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48

Multisystem vasculitic disorders that result in glomerular capillary inflammation

are the most common cause of RPGN.

49 Many of these patients present with

nonspecific flulike symptoms such as fever, weight loss, myalgia, and malaise with

proteinuria and hematuria.

50 Uremic symptoms can occur with severe disease. The

presence of AKI with pulmonary congestion, cough, hemoptysis, or dyspnea suggests

Wegener’s granulomatosis. The treatment for autoimmune RPGN generally involves

various regimens of immunosuppressive agents. Corticosteroid monotherapy (oral or

“pulse” intravenous) or combined with either cyclophosphamide or rituximab have

been investigated. Rituximab may improve renal outcomes in Type III idiopathic

RPGN; in addition to anti–B-cell therapy, therapy directed at T cells may improve

renal outcome.

51 Plasmapheresis is also a non-pharmacological treatment option in

selected patients. A more detailed discussion of glomerulonephritis is presented in

Chapter 28, Chronic Kidney Disease.

NONSTEROIDAL ANTI-INFLAMMATORY DRUG–INDUCED

GLOMERULOPATHY

CASE 29-3, QUESTION 5: Which drugs cause glomerulonephropathy?

Minimal-change disease and membranous nephropathy have been associated with

NSAID use.

52 The mechanism is probably related to NSAID-induced inhibition of the

cyclo-oxygenase pathway, which leads to increased arachidonate catabolism and

increased proinflammatory leukotriene production. The hallmark feature of NSAIDinduced nephropathy is nephrotic-range proteinuria. The nephropathy resolves

slowly over the course of several months once the NSAID is discontinued.

TUBULOINTERSTITIAL DISEASES

Acute Tubular Necrosis

ATN arises most often from ischemia or drug-induced causes.

53 Prolonged prerenal

conditions, such as hypotension, surgery, overwhelming sepsis, or major burns, can

lead to ischemic ATN. Unlike prerenal azotemia, tubular cell death occurs in ATN,

and immediate volume resuscitation will not reverse the damage. The

pathophysiology of ATN is complex and remains unclear. It is currently thought that

when tubular cells die, they slough off into the tubule lumen and contribute to cast

formation. The casts completely obstruct the tubule lumen and increase intratubular

pressure, which causes a back leak of ultrafiltrate across the tubular basement

membrane (Fig. 29-4). The aforementioned processes are mediated by a variety of

substances, including calcium, phospholipases, and perhaps growth factors as well

as free radical and protease activation.

TREATMENT WITH DIURETICS AND DOPAMINE

CASE 29-4

QUESTION 1: V.B. is a 86-year-old white man (height = 5 feet, 2 inches; weight = 138 pounds), who was

admitted for elective aortic valve replacement secondary to severe aortic stenosis. He became hypotensive

during surgery, requiring aggressive fluid resuscitation. He is now in the ICU and requires vasopressors for

hemodynamic support. His BUN is 88 mg/dL and his SCr is 3.5 mg/dL today. His renal function tests have

remained at these levels for the past 3 days. His baseline SCr before surgery was 1.2 mg/dL. Despite IV fluids,

V.B. is oliguric with a urine output of 15 mL/hour (350 mL/day). Do diuretics and dopamine have a role in

treating 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 nonoliguric have less extensive renal damage and are better able to maintain

fluid and electrolyte balance. Loop diuretics have been used in established ATN in

an attempt to convert patients with oliguria to a nonoliguric state despite the lack of

conclusive evidence for their benefits. 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.

9 Two large systematic

reviews of the primary literature convincingly showed that diuretic therapy plays

little role in altering the course of AKI, decreasing length of hospitalization, or

helping recover renal function.

54,55 These data suggest that although patients who are

nonoliguric generally have better outcomes, converting a patient from oliguria to

nonoliguria through pharmacologic intervention does not improve patient outcomes.

Currently, the only role that diuretic administration has in patients with established

ATN is to increase urine output, which facilitates fluid, electrolyte, and nutritional

support.

9

Another controversy that has been debated extensively in the literature is the use of

dopamine in patients with 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 AKI. A meta-analysis of 61 clinical trials including nearly

3,500 patients failed to detect any significant improvement in variables such as

occurrence of AKI, need for renal replacement therapy, or mortality.

56

Unequivocally, dopamine has no role in preventing or treating AKI.

Other modalities such as fenoldopam or atrial natriuretic peptide (ANP) have not

been shown to be conclusively beneficial to treat AKI and hence are not

recommended to be used.

9 RRT would be the most appropriate to use if lifethreatening changes in fluid, electrolytes, or acid–base balance are noted.

p. 641

p. 642

Figure 29-4 Schematic of acute tubular necrosis (ATN). The process is initiated by ischemia or nephrotoxin

exposure that leads to tubular cell death. The cellular debris sloughs off and obstructs the proximal tubule lumen.

Once the nephron is obstructed, a back leak of the glomerular ultrafiltrate occurs across the tubular basement

membrane and impairment of glomerular filtration is seen. During the recovery phase of ATN, the obstructive

cellular casts are released into the urine and filtration begins to normalize. GFR, glomerular filtration rate.

Radiocontrast Media–Induced Acute Tubular Necrosis

CASE 29-5

QUESTION 1: K.S., a 74-year-old black man (height = 5 feet, 9 inches; weight = 210 pounds), presents to the

emergency department complaining of chest pain. His medical history is significant for advanced type 2

diabetes mellitus, 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 iopamidol (Isovue, Bracco

Diagnostics Inc., Princeton, NJ, USA) a nonionic, low-osmolar radiocontrast to enhance visualization of his

cardiac arteries. His admission BUN is 37 mg/dL and SCr is 1.5 mg/dL. Two days later, pertinent laboratory

findings include a BUN and SCr of 60 and 2.0 mg/dL, respectively, and his urine output is 700 mL/day. Why did

AKI develop in K.S.? How is his diagnosis substantiated by his clinical findings?

Radiocontrast media administration is one of the most common causes of druginduced ATN. Although no set criteria exist for its diagnosis, it is generally

considered after radiocontrast exposure when an increase in SCr of 0.5 mg/dL or

25% greater than baseline occurs in 24 to 48 hours, peaks at 3 to 5 days, and returns

to baseline in 1 to 3 weeks.

57,58 The American College of Radiology has

recommended using the AKIN criteria requiring smaller changes in serum creatinine

occurring within 48 hours after the administration of iodinated contrast media to

define contrast-induced nephropathy (CIN) in order to standardize the varying

definitions found in the literature.

59 CIN usually presents as a nonoliguric ATN, as

observed in K.S., whose urine output is more than 400 mL/day. It is also

differentiated from other forms of ATN in that the FE Na

is usually less than 1% (vs.

the typical >2%). The degree of creatinine rise and the presence of oliguria are

widely 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 have a relatively minute

risk of developing CIN; for those with recognized risk factors, prevalence may

approach 50%.

60

The mechanisms by which radiocontrast media induce AKI are complex. Initially,

the radiocontrast 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.

61 The ischemia is compounded by the increased medullary

oxygen consumption because of the osmotic diuresis. Consequently, disequilibrium

exists between oxygen 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.

CASE 29-5, QUESTION 2: What risk factors did K.S. have for developing CIN?

The documented risk factors for CIN are listed in Table 29-5. Any condition that

decreases renal blood flow increases the risk of nephropathy. At-risk patient

populations include individuals with underlying diabetic nephropathy or eGFR <60

mL/minute/1.72 m2

, heart failure, or volume depletion, or those receiving aggressive

diuretic regimens. Contrast volume administered during the imaging procedure as

well as type of contrast remain additional risk factors.

62 The use of the ionic highosmolar or ionic low-osmolar contrast products increases the risk of nephropathy, as

well as the previously discussed medications that markedly reduce renal perfusion

(e.g., diuretics, NSAIDs, COX-2 inhibitors, ACE inhibitors, and ARBs). However,

newer nonionic low-osmolar agents may be less nephrotoxic than older agents, but

still can cause nephrotoxicity in patients at risk. Nonionic iso-osmolar contrast

appears to be better tolerated.

63

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p. 643

Table 29-5

Proven Risk Factors for Developing Radiocontrast Media–Induced Acute

Tubular Necrosis

Diabetic nephropathy

Chronic kidney disease

Severe heart failure

Diabetes and multiple myeloma

Volume depletion and hypotension

Dosage and frequency of contrast administration

Ionic radiocontrast agents

On the basis of the published literature, gadolinium-based contrast (GBC) agents

are less nephrotoxic than iodinated radiocontrast; however, when GBC agents are

used in high dosage with arterial injection in patients with advanced kidney disease,

AKI can occur. More concerning is the development of debilitating nephrogenic

systemic fibrosis (NSF), which is sometimes fatal. There is no cure for NSF. Patients

with AKI or CKD with GFR <30 mL/minute, who have had imaging studies (e.g.,

magnetic resonance angiography) with GBC agents are at high risk for developing

NSF. The U.S. Food and Drug Administration (FDA) has issued an advisory Black

Box Warning to avoid using these currently approved GBC agents (Ablavar,

Doterem, Eovist, Magnevist, Multihance, Omniscan, Optimark, Prohance) in AKI and

stage 4 and 5 CKD.

64–66

K.S. is at high risk for developing radiocontrast-induced ATN. He is volume

depleted, as evidenced by his admission BUN:SCr ratio, which is greater than 20:1.

Second, it is very likely that K.S. has underlying diabetic nephropathy, as evidenced

by his elevated admission SCr. The presence of retinopathy, coronary artery disease,

and peripheral vascular disease suggest long-term uncontrolled diabetes mellitus, a

risk factor for nephropathy.

PREVENTION

CASE 29-5, QUESTION 3: What strategies could have been performed in K.S. to prevent the occurrence of

CIN?

Attempts have been made to minimize or prevent CIN using a variety of

approaches. Decreasing contact time and the concentration of contrast media within

the kidney tubule lumen may reduce its direct toxic effects. A higher urine output is

associated with a lower incidence of CIN in high-risk patients.

67,68 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. Intravenous hydration with normal saline, hypotonic saline (0.45% sodium

chloride), and sodium bicarbonate in dextrose 5% and water have all shown benefits

in preventing CIN in high-risk patients. Infusion rates usually start at 1 mL/kg/hour to

maintain a goal urine output of 150 mL/hour.

Sodium bicarbonate may be of value, but larger multicenter studies are needed to

determine its true effectiveness.

68 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. However, sodium overload is problematic and sodium

bicarbonate should be avoided in compromised cardiac states.

Data suggest normal saline should be infused at least 6 hours before and 12 hours

after the imaging study to adequately reduce the risk of developing nephropathy. In

contrast, sodium bicarbonate should be infused 1 hour before and 6 hours after the

imaging study. The antioxidant N-acetylcysteine (NAC) has also been used for its

renal-sparing effects relative to radiocontrast media, but its role in preventing CIN

remains unclear.

69 NAC is believed to work by protecting renal tubule cells from

apoptosis related to the reactive oxygen species.

70 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. Given the safety profile and minimal cost

impact as well as the significant morbidity associated with CIN in high-risk patients,

its continued use is not inappropriate. At this time, recommending a specific dose of

NAC is difficult. The commonly accepted regimens at many institutions is 600 or

1,200 mg orally twice daily the day before and the same day of the contrast

procedure for a total of four doses along with concomitant intravenous hydration

therapy.

71 Higher doses (total of 6,000 mg over 48 hours) may be required for highrisk patients (those with CKD or HF) and needs further investigation.

72

Currently, a large randomized, double-blind, multicenter trial ongoing trial, The

Prevention of Serious Adverse Events following Angiography (PRESERVE),

73 will

compare the effectiveness of intravenous bicarbonate versus intravenous normal

saline and oral NAC versus oral placebo for prevention of contrast-induced AKI.

The trial (ClinicalTrials.gov NCT01467466) will enroll 8,680 high-risk patients

undergoing coronary or noncoronary angiography.

Another important point is that the administration of diuretics such as mannitol and

furosemide should be avoided.

74 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 and meta-analysis of aminophylline and theophylline have

affirmed a renoprotective effect in patients who have underlying CKD; however,

large-scale clinical trials are lacking.

75Although the use of calcium-channel blockers

theoretically seems rational to prevent contrast-induced ATN, limited clinical data

exist. HMG CoA reductase inhibitors have been proposed for prevention of CIN

given their antioxidant and anti-inflammatory properties; however, recent studies

have not shown a benefit.

76,77 Limited data suggest that ascorbic acid before and after

the procedure may be beneficial in preventing contrast nephropathy given its

antioxidant effects

78

; however, a recent published report comparing ascorbic acid to

NAC showed a greater benefit of high-dose NAC than ascorbic acid in preventing

CIN in patients at risk.

79 High doses and long-term use of ascorbic acid should be

avoided because of the risk of hyperoxalurea, oxalate-containing urinary stones, and

renal damage.

When possible, alternative imaging studies that do not require radiocontrast should

be attempted. If this is not practical, the lowest effective dose of nonionic lowosmolar or iso-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

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p. 644

is also a risk factor. It is not a nephrotoxin; however, its use has been associated

with the development of AKI, systemic complications, and death in rare cases.

Metformin should also be discontinued 1 day before giving radiocontrast media and

held for at least 2 days after the imaging study because it may cause lactic acidosis if

patients experience AKI. If patients are receiving calcium-channel blockers for

underlying cardiovascular disease, no change in therapy is warranted. All patients

should be well hydrated with normal saline or sodium bicarbonate fluids before and

after radiocontrast administration to prevent CIN. The addition of NAC is optional.

CASE 29-5, QUESTION 4: What treatment options are available for established radiocontrast-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

nonoliguria with furosemide and mannitol have been largely unsuccessful.

Aminoglycoside-Induced Acute Tubular Necrosis

CASE 29-6

QUESTION 1: T.G. is a 81-year-old, 80 kg white male (height 5 feet, 10 inches) being treated for

Streptococcus bovis prosthetic valve endocarditis. T.G. is known to have systolic congestive heart failure with

an ejection fraction of 25%. T.G. has a low BP at 90/50 mm Hg, pulse 110 beats/minute. Since admission, T.G.

has received ceftriaxone 2 g IV daily, and gentamicin 80 mg IV q8 hours. Today, (hospital day 7), significant

laboratory values are as follows:

BUN, 67 mg/dL

SCr, 5.4 mg/dL (baseline 0.9 mg/dL)

WBC count, 16,700 cells/μL with continued left shift

FENa 3%

During the last 2 days, T.G.’s urine output has steadily declined, and today it is 700 mL/24 hours. A urinalysis

revealed many WBCs, 3% RBC casts, brush-border cells, and granular casts with an osmolality of 250

mOsm/kg. A serum trough gentamicin concentration obtained with the last dose is 6 mg/L (target, <1.0 mg/L).