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JUNE 2012
Kidney Failure in an HIV-Positive Patient
CLINICAL PRESENTATION
A 71-year-old man was admitted with a recent decrease in kidney
function. In March 2008, HIV (human immunodeficiency virus)-1
was diagnosed and cART (combination antiretroviral therapy) was
started with atazanavir, tenofovir, emtricitabine, and ritonavir. Eight
months later, he developed acute kidney injury (AKI) as his serum
creatinine level increased from 1.0 mg/dL (88.4 ␮mol/L; estimated
glomerular filtration rate [eGFR], 79 mL/min/1.73 m2 [1.32 mL/s/
1.73 m2] calculated using the 4-variable MDRD [Modification of
Diet in Renal Disease] Study equation) to 4.3 mg/dL (380 ␮mol/L;
eGFR, 15 mL/min/1.73 m2 [0.25 mL/s/1.73 m2]), associated with
glycosuria, microhematuria, and non-nephrotic proteinuria.Antiretroviral therapy was changed to atazanavir, abacavir, lamivudine,
and ritonavir, with normalization of urinalysis results and a decrease in serum creatinine level to 2.4 mg/dL (212 ␮mol/L; eGFR,
29 mL/min/1.73 m2 [0.48 mL/s/1.73 m2]). After a second AKI
episode, kidney function progressively worsened, with persistent
sterile leukocyturia and crystalluria. The patient received no other
medications besides antiretrovirals. Viral load remained ⬍200
copies/mL and CD4 count was ⬎200 cells/␮L since the initiation
of cART (Fig 1).
On admission, physical examination findings were unremarkable. Laboratory data were significant for serum urea
level of 187 mg/dL (67 mmol/L) and serum creatinine level
of 7.1 mg/dL (628 ␮mol/L; eGFR, 8 mL/min/1.73 m2 [0.13
mL/s/1.73 m2]). Urinalysis was negative for protein, glucose,
and nitrites. Urinary sediment showed 75 leukocytes per
high-power field, fine needle crystals, and no red blood cells
or cellular casts. Test results for hepatitis B, hepatitis C, and
cryoglobulin were negative. Ultrasound showed normalsized kidneys. A kidney biopsy was performed (Figs 2 and 3).
Figure 1. Changes in serum creatinine level (solid line) and viral
load (dashed line) since HIV (human immunodeficiency virus)
diagnosis. Conversion factor for serum creatinine in mg/dL to
␮mol/L, ⫻88.4. Abbreviation: AKI, acute kidney injury.
Figure 2.
⫻200).
Hematoxylin and eosin stain (original magnification,
 What are the kidney manifestations
of HIV?
 How has cART changed
HIV-associated kidney diseases?
 How do you interpret the kidney
biopsy?
Am J Kidney Dis. 2012;59(6):xxvii-xxx
Figure 3. Epoxy resin semithin section stained with methylene
blue (original magnification, ⫻200).
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 What is the most likely cause of the
progressive decrease in kidney
function in this patient?
QUIZ PAGE
JUNE 2012
ANSWERS
DISCUSSION
f What are the kidney
manifestations of HIV?
Kidney disorders are frequent in
HIV infection at all stages (Box
1).1,2 Patients with HIV are at
increased risk of AKI, with hypoperfusion being the most frequent
cause.2 The most common HIVassociated glomerular injuries are
due to focal segmental glomerular sclerosis, known as HIV-associated nephropathy, or to HIV immune-complex kidney disease.
However, different diseases related to common comorbid conditions can be found.1,3
Box 1. Differential Diagnosis of Kidney Disease in HIV
AKI
●
●
●
●
CKD
●
●
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f How has cART changed
HIV-associated kidney
diseases?
The advent of cART has changed
the pattern of kidney disease in
patients with HIV infection, decreasing the incidence of AKI related to infection and HIV-associated nephropathy, but increasing
nephrotoxicity related to antiretroviral therapy.4 Mechanisms of that
nephrotoxicity include myoglobinuria, direct tubular toxicity,
acute interstitial nephritis, and
crystal nephropathy.5
Intratubular kidney precipitation of medications can promote
acute and chronic kidney injury,
termed crystal nephropathy (Box
2).6,7 Patients with HIV are commonly exposed to drugs that may
promote intratubular crystal precipitation, but the real magnitude
of this nephrotoxicity may be underestimated.
xxviii
Common non–HIV-specific causes
Opportunistic infectionsa
〫 Kidney hypoperfusion and ischemia
〫 AIN
〫 Rhabdomyolysis
b
〫 Urinary tract obstruction: blood clots, fungus balls, or crystalluria
HIV-specific glomerulopathiesa
Drugsc
●
HIV-specific glomerulopathiesa
〫 HIV-associated nephropathy
〫 HIV immune-complex kidney disease
 Immune complex–mediated GN
 IgA nephritis
 Mixed sclerotic/inflammatory disease
 Lupus-like disease
〫 Thrombotic microangiopathy
Common HIV-nonspecific glomerulopathiesb
〫 HCV-related MPGN/cryoglobulinemia
〫 Postinfectious GN
〫 Amyloidosis
〫 Membranous glomerulopathy
〫 Classic FSGS
〫 Diabetic nephropathy
〫 Minimal change disease
〫 IgA nephropathy
Drugsc
Fluid and Electrolyte Disorders
●
●
●
Disorders of osmolality
Potassium disorders
Acid-base disorders
Antiretroviral Nephrotoxicity
●
●
●
●
●
●
●
●
AKI: abacavir, atazanavir, didanosine, indinavir, ritonavir, saquinavir, tenofovir
CKD: abacavir, atazanavir, indinavir, lopinavir, tenofovir
AIN: abacavir, atazanavir, indinavir
Fanconi syndrome: tenofovir, didanosine, abacavir
Renal tubular acidosis: lamivudine, stavudine
Crystalluria, lithiasis: see Box 2
Nephrogenic diabetes insipidus: didanosine, tenofovir
Others
Abbreviations: AIN, acute interstitial nephritis; AKI, acute kidney injury; cART,
combination antiretroviral therapy; CKD, chronic kidney disease; FSGS, focal
segmental glomerulosclerosis; GN, glomerulonephritis; HCV, hepatitis C virus;
HIV, human immunodeficiency virus; IgA, immunoglobulin A; MPGN, membranoproliferative glomerulonephritis.
a
Less common cause since cART introduction.
b
More common cause since cART introduction.
c
Including antiretroviral drugs listed in Antiretroviral Nephrotoxicity.
Am J Kidney Dis. 2012;59(6):xxvii-xxx
Box 2. Agents Associated With Crystal Nephropathy
● Antiretrovirals
〫 Atazanavir
a
〫 Indinavir
● Antivirals
a
〫 Acyclovir
〫 Foscarnet
● Antibiotics
〫 Ampicillin
〫 Cephalexin
〫 Ciprofloxacin
a
〫 Sulfonamides
● Other drugs
〫 Aspirin
a
〫 Methotrexate
〫 Oral sodium phosphate
〫 Piridoxylate
〫 Primidone
〫 Sulfa-containing medications
a
〫 Trianterene
〫 Vitamin C
〫 Xylitol
Note: HIV (human immunodeficiency virus)–positive patients are frequently exposed to multiple drugs that
can precipitate into crystals.
a
Most commonly prescribed medications associated with crystal nephropathy.
f How do you interpret the
kidney biopsy?
Am J Kidney Dis. 2012;59(6):xxvii-xxx
length (Figs 5 and 6). Negative
periodic acid–Schiff and von
Kossa staining excludes polysaccharides and phosphate content,
respectively. Immunofluorescence microscopy is negative.
f What is the most likely
cause of the progressive
decrease in kidney
function in this patient?
Our patient presented with progressive chronic kidney disease.
The absence of proteinuria/hematuria and the kidney biopsy excluded glomerulopathies.
Although AKI may have a multitude of causes, the patient had
neither opportunistic infections
nor other non–HIV-related causes.
The first episode was associated
with tubular toxicity and improved
after tenofovir withdrawal, making this drug a likely culprit.8
Crystalluria was not appreciated
as a possible cause of the second
AKI episode, and the cART regimen continued; however, this
could have represented acute crystal nephropathy that later progressed to chronic disease.
Crystal deposition likely was
caused by atazanavir, the only drug
taken by the patient known to be
associated with urinary crystal formation. Urinary crystals disappeared after atazanavir withdrawal.
It is likely that the nephrotoxic effect, first with tenofovir and then
with atazanavir, significantly contributed to chronicity.
Despite atazanavir withdrawal
and a course of steroid therapy,
Figure 5. Urinary sediment (original magnification, ⫻200).
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Light microscopy shows a glomerulus with mild nonspecific
ischemic collapse and pericapsular fibrosis (Fig 2). There is diffuse and mild active interstitial
infiltration by mononuclear cells,
associated with giant cell reaction, surrounding numerous
crystals distributed in the interstitium and within distal or collecting tubules (Figs 3 and 4).
Crystals appear generally clear
with characteristic serrated edges
and are nonbirefringent upon polarization. Electron microscopy
shows crystal-shaped clefts similar in outline to the crystals seen
in the urinary sediment, with
aggregations of fine needle crystals ranging in size from 150270 nm in diameter and reaching several micrometers in
Figure 4. Periodic acid–Schiff stain (original magnification, ⫻400).
4. Roe J, Campbell LJ, Ibrahim
F, Hendry BM, Post FA. HIV care
and the incidence of acute renal
failure. Clin Infect Dis. 2008;47:
242-249.
5. Izzedine H, Harris M, Perazella
MA. The nephrotoxic effects of
HAART. Nat Rev Nephrol. 2009;5:
563-573.
6. Izzedine H, Launay-Vacher V,
Deray G. Antiviral drug–induced
nephrotoxicity. Am J Kidney Dis.
2005;45:804-817.
7. Perazella MA. Crystal-induced
acute renal failure. Am J Med. 1999;
106:459-465.
8. Fernandez-Fernandez B, Montoya-Ferrer A, Sanz AB, et al. Tenofovir nephrotoxicity: 2011 update. AIDS
Res Treat. 2011;2011:354908.
Figure 6. Electron microscopy (original magnification, ⫻3,000).
the patient did not recover kidney
function, and long-term hemodialysis therapy was started. A
timely diagnosis may have led to
a better outcome.
FINAL DIAGNOSIS
Atazanavir crystal–induced nephropathy as a part of multifactorial end-stage renal disease.
ACKNOWLEDGEMENTS
QUIZ PAGE
Ana Isabel Silva, Luis Inchaustegui,
Bruno Rodrigues, and Pedro Fidalgo
are gratefully acknowledged.
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REFERENCES
1. Fine DM, Perazella MA, Lucas
GM, Atta MG. Kidney biopsy in HIV:
beyond HIV-associated nephropathy.
Am J Kidney Dis. 2008;51:504-514.
2. Franceschini N, Napravnik S,
Eron JJ Jr, Szczech LA, Finn WF.
Incidence and etiology of acute renal
failure among ambulatory HIV-infected patients. Kidney Int. 2005;67:
1526-1531.
3. Flandre P, Pugliese P, Cuzin L,
et al. Risk factors of chronic kidney
disease in HIV-infected patients.
Clin J Am Soc Nephrol. 2011;6:
1700-1707.
CASE PROVIDED AND AUTHORED BY
Silvia Coelho, MD,1 Samuel Rodrigues Aparicio, MD,2 Rita
Manso, MD,2 and Karina Soto,
MD, PhD,1 Departments of 1Nephrology and 2Pathology, Hospital Fernando Fonseca, Lisbon,
Portugal.
Address correspondence to Karina
Soto, MD, PhD, IC 19, Hospital
Fernando Fonseca EPE, 2720276 Amadora, Lisboa, Portugal.
E-mail: ksoto.nefro@gmail.com
© 2012 by the National Kidney
Foundation, Inc.
http://dx.doi.org/10.1053/j.ajkd.
2012.03.005
SUPPORT: None.
FINANCIAL DISCLOSURE: The authors
declare that they have no relevant
financial interests.
Am J Kidney Dis. 2012;59(6):xxvii-xxx