CASE 29-2, QUESTION 2: Are there other factors that predispose patients to ACE inhibitor–induced AKI?

G.B. has extensive atherosclerotic disease indicated by the presence of coronary

artery and peripheral vascular disease. Atherosclerosis not only affects major blood

vessels but also the macrovasculature and microvasculature of the kidney; indeed,

atherosclerosis is a major cause of renal artery occlusion and decreased renal

perfusion. This activates the RAAS, 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.

45

In addition to the previous

situation, three other general scenarios will result in the development of AKI with

ACE inhibitors. First, conditions of sodium and water depletion (e.g., dehydration,

overdiuresis, poor fluid intake, low-sodium diet) can increase the dependency of the

efferent arteriole on AT II. Dehydration from diuretic use and decreased fluid intake

during the heat spell may have compromised effective circulating volume and led to

decreased renal blood flow in G.B. When ACE inhibitors are given in these

situations, GFR can fall dramatically, and SCr rises. AKI can be averted by

withholding 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). The ACE inhibitor can be restarted at the same dose after adequate

hydration when SCr returns to baseline. 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 or in situations in which the

pharmacologic half-life of the ACE inhibitor is prolonged (e.g., preexisting renal

disease). Finally, ACE inhibitors may precipitate AKI in patients who are taking

concomitant drugs with renal afferent arteriole vasoconstricting effects, most notably

cyclosporine and NSAIDs. In AKI, another important consideration is thiazides

(except metolazone), which are less effective in the presence of ClCr <30 mL/minute

and can be restarted when renal function improves.

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p. 639

Figure 29-3 Compensatory hormonal mechanisms of decreased renal perfusion.

CASE 29-2, QUESTION 3: How should G.B.’s ACE inhibitor–induced AKI be managed?

Patients who are receiving ACE inhibitors should be monitored judiciously with

regard to their SCr and electrolyte concentrations. Once an ACE inhibitor is initiated,

an increase in SCr of 20% to 30% can be expected.

44 This slight increase should not

worry clinicians, because SCr typically normalizes within 2 to 3 months. SCr

increases greater than this along with reduced urine output signal AKI, however. AKI

related to ACE inhibitors is usually reversible, principally because the AKI is

caused by inadequate glomerular capillary pressure, which is restored as soon as

sufficient AT II is produced. This normally takes 2 to 3 days to re-equilibrate.

Anecdotally, AKI appears to develop more commonly in hypotensive patients or in

those with intravascular volume depletion (e.g., patients with HF receiving high-dose

diuretics, inadequate fluid intake with diuretic use). In these conditions, it is prudent

to replete the intravascular fluid volume or temporarily discontinue diuretic therapy

until renal function improves. G.B.’s ACE inhibitor therapy should be temporarily

discontinued and reinstituted when she has a normalized intravascular volume and is

hemodynamically stable and kidney function has returned to baseline or stabile

kidney function is established. See Chapter 14, Heart Failure, for a discussion on the

use of ACE inhibitors and concurrent diuretic therapy in patients with heart failure.

CASE 29-2, QUESTION 4: Do angiotensin II–receptor blockers (ARBs) cause less AKI compared with

ACE inhibitors?

The ARBs competitively inhibit the angiotensin II receptor. At least two subtypes

of the angiotensin II receptors exist: AT1 and AT2. The ARBs exert their

pharmacologic effect at the AT1 receptor subtype, which is responsible for most, if

not all, of the cardiovascular effects of angiotensin II, such as vasoconstriction,

aldosterone release, and β-adrenergic stimulation. Few differences are seen in the

incidence of AKI between ACE inhibitors and ARBs

45 and one should not be

interchanged with the other in an attempt to decrease AKI risk. See Chapter 14, Heart

Failure, for further discussion.

HgA1c and urine ACR are elevated. The patient may be at risk for diabetic

nephropathy from uncontrolled diabetes. Initially, albuminuria (at least 2 out of 3

elevated ACR values >30 and <300 mg/g within 3 months) is considered a renal

marker indicative of early stage CKD with or without an increase in baseline SCr.

ACE inhibitors or ARBs are prescribed as anti-proteinuric agents to manage

albuminuria and delay the progression of CKD with or without underlying

hypertension. ACE inhibitors are the preferred anti-proteinuric agents in type 1

diabetes, whereas ARBs are preferred in type 2 diabetes and in patients intolerant to

cough associated with ACE inhibitors. After AKI resolves in G.B., an ACE inhibitor

is appropriate to consider treating hypertension and delay the progression of CKD.

INTRINSIC ACUTE KIDNEY INJURY

Intrinsic AKI is a general term that connotes damage at the parenchymal level of the

kidney. The term acute tubular necrosis is often used to describe this type of AKI, but

this is a histologic diagnosis that describes only one of several intrinsic disorders.

Pragmatically, intrinsic AKI can be subdivided into vascular, glomerular, or tubular

disorders.

Disorders involving the large renal vessels are relatively uncommon. Acute renal

artery or vein occlusion can be caused by vasculitis, atheroembolism,

thromboembolism, dissection, or clamping of the ascending aorta during surgery. To

affect BUN and Scr, occlusion must be bilateral, or it can be unilateral in patients

with concomitant renal insufficiency or one functioning kidney. Reduced blood flow

to the renal microvasculature and glomeruli also can result in AKI. Common

examples are rapidly progressing glomerulonephritis (RPGN) and vasculitis. If these

conditions become sufficiently severe, they can cause ischemia, resulting in

superimposed ATN. Any disorder that produces tubular ischemia, such as prolonged

hypotension or shock syndromes, can result in ATN.

Nephrotoxic drugs are a common cause of ATN, especially when given in septic

or volume-contracted patients. The various mechanisms by which drugs can cause

ATN are explained in detail later in this chapter. Although relatively uncommon,

drug-induced AIN is another type of intrinsic AKI. This is a hypersensitivity reaction

that results from the formation of drug–antibody complexes that subsequently deposit

in the glomerular membrane.

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Acute Glomerulopathies

POSTSTREPTOCOCCAL GLOMERULONEPHRITIS

CASE 29-3

QUESTION 1: B.M. is an 18-year-old white male college freshman (height = 5 feet, 8 inches; weight = 150

pounds) 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 from a routine physical examination 2 months ago reveal a BUN and SCr of 10 and 0.8 mg/dL,

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 and WBC casts, and epithelial cells. B.M.’s SCr has increased to 7.1 mg/dL.

Based on the history, physical examination, and laboratory findings, what is the most likely cause of AKI in this

patient?

B.M.’s recent history of a streptococcal infection with the development of AKI

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. Certain

serologic subtypes of group A β-hemolytic streptococci, known as nephritogenic

strains, cause PSGN. The M and T proteins located in the bacterial cell wall are

used to classify streptococci. Nephritogenicity has been shown with certain M

serotypes (e.g., 1, 2, 4, 12, 18, 25, 49, 55, 57, and 60).

46 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. The overall risk of developing PSGN by

the M type 49 subtype when present in the throat is about 5% and increases to 25% if

it is found in the skin. Acute PSGN has also been described after infection with group

C streptococci in epidemics outside of the United States.

47 Positive diagnosis of

PSGN requires identification of a nephritogenic strain; objective urinalysis findings

suggestive of glomerular damage, such as proteinuria, hematuria, and casts; and

elevated streptococcal antibody titers.

B.M. exhibits the classic physical and laboratory findings associated with PSGN.

The pertinent positive physical findings include periorbital, pulmonary, and

peripheral edema; tea-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 SCr, and urinalysis positive for

hematuria, proteinuria, WBC casts, and epithelial cells. Hematuria, which is found in

almost all patients with PSGN, accounts for the reddish-brown, tea-colored urine.

Other commonly found urine sediments include cellular casts and hyaline and

granular casts. Oliguria is common in PSGN, but anuria is rare.

Given that B.M. has received a 10-day course of amoxicillin, it is unlikely that

throat cultures for the nephritogenic group A hemolytic streptococcal strain will be

positive. Cultures of close contacts may, however, be positive for the streptococcal

strain, even if they are asymptomatic. The presence of circulating antibodies to the

nephritogenic streptococcal strains indicates recent exposure. The antistreptolysin O

(ASO), antihyaluronidase (AHase), antideoxyribonuclease B (ADNase B), and

antinicotyladenine dinucleotidase (NADase) antibody titers can be measured

clinically. ASO titers begin to rise 2 weeks after pharyngeal infection, peak at 4

weeks, and slowly decline over the course of 1 to 6 months. No correlation exists

between degree of ASO rise and nephrogenicity. In fact, ASO titers may not be

elevated at all if early antibiotic treatment is initiated or in cases of streptococcal

skin infections. The use of ADNase and AHase titers is more specific to detect recent

infection in these situations.

CASE 29-3, QUESTION 2: Are there other tests that can be used to confirm this diagnosis?

The streptozyme test, which can be used clinically for rapid screening purposes,

uses several antistreptococcal antibody assays. False-positive and false-negative

results are common, however, because of cross-reactivity between the antibody and

normal collagen.

Serial complement determinations may be of value in diagnosing PSGN.

Decreased levels of C3 protein and hemolytic complement activity (CH50) are

observed in nearly all patients with active PSGN. Serum C3 levels can fall by nearly

50% of normal in the first weeks of infection and return to normal within 8 weeks

after infection. No correlation, however, exists between the degree of C3 depression

and severity of nephritis. Circulating antibody complexes of C3 can be found in

patients with acute infection.

Renal biopsy is rarely needed, but it may be prudent in patients who present with

atypical symptoms, such as anuria, prolonged oliguria, marked azotemia, hematuria

for more than 3 weeks, or in those who have no streptococcal antibody titers.

CASE 29-3, QUESTION 3: What are the therapeutic goals and treatment options for PSGN?

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 in

preventing 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. Given his age and previous health,

B.M.’s prognosis is very good. In general, prognosis is excellent in youth, but

significantly worse in the elderly and in patients with other risk factors for CKD,

such as diabetes and hypertension.

47

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

CASE 29-3, QUESTION 4: Are there other glomerulopathies that cause AKI?

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p. 641

Yes. Rapidly progressive glomerulonephritis (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 hematuria, nephritic

syndrome with 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 death is 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 depositions in the glomerular microvasculature and

mesangium, suggesting immune complex deposition. Type III idiopathic RPGN is

also called pauci-immune because there are no hallmark immunoglobulin or

complement findings on immunofluorescence microscopy. Type III idiopathic RPGN

is identified by the presence of circulating antineutrophil cytoplasmic antibodies

(ANCA). Type IV, known as double-antibody disease, is characterized by anti-GBM

antibodies and ANCA seen in Types I and III RPGN.