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Nephrology I. ACUTE KIDNEY INJURY OR ACUTE RENAL FAILURE A. Definitions and Background 1. A KI is defined as an acute decrease in kidney function or GFR over hours, days, or even weeks and is associated with an accumulation of waste products and (usually) volume. 2. Criteria and classification o...

Nephrology I. ACUTE KIDNEY INJURY OR ACUTE RENAL FAILURE A. Definitions and Background 1. A KI is defined as an acute decrease in kidney function or GFR over hours, days, or even weeks and is associated with an accumulation of waste products and (usually) volume. 2. Criteria and classification of AKI a. Definition of AKI according to KDIGO (not graded) i. Increase in SCr of 0.3 mg/dL or more within 48 hours; or ii. Increase in SCr to 1.5 times baseline or more (baseline known or presumed within prior 7 days); or iii. Urinary volume less than 0.5 mL/kg/hour for at least 6 hours b. Urinary output classification i. Anuric: Less than 50 mL/24 hours; associated with worse outcomes ii. Oliguric: Less than 0.5 mL/kg/hour for 12 hours or more iii. Nonoliguric: More than 500 mL/24 hours; associated with better patient outcomes and easier to manage because of fewer problems with volume overload c. Staging of AKI (Table 1): Can categorize according to risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) categories or into stages 1–3 (Acute Kidney Injury Network [AKIN] AKIN or KDIGO) on the basis of changes in SCr and urinary output d. Common complications include fluid overload and acid-base and electrolyte abnormalities. Table 1. Staging of AKI RIFLE Classification (2004) R I F L E Classification SCr or GFR Criteria Risk of renal SCr increase to dysfunction 1.5 × baseline or GFR decrease > 25% Injury to SCr increase to kidney 2 × baseline or GFR decrease > 50% Failure of SCr increase to kidney 3 × baseline function or GFR decrease > 75% or SCr ≥ 4 mg/dL with acute rise of > 0.5 mg/dL per table in the consensus guideline Loss of Complete loss of kidney kidney function for function > 4 wk End-stage Complete loss of kidney kidney function for disease > 3 mo AKIN Criteria (2007) KDIGO Staging (2012) Common Criteria Stage SCr 1 ≥ 0.3-mg/dL increase or 1.5–2.0 × baseline 2 2–3 × baseline Stage SCr 1 ≥ 0.3-mg/dL increase or 1.5–1.9 × baseline 2 2.0–2.9 × baseline Urinary Output < 0.5 mL/kg/hr for 6–12 hr 3 > 3 × baseline or SCr ≥ 4 mg/dL with an acute increase of ≥ 0.5 mg/dL; or on RRT 3 ≥ 3 × baseline or increase to ≥ 4.0 mg/ dL or Initiation of RRT or in patients < 18 yr, decrease in eGFR to < 35 mL/min/1.73 m2 < 0.5 mL/kg/hr for ≥ 12 hr < 0.3 mL/kg/hr for ≥ 24 hr or Anuria for ≥ 12 hr AKIN = Acute Kidney Injury Network; KDIGO = Kidney Disease: Improving Global Outcomes; RIFLE = risk, injury, failure, loss, end-stage (stages of AKI); RRT = renal replacement therapy. Information from: Bellomo R, Ronco C, Kellum JA, et al.; the ADQI Workgroup. Acute renal failure – definition, outcome measures, animal models, and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-12; Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO practice guideline for acute kidney injury. Kidney Int Suppl 2012;2:1-138. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-261 Nephrology 3. Community-acquired AKI a. Low incidence (0.02%) in otherwise healthy patients b. As high as 13% incidence among patients with CKD c. Usually has a very high survival rate (70%–95%) d. Single insult to the kidney, often drug induced e. SCr may return to baseline but may lead to development or progression of CKD 4. Hospital-acquired AKI a. Has a moderate incidence (2%–5%) and moderate survival rate (30%–50%) b. Single or multifocal insults to the kidney c. Can still be reversible 5. A 2015 international study of critically-ill patients found AKI in over 50% of intensive care unit patients, with mortality 4–5 times higher than in those without AKI (Int Care Med 2015;41:1411-23). 6. Estimating kidney function in AKI a. Difficult because commonly used SCr-based equations (Cockcroft-Gault, Modification of Diet in Renal Disease [MDRD], and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) are not appropriate (assume stable SCr) b. Equations by Brater and Jelliffe are probably more accurate than the Cockcroft-Gault equation but have not been rigorously tested. c. The Chen formula for kinetic eGFR provides a promising, simple method to estimate kidney function when SCr is not stable. Further study is still needed. d. If patient is nonoliguric, can calculate creatinine clearance (CrCl) according to a timed urine collection and using the average of SCr samples obtained before and after the urine collection B. Risk Factors Associated with AKI 1. Preexisting CKD (eGFR less than 60 mL/minute/1.73 m2) 2. Volume depletion: Vomiting, diarrhea, poor fluid intake, fever, diuretic use, intravascular or effective volume depletion (e.g., heart failure, liver disease with ascites) 3. Use of nephrotoxic agents or medications a. Intravenous radiographic contrast b. Aminoglycosides and amphotericin c. Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors d. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) e. Cyclosporine and tacrolimus f. Combination of piperacillin/tazobactam plus vancomycin (Crit Care Med 2018;46:12-20). 4. Obstruction of the urinary tract C. Classifications of AKI (Table 2) 1. Prerenal AKI a. Initially, the kidney is undamaged. b. Characterized by hypoperfusion to the kidney i. Systemic hypoperfusion: Hemorrhage, volume depletion, drugs, heart failure ii. Isolated kidney hypoperfusion: Renal artery stenosis, emboli c. Physical examination: Hypotension, signs of volume depletion d. Urinalysis will initially be normal (no sediment) but concentrated. 2. Functional AKI a. Kidney is undamaged; often classified as prerenal azotemia b. Caused by reduced glomerular hydrostatic pressure; often without hypotension ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-262 Nephrology c. In general, medication-related (cyclosporine, ACEIs and ARBs, and NSAIDs) or seen in patients with low effective blood flow (patients with HFrEF, patients with liver disease, and older adults) who cannot compensate for alterations in afferent and efferent tone d. Concentrated urine 3. Intrinsic AKI a. Kidney is damaged, and damage can be linked to the structure involved: Small blood vessels, glomeruli, renal tubules, and interstitium b. Most common cause is ATN; other causes include AIN, vasculitis, and acute glomerulonephritis. c. History: Identifiable insult, drug use, infections d. Physical examination: Normotensive, euvolemic, or hypervolemic depending on the cause; check for signs of allergic reactions or embolic phenomenon e. Urinalysis will reflect damage (e.g., granular casts, epithelial cell casts); urine generally is not concentrated. 4. Postrenal AKI a. Kidney is initially undamaged. Bladder outlet obstruction is the most common cause of postrenal AKI. Lower urinary tract obstruction may be caused by calculi. Ureteric obstructions may be caused by clots or intraluminal obstructions. Extrarenal compression can also cause postrenal disease. Elevated intraluminal pressure upstream of the obstruction will result in damage if the obstruction is not relieved. b. History: Trauma, benign prostatic hyperplasia, cancers c. Physical examination: Distended bladder, enlarged prostate d. Urinalysis may be nonspecific. e. Radiography or ultrasonography may reveal hydronephrosis and help identify obstruction. Table 2. Classifications of AKI Prerenal and Functional Intrinsic (ATN and AIN) History and clinical presentation Volume depletion Renal artery stenosis Heart failure Hypercalcemia NSAID, ACEI, and ARB use Cyclosporine Kidney stones Longstanding renal hypoperfusion Nephrotoxins (e.g., contrast or antibiotics) BPH Cancers Vasculitis Glomerulonephritis Postrenal Physical examination Hypotension Dehydration Petechia if thrombotic Ascites Rash, fever (with AIN) Persistent hypotension Distended bladder Enlarged prostate Serum BUN/SCr ratio > 20:1 10–15:1 10–15:1 Urinary sodium < 20 mEq/L > 40 mEq/L > 40 mEq/L FENa < 1% > 2% > 2% FeU < 35% > 50% > 50% Urinary osmolality High urine osmolality Low urine osmolality Low urine osmolality Urinary sediment Normal Consider adding Hyaline casts Muddy brown granular casts; tubular epithelial casts; hyaline casts Variable; may be normal a ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-263 Nephrology Table 2. Classifications of AKI (continued) Prerenal and Functional Intrinsic (ATN and AIN) Postrenal Urinary WBC Negative 2–4+ Variable Urinary RBC Negative 2–4+ 1+ Proteinuria Negative Positive Negative ACEI = angiotensin-converting enzyme inhibitor; AIN = acute interstitial nephritis; ARB = angiotensin II receptor blocker; ATN = acute tubular necrosis; BPH = benign prostatic hypertrophy; FENa = fractional excretion of sodium; FeU = fractional excretion of urea; NSAID = nonsteroidal anti-inflammatory drug; RBC = red blood cell count. Calculation of fractional excretion of sodium (FENa − percentage of Na filtered at the glomerulus that is excreted in the urine) a FENa (%) = ____________________________ (urinary sodium)/(serum sodium) × 100 (urinary creatinine)/(SCr) D. Prevention of AKI 1. Avoid nephrotoxic drugs, when possible. 2. Ensure adequate hydration. 3. Educate patient. 4. Use drug therapies to decrease the incidence of contrast-induced nephropathy (see section II, “DrugInduced Kidney Damage”). E. Treatment and Management of Established AKI 1. Prerenal azotemia: Correct primary hemodynamics. a. Intravenous normal saline, Lactated Ringer solution or other balanced crystalloid, if volume depleted b. Blood pressure management, if needed c. Blood products, if needed d. Hold or discontinue medications that affect renal hemodynamics (i.e., ACEIs, ARBs, NSAIDs). 2. Intrinsic: No specific therapy universally effective a. Eliminate the causative hemodynamic abnormality or toxin. b. Avoid additional insults. c. Manage fluid and electrolytes to prevent volume depletion or overload and electrolyte imbalances. d. Nutrition support is important, but no specific recommendations are widely accepted. e. Medical therapy recommendations according to the KDIGO guidelines i. Loop diuretics: Recommend not using to prevent AKI (grade 1B) and suggest not using to treat AKI, except to manage hypervolemia (grade 2C) ii. Therapeutic agents (e.g., dopamine, nesiritide, fenoldopam, mannitol) are not indicated in AKI management and may be harmful for the patient. 3. Postrenal AKI: Monitor fluid balance and manage fluid losses from postobstructive diuresis. Early identification is important. Consult urology or radiology. 4. Indications for renal replacement therapy (RRT) in AKI a. BUN greater than 100 mg/dL or signs of uremia (e.g., encephalopathy, pericarditis) b. Volume overload unresponsive to diuretics c. Life-threatening electrolyte imbalance: Hyperkalemia, hypermagnesemia d. Refractory metabolic acidosis ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-264 Nephrology Patient Cases 6. A 67-year-old man is referred for intermittent chest pain. His medical history is significant for CKD KDIGO category G3a, type 2 diabetes, and hypertension. Medications include enalapril, hydrochlorothiazide, and pioglitazone. Laboratory values include SCr 1.8 mg/dL, glucose 189 mg/dL, Hgb 12 g/dL, and hematocrit (Hct) 36%. His physical examination is normal. The treatment plan is elective cardiac catheterization. Which is best for hydration? A. 0.9% sodium chloride. B. 0.45% sodium chloride. C. 5% dextrose/0.45% sodium chloride. D. Oral hydration with water. 7. After the administration of radiocontrast, which best represents the optimal time to reevaluate renal function to assess for the development of contrast-associated nephropathy? A. 6 hours. B. 24 hours. C. 4 days. D. 7 days. II. DRUG-INDUCED KIDNEY DAMAGE A. Introduction: Drugs can cause kidney damage through many mechanisms. Evaluate potential drug-induced nephropathy on the basis of the period of ingestion, patient risk factors, and the propensity of the suspected agent to cause kidney damage. 1. Risk factors a. History of CKD b. Advanced age c. Critical illness 2. Epidemiology a. 7% of all drug toxicities b. 18%–27% of AKI in hospitals c. 1%–5% of NSAID users in community d.  Most implicated medications: Aminoglycosides, NSAIDs, ACEIs, intravenous contrast dye, amphotericin, piperacillin/tazobactam plus vancomycin 3. The kidneys are at elevated risk of toxic injury because: a. High exposure to toxin: Kidney receives 20%–25% cardiac output. b. Autoregulation and specialized blood flow through glomerulus c. High intrarenal drug metabolism d. Tubular transport processes e. Concentration of solutes (i.e., toxins) in tubules f. High energy requirements of tubule epithelial cells g. Urine acidification 4. Pseudo-nephrotoxicity a. Drugs that inhibit the tubular secretion of creatinine: Trimethoprim, cimetidine b. Drugs that increase BUN: Corticosteroids, tetracycline c. Drugs that interfere with the creatinine assay: Cefoxitin and other cephalosporins ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-265 Nephrology B. Acute Tubular Necrosis 1. Most common drug-induced kidney disease in the inpatient setting 2. Aminoglycoside nephrotoxicity a. Incidence: 1.7%–58% of patients b. Pathogenesis i. Caused by proximal tubular damage leading to obstruction of the lumen ii. Cationic charge of drug leads to binding to tubular epithelial cells and uptake into those cells. iii. Accumulation of phospholipids and toxicity c. Presentation i. Gradual rise in SCr concentrations and decrease in GFR after 6–10 days of therapy ii. Patients usually have nonoliguric kidney failure. iii. Wasting of electrolytes (i.e., hypokalemia and hypomagnesemia) may occur. d. Risk factors i. Related to dosing: Large total cumulative dose, prolonged therapy, trough concentration exceeding 2 mg/L, recent previous aminoglycoside therapy ii. Concurrent use of other nephrotoxins (cyclosporine, amphotericin B, diuretics, vancomycin) iii. Patient related: Preexisting kidney disease or damage, advanced age, poor nutrition, shock, gram-negative bacteremia, liver disease, hypoalbuminemia, obstructive jaundice, dehydration, and K and magnesium deficiencies e. Prevention i. Avoid use in high-risk patients. ii. Maintain adequate hydration. iii. Limit the total cumulative aminoglycoside dose. iv. Avoid use of other nephrotoxins. v. Use extended-interval (once daily) dosing; monitor these and other high-risk patients closely. vi. Close therapeutic drug monitoring is necessary in patients with preexisting kidney disease. 3. Radiographic contrast media nephrotoxicity related to intravenous contrast use a. Incidence i. Third leading cause of inpatient AKI ii. Less than 2% and up to 50% of patients, depending on risk iii. Associated with a high (34%) in-hospital mortality rate iv. Commonly used in procedures such as contrast-enhanced computed tomography (CT), cardiac catheterization, angiography, and venography b. Pathogenesis i. Renal ischemia caused by alteration in intrarenal hemodynamics (a) Osmotic diuresis and dehydration. Contrast media based on osmolality: (1) High-osmolar contrast media about 2000 mOsm/kg (2) Low-osmolar contrast media 600–800 mOsm/kg (3) Iso-osmolar contrast media 290 mOsm/kg (b) Some contrast agents also cause systemic hypotension on injection and renal vasoconstriction caused by the release of adenosine, endothelin, and other vasoconstrictors. ii. Direct tubular toxicity caused by reactive oxygen species; directly influenced by tubular flow rates and duration of exposure of tubules c. Presentation i. Initial transient osmotic diuresis, followed by tubular proteinuria ii. SCr rises within 24 hours and peaks 2–5 days after the procedure. iii. 50% of patients develop oliguria, and some will need dialysis. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-266 Nephrology d. Risk factors for toxicity i. Preexisting kidney disease (SCr more than 1.5 mg/dL or eGFR less than 60 mL/minute/1.73 m2) ii. Diabetes mellitus iii. Volume depletion iv. Age 75 and older v. Anemia vi. Conditions with decreased blood flow to the kidney (e.g., HFrEF) vii. Hypotension viii. Other nephrotoxins ix. Large doses of contrast (more than 140 mL) or hyperosmolar contrast agents e. Prevention i. Volume expansion with either intravenous isotonic saline or sodium bicarbonate (KDIGO recommendation, grade 1A) beginning 6–12 hours before the procedure; maintain urinary output greater than 150 mL/hour. Recent data analyses from the PRESERVE trial suggested no added benefit on short-term AKI or long-term outcomes from the use of intravenous sodium bicarbonate compared with isotonic saline (N Engl J Med 2018;378:603-14). ii. Use an alternative imaging study, if possible. iii. Discontinue nephrotoxic agents and avoid diuretics. iv. Use low-osmolar or iso-osmolar contrast agents in patients at risk (KDIGO recommendation, grade 1B). v. Medications used to prevent contrast-induced nephropathy (a) Acetylcysteine: Antioxidant and vasodilatory mechanism. Accumulation of glutathione takes time, so it may not be as effective in emergencies. Various dosing recommendations. Widely used. Considered safe. May use oral acetylcysteine in addition to intravenous hydration (KDIGO suggestion, grade 2D). Recent studies suggest no additional benefit over intravenous hydration (PRESERVE trial: N Engl J Med 2018;378:603-14 and ACT: Circulation 2011;124:1250-9). (b) Ascorbic acid: Antioxidant. One large study showed benefit when used immediately before. Not confirmed. Give oral ascorbic acid 3 g before procedure and 2 g twice daily for two doses after procedure. May play a role in emergencies (c) Theophylline: Do not use (KDIGO suggestion, grade 2C). (d) Fenoldopam: Do not use (KDIGO recommendation, grade 1B). (e) Prophylactic hemodialysis (HD) and hemofiltration: Do not use (KDIGO suggestion, grade 2C). f. Joint Commission standards on medication management regarding radiologic contrast media i. Treated as a drug ii. Subject to all the standards for medication management in a health system g. Nephrogenic systemic fibrosis (a.k.a. nephrogenic fibrosing dermopathy) i. Rare but associated with gadolinium-based agents used in high doses for magnetic resonance imaging/angiogram ii. Occurs in patients with moderate CKD to end-stage renal disease (ESRD) given intravenous contrast, and systemic acidosis seems to be a risk factor iii. Although gadolinium does not cause AKI, it is considered inappropriate for use in patients with AKI or CKD. iv. Onset 2–18 days after exposure v. Presents as burning; itching; swelling, hardening, or tightening of skin; skin patches; spots on eyes; joint stiffness; and muscle weakness ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-267 Nephrology vi. Can cause organ damage, and deaths have occurred vii. In 2010, the U.S. Food and Drug Administration (FDA) required the addition of a warning to prescribing information. 4. Cisplatin nephrotoxicity a. Incidence: 6%–13% with appropriate dosing and administration b. Pathogenesis: Complex; direct tubular toxin c. Presentation i. SCr peaks 10–12 days after therapy begins but may continue to rise with subsequent cycles of therapy. ii. Renal magnesium wasting is common (may be severe with central nervous system symptoms) and may be accompanied by hypokalemia and hypocalcemia. iii. May result in irreversible kidney damage d. Risk factors for toxicity: Many courses of cisplatin, advanced patient age, dehydration, concurrent nephrotoxins, kidney irradiation, alcohol abuse e. Prevention i. Avoid concurrent use of nephrotoxins. ii. Use smallest dose possible and decrease frequency of administration. iii. Aggressive intravenous hydration: 1–4 L within 24 hours of high-dose cisplatin iv. Amifostine: Cisplatin-chelating agent may be considered in patients at risk of nephrotoxicity v. Alternative platinum analogs (i.e., carboplatin or oxaliplatin) can be used in patients at high risk of nephrotoxicity. 5. Amphotericin B nephrotoxicity a. Incidence i. Increases as cumulative dose increases ii. Approaches 80% with cumulative doses of 4 g or more b. Pathogenesis i. Direct proximal and distal tubular toxicity ii. Arterial vasoconstriction c. Presentation i. Manifests after administration of 2–3 g ii. Loss of tubular function leads to electrolyte wasting (especially K+, Na+, and Mg2+) and distal tubular acidosis. iii. Patients may need substantial K+ and Mg2+ replacement. iv. SCr increases and GFR decreases because of a decrease in kidney blood flow from vasoconstriction caused by amphotericin. d. Risk factors for toxicity: Existing kidney dysfunction, high average daily doses, diuretic use, volume depletion, concomitant nephrotoxins, rapid infusion e. Prevention i. Avoid other nephrotoxins (especially cyclosporine) and limit the total cumulative dose. ii. Intravenous hydration with 0.9% sodium chloride at least 1 L/day before each dose iii. Use a liposomal product in high-risk patients. C. Functional (Hemodynamically Mediated) AKI 1. Caused by a decrease in intraglomerular pressure through the vasoconstriction of afferent arterioles or the vasodilation of efferent arterioles 2. ACEIs and ARBs a. Pathogenesis i. Vasodilation of the efferent arteriole ii. Leads to a decrease in glomerular hydrostatic pressure and a resultant decrease in GFR ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-268 Nephrology b. Presentation i. Exerts a predictable dose-related reduction in GFR ii. SCr is usually expected to rise by up to 30%. (a) Usually occurs within 2–5 days (b) Usually stabilizes in 2–3 weeks (c) Increases greater than 30% may be harmful. (d) Usually reversible on drug discontinuation c. Risk factors for toxicity: Patients with bilateral (or unilateral with a solitary kidney) renal artery stenosis, decreased effective kidney blood flow (HFrEF, liver disease), preexisting kidney disease, and volume depletion d. Prevention i. Initiate therapy with low doses and gradually titrate. ii. Change to long-acting agents once tolerance is established. iii. Initially, monitor kidney function and SCr concentrations daily for inpatients and weekly for outpatients. iv. Avoid concomitant use of diuretics, if possible, during therapy initiation. v. Avoid concomitant use of NSAIDs. 3. NSAIDs a. Incidence: Estimates indicate that 500,000–2.5 million people develop NSAID-induced nephrotoxicity annually in the United States. b. Pathogenesis i. Vasodilatory prostaglandins help maintain glomerular hydrostatic pressure by afferent arteriolar dilation, especially in times of decreased kidney blood flow. ii. NSAID administration in the setting of decreased kidney perfusion reduces this compensatory mechanism by decreasing the production of prostaglandins, resulting in afferent vasoconstriction and reduced glomerular blood flow. c. Presentation i. Can occur within days of starting therapy ii. Patients generally have low urinary volume and Na; may also have an increase in BUN, SCr, K+, edema, and weight d. Risk factors for toxicity: Preexisting kidney disease, systemic lupus erythematosus, high plasma renin activity (e.g., HFrEF, liver disease), diuretic therapy, atherosclerotic disease, and advanced age e. Prevention i. Use therapies other than NSAIDs, when appropriate (e.g., acetaminophen for osteoarthritis). ii. COX-2–specific inhibitors have not been shown to cause less kidney dysfunction, and they increase cardiovascular complications. f. Treatment i. If NSAID-induced AKI is suspected, discontinue drug and give supportive care. ii. Avoid concomitant use of medications affecting the renin-angiotensin-aldosterone system. iii. Recovery is usually rapid. 4. Cyclosporine and tacrolimus a. Incidence i. 5-year risk of developing CKD after transplantation of a nonrenal organ is 7%–21%. ii. Occurrence of kidney failure in the transplant recipient population increases the risk of death by 4-fold. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-269 Nephrology b. Pathogenesis i. Caused by a dose-related hemodynamic mechanism; calcineurin inhibitors may also cause chronic interstitial nephritis through a separate mechanism that is not dose related ii. Causes vasoconstriction of afferent arterioles through possible increased activity of various vasoconstrictors (thromboxane A2, endothelin, sympathetic nervous system) or decreased activity of vasodilators (nitric oxide, prostacyclin) iii. Increased vasoconstriction from angiotensin II may also contribute. iv. Effects usually resolve with a dose reduction. c. Presentation i. Can occur within days of starting therapy ii. SCr rises and eGFR decreases. iii. Patients often have hypertension, hyperkalemia, and hypomagnesemia. iv. A biopsy is often needed for kidney transplant recipients to distinguish drug-induced injury from acute allograft rejection. d. Risk factors for toxicity include advanced age, high initial cyclosporine dose, kidney graft rejection, hypotension, infection, and concomitant nephrotoxins. e. Prevention i. Monitor serum cyclosporine and tacrolimus concentrations closely. ii. Use lower doses in combination with other nonnephrotoxic immunosuppressants (e.g., steroids, mycophenolate mofetil). iii.  Calcium channel blockers may help antagonize the vasoconstrictor effects of cyclosporine by dilating afferent arterioles. D. Tubulointerstitial Disease 1. Involves the renal tubules and the surrounding interstitium 2. Onset can be acute or chronic. a. Acute onset generally involves interstitial inflammatory cell infiltrates, rapid loss of kidney function, and systemic symptoms (i.e., fever and rash). b. Chronic onset shows interstitial fibrosis, slow decline in kidney function, and no systemic symptoms. 3. Acute allergic interstitial nephritis a. Cause of up to 3% of all AKI cases; caused by an allergic hypersensitivity reaction that affects the interstitium of the kidney b. Many medications and medication classes can cause this type of kidney failure, including β-lactams and NSAIDs (although the presentations are different). i. Penicillins: Classic presentation of acute allergic interstitial nephritis. Signs and symptoms occur about 1–2 weeks after therapy initiation and include fever, maculopapular rash, eosinophilia, pyuria, hematuria, and proteinuria. Eosinophiluria may also be present. ii. NSAIDs: Onset much more delayed; typically begins about 6 months into therapy. Usually occurs in older adults receiving chronic NSAID therapy. Patients do not usually have systemic symptoms. c. Kidney biopsy may be needed to confirm the diagnosis. d. Treatment includes discontinuing the offending agent and possibly initiating steroid therapy. 4. Chronic interstitial nephritis a. Often progressive and irreversible b. Lithium i. Toxicity results from a duration-related decrease in response to antidiuretic hormone after long-term use (more than 10 years of therapy). ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-270 Nephrology ii. Clinical presentation (a) Often asymptomatic, with slow progression over years (b) May be recognized by slow increases in blood pressure or BUN and SCr iii. Risks include long duration of use, elevated serum concentrations, and repeated episodes of AKI from lithium toxicity. iv. Prevention is accomplished by maintaining the lowest serum lithium concentrations possible, avoiding dehydration, and monitoring kidney function closely. c. Cyclosporine and tacrolimus: Presents later in therapy (about 6–12 months) than hemodynamically mediated toxicity 5. Papillary necrosis a. Form of chronic interstitial nephritis affecting the papillae, causing necrosis of the collecting ducts b. Results from the long-term use of analgesics i. “Classic” example was with products that contained phenacetin. ii. Occurs more often with combination products iii. Products containing caffeine may also increase risk. c. Evolves slowly as time progresses d. Affects women more often than men e. Difficult to diagnose, and much controversy remains about risk, prevention, and cause E. Postrenal (Obstructive) Nephropathy 1. Results from obstruction of the flow of urine after glomerular filtration 2. Renal tubular obstruction a. Caused by intratubular precipitation of tissue degradation products or precipitation of drugs or their metabolites i. Tissue degradation products (a) Uric acid intratubular precipitation after tumor lysis after chemotherapy (b) Drug-induced rhabdomyolysis leading to intratubular precipitation of myoglobin (c) Results in rapid decline in kidney function, with resultant oliguric or anuric kidney failure ii. Drug precipitation: Sulfonamides, methotrexate, acyclovir, ascorbic acid; needlelike crystals observed in leukocytes found on urinalysis can prompt diagnosis b. Prevention includes pretreatment hydration, maintenance of high urinary volume, and alkalinization of the urine. 3. Extrarenal urinary tract obstruction a. Benign prostatic hypertrophy can be worsened by anticholinergics. b. Bladder outlet or ureteral obstruction from fibrosis after cyclophosphamide for hemorrhagic cystitis 4. Nephrolithiasis a. Usually does not affect GFR, so does not have the classic signs and symptoms of nephrotoxicity b. Some medications contribute to the formation of kidney stones: triamterene, sulfadiazine, indinavir, and ephedrine derivatives. F. Glomerular Disease 1. Proteinuria is the hallmark of glomerular disease and may occur with or without a decrease in GFR. 2. A few distinct drugs can cause glomerular disease. a. NSAIDs: Associated with acute allergic interstitial nephritis b. Heroin: Can be caused by direct toxicity or toxicity from additives or infection from injection, and ESRD develops in most cases c. Parenteral gold: Results from immune complex formation along glomerular capillary loops ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-271 Nephrology III. CHRONIC KIDNEY DISEASE A. Background 1. Prevalence: According to the 2020 U.S. Renal Data System Annual Report: 14.9% of the U.S. adult population (20 years and older) in the National Health and Nutrition Examination Survey (2015–2018) had CKD. There were 554,038 patients on dialysis in 2018 and 229,887 transplant recipients. Incidence rate is flat, so growth in the number of patients with ESRD results mainly from the longer life span of these patients. 2. Definition of CKD a.  According to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI), CKD is kidney damage for more than 3 months, as defined by structural or functional abnormality of the kidney, with or without decreased GFR. Manifested by either pathologic abnormalities or markers of kidney damage – including albuminuria, abnormal urine sediment, serum electrolyte abnormalities, abnormal histology, or abnormalities in imaging tests – or GFR less than 60 mL/minute/1.73 m2 for 3 months, with or without kidney damage (Table 3) Table 3. KDOQI Stages in CKD Stage of Renal Disease Increased risk of developing kidney disease Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Damage Risk factors for CKD (diabetes, HTN, family history) Kidney damage with normal GFR Kidney damage with mild decrease in GFR Moderate decrease in GFR Severe decrease in GFR Kidney failure GFR (mL/min/1.73 m2) ≥ 90 ≥ 90 60–89 30–59 15–29 < 15 CKD = chronic kidney disease; HTN = hypertension. b. According to the KDIGO clinical practice guideline for the evaluation and management of CKD, CKD is defined as abnormalities in kidney structure or function for more than 3 months. These abnormalities may be seen as persistent markers of kidney damage or GFR less than 60 mL/minute/ 1.73 m 2 (Table 4). Table 4. KDIGO Categories in CKD GFR Category G1 G2 G3a G3b G4 G5 Terms Kidney damage with normal or high GFR Kidney damage with mildly decreased GFR Mildly to moderately decreased GFR Moderately to severely decreased GFR Severely decreased GFR Kidney failure GFR (mL/min/1.73 m2) ≥ 90 60–89 45–59 30–44 15–29 < 15 B. Etiology 1. Diabetes (45% of new cases of ESRD in the United States) 2. Hypertension (28% of new cases) 3. Glomerulonephritis (7.4%) 4. Others: Urinary tract disease, polycystic kidney disease, lupus, analgesic nephropathy, unknown ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-272 Nephrology C. Risk Factors 1. Susceptibility (associated with an increased risk but not proven to cause CKD): Advanced age, reduced kidney mass, low birth weight, racial or ethnic minority, family history, low income or education, systemic inflammation, and dyslipidemia; mostly not modifiable 2.  Initiation (directly cause CKD): Diabetes, hypertension, autoimmune disease, polycystic kidney diseases, and drug toxicity; may be modifiable by drug therapy 3. Progression (result in faster decline in kidney function): Hyperglycemia, elevated blood pressure, proteinuria, and smoking Patient Cases Questions 8–11 pertain to the following case. A 55-year-old man has a history of hypertension and newly diagnosed type 2 diabetes. He denies alcohol use but does smoke cigarettes (1 pack/day). His medications include atenolol 50 mg/day and a multivitamin. At your pharmacy, his blood pressure is 149/92 mm Hg. His ACR is 400 mg/g. A recent SCr is 1.9 mg/dL, which is consistent with a value measured 3 months earlier. His eGFR is 50 mL/minute/1.73 m2. 8. Which category best reflects his kidney disease, according to the KDIGO criteria? A. G2. B. G3a. C. G3b. D. G4. 9. Using the KDIGO categorization, which best assesses this patient’s albuminuria? A. Category A1. B. Category A2. C. Category A3. D. Nephrotic-range proteinuria. 10. Assuming that nonpharmacologic approaches have been optimized, which is best to limit the progression of his kidney disease? A. Add nifedipine. B. Add diltiazem. C. Add enalapril. D. Increase atenolol. 11. Enalapril is added to this patient’s regimen. Two weeks later, he returns for a follow-up. His blood pressure is 139/89 mm Hg. A repeat SCr is 2.3 mg/dL, and serum potassium is 5.2 mEq/L. Which is the best recommendation for this patient? A. Add chlorthalidone 50 mg/day. Monitor blood pressure, SCr, and K in 2 weeks. B. Change enalapril to diltiazem extended release. Monitor blood pressure, SCr, and K in 2 weeks. C. Change enalapril to valsartan. D. Increase atenolol. ACCP Updates in Therapeutics® 2022: Pharmacotherapy Preparatory Review and Recertification Course 2-273