Acute Renal FailureCases

•Mohammad Ruhal Ain•R Ph, PGDPRA, M Pharm (Clin.

Pharm)•Department of Clinical Pharmacy

PRERENAL AND FUNCTIONAL ACUTE

RENAL FAILURE

Congestive Heart Failure and Nonsteroidal Anti-Inflammatory Drug Use

1 .A.W. is a 71-year-old white man who had a ST-segment elevation myocardial infarction (STEMI) 2 months ago. His ejection fraction is currently 15% (normal, 50%–60%). He presents today for his 2-month follow-up clinic appointment complaining of shortness of breath, dyspnea on exertion, and inability to produce much urine. His medical history is significant for longstanding hypertension, coronary artery disease, osteoarthritis, and recent-onset heart failure (HF) after his MI. His home medications include furosemide 40 mg every day, enalapril 5 mg daily, metoprolol XL 100 mg daily, digoxin 0.125 mg daily, atorvastatin 40 mg QD, and naproxen sodium 550 mg twice daily (BID), all of which are taken orally (PO).With the exception of naproxen, A.W often forgets to take his medications. Physical examination reveals lower leg 3+pitting edema, pulmonary crackles and wheezes, positive jugular venous distention, and an S3 heart sound. His vitalsigns are significant for a blood pressure (BP) of 198/97 mm Hg and a weight gain of 4 kg since his last visit 2 months ago. Last month, his BUN and SrCr were

23 (normal, 5–20) and 1.2 mg/dL (normal, 0.5–1.2), respectively .

What are A.W.’s risk factors for ARF?

CASE 1 Part 1

[SI units: BUN, 8.2 mmol/L (normal, 1.8–7.1); SrCr, 106 mol/L (normal, 44.2–106)]

ANSWER-A.W.’s risk factors for ARF are CHF with poor cardiac

output (ejection fraction, 15%) that resulted from his STEMI and his medication, naproxen sodium. CHF is a major cause of functional ARF.

-A.W.’s diminished cardiac output has resulted in decreased effective circulating volume and activation of the RAA system, which are impairing his renal perfusion.

-In states of decreased renal perfusion, prostaglandins

E2 and I2 compensate for the afferent arteriole vasoconstriction by stimulating afferent arteriole vasodilation, and thereby enhancing renal blood flow. Prostaglandin synthesis is mediated predominantly by cyclooxygenase-1 (COX-1) and perhaps

cyclooxygenase-2 (COX-2) .

-Nonsteroidal anti-inflammatory drugs (NSAID), such as naproxen, are often overlooked as causes of ARF.

-NSAID exert their pharmacologic effect by inhibiting prostaglandin synthesis, thereby negating compensatory vasodilation. NSAIDs induce abrupt decreases in GFR in at-risk patient populations, specifically those with CHF, liver disease, the elderly, or dehydrated patients. Indomethacin is associated with the highest risk of NSAIDs-induced renal ischemia, whereas aspirin appears to have the lowest risk.

-Naproxen, ibuprofen, piroxicam, and diclofenac are considered intermediate in their relative capacities to acutely compromise renal perfusion.

-Sulindac is a prodrug that is converted to its active sulfide metabolite by the liver and then becomes reversibly oxidized back to its parent compound in the kidney; renal prostaglandin synthesis is essentially unaltered by sulindac.Cases of sulindac-induced renal dysfunction have been reported when the drug was administered to patients with cirrhosis and ascites.

2 .A.W.’s cardiologist obtains a stat digoxin level, electrolyte panel, urinalysis, and urine electrolyte panel. The digoxin level is reported as “not detectable” (target, 0.5–0.8 ng/mL). Other significant serum laboratory values include Na+ of 140 mEq/L(normal, 135–145), BUN 56mg/dL (normal, 5–20), and creatinine of 1.5 mg/dL (normal, 0.5–1.2). The urinalysis is significant for a urinary osmolality of 622mOsm/kg (normal, 300–500mOsm/kg), and specific gravity of 1.092 (normal, 1.010–1.020). The urine electrolytes are significant for Na+ of 12 mEq/L (normal, 20–40) and creatinine of 87 mg/dL.

What laboratory findings suggest functional ARF?

[SI units: sodium, 140 mmol/L(normal, 135–145); BUN, 20 mmol/L (normal,1.8–7.1); SrCr, 132.6 mol/L (normal, 44.2–106); urine Cr, 7691 mol/L]

CASE 1 Part 2

A.W. has classic laboratory findings associated with poor renal perfusion (Table 30-2). It is important to compare the current and previous laboratory data to assess acute changes inrenal function. Compared with last month, A.W.’s renal function has deteriorated based on substantial increases in BUN and SrCr concentrations; BUN has increased nearly twofoldand creatinine by 25%. The BUN:SrCr ratio is >20:1, suggesting poor renal blood flow, which is corroborated by other urinary indices such as the urinary Na+ 12 mEq/L; specificgravity (elevated), 1.090; urine osmolality, 622 mOsm/kg; and the calculated FENa+ , 0.14%. These values reflect the ability of the renal tubules to respond to vasopressin and aldosterone in an attempt to expand effective circulating volume and restore renal perfusion.

ANSWER

-Another consideration is furosemide-induced volume depletion. ;

-however, the non detectable serum digoxin level indicates likely noncompliance with his

medications .

3 .How should A.W.’s prerenal azotemia be treated? -Restoring and improving A.W.’s cardiac output and renal perfusion will

rapidly correct the prerenal azotemia .This can be achieved by:

)a( assuring adherence to his heart failure medications (furosemide, enalapril, metoprolol XL, and digoxin) ,

)b (controlling BP to a goal of <135/85 mm Hg by decreasing both preload and afterload.

)c (modifying any drug therapy that has deleterious effects on the renal hemodynamics (e.g., NSAID). Naproxen should be discontinued and substituted with acetaminophen to treat his osteoarthritis. - Normal renal function should return in a few days after correction of the underlying causes.

CASE 1 Part 3

Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Induced Acute Renal Failure

PRERENAL AND FUNCTIONAL ACUTE RENAL FAILURE

CASE 2 Part 14 .G.B. is a 53-year-old white woman with hypertension, coronary artery disease,

peripheral vascular disease, and diabetes, for which she had been taking hydrochlorothiazide 25 mg PO daily, atorvastatin 10 mg PO daily, aspirin 81 mg PO daily, and NPH insulin 30 U subcutaneously Q morning and 15 U subcutaneously Q evening. At last week’s clinic visit, she had two consecutive BP readings of 187/96 and 193/95 mm Hg, respectively, measured 20 minutes a part. At that time, G.B.’s primary care physician discontinued her hydrochlorothiazide and started her on lisinopril 5mg PO daily. She returns to the clinic today for her 1 week follow-up appointment complaining of dizziness, very little urine production over the past week, and swelling in her ankles . Her BP is 98/43 mm Hg. A stat serum electrolyte panel is significant for a BUN of 62 mg/dL (normal, 5–20) and an SrCr of 6.1 mg/dL (normal, 0.5–1.2).

Why is G.B. experiencing ARF?[SI units: BUN, 22.1 mmol/L (normal, 1.8–7.1); SrCr, 539 mol/L (normal, 44.2–106)]

-Inhibition of the RAA system in patients with compromised renal blood flow is a common cause of functional ARF .

-A basic understanding of the effects of the RAA system on renal hemodynamics is necessary in this situation .

-When renal perfusion is impaired, the juxtaglomerular cells of the kidney secrete renin into the plasma and lymph. Renin cleaves circulating angiotensinogen to form angiotensin I (AT I), which is further cleaved by angiotensin-converting enzyme (ACE), to form angiotensin II (AT II). AT II induces two physiologic events to improve renal perfusion:

First, it directly causes systemic vasoconstriction, which shunts blood to the major organs, and indirectly increases intravascular volume through aldosterone- and vasopressin-mediated activity. Second, it preferentially vasoconstricts the efferent renal arteriole to maintain adequate intraglomerular hydrostatic pressure. Under conditions of decreased arterial pressure or effective circulating volume, the RAA system is activated and plasma renin and AT II activity are increased.

ANSWER

-G.B. has extensive atherosclerotic disease indicated by the presence of coronary artery and peripheral vascular disease .

-Atherosclerosis is a major cause of renal artery occlusion and decreased renal perfusion.

-This activates the RAA system, which causes sodium and water

reabsorption and AT II-mediated efferent arteriole vasoconstriction, in an attempt to restore normal renal perfusion and intraglomerular hydrostatic pressure.

-The administration of ACE inhibitors directly inhibits the formation of AT II, which is necessary for efferent arteriole vasoconstriction. Consequently, the compensatory physiologic event that maintains G.B.’s renal blood flow is inhibited, thereby reducing her intraglomerular hydrostatic pressure and GFR.

-ACE inhibitors are contraindicated in patients with bilateral renal artery stenosis or unilateral stenosis in patients with a single functioning kidney.

5 .Are there other factors that predispose patients to ACE inhibitor-induced ARF?

In addition to the above situation, three other general scenarios will result in the development of ARF with ACE inhibitors:

-First, conditions of sodium and water depletion(e.g,.dehydration, over diuresis, poor fluid intake, low-sodium diet) can increase the dependency of the efferent arteriole on AT II.

CASE 2 Part 2

-When ACE inhibitors are given in these situations, GFR can fall dramatically, and SrCr rises .

-ARF can be averted by with holding the ACE inhibitor (or diuretic, or both) for a day and repleting the intravascular fluid volume with a saline-containing fluid (e.g., normal saline or 0.45% saline) .

-Second, ACE inhibitors can decrease the mean arterial pressure to such a degree that renal perfusion cannot be sustained. This is more likely to occur with long-acting agents.

-Finally, ACE inhibitors may precipitate ARF in patients who are taking concomitant drugs with renal afferent arteriole vasoconstricting effects, most notably cyclosporine and NSAIDs.

6 .How is ACE inhibitor-induced ARF managed?

-Patients who are receiving ACE inhibitors should be monitored judiciously with regard to their serum creatinine and electrolyte concentrations.

-Once an ACE inhibitor is initiated, an increase in SrCr of 20% to

30% can be expected.

-This slight increase should not worry clinicians, because it typically normalizes within 2 to 3months.

CASE 2 Part 3

- SrCr rises greater than this along with reduced urine output signal ARF, however. ARF related to ACE inhibitors is usually reversible, principally because the ARF is caused by inadequate glomerular capillary pressure, which is restored as soon as sufficient AT II is produced.

-ARF appears to develop more commonly in hypotensive patients or in those with intravascular volume depletion (e.g., patients with HF receiving high-dose diuretics). In these conditions, it is prudent to replete the intravascular fluid volume or temporarily discontinue diuretic therapy.

-ACE inhibitor therapy should be temporarily discontinued when

the patient has a normalized intravascular volume and is hemodynamically stable.

7 .Do angiotensin II–receptor blockers (ARB) cause less ARF compared with ACE inhibitors?

-The ARBs competitively inhibit the angiotensin II receptor. -At least two subtypes of the angiotensin II receptors exist:AT I and AT II .

-Few differences are seen in the incidence of ARF between ACE inhibitors and ARBs,and one should not be interchanged with the other in an attempt to decrease ARF risk.

CASE 2 Part 4

INTRINSIC ACUTE RENAL FAILURE

Acute Glomerulopathies

Poststreptococcal Glomerulonephritis

CASE 3 Part 18 .B.M. is an 18-year-old male college freshman in otherwise good health who

recently developed strep throat. He received a 10-day course of amoxicillin, which cleared the infection. He returns to the student health center after completing his 10-day course complaining of “puffy eyes,” swelling in his legs, a cough productive of clear sputum, and decreased urine output that appears “tea-colored.” Other than the amoxicillin, he is not on any medication. Baseline records froma routine physical examination 2 months ago revealed a serum BUN and creatinine of 10 mg/dL and 0.8 mg/dL (normal, 5–20 and 0.5–1.2), respectively, and a BP of 120/80 mm Hg. Today, the physical examination is significant for a BP of 176/95 mm Hg, 2+ peripheral edema, and bilateral pulmonary rales.The urinalysis is significant for gross hematuria, nephritic-range proteinuria, RBC andWBC casts, and epithelial cells. B.M.’s SrCr has increased to 7.1 mg/dL. Based on the history, physical examination, and laboratory findings.

what is the most likely cause of ARF in this patient?

[SI units: BUN, 3.6 mmol/L (normal, 1.8–7.1); SrCr, 70.7 and 627.6 mol/L,respectively (normal, 44.2–106)]

B.M.’s recent history of a streptococcal infection with the development of ARF suggests poststreptococcal glomerulonephritis (PSGN), which results from the formation of

antibodies against streptococcal antigens .The streptococcal antigen immune complexes are deposited in the glomerulus, resulting in complement, cytokine, and clotting cascade activation; neutrophils and monocytes attack the glomerulus causing glomerulonephritis.

The onset of PSGN is usually 7 to 21 days after the start of the pharyngeal infection .PSGN is the most common acute-onset, immune-mediated, diffuse glomerulopathy .

It primarily affects children, although it can affect any age group and is more prevalent in males than in females .

Only certain serologic subtypes of group A hemolytic streptococci,known as nephritogenic strains, cause PSGN. Strains that follow pharyngeal infections (e.g., strep throat) include types 1,3, 4, 6, 12, 25, and 49. Type 49 is the most prevalent

strain worldwide .Positive diagnosis of PSGN requires identification of a nephritogenic group A hemolytic streptococcal strain; objective urinalysis findings suggestive of glomerular damage such as proteinuria, hematuria, and casts; and elevated streptococcal antibody titers.

ANSWER

.B.M. exhibits the classic physical and laboratory findings associated with PSGN. The pertinent positive physical findings include periorbital, pulmonary, and peripheral edematea-colored urine, hypertension, and decreased urine output Edema is a common manifestation, with periorbital edema typically being the first to appear.

Reduced GFR, proteinuria, and sodium retention by the kidney all contribute to edema formation.When protein, principally albumin, is lost in the urine, the intravascular oncotic pressure declines, causing a shift of fluid into the extravascular space .

The loss of intravascular volume stimulates sodium and water reabsorption by the kidney via aldosterone and vasopressin, which often produces stage 1 to 2 hypertension.

Pertinent laboratory data in B.M. include elevated SrCr, and urinalysis positive for hematuria, proteinuria,WBC casts, and epithelial cells.Hematuria,which is found in almost all patientswith PSGN, accounts for the reddish-brown, tea-colored urineOther commonly found urine sediments include cellular casts and hyaline and granular casts. Oliguria is common in PSGN but anuria is rare.

10 .What are the therapeutic goals and treatment options for PSGN?CASE 3 Part 2

The therapeutic goals are to minimize further kidney damage and to provide symptomatic relief for B.M. The underlying streptococcal infection should be treated with appropriate

antibiotics, but as illustrated by B.M., this has no effect inpreventing PSGN .Family members and close contacts of the infected patient should receive antibiotic prophylaxis as well.

Restriction of protein to 0.8 g/kg/day may be beneficial in patients with marked proteinuria,

and antihypertensive drugs can be used on a short-term basis to control BP.

Sodium and water restriction is beneficial in reducing edema, and loop diuretics may be used as needed for symptomatic pulmonary or peripheral edema.

Close monitoring of electrolytes is warranted if diuretics are used. Dialysis is rarely required.

CASE 3 Part 311 .Are there other glomerulopathies that cause ARF?

Yes. RPGN, also called crescentic glomerulonephritis, is a clinical syndrome of rapid decline in renal function (from days to weeks) combined with the hallmark findings of gross hema-

turia, proteinuria, and the presence of extensive glomerular crescents (>50% of glomeruli) on renal biopsy .

It is not uncommon for patients with RPGN to have a 50% decline in GFR in only a few weeks. RPGN is a medical emergency, and treatment success depends on how early therapy is initiated. If left untreated, progression to end-stage renal disease or deathis almost certain.

Idiopathic RPGN is divided into three categories based on immunofluorescence microscopy .

-Type I idiopathic RPGN is characterized by linear deposition of immunoglobulins, primarily IgG, along the glomerular basement membrane (GBM) indicating anti-GBM antibodies.

-Type II idiopathic RPGN is identified by granular immunoglobulin and complement depo-sitions in the glomerularmicrovasculature andmesangiumsuggesting immune complex deposition.Type III idiopathicRPGN is also called pauci-immune because there are no hallmark immunoglobulin or complement findings on immunofluorescencemicroscopy.

-Type III idiopathicRPGNis identified by the presence of circulating antineutrophil cytoplasmic antibodies.

Multisystem vasculitic disorders that result in glomerular capillary inflammation are themost common cause ofRPGN.

Many of these patients present with nonspecific flu-like symptoms such as fever, weight loss, myalgia, and malaise with proteinuria and hematuria.

Uremic symptoms can occur with severe disease. The presence of ARF with pulmonary congestion, cough, hemoptysis, or dyspnea suggests Wegener’s granulomatosis. The treatment for autoimmune RPGN generally involves immunosuppressive agents, such as prednisone, azathioprine.

CASE 3 Part 412 .What drugs cause glomerulonephropathy?

Minimal-change disease and membranous nephropathy have been associated with NSAID use.The mechanism is probably related to NSAID-induced inhibition of the cyclooxygenase pathway, which leads to increased arachidonate catabolism and increased proinflammatory leukotriene production .

The hallmark feature of NSAID-induced nephropathy is nephrotic-range proteinuria .

The nephropathy resolves slowly over several months once the NSAID is discontinued .

INTRINSIC ACUTE RENAL FAILURE

TUBULOINTERSTITIAL DISEASES

Acute Tubular Necrosis

Treatment With Diuretics and Dopamine

13 .Do diuretics and dopamine have a role in treating established ATN?

It is well documented that patients with nonoliguric renal failure have significantly better outcomes compared with those with oliguria. This is probably because patients who are nono-liguric have less extensive renal damage and are better able to maintain fluid and electrolyte balance.

Loop diuretics are commonly used in established ATN in an attempt to convert patients with oliguria to a nonoliguric state .

Numerous clinical trials, however, have failed to demonstrate improved mortality or duration of azotemia in oliguric patients who receive loop diuretics, despite improved urine output .

Two large systematic reviews of the primary literature convincingly showed that diuretic therapy plays little role in altering the course of ARF, decreasing length of hospitalization, or helping recover renal function.

These data suggest that, although patients who are nonoliguric generally have better outcomes, converting a patient from oliguria to non oliguria through pharmacologic in-tervention does not improve patient outcomes .

Currently, the only role that diuretic administration has in patientswith established ATN is to increase urine output, which facilitates fluid, electrolyte, and nutritional support.Another controversy that has been debated extensively in the literature is the use of dopamine in patientswith established ATN.

Dopamine is a catecholamine that stimulates dopaminergic receptors at low dosages (1–3 mcg/kg/minute), and α- and β-receptors at higher dosages (5–20 mcg/kg/minute). Animal and human studies have demonstrated that low-dose dopamine improves renal blood flow by inducing afferent arteriolar vasodilation .

No data, however, support the use of dopamine in the treatment of established ARF.

A recent meta-analysis of 61 clinical trials including nearly 3,500 patients failed to detectany significant improvement in variables such as occurrence of ARF, need for renal replacement therapy, or mortality.

Unequivocally, dopamine has no role in preventing or treating ARF

Radiocontrast Media–Induced Acute Tubular Necrosis

CASE 4 Part 114 .K.S., a 74-year-old man, presents to the emergency department

complaining of chest pain. His medical history is significant for advanced type 2 diabetesmellitus,with retinopathy, peripheral vascular disease, and advanced coronary artery disease. Based on cardiac enzymes, K.S. is ruled in for STEMI. He is taken to the cardiac catheterization laboratory for a percutaneous coronary intervention. Immediately before the procedure, K.S. is given io-

hexol PO to enhance visualization of his cardiac arteries. His admission BUN is 37 mg/dL (normal, 5–20) and SrCr is 1.5 mg/dL (normal, 0.5–1.2). Two days later, pertinent laboratory findings include a BUN and SrCr of 60 and 2.0 mg/dL, respectively, and his urine output is 700 mL/day .

Why did K.S. develop ARF?

Radiocontrastmedia administration is one of themost common causes of drug-induced ATN. Although no set criteria exist for its diagnosis, it is generally considered when the SrCr increases by >0.5 g/dL over 2 to 5 days. Contrast-induced nephropathy (CIN) usually presents as a non oliguric ATN .

It is also differentiated from other forms of ATN in that the FENa+ is usually <1% (vs. the typical >2%). Nephropathy is indicated by a progressive rise in creatinine 24 to 48 hours after contrast administration, which usually peaks within 5 days .

The degree of creatinine rise and the presence of oliguria arewidely variable. Because of the lack of an accepted CIN definition and differences in both clinical trial design and populations studied, estimating the true prevalence of CIN is daunting. Nevertheless, patients without risk factors prevalence have a relatively minute risk of developing CIN; for those with recognized risk factors prevalence may approach 50%.

ANSWER

The mechanisms by which radio contrast media induce ARF are complex .

Initially, the radio contrast medium produces renal vasodilation and an osmotic diuresis. This, however, is followed by intense vasoconstriction in the medullary portion of the kidney, which has been demonstrated by significant decreases in medullary Po2 after contrast administration.

The ischemia is compounded by the increased medullary O2 consumption because of the osmotic diuresis. Consequently, disequilibrium exists between O2 supply and demand creating ischemic ATN. Various vasoactive substances are suspected of decreasing medullary blood flow, including oxygen-free radicals, prostaglandins, endothelin, nitric oxide, angiotensin II, and adenosine. Endothelin and adenosine are potent vasoconstrictors that are directly released from endothelial cells on exposure to radiocontrast media.

15 .What are the risk factors for CIN?

CASE 4 Part 2

Any condition that decreases renal blood flow increases the risk of nephropathy. At-risk patient populations include individuals with underlying diabetic nephropathy or chronic renal insufficiency, CHF, volume depletion, or those receiving aggressive diuretic regimens.

The use of the ionic high-osmolar or low-osmolar contrast products also increases the risk ofnephropathy, as well as the previously discussed medications that markedly reduce renal perfusion (e.g., NSAIDs, COX-2 inhibitors, ACE inhibitors). Iso-osmolar contrast appears to bebetter tolerated.

K.S. was at high risk for developing radiocontrast-induced ATN. He was volume depleted, as evidenced by his admission BUN:SrCr ratio, which was >20:1. Second, it is very likelythat K.S. had underlying diabetic nephropathy, as evidenced by his elevated admission SrCr. The presence of retinopathy, coronary artery disease, and peripheral vascular disease sug-gest long-term uncontrolled diabetes mellitus, a risk factor for nephropathy .

ANSWER

CASE 4 Part 316 .What strategies can be performed to prevent the

occurrence of CIN?

Attempts have been made to minimize or prevent CIN using a variety of approaches. Modularly vasodilation with dopamine infusions have generally had disappointing results .

Volume expansion, mannitol, and furosemide have been tried as a means of “flushing” radiocontrast from the kidney .

Volume expansion is a rational approach to prevent renal dysfunction in this population because human and animal data have revealed dehydration as a major risk factor for developing CIN. Hydration with normal saline, hypotonic saline (0.45% sodium chloride), and sodium bicarbonate in dextrose have all shown benefits in preventing CIN.

Notably, sodium bicarbonate may be more beneficial in decreasing the incidence of radiocontrast nephropathy relative to other fluids because it reduces oxygen-free radicals in the renal medulla and, therefore, increases the medullary pH. Whatever fluid is given, data suggest it should be infused before and after the procedure to adequately reduce the risk of developing nephropathy. Another important point is that the administration of diuretics such as mannitol and furosemide should be avoided. These diuretics result in volume depletion and increase oxygen demand in the medullary portion of the kidney when diuresis occurs, thereby counteracting the benefits of hydration. Other therapeutic modalities for the prevention of CIN have been studied. A systematic review andmeta-analysis of aminophylline and theophylline have affirmed a renoprotective effect in patients who have underlying chronic kidney disease; however, large-scale clinical trials are lacking.

Although the use of calciumchannel blockers theoretically seems rational to prevent contrast-induced ATN, limited clinical data exist. Other emerging data suggest that ascorbic acid may be beneficial in preventing contrast nephropathy given its antioxidant effects; however, large-scale prospective trials are lacking.

N-acetylcysteine (NAC) has received the most attention for its renal-sparing effects relative to radiocontrast media. Indeed, since 2001, nearly 30 primary studies and more than

10 meta-analyses have been conducted to assess its prophylactic effects.

Although much data have been generated with NAC, many of these studies have significant pitfalls, including relatively small sample size; single-center design; heterogeneity of patient populations; differing doses, dosage forms, and schedules of NAC therapy; and differing hydration regimens.

Therefore, trying to delineate meaningful conclusions from this body of literature is daunting. At this time, recommending a specific dose of NAC is difficult. The commonly acceptedregimen at many institutions is 600 mg orally twice daily pre and postprocedure for a total of four doses along with concomitant hydration therapy.

Figure 30-5 summarizes one possible strategy to prevent CIN in high-risk populations. When possible, alternative imaging studies that do not require radiocontrast should be attempted. If this is not practical, the lowest effective dose of nonionic, iso- or low-osmolar radiocontrast media should be used. Concomitant drug therapy that can impair renal perfusion, such as diuretics, NSAIDs, COX-2 inhibitors, ACE inhibitors, and ARBs, should be discontinued 1 day before and 1 day after radiocontrast administration. Metformin should also be discontinued before giving radiocontrastmedia and held for at least 48 hours because it can cause lactic acidosis if patients develop ARF. If patients are receiving calcium channel blockers for underlying cardiovascular disease, no change in therapy is warranted. All patients should be well hydrated with saline or sodium bicarbonate fluids before and after radiocontrast administration .

CASE 4 Part 317 .What treatment options are available for established radio

contrast-induced ATN?

Few data exist regarding treatment of existing radiocontrast- induced ATN. The acute management largely involves supportive care that includes strict fluid and electrolyte management to prevent undue sequelae. Approximately 25%of patients will require temporary dialysis therapy; patients who are oliguric generally require long-term dialysis therapy. As already noted, attempts to convert oliguria to nono liguria with furosemide and mannitol have been largely unsuccessful.

Aminoglycoside-Induced Acute Tubular Necrosis

CASE 5 Part 118 .H.H. is a 43-year-old, 80-kg man being treated for gram-negative septic shock.

He was admitted to the hospital 6 days ago, but he has spent the last 3 days intubated in the medical respiratory ICU because of hypotension, respiratory failure, and altered mental status. Since admission, H.H. has received ceftriaxone 2 g/day and gentamicin 140 mg IV Q 8 hr. Admission laboratory results were significant for the following: BUN, 13 mg/dL (nor-

mal, 5–20); SrCr, 0.9 mg/dL (normal, 0.5–1.2); and WBC count, 23,500 cells/mm3)normal, 4,000–9,000 (with a left shift (90% polymorphonuclear leukocytes

]PMN[ and 12% bands). Serial blood, urine, and sputum cultures were positive for Acinetobacter baumanii sensitive to ceftriaxone and gentamicin. In addition to the previously listed antibiotics, his current medication regimen includes norepinephrine IV 18 mcg/minute, pancuronium 0.02mg/kg IV Q 3 hr, famotidine 20 mg IV Q 12 hr, and lorazepam IV 2mg/hour.Today (hospital day 7),H.H.’s vital signs include the following: temperature, 101.5◦F (38.6◦C); BP, 90/40 mm Hg; pulse,135 beats/minute; and respirations, 20 breaths/minute. Significant laboratory values are as follows: BUN, 67 mg/dL; SrCr,

5.4 mg/dL; and WBC count, 16,700 cells/mm3with continued left shift .

Over the last 2 days, H.H.’s urine output has steadily declined, and today it is 700 mL/24 hours (normal, 1,500–2,500). Urine electrolytes were obtained and reveal Na+, 55 mEq/L (normal, 20–40) and creatinine, 26 mg/dL (normal, 50–100). A uri-

nalysis revealed many WBC (normal, 0–5), 3% RBC casts (normal, 0%–1%), brush-border cells (normal, negative), and granular casts (normal, negative) with an osmolality of 250 mOsm/kg(normal, 400–600). Serum gentamicin concentrations obtained with the last dose reveal a peak of 15 mg/dL (target, 6–10) and atrough of 9.1 mg/dL (target,<2.0). Given the history and laboratory data ,

what is the likely source of H.H.’s ARF?

ANSWER

The source of ARF in this situation is likely multifactorial(Table 30-1).

First, H.H. is experiencing diminished renal perfusion from profound hypotension and septic shock .

As a result, he is receiving high-dose norepinephrine, a potent vasopressor .

Consequently, the combination of these variables reduces renal perfusion further, resulting in prolonged renal ischemia .

Second, H.H. has received 1 week of gentamicin, a well-known nephrotoxic antibiotic. The risk factors for developing aminoglycoside nephrotoxicity are listed in Table 30-5.

The latest gentamicin trough concentration of 9.1 mg/L is far higher than the target value of <2 mg/L for a traditional three- times-daily dosing regimen. Given the laboratory data (Table30-2) and the clinical course of prolonged hypotension, vasopressor, and aminoglycoside administration, nonoliguric ATN is the most likely diagnosis.

CASE 5 Part 219 .How does aminoglycoside-induced ATN present, and

what are the mechanisms of toxicity?H.H. illustrates the typical presentation of aminoglycoside-induced

nephrotoxicity .Generally, the onset occurs after 5 to 7 days of treatment and presents as a hypo-osmolar, nonoliguric renal failure with a slow rise in SrCr.

Because of the tubular necrosis that occurs, the urinalysis is often positive forlow-molecular-weight proteins, tubular cellular casts, epithelial cells, WBC, and brush-border cells.

H.H.’s plasma and urinary laboratory indices are consistent with those listed forATN in Table 30-2.

The mechanism of aminoglycoside-induced ATN is complex. Approximately 5% of filtered aminoglycoside is actively reabsorbed by the proximal tubule cells .

These agents are poly cationic and bind to the negatively charged brush-border cells within the tubule lumen. Once attached, these agents undergo pinocytosis and enter the intracellular space, setting off complex biochemical events that result in the formation of myeloid bodies. With continued formation of myeloid bodies, the brush-border cells swell and burst, releasing large concentrations of aminoglycoside and lysosomal enzymes into the tubule lumen,thereby beginning a cascade of further tubular destruction.

The following rank order of nephrotoxicity has been collated from human and animal data: neomycin > gentamicin = tobramycin = amikacin = netilmicin > streptomycin.

Extended-Interval Dosing

20 .Is “extended-interval” aminoglycoside dosing less nephrotoxic than multiple daily dosing regimens?

Extended-interval aminoglycoside dosing entails the administration of one large daily aminoglycoside dose. This dos ng scheme takes advantage of the concentration-dependent killing activity and postantibiotic effect observed with aminoglycosides while

minimizing time-dependent toxicity .The net effect of this dosing scheme, purportedly, is greater efficacy with reduced

toxicity .Aminoglycoside nephrotoxicty is a function of drug exposure, and it might be minimized with extended-interval dosing because of saturable upake kinetics in the proximal tubule. That is, only a maximal amount of aminoglycoside is transported into the tubule cell,no matter how much aminoglycoside is present in the tubule.

Consequently, once saturation occurs, the remaining aminoglycoside concentration passes through the proximal tubule without being absorbed, and is excreted in the urine.

Accumulation is therefore averted.This concept is supported by studies demonstrating that continuous-rate gentamicin infu-

sions, which produce sustained low plasma concentrations, result in greater proximal tubule uptake and nephrotoxicity than extended-interval regimens.

CASE 5 Part 3

This is probably because the achieved drug concentrations are well below those required to saturate the uptake mechanism .

Extended-interval dosing results in very high peak concentrations to improve efficacy and generally undetectable trough concentrations before the next dose,

thus minimizing accumulation .Numerous clinical trials and meta-analyses have compared the efficacy and toxicity of extended-interval aminoglycoside dosing with conventional multiple daily dosing regimens.

Many of these meta-analyses concluded that less nephrotoxicity was associated with extended-interval aminoglycoside dosing. Given the inherent biases of

meta-analyses, these results, however, must be interpreted cautiously .

For example, meta analyses combine results from different clinical trials, which can differ in patient population, severity of illness scores, degree of underlying

renal dysfunction, and dosing regimen and duration of therapy .Most of the clinical trials did not show a clinically or statistically significant difference in efficacy or toxicity between regimens. Contemporary practice suggests that patients should receive extended-interval aminoglycoside dosing unless they have specific contraindications

In summary, extended-interval aminoglycoside dosing appears to result in similar or greater efficacy, with similar or reduced toxicity .

This dosing schedule is also less costly when considering therapeutic drug monitoring, preparation, and administration costs. Although the typical extended interval inpatients with normal renal function is dosing every 24 hours, the inter valmay have to be prolonged to several days in patients with renal failure.

Drug-Induced Acute Interstitial Nephritis (AIN)

Penicillin-Induced AIN

CASE 6 Part 121 .J.S. is a 50-year-old woman who developed a cellulitis 3 days after a car door

was closed on her right hand. She was admitted to the hospital, where blood and wound cultures were found to be positive for methicillin-sensitive Staphylococcus aureus. She received two full days of nafcillin 2 g IV Q 4 hr before being discharged to complete a 14-day course with dicloxacillin 500mg PO four times daily (QID). Ten days after discharge, J.S. returned to the emergency department complaining of malaise, fever, diffuse rash, hematuria, and reduced urine output. The following laboratory values were significant:BUN, 39mg/dL(normal, 5–20); SrCr, 2.3 mg/dL (normal, 0.5–1.2); and WBC count, 18,500 cells/mm3 (normal, 4,000–9,000) with 18% eosinophils. The urinalysis was positive for elevated specific gravity, WBC, RBC, eosinophiluria, and a

FENa+ of 3% .

What objective data suggest drug-induced AIN?

ANSWERJ.S.’s onset of symptoms suggests drug-induced AIN. As illustrated by this case, the median onset of penicillin-induced AIN generally occurs 6 to 10 days after drug exposure. Hallmark symptoms of AIN include fever, macular rash, and malaise. Fever is present in nearly all patients with AIN, whereas rash occurs in 25%to 50%of patients. J.S.’s objective laboratory data that suggest AIN include azotemia, elevated SrCr, proteinuria, cellular urinary sediment, eosinophilia, and eosinophiluria. Her FENa+ of 3% suggests intrinsic renal disease and her eosinophiluria and eosinophilia indicate an immune-mediated allergic reaction. Drug-induced AINis generally nonoliguric, but oliguria can develop in severe cases of AIN.

CASE 6 Part 222 .How should J.S.’s drug-induced AIN be treated?

The dicloxacillin should be stopped immediately because most patients recover normal kidney function once the offending agent is discontinued .

1-General supportive measures that maintain fluid and electrolyte balance are necessary .

2-Corticosteroids have been used with variable results to shorten the duration of ARF, but no clinical guidelines have been developed to delineate when to administer them and for how long.

3-Some administer prednisone 1 mg/kg for 7 days and then gradually taper the dose over the next several weeks .The response to corticosteroids may be delayed or absent in some patients .

3-Dialysis may be needed in patients who are oliguric, but it is usually not required for those who are nonoliguric.

The clinician should document J.S.’s allergic reaction to penicillins because repeated exposure is likely to result in similar reactions.

POSTRENAL ACUTE RENAL FAILURE

23 .T.C., a 48-year-old man, presents to the emergency department complaining of sharp flank pain radiating to the groin, gross hematuria, and dysuria. He states that these symptoms have been present for 4 hours and that they are similar to previous episodes

of calcium nephrolithiasis he has experienced .Serum chemistries are ordered and are significant only for a BUN of 34 mg/dL (normal, 5–20) and an SrCr of 1.5mg/dL (normal, 0.5–1.2), which are up from his

baseline values of 15 and 0.9 mg/dL, respectively .Aurine sample was obtained and visualized with microscopy. It was determined that T.C. passed a kidney stone, based on the large amount of calcium oxalate crystals found in the urinary sediment.

On questioning, he admits that he has not been drinking much fluid over the past week owing to a busy work schedule, and his urine volume has been markedly lower than usual. What are the common subjective and objective data that suggest nephrolithiasis, and

how can this be prevented from occurring in the future?

CASE 7 Part 1

T.C. illustrates the classic presentation of nephrolithiasis: acute, severe flank pain that radiates to the groin. It is usually accompanied by gross or microscopic hematuria, dysuria, or frequency. Of symptomatic calculi, 90% pass spontaneously, as in T.C.’s case, and invasive surgical treatment is rarely necessary.

The risk factors that predispose T.C. to stone recurrence include a previous episode of nephrolithiasis, age within the fourth decade, and decreased fluid intake and urine output.

ANSWER

T.C. should take preventive measures to reduce the likelihood of stone recurrence. Many randomized trials have demonstrated that nondrug and pharmacologic mechanisms can pre-vent stone formation .

The most cost-effective way to prevent stone formation is to1 -Increase fluid intake.Aclassic 5-year randomized study compared

a high fluid intake group (>2 L/day) with one that had normal daily fluid intake ( 1 L/day)∼.

The results demonstrated a significantly longer time to stone recurrence (39 vs. 25 months) in the high fluid intake group.

2-Dietary modifications remain controversial. Although it appears that limiting protein, calcium, and sodium intake should decrease the likelihood of recurrent nephrolithiasis, the data are conflicting.

In summary, a high calcium intake probably increases the risk of nephrolithiasis but only in patients with absorptive hypercalciuria and not in normal subjects.

Pharmacologic control of calcium oxalate stones has been Tried with thiazide diuretics.

1-Thiazide diuretics promote calcium reabsorption in the distal tubule, which decreases the concentration in the lumen .

Thiazides also may decrease intestinal calcium absorption in patients with absorptive hypercalciuria, although this remains unclear .

2-Patients receiving thiazide diuretics should be sodium restricted because excessive sodium intake negates their hypocalciuric effect. 3-Allopurinol has been used successfully to prevent recurrent calciumoxalate nephrolithiasis, presumably by inhibiting purine and uric acid metabolism.

4-Alkalization of the urine with potassium citrate and potassium-magnesium citrate also prevents recurrent calcium oxalate nephrolithiasis.

T.C. should be instructed to drink at least 2Lof fluid ( eight 8-ounce glasses) daily∼ .

Given his busy work schedule, a thiazide diuretic probably is not the most convenient option for T.C., and noncompliance is likely.

Allopurinol 200 mg orally once daily is probably the most convenient preventive strategy for T.C., and data suggest it is effective in preventing recurrent nephrolithiasis .

Alternatively, urinary alkalinization with potassium citrate or potassium-magnesium citrate is likely to benefit T.C., but it may be less convenient because it needs to be administered two to four times daily.

Drug-Induced Nephrolithiasis

CASE 7 Part 224 .Can drugs crystallize in the urine and cause ARF?

Many commonly prescribed drugs are insoluble in urine and crystallize in the distal tubule (Table 30-7).

Risk factors that predispose patients to crystalluria include severe volume contraction, underlying renal dysfunction, or acidotic or alkalotic urinary pH. In conditions of renal hypoperfusion, high concentrations of drug become stagnant in the tubule lumen.

Drugs that are weak acids (e.g., methotrexate, sulfonamides) precipitate in acidic urine; drugs that are weak bases (e.g., indinavir, other protease inhibitors) precipitate in alkaline urine.

Prevention of crystal-induced ARF is targeted at dosage adjustment for patients with underlying renal dysfunction, volume expansion to increase urinary output, and urine alkalization.Similarly, for established crystal-induced ARF, the above general supportive measures of urinary alkalization and volume expansion should be performed .

Dialysis may be necessary in a small percentage of patients .

With appropriate pharmacotherapy, crystal-induced ARF is usually reversible without long-term complications.

SUPPORTIVE MANAGEMENT OF ACUTE RENAL FAILURE

25 .What is the supportive management of ARF?Despite years of study, no pharmacologic “cure” for ARF exists. Therefore, supportive therapy is directed at preventing its morbidity and mortality .This is achieved by close patient monitoring;

1-Strict fluid, electrolyte, 2-And nutritional management ;

3-Treatment of life-threatening conditions, such as pulmonary edema, hyperkalemia, and metabolic acidosis ;

4-Avoidance of nephrotoxic drugs; 5-and the initiation of dialysis or continuous renal replacement

therapies (CRRT).

Clinicians should closely monitor patient vital signs (e.g., weight, temperature, BP, pulse, respirations, and fluid intake and output) at least once every shift.

Daily weights can forewarn the clinician of edematous weight gain .The patient’s medication profile should be reviewed daily to assess for

appropriate dosage adjustment in renal dysfunction .Because estimation of ClCr is difficult in patients with rapidly changing renal function, therapeutic drug monitoring should be performed when using drugs with narrow therapeutic indices.

When possible, nephrotoxic drugs should be avoided, but this may be difficult in patients who are septic or hypotensive and require nephrotoxic antibiotics and vasopressors.

Preventive measures to reduce the likelihood of ARF should be used, such as ensuring adequate hydration, using dosing strategies or products that are associated with less nephrotoxicity, and avoiding drug therapy combinations that enhance nephrotoxicity (e.g., NSAID, aminoglycosides).

If patients with ARF are receiving total parenteral nutrition, close monitoring of serum chemistries is needed to identify fluid and electrolyte abnormalities.Supportive drug therapy may be used to reduce ARF symptoms .

As discussed, diuretics currently have no role in preventing ARF progression or reducing mortality, but they can prevent complications, such as pulmonary and peripheral edema, and they may prevent tubular obstruction from ATN.

The patient’s volume status should be assessed daily, and fluids should be adjusted based on laboratory chemistries, urine output, and gastrointestinal and insensible losses. Dietary sodium restriction of 2 to 2.5 g/day should be instituted to prevent edema formation.

Estimating Drug Removal

26 .Are there ways to calculate drug removal in extracorporeal CRRT modalities?

Two recent reviews provide an excellent background on dosing drugs in patients receiving CRRT.

The principles for drug removal in hemofiltration are basically identical with those for removal in hemodialysis.

For example, drugs with a small volume of distribution and low protein binding are removed readily by these modalities .

The sieving coefficient (SC) of a drug is the non–protein-bound fraction of the drug that is in plasma. For example, an SC of 0.8 means that 80% of the drug is unbound in plasma. Drug SC can be obtained from the literature or by measuring concentrations

simultaneously in the prefilter blood and ultrafiltrate .The ratio of the ultrafiltrate concentration to plasma concentration is the SC.

Drug clearance can be calculated by multiplying the SC by the ultrafiltration rate. For example, if a patient is receiving CVVH at an ultrafiltration rate of 1 L/hour, and he or she is receiving vancomycin (which has an SC of 0.8) 1 g/day, the vancomycin clearance while receiving CVVH is 0.8 × 1,000 mL/hour = 800 mL/hour or 13 mL/minute.

Calculating drug clearance is much more difficult in hemodiafiltration modalities (CAVHDF, CVVHDF) because both convection and diffusion account for drug clearance and it is difficult to predict drug clearance precisely .

The use of SC can be useful for small–molecular-weight drugs, but the accuracy declines with larger drug molecules, such as vancomycin .

When possible, therapeutic drug monitoring should be performed to maintain therapeutic concentrations and to maximize drug therapy.