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.
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.
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
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
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 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 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
POSTSTREPTOCOCCAL GLOMERULONEPHRITIS
pounds) in otherwise good health who recently developed strep throat. He received a 10-day course of
records from a routine physical examination 2 months ago reveal a BUN and SCr of 10 and 0.8 mg/dL,
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).
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.
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
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
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.
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
CASE 29-3, QUESTION 4: Are there other glomerulopathies that cause AKI?
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
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