/2022 By Belayneh K.
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    Management of anemiain CKD • Erythropoiesis stimulating agents (ESAs) –Abnormalities found during the anemia workup should be corrected before initiating ESAs, particularly iron deficiency –If Hgb is <10 when all other causes of anemia have been corrected, EPO deficiency should be assumed. –May be considered if Hgb levels remain persistently low to improve symptoms of anemia 97 4/12/2022 By Belayneh K.
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    Management of anemiain CKD • Erythropoiesis stimulating agents (ESAs) – Epoetin alfa (SC preferred): • 50-100 units/kg SC 2-3x per week – Darbepoetin alfa (IV or SC): • 0.45 mcg/kg once weekly – Use of this agents beyond 12 g/dL Hgb levels is associated with increased mortality – SC administration of ESA produces a more predictable & sustained response than IV administration – The maximum target Hgb should not exceed 11 g/dL 98 4/12/2022 By Belayneh K.
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    Erythropoiesis stimulating agents(ESAs): adverse effects • Increased blood pressure –May require antihypertensive agents to control BP • Seizures & pure red cell aplasia • Increased blood viscosity & hemoconcentration, which occurs when large amounts of fluid are removed during hemodialysis 99 4/12/2022 By Belayneh K.
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    100 Algorithm for managementof anemia of CKD 4/12/2022 By Belayneh K.
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    Outcome Evaluation • EvaluateHgb monthly when ESA therapy is initiated or the dose is adjusted to ensure Hgb does not exceed 11.5 g/dL • The ESA dose can increase monthly if Hgb is below goal. • Once a stable Hgb is attained, evaluate Hgb every 3 months thereafter. • While the patient is receiving ESA therapy, monitor iron stores at least every 3 months 102 4/12/2022 By Belayneh K.
  • 103.
    Secondary Hyperparathyroidism &Renal Osteodystrophy • Increases in parathyroid hormone (PTH) occur early as renal function begins to decline • As many as 75-100% of patients with stage 3 CKD have renal osteodystrophy • High bone turnover is the most common cause of bone abnormalities in patients with CKD • As renal function declines in patients with CKD, decreased phosphorus excretion disrupts the balance of calcium & phosphorus homeostasis 103 4/12/2022 By Belayneh K.
  • 104.
    Pathogenesis of SecondaryHyperparathyroidism & Renal Osteodystrophy in patients with CKD 104 FGF: Fibroblast growth factor 4/12/2022 By Belayneh K.
  • 105.
    Clinical Presentation ofsecondary Hyperparathyroidism & Renal Osteodystrophy • Symptoms –Usually asymptomatic in early disease –Calcification in the joints can be associated with decreased range of motion –Conjunctival calcifications are associated with a gritty sensation in the eyes, redness, and inflammation 105 4/12/2022 By Belayneh K.
  • 106.
    Clinical Presentation ofsecondary Hyperparathyroidism & Renal Osteodystrophy Signs • Cardiovascular: Increased HR, DBP & MAP • Musculoskeletal: Bone pain, muscle weakness • Dermatologic: Pruritus 106 4/12/2022 By Belayneh K.
  • 107.
    Laboratory investigations • Increasedserum phosphorus levels • Low to normal serum calcium levels • Increased Ca-P product • Increased PTH levels • Decreased vitamin D levels • Radiographic studies show calcium-phosphate deposits in joints and/or cardiovascular system 107 4/12/2022 By Belayneh K.
  • 108.
    Management of secondaryHyperparathyroidism & Renal Osteodystrophy • Management of bone disease in CKD is based on –Corrected serum levels of calcium & phosphorus –The Ca-P –Intact PTH levels • The target levels of each vary with the stage of CKD 108 4/12/2022 By Belayneh K.
  • 109.
  • 110.
    Management of secondaryHyperparathyroidism & Renal Osteodystrophy • Non-pharmacologic Therapy • Pharmacological therapy 110 4/12/2022 By Belayneh K.
  • 111.
    Non-pharmacologic Therapy • Dietaryphosphorus restriction to 800-1000 mg/day in patients with stage 3 CKD or higher who have phosphorus levels at the upper limit of the normal range or elevated iPTH levels • Foods high in phosphorus are also high in protein (meat, milk, legumes, carbonated beverages) –Which can make it difficult to restrict phosphorus intake while maintaining adequate protein intake to avoid malnutrition 111 4/12/2022 By Belayneh K.
  • 112.
    Non-pharmacologic Therapy • Hemodialysis& peritoneal dialysis can remove up to 2-3 g of phosphorus per week – Insufficient to control hyperphosphatemia & pharmacologic therapy is necessary • Restriction of aluminum exposure – Ingestion of aluminum containing antacids & other aluminum-containing products should be avoided in patients with stage 4 CKD or higher b/c of the risk of Al toxicity & potential uptake into the bone 112 4/12/2022 By Belayneh K.
  • 113.
    Non-pharmacologic Therapy • Parathyroidectomy –Aportion or all of the parathyroid tissue may be removed –a treatment of last resort for sHPT –but should be considered in patients with persistently elevated PTH levels >800 pg/mL (800 ng/L) that is refractory to medical therapy 113 4/12/2022 By Belayneh K.
  • 114.
    Pharmacological therapy • Phosphate-BindingAgents –used when serum phosphorus levels cannot be controlled by restriction of dietary intake –used to bind dietary phosphate in the GI tract to form an insoluble complex that is excreted in the feces –Phosphorus absorption is decreased, thereby decreasing serum phosphorus levels 114 4/12/2022 By Belayneh K.
  • 115.
    Phosphate-Binding Agents • Calcium-basedphosphate binders – calcium carbonate & calcium acetate, are effective in decreasing serum phosphate levels, as well as increasing serum calcium levels – Calcium citrate is usually not used as a phosphate binding agent because the citrate salt can increase Al absorption – Doses should not be >1500 mg of elemental calcium/ day – Total elemental calcium intake per day should not exceed 2000 mg, including medication and dietary intake – Adverse effects: constipation & hypercalcemia 115 4/12/2022 By Belayneh K.
  • 116.
  • 117.
    sevelamer hydrochloride &lanthanum carbonate • Phosphate-binding agents that do not contain calcium, magnesium, or aluminum • Particularly useful in patients with hyperphosphatemia who have elevated serum calcium levels or who have vascular or soft tissue calcifications 117 4/12/2022 By Belayneh K.
  • 118.
    Sevelamer • A cationicpolymer that is not systemically absorbed and binds to phosphate in the GI tract, and prevents absorption and promotes excretion of phosphate through the GI tract via the feces • Has an added benefit of reducing LDL-C by up to 30% and increasing HDL-C levels • Adverse effects: nausea, constipation & diarrhea 118 4/12/2022 By Belayneh K.
  • 119.
  • 120.
  • 121.
    Vitamin D Therapy •Exogenous vitamin D compounds that mimic the activity of calcitriol act directly on the parathyroid gland to decrease PTH secretion • Particularly useful when reduction of serum phosphorus levels does not sufficiently reduce PTH levels 121 4/12/2022 By Belayneh K.
  • 122.
    Calcitriol • The activeform of vitamin D • Effects are mediated by upregulation of the vitamin D receptor in the parathyroid gland – Which decreases parathyroid gland hyperplasia and PTH synthesis and secretion • Vitamin D receptor upregulation also occurs in the intestines – increases calcium & phosphorus absorption – increasing the risk of hypercalcemia & hyperphosphatemia 122 4/12/2022 By Belayneh K.
  • 123.
    Calcitriol • Serum calcium& phosphorus levels should be within the normal range for the stage of CKD and the Ca-P product <55 mg2/dL2 prior to starting calcitriol therapy 123 4/12/2022 By Belayneh K.
  • 124.
    Paricalcitol • Less effecton vitamin D receptors in the intestines –decreasing the effects on intestinal calcium & phosphorus absorption –more useful in patients with an elevated Ca-P product • Retaining the effects on parathyroid gland hyperplasia and PTH synthesis and secretion 124 4/12/2022 By Belayneh K.
  • 125.
    Doxercalciferol • Has similareffects as calcitriol on vitamin D receptors in the parathyroid glands and intestines • Like calcitriol, calcium & phosphorus levels and the Ca-P product should be within the normal range for the stage of CKD prior to starting 125 4/12/2022 By Belayneh K.
  • 126.
  • 127.
    Calcimimetics • Cinacalcet –a calcimimeticthat increases the sensitivity of receptors on the parathyroid gland to serum calcium levels to reduce PTH secretion –may be beneficial in patients with an increased Ca-P product who have elevated PTH levels & cannot use vitamin D therapy 127 4/12/2022 By Belayneh K.
  • 128.
    Cinacalcet • Should notbe used if serum calcium levels are below normal – b/c of the effects on PTH can reduce serum calcium levels and result in hypocalcemia • dose: 30mg PO/day 128 4/12/2022 By Belayneh K.
  • 129.
    Patient monitoring • phosphate-bindingagents –Monitor serum calcium & phosphorus levels regularly –Monitor serum levels every 1-4 weeks depending on the severity of hyperphosphatemia –Once target levels are achieved, monitor serum calcium & phosphorus levels every 1-3 months 129 4/12/2022 By Belayneh K.
  • 130.
    Patient monitoring • vitaminD therapy – Monitor intact PTH levels monthly while initiating, then every 3 months once stable iPTH levels are achieved. • cinacalcet – When starting or increasing the dose monitor serum Ca++& phosphorus levels within 1 week and iPTH levels should be monitored within 1-4 weeks – Once target levels are achieved, then monitor every 3 months 130 4/12/2022 By Belayneh K.
  • 131.
    Metabolic Acidosis • Thekidneys play a key role in acid-base homeostasis in the body by regulating excretion of H+ ions • With normal kidney function, HCO3- is freely filtered through the glomerulus & completely reabsorbed via the renal tubules • H+ ions generated during metabolism of ingested food are excreted at the same rate by the kidney 131 4/12/2022 By Belayneh K.
  • 132.
    Metabolic Acidosis • Askidney function declines – Reduced HCO3- reabsorption – H+ ion excretion is decreased • The positive hydrogen balance leads to metabolic acidosis • As nephron function declines, production of NH3 is increased to compensate for a decrease in secretion of H+ions • Once the maximal capacity for NH3 production is reached, acidosis develops 132 4/12/2022 By Belayneh K.
  • 133.
    Metabolic Acidosis • Approximately80% of patients with a GFR <20- 30 mL/minute can develop metabolic acidosis • Can increase protein catabolism & decrease albumin synthesis • Can contribute to bone disease by promoting bone resorption 133 4/12/2022 By Belayneh K.
  • 134.
    Management of MetabolicAcidosis • Treatment goal – normalizing the plasma bicarbonate concentration or at least achieving bicarbonate levels near ≥ 22 mEq/L • Pharmacologic therapy – use of preparations containing sodium bicarbonate or sodium citrate • Once dialysis starts, PO or IV bicarbonate is not required since the dialysate baths contain sodium bicarbonate 134 4/12/2022 By Belayneh K.
  • 135.
    Management of MetabolicAcidosis • Each 650-mg tablet NaHCO3 provides 8 mEq of Na+ & 8 mEq of HCO3- • The use of two to four 650-mg NaHCO3 tablets per day, usually divided into 2-3 doses (0.5-1 meq/kg /day) • When determining the dose of bicarbonate replacement, the dose is usually determined by calculating the base deficit: =[0.5 L/kg × body weight] × [(normal value of 24 mEq/L) – (patient‟s serum bicarbonate value )]. 135 4/12/2022 By Belayneh K.
  • 136.
    Management of MetabolicAcidosis • Because of the risk of volume overload resulting from the Na load administered with HCO3 replacement, the total base deficit should be administered over several days • After normalization, a maintenance regimen of HCO3- of 12-20 mEq/day in divided doses may be required • Titrate doses to maintain normal plasma bicarbonate concentrations thereafter 136 4/12/2022 By Belayneh K.
  • 137.
    Management of MetabolicAcidosis • Sodium citrate – Citrate is rapidly metabolized to bicarbonate – May be used in patients who are unable to tolerate NaHCO3, since it does not produce the bloating associated with NaHCO3 therapy – Citrate also promotes Al absorption & should not be used in patients taking Al-containing agents 137 4/12/2022 By Belayneh K.
  • 138.
    Patient monitoring • Monitorserum electrolytes & arterial blood gases regularly • Correct metabolic acidosis slowly to prevent the development of metabolic alkalosis or other electrolyte abnormalities 138 4/12/2022 By Belayneh K.
  • 139.
    Uremic Bleeding • Ureais probably not the major platelet toxin • no predictable correlation b/n the BUN & the bleeding time in patients with renal failure • Studies in uremic patients have shown that platelet NO synthesis is increased & that uremic plasma stimulates NO production – NO is an inhibitor of platelet aggregation • The increase in NO synthesis may be due to elevated levels of guanidinosuccinic acid, a uremic toxin that may be a precursor for NO 139 4/12/2022 By Belayneh K.
  • 140.
    Uremic Bleeding • Uremiacan lead to a number of alterations in clotting ability, resulting in hemorrhage • Bleeding complications associated with CKD: –Ecchymoses –Prolonged bleeding from mucous membranes –GI bleeding, intramuscular bleeding 140 4/12/2022 By Belayneh K.
  • 141.
    Uremic Bleeding • Uremiaalters a number of mechanisms that contribute to bleeding • Platelet function & aggregation is altered through decreased production of thromboxane • Platelet–vessel wall interactions are also altered in patients with uremia b/c of decreased activity of von Willebrand factor 141 4/12/2022 By Belayneh K.
  • 142.
    Management of UremicBleeding • Non-pharmacologic Therapy – Dialysis initiation improves platelet function & reduces bleeding time – hemodialysis or peritoneal dialysis can partially correct the bleeding time in approximately two- thirds of uremic patients • Pharmacologic Therapy – Cryoprecipitate – Desmopressin – Conjugtaed Estrogen 142 4/12/2022 By Belayneh K.
  • 143.
    Cryoprecipitate • Contains variouscomponents important in platelet aggregation & clotting, such as von Willebrand factor & fibrinogen • Decreases bleeding time within 1hr in 50% of patients • Dose: 10 units IV every 12-24hrs • cost & the risk of infection have limited the use of cryoprecipitate 143 4/12/2022 By Belayneh K.
  • 144.
    Desmopressin The vasopressin V2receptor agonist causes release of von Willebrand factor (vWF) & factor VIII from endogenous storage sites Bleeding time is promptly reduced, within 1hr of administration & sustained for 4-8 hrs • Doses used for uremic bleeding – 0.3 - 0.4 mcg/kg IV over 20 - 30 minutes – 0.3 mcg/kg SC or – 2-3 mcg/kg intranasally 144 4/12/2022 By Belayneh K.
  • 145.
    Conjugated Estrogens • Usedto decrease bleeding time • Onset of action is slower than Desmopressin • Dose – 0.6 mg/kg IV daily for five days – 2.5-25 mg Po/ day for five days or – 50-100 microgram of transdermal patches twice weekly • IV administration – decreases bleeding time within 6 hours of administration & produces an effect that lasts up to 2 weeks after stopping therapy 145 4/12/2022 By Belayneh K.
  • 146.
    Conjugated Estrogens • MOA –Notwell understood –Preliminary studies suggest an increase in platelet reactivity may be important perhaps due to decreased generation of NO –estrogens act by reducing the production of L- arginine, the precursor of NO 146 4/12/2022 By Belayneh K.
  • 147.
    Pruritus • Can affect25-86% of patients with advanced stages of CKD • Not related to the cause of renal failure • Can be significant & has been linked to mortality in patients receiving hemodialysis 147 4/12/2022 By Belayneh K.
  • 148.
    Pathophysiology of Pruritusin CKD • Cause is unknown, although several mechanisms have been proposed • Vitamin A is known to accumulate in the skin & serum of patients with CKD, but a definite correlation with pruritus has not been established • Histamine may also play a role in the development of pruritus, which may be linked to mast cell proliferation in patients receiving hemodialysis • Hyperparathyroidism has also been suggested as a contributor to pruritus, although serum PTH levels do not correlate with itching 148 4/12/2022 By Belayneh K.
  • 149.
    Management of Pruritusin CKD • Non-Pharmacological therapy –Adequate dialysis (1st line of treatment) –Maintaining proper nutritional intake, especially with regard to dietary phosphorus and protein intake –Warming or cooling the skin using baths, three times weekly 149 4/12/2022 By Belayneh K.
  • 150.
    Pharmacologic Therapy • PharmacologicTherapy • Antihistamines (first line therapy) –hydroxyzine 25-50 mg or –diphenhydramine 25-50 mg Po • Cholestyramine –at doses of 5 g twice daily 150 4/12/2022 By Belayneh K.
  • 151.
    Renal replacement therapy •Patients who progress to ESRD require renal replacement therapy • The modalities that are used for RRT are: –Dialysis: Heamodialysis (HD) & peritoneal dialysis (PD) –Kidney transplantation • The most common form of RRT is dialysis, accounting for 72% of all patients with ESRD 151 4/12/2022 By Belayneh K.
  • 152.
    Indications for Dialysis •Dialysis is initiated in most patients when the GFR falls <15 mL/minute • Symptoms that may indicate the need for dialysis – persistent anorexia, nausea, vomiting, fatigue & pruritus • Other criteria that indicate the need for dialysis – declining nutritional status – declining serum albumin levels – uncontrolled hypertension – volume overload which may manifest as chronic heart failure – hyperkalemia – BUN & SCr 152 4/12/2022 By Belayneh K.
  • 153.
    Haemodialysis 153 •a process thatuses a man-made membrane (dialyzer) to: Remove wastes, such as urea, from the blood. 4/12/2022 By Belayneh K.
  • 154.
    Haemodialysis • Involves theexposure of blood to a semipermeable membrane (dialyzer) against which a physiologic solution (dialysate) is flowing • The dialysate is composed of purified water & electrolytes • usually carried out for 3–5 hrs 3x weekly • Allows for the removal of several substances from the bloodstream, including water, urea, creatinine, uremic toxins & drugs 154 4/12/2022 By Belayneh K.
  • 155.
    Haemodialysis • Although thedialysate is not sterilized, the membrane prevents bacteria from entering into the bloodstream. • If the membrane ruptures during hemodialysis, infection becomes a major concern for the patient 155 4/12/2022 By Belayneh K.
  • 156.
    Concentrations of dialysatecomponents used in hemodialysis Sodium (meq/L) 135 to 155 Potassium (meq/L) 0-4 Calcium (mmol/L) 1.25 to 1.75 (2.5 to 3.5 meq/L) Magnesium (mmol/L) 0 to 0.75 (0 to 1.5 meq/L) Chloride (meq/L) 87 to 120 Bicarbonate (meq/L) 25 to 40 Glucose (g/dL) 0 to 0.20 156 4/12/2022 By Belayneh K.
  • 157.
    Advantages Hemodialysis • Highersolute clearance allows intermittent treatment • Efficient; 4 hrs three times per wk is usually adequate • The technique‟s failure rate is low 157 4/12/2022 By Belayneh K.
  • 158.
    Disadvantages of Hemodialysis •Requires multiple visits each week to the hemodialysis center • May require months before patient adjusts to hemodialysis • Vascular access is frequently associated with infection & thrombosis • Decline of residual renal function is more rapid compared to peritoneal dialysis 158 4/12/2022 By Belayneh K.
  • 159.
    Complications of Hemodialysis •Hypotension – due to fluid removal from the bloodstream. – Management • placing the patient in the Trendelenburg position (with the head lower than the feet) • administration of normal saline (100 to 200 mL) to restore intravascular volume • Myalgia – due to hypoperfusion of the muscles • Thrombosis • Infection – usually related to organisms found on the skin, namely Staphylococcus epidermidis & S. aureus 159 4/12/2022 By Belayneh K.
  • 160.
    Vitamin Replacement • Water-solublevitamins removed by hemodialysis (HD) contribute to malnutrition & vitamin deficiency syndromes • Patients receiving HD often require replacement of water soluble vitamins to prevent adverse effects • The vitamins that may require replacement are ascorbic acid, thiamine, biotin, folic acid, riboflavin, and pyridoxine 160 4/12/2022 By Belayneh K.
  • 161.
    Vitamin Replacement • Patientsreceiving HD should receive a multivitamin B complex with vitamin C supplement • but should not take supplements that include fat- soluble vitamins, such as vitamins A, E, or K, which can accumulate in patients with renal failure 161 4/12/2022 By Belayneh K.
  • 162.
    Renal transplantation • Offersthe best chance of long-term survival in ESRD • Can restore normal kidney function and correct all the metabolic abnormalities of CKD • Compatibility of ABO blood group b/n donor and recipient is usually required • All patients with ESRD should be considered for transplantation, unless there are contraindications • Will continue to function, on average, >15 years 162 4/12/2022 By Belayneh K.
  • 163.
    Renal transplantation • Transplantpatient is less likely to be hospitalized & has a better quality of life than a dialysis patient • Secondary complications of CKD such as anaemia and bone disease resolve in many patients who are successfully transplanted • Less expensive treatment than dialysis 163 4/12/2022 By Belayneh K.
  • 164.