Académique Documents
Professionnel Documents
Culture Documents
HIV-associated nephropathy:
epidemiology, pathogenesis,
diagnosis and management
Expert Rev. Anti Infect. Ther. 6(3), 365371 (2008)
Mohamed G Atta, HIV-associated nephropathy (HIVAN) is the most well-known and aggressive kidney disease in
Gregory M Lucas HIV-1-infected patients. A variant of focal segmental glomerulosclerosis, it is characterized by
and Derek M Fine the collapse of the glomerular tuft with podocyte hypertrophy/hyperplasia and foot process
effacement, often with concurrent tubular microcystic dilation and tubulointerstitial nephritis.
Author for correspondence
The disease has been intimately linked to the direct effect of HIV-1 on the kidney. It affects
1830 E. Monument Street,
Suite 416, Baltimore, patients of African descent exclusively and is manifested by an acute decline in kidney function,
MD 21287, USA most often in conjunction with high-grade proteinuria and uncontrolled HIV-1 infection. With
Tel.: +1 410 955 5268 the widespread use of highly active antiretroviral therapy (HAART), its prevalence is declining in
Fax: +1 410 955 0485 Western countries. However, the epidemiology of the disease is not well defined in the poorest
matta1@jhmi.edu areas of the world, which bear a disproportionate share of the HIV-1 epidemic burden. Scientific
evidence suggests that HAART can prevent the development of HIVAN. Furthermore, HAART,
corticosteroids and inhibition of the reninangiotensin axis are potentially helpful in delaying
disease progression, as well as the need for renal replacement therapy.
KEYWORDS: end-stage renal disease highly active antiretroviral therapy HIV-1 HIV-associated nephropathy kidney
important as the clinical presentation of HIVAN may be mim- the diagnosis of HIVAN. The disorder is unlikely in the setting
icked by other glomerular diseases, with potentially significantly of low-grade proteinuria, suppressed viral load and low-level or
different treatment options and prognoses. normal echogencity on ultrasound.
The natural history of HIVAN without antiretroviral ther-
apy is an ominous one. When first reported in 1984 [3], Differential diagnosis
HIV-1-infected individuals presented with nephrotic-range There are myriad of glomerular diseases with clinical presenta-
proteinuria and progression to ESRD occurred within tions that resemble HIVAN but that differ from HIVAN in
816 weeks. Mortality in these patients approached 100% terms of management approach and prognosis. Other glomeru-
within 6 months of diagnosis. In the HAART era, prognosis lar diseases that have been described in HIV-1-infected individ-
remains poor in these patients compared with other kidney uals are shown in BOX 1. Therefore, although kidney biopsy car-
diseases in HIV-1-infected patients. In a recent, observational ries a small risk, the benefit of definitive diagnosis of HIVAN
study by Berliner et al. of HIV-1-infected patients who under- outweighs such a risk.
went kidney biopsy, HIVAN patients were more likely to ulti-
mately require hemodialysis (p < 0.0001) and had significantly
worse survival compared with patients without HIVAN Management
(p = 0.02) [39]. However, patients with HIVAN that were If left untreated, HIVAN almost uniformly progresses to ESRD
treated with HAART had significantly better renal survival within weeks to months. However, there have not been any
compared with untreated individuals [41]. randomized, controlled trials evaluating any type of therapy for
the management of HIVAN. Several retrospective analyses have
examined the clinical benefit of various therapies, including the
Diagnosis use of steroids, inhibition of the reninangiotensinaldosterone
Diagnosis of HIVAN requires a kidney biopsy, which should be system, and HAART.
performed promptly whenever possible and when the proce-
dure is not contraindicated. It is often difficult to distinguish Corticosteroids
HIVAN from other kidney lesions on clinical grounds alone. The scientific rationale for considering the use of corticoster-
Identifying valid, surrogate, noninvasive measures in the diag- oids in individuals with HIVAN is the significant tubulo-
nosis of HIVAN has been disappointing [42,43]. For example, interstitial inflammation present on histological examination of
nephrotic-range proteinuria, even in the presence of a low CD4 the renal tissue in these individuals. In vitro microarray data
cell count, does not reliably predict HIVAN [43]. HIVAN was have demonstrated upregulation of many of the proinflamma-
diagnosed in only 53% of 55 patients with nephrotic-range tory genes in renal tubular cells of individuals with HIVAN
proteinuria, with a sensitivity of only 73% and a positive pre- providing a potential role for proinflammatory mediators in the
dictive value of 53% [43]. In individuals with nephrotic-range development of tubulointerstitial disease [45]. The marked
proteinuria without HIVAN, common diagnoses included clas- reductions in interstitial inflammatory cells after treatment
sic FSGS, membranoproliferative glomerulonephritis, amyloid with corticosteroids provide more support for the use of corti-
A amyloidosis, diabetic nephropathy and other diagnoses [43]. costeroids in this population [46]. However, there are no long-
Measurable viremia is a typical feature of HIVAN presentation term studies examining the efficacy of corticosteroids on
and the diagnosis of HIVAN has been shown to be unlikely if HIVAN, and the benefit of corticosteroids has only been dem-
the HIV-1 RNA level is less than 400 copies/ml [44]. By con- onstrated in retrospective, nonrandomized and short-term
trast, those with HIV viral load of at least 400 copies/ml, were studies [47,48]. Interestingly, there appears to be a glomerular
diagnosed with HIVAN in only 37% (23 out of 63) of cases. effect, evidenced by a reduction in proteinuria with this treat-
Similarly, kidney size on ultrasound has not been found to pre- ment [48]. Due to the aggressiveness of HIVAN and, therefore,
dict HIVAN [42]. However, patients with HIVAN have a signif- the need for rapid intervention in order to attenuate disease, we
icantly increased renal echogenicity in comparison with HIV-1 recommend a limited course of corticosteroid therapy in
infected individuals with other renal diseases at the time of selected patients who have biopsy-proven HIVAN. This course
renal biopsy [42]. A normal or low level of renal echogenicity of corticosteroid should only be considered as long as there is
argues against the diagnosis of HIVAN. In the study by Ber- simultaneous use of HAART (see later) as the effects of steroids
liner et al. [39], the risk of HIVAN was significantly decreased as are not likely to be sustained in the absence of a more definitive
CD4 counts rose to between 200 and 500 cells/mm3 (odds therapy. Based on doses used in published studies [46,47], a start-
ratio [OR]: 0.09; 95% confidence interval [CI]: 0.020.32; ing dose of prednisone 1 mg/kg/day (up to a maximum of
p = 0.001) and then to more than 500 cells/mm3 (OR: 0.06; 60 mg) with a taper over 2 months is our standard practice.
95% CI: 0.010.60). Higher estimated glomerular filtration The use of steroids in the treatment of Pneumocystis carinii
rate (eGFR) was also a negative predictor of HIVAN pneumonia, although at lower doses and for a shorter duration
(OR: 0.93; 95% CI: 0.900.97; p = 0.001). In summary, clini- than was used for HIVAN, does not appear to be associated
cal criteria may be useful in excluding, rather than establishing, with significant risk, even in advanced HIV disease [49,50].
www.expert-reviews.com 367
Review Atta, Lucas & Fine
Key issues
HIV-associated nephropathy (HIVAN) is the most aggressive kidney disease in HIV-1-infected patients.
HIVAN almost exclusively affects uncontrolled HIV-1-infected individuals of African descent.
HIVAN presents with rapid decline in renal function, often with high-grade proteinuria.
HIVAN is a collapsing form of focal segmental glomerulosclerosis with significant tubulointerstitial injury and microcystic tubular dilation.
Only renal biopsy is diagnostic and should be performed whenever feasible since no one clinical criterion, including nephrotic range
proteinuria or kidney size by ultrasound, has a good predictive value in the diagnosis of HIVAN.
Treatment with highly active antiretroviral therapy has been shown to reduce development of HIVAN by 60% and slow progression to
end-stage renal disease by 38% in those with HIVAN. Short-term corticosteroids may also be of benefit.
Adjunctive therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should also be considered.
Response to therapy requires prompt diagnosis since, in light of the aggressiveness of the disorder, immediate therapy is likely to result
in a better outcome.
(CA, USA) and supported by the NIH, has been launched in expression of podocyte differentiation markers in HIV-1-
the USA to explore safety and efficacy of solid organ transplan- infected podocytes [61], may prove to have a potential role as an
tation in HIV-1-infected individuals with end-organ damage. adjunctive therapy for HIVAN.
This nationally coordinated effort will ultimately provide
much needed data on graft survival, drug interactions, optimal
immunosuppressive therapy and potential complications in Five-year view
this population. It will also provide the basis for future devel- In Western countries, the introduction of HAART (which
opment of clinical practice guidelines in managing transplant became the standard of care in 1996) resulted in the substan-
recipients with HIV-1 infection. tial declines of both morbidity and mortality directly linked
to complications of HIV-1 infection. As a result, the spectrum
of kidney diseases encountered in HIV-1-infected individuals
Expert commentary has changed where both incidence and prevalence of HIVAN
The lack of epidemiological data on the scope of earlier stages have declined in the HAART era [6,39,62]. Currently, this pop-
of HIVAN deters the development of an early identification ulation is faced with accelerated rates of chronic diseases that
method for the syndrome and also the design of a risk stratifica- afflict the general population, including diabetes mellitus,
tion model that may guide the assessment of different interven- hypertension, dyslipidemia and cardiovascular, liver and
tion modalities. Furthermore, clinical evaluation is also needed chronic kidney disease.
to determine whether response to HAART regimens is class
specific. If HIVAN is driven by viral replication, one may argue
that antiretroviral regimens with maximal and rapid suppres- Financial & competing interests disclosure
sion of viral replication, as well as a maximal dose-response The authors have no relevant affiliations or financial involvement
curve slope, would be the most effective in treating HIVAN. with any organization or entity with a financial interest in or
Since podocyte injury and proliferation are features of HIVAN, financial conflict with the subject matter or materials discussed in the
these pathogenic mechanisms may provide another therapeutic manuscript. This includes employment, consultancies, honoraria, stock
target. Cyclin-dependent kinase inhibitors, which inhibit cell ownership or options, expert testimony, grants or patents received or
cycle processes [60], and all-transretinoic acid, which inhibits pending, or royalties.
proliferation via cell cycle arrest at G1 and also restores the No writing assistance was utilized in the production of this manuscript.
7 Carbone L, DAgati V, Cheng JT, Appel GB. 12 Kopp JB, Winkler C. HIV-associated
References Course and prognosis of human nephropathy in African Americans. Kidney
immunodeficiency virus-associated Int. 83(Suppl.), S43S49 (2003).
1 Gardenswartz MH, Lerner CW, Seligson
nephropathy. Am. J. Med. 87(4), 389395 13 Eggers PW, Kimmel PL. Is there an
GR et al. Renal disease in patients with
(1989). epidemic of HIV Infection in the US
AIDS: a clinicopathologic study. Clin.
Nephrol. 21(4), 197204 (1984). 8 Cantor ES, Kimmel PL, Bosch JP. Effect of ESRD program? J. Am. Soc. Nephrol. 15(9),
race on expression of acquired 24772485 (2004).
2 Pardo V, Aldana M, Colton RM et al.
immunodeficiency syndrome-associated 14 Shahinian V, Rajaraman S, Borucki M,
Glomerular lesions in the acquired
nephropathy. Arch. Intern. Med. 151(1), Grady J, Hollander WM, Ahuja TS.
immunodeficiency syndrome. Ann. Intern.
125128 (1991). Prevalence of HIV-associated nephropathy
Med. 101(4), 429434 (1984).
9 Laradi A, Mallet A, Beaufils H, Allouache M, in autopsies of HIV-infected patients. Am.
3 Rao TK, Filippone EJ, Nicastri AD et al.
Martinez F. HIV-associated nephropathy: J. Kidney. Dis. 35(5), 884888 (2000).
Associated focal and segmental
outcome and prognosis factors. Groupe 15 Mazbar SA, Schoenfeld PY, Humphreys
glomerulosclerosis in the acquired
d Etudes Nephrologiques dIle de France. MH. Renal involvement in patients
immunodeficiency syndrome. N. Engl. J.
J. Am. Soc. Nephrol. 9(12), 23272335 infected with HIV: experience at San
Med. 310(11), 669673 (1984).
(1998). Francisco General Hospital. Kidney Int.
4 Winston JA, Bruggeman LA, Ross MD
10 Williams DI, Williams DJ, Williams IG, 37(5), 13251332 (1990).
et al. Nephropathy and establishment of a
Unwin RJ, Griffiths MH, Miller RF. 16 Viertel A, Weidmann E, Rickerts V,
renal reservoir of HIV type 1 during
Presentation, pathology, and outcome of Scheuermann EH, Geiger H, Brodt H.
primary infection. N. Engl. J. Med.
HIV associated renal disease in a specialist Renal involvement in HIV-infection.
344(26), 19791984 (2001).
centre for HIV/AIDS. Sex Transm. Infect. Results from the Frankfurt AIDS Cohort
5 Winston JA, Klotman ME, Klotman PE. 74(3), 179184 (1998). Study (FACS) and a review of the literature.
HIV-associated nephropathy is a late, not
11 Abbott KC, Hypolite I, Welch PG, Agodoa Eur. J. Med. Res. 5(5), 185198 (2000).
early, manifestation of HIV-1 infection.
LY. Human immunodeficiency 17 Hailemariam S, Walder M, Burger HR
Kidney Int. 55(3), 10361040 (1999).
virus/acquired immunodeficiency syndrome- et al. Renal pathology and premortem
6 Lucas GM, Eustace JA, Sozio S, Mentari associated nephropathy at end-stage renal clinical presentation of Caucasian patients
EK, Appiah KA, Moore RD. Highly active disease in the United States: patient with AIDS: an autopsy study from the era
antiretroviral therapy and the incidence of characteristics and survival in the pre highly prior to antiretroviral therapy. Swiss Med.
HIV-1-associated nephropathy: a 12-year active antiretroviral therapy era. J. Nephrol. Wkly 131(2728), 412417 (2001).
cohort study. AIDS 18(3), 541546 (2004). 14(5), 377383 (2001).
www.expert-reviews.com 369
Review Atta, Lucas & Fine
18 Nochy D, Glotz D, Dosquet P et al. Renal 30 Marras D, Bruggeman LA, Gao F et al. 42 Atta MG, Longenecker JC, Fine DM
disease associated with HIV infection: Replication and compartmentalization of et al. Sonography as a predictor of human
a multicentric study of 60 patients from HIV-1 in kidney epithelium of patients immunodeficiency virus-associated
Paris hospitals. Nephrol. Dial. Transplant with HIV-associated nephropathy. Nat. nephropathy. J. Ultrasound Med. 23(5),
8(1), 1119 (1993). Med. 8(5), 522526 (2002). 603610 (2004).
19 Nochy D, Glotz D, Dosquet P et al. Renal 31 Barisoni L, Mokrzycki M, Sablay L, 43 Atta MG, Choi MJ, Longenecker JC et al.
lesions associated with human Nagata M, Yamase H, Mundel P. Nephrotic range proteinuria and CD4
immunodeficiency virus infection: North Podocyte cell cycle regulation and count as noninvasive indicators of
American vs. European experience. Adv. proliferation in collapsing HIV-associated nephropathy. Am. J. Med.
Nephrol. Necker. Hosp. 22, 269286 glomerulopathies. Kidney Int. 58(1), 118(11), 1288.e12211288.e1226
(1993). 137143 (2000). (2005).
20 Ross MJ, Klotman PE. Recent progress in 32 Albaqumi M, Soos TJ, Barisoni L, Nelson 44 Estrella M, Fine DM, Gallant JE et al.
HIV-associated nephropathy. J. Am. Soc. PJ. Collapsing glomerulopathy. J. Am. HIV type 1 RNA level as a clinical
Nephrol. 13(12), 29973004 (2002). Soc. Nephrol. 17(10), 28542863 (2006). indicator of renal pathology in HIV-
21 Lucas GM, Mehta SH, Atta MG et al. 33 Wali RK, Drachenberg CI, Papadimitriou infected patients. Clin. Infect. Dis. 43(3),
End-stage renal disease and chronic kidney JC, Keay S, Ramos E. HIV-1-associated 377380 (2006).
disease in a cohort of AfricanAmerican nephropathy and response to highly- 45 Ross MJ, Fan C, Ross MD et al. HIV-1
HIV-infected and at-risk HIV-seronegative active antiretroviral therapy. Lancet infection initiates an inflammatory
participants followed between 1988 and 352(9130), 783784 (1998). cascade in human renal tubular epithelial
2004. AIDS 21(18), 24352443 (2007). 34 Atta MG, Gallant JE, Rahman MH et al. cells. J. Acquir. Immune Defic. Syndr.
22 Han TM, Naicker S, Ramdial PK, Antiretroviral therapy in the treatment of 42(1), 111 (2006).
Assounga AG. A cross-sectional study of HIV-associated nephropathy. Nephrol. 46 Briggs WA, Tanawattanacharoen S, Choi
HIV-seropositive patients with varying Dial. Transplant. 21(10), 28092813 MJ, Scheel PJ Jr, Nadasdy T, Racusen L.
degrees of proteinuria in South Africa. (2006). Clinicopathologic correlates of
Kidney. Int. 69(12), 22432250 (2006). 35 Scialla JJ, Atta MG, Fine DM. Relapse of prednisone treatment of human
23 Szabo S, James CW, Telford G. Unusual HIV-associated nephropathy after immunodeficiency virus-associated
presentations of primary human discontinuing highly active antiretroviral nephropathy. Am. J. Kidney Dis. 28(4),
immunodeficiency virus infection. AIDS therapy. AIDS (London, England), 21(2), 618621 (1996).
Patient Care STDS 16(6), 251254 (2002). 263264 (2007). 47 Smith MC, Austen JL, Carey JT et al.
24 Izzedine H, Wirden M, Launay-Vacher V. 36 Freedman BI, Soucie JM, Stone SM, Prednisone improves renal function and
Viral load and HIV-associated Pegram S. Familial clustering of end-stage proteinuria in human immunodeficiency
nephropathy. N. Engl. J. Med. 353(10), renal disease in blacks with HIV- virus-associated nephropathy. Am. J. Med.
10721074 (2005). associated nephropathy. Am. J. Kidney 101(1), 4148 (1996).
25 Dickie P, Felser J, Eckhaus M et al. Dis. 34(2), 254258 (1999). 48 Eustace JA, Nuermberger E, Choi M,
HIV-associated nephropathy in transgenic 37 Gharavi AG, Ahmad T, Wong RD et al. Scheel PJ Jr, Moore R, Briggs WA. Cohort
mice expressing HIV-1 genes. Virology Mapping a locus for susceptibility to study of the treatment of severe HIV-
185(1), 109119 (1991). HIV-1-associated nephropathy to mouse associated nephropathy with
chromosome 3. Proc. Natl Acad. Sci. USA corticosteroids. Kidney Int. 58(3),
26 Hanna Z, Kay DG, Cool M, Jothy S,
101(8), 24882493 (2004). 12531260 (2000).
Rebai N, Jolicoeur P. Transgenic mice
expressing human immunodeficiency virus 38 Ross MJ, Klotman PE, Winston JA. 49 Martos A, Podzamczer D,
type 1 in immune cells develop a severe HIV-associated nephropathy: case study Martinez-Lacasa J, Rufi G, Santin M,
AIDS-like disease. J. Virol. 72(1), 121132 and review of the literature. AIDS Patient Gudiol F. Steroids do not enhance the risk
(1998). Care STDS 14(12), 637645 (2000). of developing tuberculosis or other AIDS-
related diseases in HIV-infected patients
27 Hanna Z, Kay DG, Rebai N, Guimond A, 39 Berliner AR, Fine DM, Lucas GM et al.
treated for Pneumocystis carinii
Jothy S, Jolicoeur P. Nef harbors a major Observations on a cohort of HIV-infected
pneumonia. AIDS 9(9), 10371041
determinant of pathogenicity for an AIDS- patients undergoing native renal biopsy.
(1995).
like disease induced by HIV-1 in Am. J. Nephrol. 28(3), 478486 (2008).
transgenic mice. Cell 95(2), 163175 50 Gallant JE, Chaisson RE, Moore RD. The
40 DAgati V, Suh JI, Carbone L, Cheng JT,
(1998). effect of adjunctive corticosteroids for the
Appel G. Pathology of HIV-associated
treatment of Pneumocystis carinii
28 Zhong J, Zuo Y, Ma J et al. Expression of nephropathy: a detailed morphologic and
pneumonia on mortality and subsequent
HIV-1 genes in podocytes alone can lead to comparative study. Kidney Int. 35(6),
complications. Chest 114(5), 12581263
the full spectrum of HIV-1-associated 13581370 (1989).
(1998).
nephropathy. Kidney Int. 68(3), 41 Atta M, Fine D, Kirk G, Mehta S, Moore
10481060 (2005). 51 Burns GC, Matute R, Onyema D, Davis
R, Lucas G. Survival during renal
I, Toth I. Response to inhibition of
29 Bruggeman LA, Ross MD, Tanji N et al. replacement therapy among African
angiotensin-converting enzyme in human
Renal epithelium is a previously Americans infected with HIV type 1 in
immunodeficiency virus-associated
unrecognized site of HIV-1 infection. urban Baltimore, Maryland. Clin. Infect.
nephropathy: a case report. Am. J. Kidney
J. Am. Soc. Nephrol. 11(11), 20792087 Dis. 45(12), 16251632 (2007).
Dis. 23(3), 441443 (1994).
(2000).
52 Kimmel PL, Mishkin GJ, Umana WO. 57 Ahuja TS, Grady J, Khan S. Changing 62 Ahuja TS, Borucki M, Funtanilla M,
Captopril and renal survival in patients trends in the survival of dialysis patients Shahinian V, Hollander M, Rajaraman S. Is
with human immunodeficiency virus with human immunodeficiency virus in the the prevalence of HIV-associated
nephropathy. Am. J. Kidney Dis. 28(2), United States. J. Am. Soc. Nephrol. 13(7), nephropathy decreasing? Am. J. Nephrol.
202208 (1996). 18891893 (2002). 19(6), 655659 (1999).
53 Burns GC, Paul SK, Toth IR, Sivak SL. 58 Macrae J, Friedman AL, Eggers P, Friedman
Effect of angiotensin-converting enzyme EA. Improved survival in HIV-infected
inhibition in HIV-associated nephropathy. AfricanAmericans with ESRD. Clin. Affiliations
J. Am. Soc. Nephrol. 8(7), 11401146 Nephrol. 64(2), 124128 (2005). Mohamed G Atta, MD, MPH
(1997). 59 US Renal Data System. USRDS 2006 1830 E. Monument Street, Suite 416,
54 Wei A, Burns GC, Williams BA, Annual Data Report: Reference Tables of Baltimore, MD 21287, USA
Mohammed NB, Visintainer P, Sivak SL. End-stage Renal Disease in the United States. Tel.: +1 410 955 5268
Long-term renal survival in HIV-associated National Institutes of Health, National Fax: +1 410 955 0485
nephropathy with angiotensin-converting Institute of Diabetes and Digestive Diseases matta1@jhmi.edu
enzyme inhibition. Kidney Int. 64(4), and Kidney Diseases. Bethesda, MD, USA Gregory M Lucas
14621471 (2003). (2006). Department of Medicine, Division of
55 Ortiz C, Meneses R, Jaffe D, Fernandez JA, 60 Srivastava T, Garola RE, Singh HK. Infectious Diseases, Johns Hopkins
Perez G, Bourgoignie JJ. Outcome of Cell-cycle regulatory proteins in the University School of Medicine,
patients with human immunodeficiency podocyte in collapsing glomerulopathy in Baltimore, MD, USA
virus on maintenance hemodialysis. Kidney children. Kidney Int. 70(3), 529535 Derek M Fine
Int. 34(2), 248253 (1988). (2006). Department of Medicine, Division of
56 Tebben JA, Rigsby MO, Selwyn PA, 61 He JC, Lu TC, Fleet M et al. Retinoic acid Nephrology, Johns Hopkins University
Brennan N, Kliger A, Finkelstein FO. inhibits HIV-1-induced podocyte School of Medicine, Baltimore, MD, USA
Outcome of HIV infected patients on proliferation through the cAMP pathway.
continuous ambulatory peritoneal dialysis. J. Am. Soc. Nephrol. 18(1), 93102 (2007).
Kidney Int. 44(1), 191198 (1993).
www.expert-reviews.com 371