Clinical Pharmacy Chapter 10 Chronic Kidney Disease

1. Clinical PharmacyChapter 10Chronic Kidney Disease Rowa’ Al-Ramahi

2. DEFINITION • Chronic kidney disease (CKD) is a progressive loss of function over several months to years, characterized by gradual replacement of normal kidney architecture with interstitial fibrosis. • CKD is categorized by the level of kidney function, based on glomerular filtration rate (GFR), into stages 1 to 5, with each increasing number indicating a more advanced stage of the disease, as defined by a declining GFR. This classification system from the National Kidney Foundation’s Kidney Dialysis Outcomes and Quality Initiative (K/DOQI) also accounts for structural evidence of kidney damage. • CKD stage 5, previously referred to as end-stage renal disease (ESRD), occurs when the GFR falls below 15 mL/min per 1.73 m2 body surface area. The patient with stage 5 CKD requiring chronic dialysis or renal transplantation for relief of uremic symptoms is said to have ESRD.

3. PATHOPHYSIOLOGY • Susceptibility factors increase the risk for kidney disease but do not directly cause kidney damage. Susceptibility factors include advanced age, reduced kidney mass and low birth weight, racial or ethnic minority, family history, low income or education, systemic inflammation, and dyslipidemia. • Initiation factors initiate kidney damage and can be modified by drug therapy. Initiation factors include diabetes mellitus, hypertension, autoimmune disease, polycystic kidney disease, and drug toxicity. • Progression factors hasten decline in kidney function after initiation of kidney damage. Progression factors include glycemia in diabetics, hypertension, proteinuria, and smoking. • Most progressive nephropathies share a final common pathway to irreversible renal parenchymal damage and ESRD. Key pathway elements are loss of nephron mass, glomerular capillary hypertension, and proteinuria.

4. CLINICAL PRESENTATION • CKD development and progression is insidious. Patients with stage 1 or 2 CKD usually do not have symptoms or metabolic derangements seen with stages 3 to 5, such as anemia, secondary hyperparathyroidism, cardiovascular disease, malnutrition, and fluid and electrolyte abnormalities that are more common as kidney function deteriorates. • Uremic symptoms (fatigue, weakness, shortness of breath, mental confusion, nausea, vomiting, bleeding, and anorexia) are generally absent in stages 1 and 2, minimal during stages 3 and 4, and common in patients with stage 5 CKD who may also experience itching, cold intolerance, weight gain, and peripheral neuropathies. DESIRED OUTCOME • The goal is to delay the progression of CKD, minimizing the development or severity of complications.

5. TREATMENT: PROGRESSION-MODIFYING THERAPIES NONPHARMACOLOGIC THERAPY • A low-protein diet (0.6 to 0.75 g/kg/day) can delay progression of CKD in patients with or without diabetes, although the benefit is relatively small. PHARMACOLOGIC THERAPY Hyperglycemia • Intensive therapy in patients with type 1 and type 2 diabetes reduces microvascular complications, including nephropathy. Intensive therapy can include insulin or oral drugs and involves blood sugar testing at least three times daily. • The progression of CKD can be limited by optimal control of hyperglycemia and hypertension

6. Hypertension • Adequate blood pressure control can reduce the rate of decline in GFR and albuminuria in patients with or without diabetes. • Antihypertensive therapy should be initiated in diabetic or nondiabetic CKD patients with an ACEI or an ARB. Nondihydropyridine CCBs are generally used as second-line antiproteinuric drugs when ACEIs or angiotensin II receptor blockers are not tolerated. • ACEI clearance is reduced in CKD, therefore treatment should begin with the lowest possible dose followed by gradual titration to achieve target blood pressure and, secondarily, to minimize proteinuria. No individual ACEI is superior to another. • GFR typically decreases 25% to 30% within 3 to 7 days after starting ACEIs because this class reduces intraglomerular pressure. Sustained increases in the serum creatinine by more than 30% after starting ACEIs may be due to the ACEI and discontinuation should be strongly considered. Serum potassium should also be monitored after initiating or increasing the dose of an ACEI.

7. Supportive Therapies • Dietary protein restriction, lipid-lowering medications, smoking cessation, and anemia management may help slow the rate of CKD progression. • The primary goal of lipid-lowering therapies in CKD is to decrease the risk for progressive atherosclerotic cardiovascular disease. • A secondary goal is to reduce proteinuria and renal function decline seen with administration of statins.

8. TREATMENT: MANAGEMENT OF COMPLICATIONS • Progression of CKD to ESRD can occur over years to decades, with the mechanism of kidney damage dependent on the etiology of the disease; however, the consequences and complications of marked reductions in kidney function are fairly uniform irrespective of the underlying etiology. • No single toxin is responsible for all of the signs and symptoms of uremia observed in stage 4 or 5 CKD. Toxins accumulate as a result of increased secretion, decreased clearance secondary to reduced metabolism within the kidney, and/or decreased renal clearance of by-products of protein metabolism. • The overall goal of therapy is to optimize the patient’s duration and quality of life. Patients who reach CKD stage 4 almost inevitably progress to ESRD, requiring dialysis to sustain life.

9. FLUID AND ELECTROLYTE ABNORMALITIES • Serum sodium concentration is generally maintained by an increase in fractional excretion of sodium, resulting in a volume-expanded state. The most common manifestation of increased intravascular volume is systemic hypertension. • The kidney’s ability to adjust to abrupt changes in sodium intake is diminished in patients with ESRD. Sodium restriction beyond a no-added salt diet is not recommended unless hypertension or edema is present. A negative sodium balance can decrease renal perfusion and cause a further decline in GFR. • Diuretic therapy or dialysis may be necessary to control edema or blood pressure. • Loop diuretics, particularly when administered by continuous infusion, increase urine volume and renal sodium excretion. Although thiazide diuretics are ineffective when creatinine clearance is less than 30 mL/min, adding them to loop diuretics can enhance excretion of sodium and water.

10. POTASSIUM HOMEOSTASIS • Serum potassium concentration is usually maintained in the normal range until the GFR is less than 20 mL/min per 1.73 m2, when mild hyperkalemia is likely to develop. • The definitive treatment of severe hyperkalemia in ESRD is hemodialysis. Temporary measures include calcium gluconate, insulin and glucose, nebulized albuterol, and sodium polystyrene sulfonate.

11. ANEMIA • The primary cause of anemia in patients with CKD or ESRD is erythropoietin deficiency. Other contributing factors include decreased lifespan of red blood cells, blood loss, and iron deficiency. • Iron supplementation is necessary to replete iron stores. Parenteral iron therapy improves response to erythropoietic therapy and reduces the dose required to achieve and maintain target indices. In contrast, oral therapy is often inadequate. • Adverse effects of IV iron include allergic reactions, hypotension, dizziness, dyspnea, headaches, lower back pain, arthralgia, syncope, and arthritis. Some of these reactions can be minimized by decreasing the dose or rate of infusion. Sodium ferric gluconate and iron sucrose have better safety records than iron dextran. Iron dextran requires a test dose to reduce the risk of anaphylactic reactions. • SC administration of epoetinalfais preferred because IV access is not required, and the SC dose that maintains target indices is 15%-30% lower than the IV.

12. Darbepoetin alfa has a longer half-life than epoetin alfa and prolonged biologic activity. Doses are administered less frequently, starting at once a week IV or SC. • Erythropoietic agents are well tolerated. Hypertension is the most common adverse event. Evaluation of Therapeutic Outcomes • Iron indices (transferrin saturation [TSat]; ferritin) should be evaluated before initiating an erythropoietic agent. To avoid errors, clinicians should wait at least 2 weeks after a loading dose of IV iron to reassess them. • For monitoring purposes, hemoglobin is preferred to hematocrit because the latter fluctuates with volume status. The target hemoglobin is 12 g/dL. • After an erythropoietic agent is initiated, hemoglobin response is typically delayed. Steady-state levels do not occur until after the life span of a red blood cell (mean 2 m; range 1-4 m). To avoid making premature dosing changes, clinicians should evaluate response over several weeks. • Patients should be monitored for potential complications, such as hypertension, which should be treated before starting an erythropoietic agent.

13. SECONDARY HYPERPARATHYROIDISMAND RENAL OSTEODYSTROPHY Pathophysiology and Clinical Presentation • As kidney disease progresses, renal activation of vitamin D is impaired, which reduces gut absorption of calcium. Low blood calcium concentration stimulates secretion of parathyroid hormone (PTH). As renal function declines, serum calcium balance can be maintained only at the expense of increased bone resorption, ultimately resulting in renal osteodystrophy. • Secondary hyperparathyroidism can cause altered lipid metabolism, altered insulin secretin, resistance to erythropoietic therapy, impaired neurologic and immune functions, and increased mortality. • ROD progresses insidiously for several years before the onset of symptoms such as bone pain and fractures. Skeletal complications include osteitis fibrosa cystica (high bone turnover), osteomalacia (low bone turnover) and adynamic bone disease. When ROD symptoms appear, the disease is not easily amenable to treatment.

14. Treatment • Preventive measures should be initiated in patients in early stages of CKD to improve outcomes by the time they reach stage 5 CKD or ESRD. • Dietary phosphorus restriction (800 to 1,000 mg/day) should be first-line intervention for stage 3 or higher CKD. • By the time ESRD develops, most patients require a combination of phosphate-binding agents, vitamin D, and calcimimetic therapy to achieve K/DOQI goals. Phosphate-Binding Agents • Phosphate-binding agents decrease phosphorus absorption from the gut and are first-line agents for controlling both serum phosphorus and calcium concentrations.

15. K/DOQI guidelines recommend that elemental calcium from calcium containing binders should not exceed 1,500 mg/day and the total daily intake from all sources should not exceed 2,000 mg. This may necessitate combination of calcium- and noncalcium-containing products (e.g., sevelamer HCL, lanthanum carbonate). • Adverse effects of calcium-containing phosphate binders, as well as sevelamer and lanthanum, include constipation, diarrhea, nausea, vomiting, and abdominal pain. The risk of hypercalcemia is also a concern. To avoid potential drug interactions, phosphate binders should be administered 1 hour before or 3 hours after other oral medications. Vitamin D Therapy • Calcium (less than 9.5 mg/dL) and phosphorus (less than 4.6 mg/dL) must be controlled before vitamin D therapy is initiated. Calcitriol , 1,25-dihydroxyvitamin D 3 , directly suppresses PTH synthesis and secretion and upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia.

16. The newer vitamin D analogs paricalcitol and doxercalciferol may be associated with less hypercalcemia and, for paricalcitol, hyperphosphatemia. Vitamin D therapy, regardless of agent, is associated with decreased mortality. Calcimimetics • Cinacalcet reduces PTH secretion by increasing the sensitivity of the calcium-sensing receptor. The most common adverse events are nausea and vomiting. • The most effective way to use cinacalcet with other therapies has not been decided.

17. METABOLIC ACIDOSIS • A clinically significant metabolic acidosis is commonly seen when the GFR drops below 20 to 30 mL/min (stage 4 CKD). The goals of therapy in CKD are to normalize the blood pH (7.35 to 7.45) and serum bicarbonate (22 to 26 mEq/L). Consequences of metabolic acidosis include renal bone disease, reduced cardiac contractility, predisposition to arrhythmias, and protein catabolism. • Oral alkalinizing salts (e.g., sodium bicarbonate, Shohl solution, and Bicitra= CITRIC ACID / SODIUM CITRATE) can be used in patients with stage 4 or 5 CKD. Polycitra , which contains potassium citrate, should not be used in patients with severe CKD because hyperkalemia may result. • Metabolic acidosis in patients undergoing dialysis can often be managed by using higher concentrations of bicarbonate or acetate in the dialysate.

18. HYPERTENSION • The pathogenesis of hypertension in patients with CKD is multifactorial and includes fluid retention, increased sympathetic activity, an endogenous digitalis-like substance, elevated levels of endothelin-1, erythropoietin use, hyperparathyroidism, and structural arterial changes. • In early stage CKD, the target blood pressure for cardiovascular risk reduction is 130/80 mm Hg. The K/DOQI guidelines propose a predialysis blood pressure of less than 140/90 mm Hg and a postdialysis blood pressure of less than 130/80 mm Hg. • Salt (2 to 3 g/day) and fluid intake should be restricted. • Most patients with ESRD require three or more antihypertensive agents to achieve target blood pressure. As with less advanced CKD ACEIs, ARBs, and dihydropyridine calcium channel blockers are the preferred agents. • Blood pressure should be monitored at each visit, and at home when feasible.

19. HYPERLIPIDEMIA • The prevalence of hyperlipidemia increases as renal function declines. Hyperlipidemia should be managed aggressively in patients with ESRD to a low-density lipoprotein cholesterol goal of less than 100 mg/dL. Statins are the drugs of first choice. Although well tolerated by otherwise healthy patients, statins have the potential to cause myotoxic effects when administered in patients with hepatic disease or with interacting drugs such as azole antibiotics, cyclosporine, gemfibrozil, and niacin. • In patients with ESRD, lipid profile should be reassessed at least annually and 2 to 3 months after changing treatment.

20. OTHER SECONDARY COMPLICATIONS Pruritus Nutritional Status • Protein-energy malnutrition is common in patients with stage 4 or 5 CKD. Daily protein intake should be 1.2 g/kg for patients undergoin hemodialysis and 1.2 to 1.3 g/kg for those undergoing peritoneal dialysis. • Daily energy intake should be 35 kcal/kg for patients undergoing any type of dialysis. The intake should be lowered to 30 to 35 kcal/kg for patients older than 60 years. • Vitamins A and E are elevated in ESRD whereas water-soluble vitamins should be supplemented to replace dialysis-induced loss. Uremic Bleeding • Nondialytic therapies that may temporarily shorten increased bleeding time include cryoprecipitate, and estrogens.

21. What makes me weak? My fears. What keeps me standing? My faith. What sustains my mind? My quest for knowledge. What teaches me all lessons? My mistakes. What empowers me? My God & Me. What if I can't go on? Not an option.