ANNUAL REVIEWS
Annu. Rev. Med. 1991. 42.·391-4!J1 Copyright © 1991 by Annual Reviews Inc. All rights reserved
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HUMAN IMMUNODEFICIENCY VIRUS (HIV) ASSOCIATED
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
NEPHROPATHY T. K. Sreepada Rao, M.D., F.A.C.P. Department of Medicine, S UNY Health Science Center at Brooklyn, Brooklyn, New York KEY
WORDS:
11203-2098
focal and segmental glomerulosclerosis, end-stage renal disease, nephrotic syndrome, acute renal failure, hemodialysis
ABSTRACT
Patients with HIV infection can manifest a spectrum of potentially revers ible forms of acute renal failure and a unique form of nephropathy clin ically characterized by nephrotic syndrome, a rapid progression to irre versible uremia in weeks, and a poor prognosis despite maintenance dialysis therapy. Typical histologic features consist of focal and segmental glomerulosclerosis, with some distinct and unusual e lectron microscopic features in the kidney. HIV-associated nephropathy ( HIVAN) is pre dominantly a disease of young black men; about half are intravenous drug addicts and the remaining half belong to various groups at risk for HIV infection. Evidence points to a viral etiology in the pathogenesis of HIVAN. Currently, no effective forms of therapy are available for HIV associated nephropathy. It is hoped that the newer antiviral agents given early and for·prolonged periods may change the natural history of HIV AN, which at present is a fulminant form of irreversible renal syndrome.
INTRODUCTION Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by the human immunodeficiency virus ( HIV), a retrovirus with special trophism for the T helper lymphocytes. AIDS is primarily a dis order of cellu lar immunity consequent to depietion of circulating CD4 lymphocytes by HIV; thus it predisposes affected patients to develop
391 0066-4219/91/0401-0391$02.00
392
RAO
unusual life-threatening infections and malignancies. HIV is acquired through needle sharing by intravenous drug addicts, contaminated blood transfusions, intercourse (either homosexual or heterosexual) with infected persons, and transplacentally by fetuses from their infected mothers. In certain areas of the United States, notably in Brooklyn, New York, and in Miami, Florida, there is an increased incidence of HIV infection in persons who have recently immigrated from Haiti, but who have no history of homosexuality or needle sharing; here the mode of viral transmission is unclear.
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
In the early stages of the disease, patients are generally asymptomatic carriers of the virus, and can be identified by HIV seropositivity ( E LISA screening with Western Blot confirmation) and viral cultures. With time, patients develop nonspecific clinical signs and symptoms such as prolonged fever, weight loss, persistent diarrhea, and generalized lymphadenopathy; this is referred to as AIDS-related complex (ARC). As the disease advances and more CD4 lymphocytes are affected, clinical AIDS results
(1).
As
defined by the Centers for Disease Control (CDC), AIDS is characterized by the occurrence of conventional as well as opportunistic infections and by unusual malignancies (lymphomas, and Kaposi's sarcoma). The devel
opment of opportunistic infections in patients with HJV infection (onset of clinical AIDS) generally signifies a poor prognosis whether or not functional impairment of other organs is present. Because HIV preferentially depletes the CD4 lymphocytes, infectious complications and malignancies dominate the clinical picture in patients with AIDS. However, it is increasingly evident that HIV infection can also result in a multisystem disease involving various organs, even those lacking specific receptors to CD4 cells. One such sequela, renal involvement sec ondary to HIV, was first reported from New York area about three years after the initial description of AIDS (2). As the HIV -infected patient pool expands worldwide, renal syndromes are being recognized with increasing frequency not only in various parts of the United States, but in many other countries as well. For the primary physician, nephrological problems offer unique challenges in diagnosis and management. The existence of prior renal disease also greatly influences the physician'S choice of which drug (of the rapidly increasing number currently employed or being tested) to use in the treatment of patients with AIDS (HIV infection). Many of the drugs can themselves induce renal disease and contribute to morbidity and mortality in patients. It is therefore necessary for physicians caring for patients with HIV disease to familiarize themselves with various renal manifestations encountered in such subjects, so as to minimize any adverse effects that may result from therapeutic interventions. Both a coincidental and an unusual (specific?) fulminant form of HIV-
393
HIV-ASSOCIATED NEPHROPATHY Table 1
Renal syndromes in patients with HIV infection
I. Coincidental rcnal disorders A. Potentially reversible acute renal failure
B. Acid-base and fluid-electrolyte derangements C. Infections in the kidney (bacterial, fungal, viral) D. Infiltrations in the kidney II. Specific(?) renal disorder; HIV-associated nephropathy A. Focal and segmental glomerulosclerosis
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
B. Other forms of glomerulonephritis III. Renal disease occurring in HIV seropositive patients A. Heroin-associated nephropathy
B. Diabetic glomerulosclerosis, polycystic kidney disease, etc C. Obstructive uropathy IV. Superimposed HIV infection in those with renal replacement therapy A. Maintenance dialysis patients acquiring HIV from blood transfusions, intravenous drug abuse, and sexual contacts
B. Renal transplant recipients developing HIV infection through renal allograft, blood transfusions, intravenous drug abuse, and sexual contacts
associated nephropathy (HIVAN) have been reported in AIDS patients. Also, patients suffering from end-stage renal disease (ESRD) from various other unrelated causes may acquire HIV during the course ofrenal replace ment therapy (either maintenance dialysis or renal transplantation)
(3).
From a review ofthe available studies (4,5), the spectrum ofrenal disorders in patients with HIV disease can be classified as shown in Table
1.
This
chapter deals primarily with a specific renal syndrome referred to as HIV associated nephropathy, with brief references to various forms of coinci dental renal diseases observed in AIDS patients and to other issues relevant to renal physicians.
COINCIDENTAL RENAL DISORDERS IN HIV Coincidental renal lesions refers to those disorders that are not directly attributable to HIV infection but that are also encountered in the usual nephrologic practice. In Table
2,
a detailed classification of coincidental
renal disorders reported in patients with HIV is tabulated. Commonest of these problems seen in AIDS patients are acute renal failure (ARF) from a variety of causes, and fluid-electrolyte and acid-base derangements. While a multitude of systemic infectious complications and malignancies domi nate the clinical manifestations in patients with AIDS during life, kidney infections secondary to fungal, mycobacterial, and viral agents, and
394 Table 2
RAO Co-incidental renal syndromes and HIV
Acute renal failurc (ARF) Acute tubular necrosis from hypovolemic, anoxic, and toxic injuries AlIergic interstitial nephritis from drugs Azotemia from nonsteroidal antiinflammatory drugs Renal failure from massive proteinuria and severe hypoalbuminemia (intrarenal edema) Postinfectious immune complex glomerulonephritis Sulfadiazine and acyclovir crystal induced renal failure Plasmacytic interstitial nephritis
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Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura Acid-base and fluid-electrolyte derangements Hypo- and hypernatremia Inappropriate secretion of antidiuretic hormone (ADH) Hypo- and hyperkalemia Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) Metabolic alkalosis Hypomagnesemia Hypouricemia Infections in the kidney Microabscesses from bacterial infections
(Staphylococcus aureus)
Tuberculosis of the kidney (both typical and atypical mycobacterium) Cytomegalovirus infection Candida, cryptococcal, aspergillus and other fungal infections Infiltrations in the kidney Lymphoma of the kidney Kaposi's sarcoma Amyloidosis of the kidney Calcifications of the kidney
renal infiltrative lesions such as lymphoma and Kaposi's sarcoma are usually incidental findings recognized only during autopsy. For clinicians, the most significant life-threatening renal problem found in AIDS is a spectrum of potentially reversible acute kidney failure, similar to that observed in patients severely ill from any other cause. Acute tubular necrosis (A TN), a fairly common occurrence in hospi talized AIDS patients, results from ischemic insult sustained by the kidneys secondary to septicemia or to extracellular fluid depletion from vomiting, diarrhea, and hypotension. Contributing factors include hyponatremia, systemic acidosis, varying degrees of respiratory insufficiency, and the use of radiocontrast agents and/or nephrotoxic antibiotics. Usual therapeutic agents that cause A TN in AIDS patients are aminoglycoside antibiotics, pentamidine, amphotericin, and some antineoplastic drugs. Considering the nature of the clinical setting-severely ill AIDS patients hospitalized
HIV-ASSOCIATED NEPHROPATHY
395
for multiple infections with compromised hemodynamic status and exposed to ischemic and toxic renal injuries-it is not surprising to find an increased incidence of A TN. Both oliguric and nonoliguric forms of ATN are seen, with a triad of high fractional excretion of sodium (urine sodium concentration of > 20 meq/liter); isosthenuria (urine to plasma osmolality ratio of close to one); and rising concentrations of serum cre atinine, blood urea nitrogen ( BUN), and other nitrogenous products. ATN in AIDS patients follows the usual pattern of azotemic (oliguric) phase, followed by diuresis in days or weeks, with a return of kidney function if
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
the patient survives the primary illness. In many patients, renal failure is mild to moderate in severity, and with conservative therapy alone (cor rection of volume depletion and acidosis) and removal of the offending nephrotoxic agent, the disease is self-limiting. In others, ATN is a terminal morbid event and all heroic measures, including intensive dialysis, fail to alter thc mortality from overwhelming infections and respiratory failure. Another cause of acute renal failure in AIDS patients is allergic inter stitial nephritis (AIN) caused by a hypersensitivity to the therapeutic agents used, such as trimethoprim sulphamethaxazole, or phenytoin. Allergic nephritis (also referred to as hypersensitive nephropathy) usually manifests as an abrupt onset of azotemia in patients who have received the offending drug while lacking an obvious ischemic renal insult. AIN is accompanied by fever, oliguria, azotemia with mild proteinuria, and benign urinary sediment (absence of red cell casts in the urine), generalized skin rash with eosinophilia, and eosinophiluria (in about 50% of patients). Renal histology reveals normal glomeruli and renal tubules, and diffuse inter stitial edema with infiltration by lymphocytes, plasma cells, and eosino phils. Stopping administration of the offending agent and instituting sup portive care, including dialysis when indicated, usually restore renal function in a few days. Severe but reversible renal failure is occasionally seen in a volume depleted AIDS patient receiving nonsteroidal antiinflammatory drugs. The failure is attributed to renal prostaglandin inhibition and unopposed renal vasoconstriction. On rare occasions, massive proteinuria and severe hypoalbuminemia (secondary to HIV-associated nephropathy, described below) may result in acute renal insufficiency, probably secondary to severe intrarenal (interstitial) edema. Renal function in these patients improves after a brief period of dialysis, though many of them progress to irreversible uremia. An increasing number of recent reports of poorly understood entities, thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome with irreversible ARF, along with a generally poor patient prognosis, suggests a possible role for HIV infection in causing these disorders.
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RAO
Irrespective of etiology, ARF adds significantly to the morbidity and mortality in patients with AIDS. Renal failure is a terminal event in many who suffer a combination of sepsis and multiorgan failure. The majority of such patients are hemodynamically unstable and all measures, including dialysis support, fail to improve the prognosis. Ncvertheless, it is important to recognize that ARF is potentially reversible and is a manageable com plication in many AIDS patients. With a coordinated approach including correction of fluid-electrolyte and acid-base abnormalities, early dialysis intervention, and nutritional supplementation (essential amino acids),
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
renal recovery is likely, which then gives the physician more time to treat the surviving patient with newer antiviral agents. Physicians caring for acutely ill AIDS patients should therefore take steps to minimize this renal complication. Preventive measures include avoiding renal injury whenever possible, a careful assessment of renal functional status before and during the administration of nephrotoxic drugs (primarily antibiotics and radiocontrast agents), monitoring drug levels of antibiotics, main taining good hydration, and an appropriate management of acid-base and fluid-electrolyte derangements. Consequently, an approach integrating both conservative and aggressive dialytic support is indicated for patients
with AIDS and ARF.
HIV-ASSOCIATED NEPHROPATHY In the early years, prior to the introduction of serological markers (ELISA and Western Blot tests) to detect HIV infection, the Centers for Disease Control (CDC) established clinical criteria for diagnosing patients with AIDS. Consequently, in 1984 the initial descriptions of a renal syndrome then referred to as AIDS-associated nephropathy included only those patients in whom CDC-defined guidelines for clinical AIDS were met. With a better understanding of HIV disease, however, and an expansion of serological testing to diagnose viral infection even in asymptomatic subjects, it became obvious that nephropathy may predate clinical ARC/AIDS in many patients by several months. Appropriately, the ter minology was then changed to HIV-associated nephropathy ( HIVAN), a comprehensive label that includes renal disease in individuals with HIV disease, irrespective of the clinical stage of their illness. Studies indicate that more than half the patients with nephrotic syn drome ( HIVAN) may be either asymptomatic, seropositive carriers of the virus or those with ARC. Although initial descriptions of HIVAN originated from New York and Miami, reports have since appeared from many centers in the US and from several other countries, including Brazil,
HIV-ASSOCIATED NEPHROPATHY
397
Canada, France, Mexico, Spain, Trinidad, and the United Kingdom. The number of cases of HIVAN seen at institutions in New York, Miami, and other urban centers in the US is also increasing. Approximately half the patients with HIVAN are intravenous drug addicts; others are gay men, recent immigrants to US from Haiti, who deny intravenous drug use or homosexuality (mostly in Brooklyn and Miami areas), recipients of contaminated blood or blood products, sexual partners of HIV-infected persons, and children born to infected mothers. HIVAN is a disease primarily of young black men (less than 10% in published reports are
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
Caucasians). About 80 cases of renal disease in HIV-afflicted children have also been reported
(4-6).
Massivc protcinuria, discovered either through routine urine exam ination during a clinic visit or while investigating patients with generalized edema, is the commonest clinical manifestation of HIVAN. Proteinuria is usually a component of the nephrotic syndrome (greater than 3.5 grams in a 24-hour urine sample), accompanied by hypoalbuminemia (serum albumin of less than 2.5 g/dl), along with edema and hyperlipidemia. Elevated lipid levels in the blood occur less often in HIVAN than in other primary glomerulopathies. Nephrotic range proteinuria may be associated with normal glomerular filtration rate (Ccr) or varying degrees of azotemia. Of our patients, 90% presented with nephrotic syndrome along with nor mal to impaired Ccr; only 10% had mild to moderate azotemia with hematuria (gross or microscopic) and proteinuria of less than 2 grams per day. The onset of edema with massive proteinuria and renal insufficiency can sometimes be very abrupt. Such was the finding in many of our patients followed in the HIV clinic, with no evidence of prior renal disease but who presented with an explosive onset of edema and/or severe azotemia during routine follow-up visits. Investigations fail to reveal known sec ondary or other systemic causes for the renal disease. The serum com plement levels are normal, and diffuse elevation in the concentrations of IgG and IgM in the blood are detectable. All these patients are seropositive to HIV antibody, and the absolute levels of circulating CD4 cells are low; in addition the ratio of T4 to T8 cells is reversed (even in asymptomatic individuals with the nephrotic syndrome). Ultrasound studies reveal large echogenic kidneys during the nephrotic phase of the illness. With progression to ESRD, the renal size still remains large. An important clinical finding in patients with HIVAN is the notable absence of hypertension during both early and late stages of the disease (despite severe renal failure). One of the distinctive features of the syn drome is its malignant nature, as seen in the rapidity with which renal function is lost in the absence of additional anoxic and nephrotoxic injuries. In most studies, ESRD developed in 4-6 months from the initial discovery
39 8
RAO
of proteinuria, although wide variations in time course to renal deterio ration are observed
(7, 8).
In our experience, the mean duration from
proteinuria to irreversible renal failure was 16 weeks. This finding is in distinct contrast to that in other common disorders in these young black men, namely heroin-associated nephropathy (HAN) and idiopathic focal and segmental glomerulosclerosis, in which progression to ESRD occurs over several months to years. The reasons for the rapid deterioration in renal function in HIVAN are unclear. Some have speculated that direct HIV invasion of the kidneys per se is responsible, and that HIVAN
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is a unique disease of combined glomerular, tubular, and interstitial involvement. The most frequently encountered renal pathology in HIVAN is focal and segmental glomerulosclerosis (FSGS). Other uncommonly reported renal histologic findings include minimal change disease, glomerular mesangial changes, and membranous and membranoproliferative glo merulonephritis. If the mesangial lesions represent an early change before evolution to focal sclerosis, then FSGS accounts for about 95% of all renal histological changes described in HIVAN. In the early stages of the disease, the visceral epith elial cells are enlarged, with coarse cytoplasmic
vacuoles, and underlying capillary walls collapse. Later, there is pro nounced obliteration of capillary lumen, with an increase in the mesangial matrix and advanced glomerular sclerosis. The proximal renal tubular cells contain numerous protein absorption droplets. But the most striking feature is the dilatation of renal tubular lumen with pale staining casts, referred to as "microcystic dilatation." These changes are present through out the cortex and medulla. Interstitial fibrosis, renal tubular atrophy, and vascular changes of arteriolosclerosis are minimally present or strikingly absent. There is usually only a sparse infiltration of interstitium by lym phocytes and other mononuclear cells. Immunofluorescent studies reveal intraglomerular deposition of IgM, C l q, and C3, and rarely IgG in the mesangium and sclerotic areas, the nature of which is unknown. They may represent deposited immune complexes or nonspecific trapping of immunoglobulins in the mesangium and in the sclerotic areas. Ultrastructural renal changes consist of fusion of epithelial foot processes, increase in mesangial matrix, and detachment of epithelial cells from the basement membrane, plus electron dense deposits in the mesan gium. Most notable is the presence of abundant tubuloreticular structures in the endothelium of glomerular and peritubular capillaries, interstitial cells, and leukocytes. Other distinctive ultrastructural changes in HIVAN include peculiar nuclear cell bodies in the tubular and interstitial cells, a granulofibrillary transformation of tubular and interstitial cell chromatin, and the presence of intracytoplasmic and intranuclear inclusions of test-
HIV-ASSOCIATED NEPHROPATHY
399
tube- and ring-shaped forms in different renal cells (9- 1 1). These findings favor a viral etiology for HIVAN. Recent in situ hybridization studies employing cDNA probes demonstrated the localization of proviral HTV nucleic acid in the glomerular and renal tubular epithelium. These studies offer strong support for direct HIV infection as the cause of HIVAN. The clinical and some pathological features of HIVAN are similar to those seen in heroin-associated nephropathy (HAN), which is also a disease commonly seen in young black addicts. In some patients this distinction may be impossible, yet the two diseases can generally be distinguished by
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
some unusual characteristics, as described below. As compared to heroin related, idiopathic, or other forms of focal sclerosis, the differentiating features in HIV-associated FSGS include a greater percentage of "col lapsed" glomeruli, greater degree of tubular degeneration, and microcystic dilatation of renal tubules. Ultrastructurally, there is an abundance of tubuloreticular inclusions in the glomerular endothelial cells in HIVAN, which arc distinctively rare or absent in other forms of FSGS. Another distinction is that children, Haitian immigrants, and gay men constitute about 50% of patients with HIV AN, while HAN by definition includes only intravenous drug addicts. A fulminant clinical course of ESRD devclops in 3-4 months, kidney size is large, and normotension persists despite severe uremia in HIVAN. In contrast, patients with HAN have azotemia accompanied by severe hypertension, small shrunken kidneys along with global glomerulosclerosis, severe arteriolosclerosis, tubular atrophy, and marked interstitial fibrosis. The pathogenesis of HIVAN is poorly understood, and the role (if any) of presumed immune complexes
(IgM, C3,
and
IgG
seen on immu
nofluorescent studies) in the development of glomerulosclerosis remains speculative. These immune globulins may represent deposited immune complexes, or merely a nonspecific trapping in the injured glomerulus. Attempts to localize
HIV antigens in the glomeruli have been unsuccessful.
Nevertheless, the electron microscopic features and the in situ hybrid ization studies strongly support a direct role for HIV in the initiation and possibly in the progression of renal disease. At present, the exact mechanisms of HIV-induced renal injury, in the absence of CD4 receptors in various target cells in the kidney are unknown. No specific treatment is available for HIV-associated nephropathy other than alleviating the symptoms of edema and hypoalbuminemia through salt restriction, diuretics, and protein supplementation. Neither short- nor long-term use of corticosteroids or other immunosuppressive agents has been tested because of the risk of further compromising the immune system and precipitating lethal infectious complications. Isolated case reports indicating beneficial effects of zidovudine (AZT) in the treatment of some
400
RAO
patients with HIVAN offer hope for the future. These preliminary results need to be confirmed by large-scale studies. The survival and rehabilitation of patients with clinical AIDS and chronic uremia who are treated by maintenance dialysis are dismal. Despite renal replacement therapy, the majority of AIDS patients with ESRD survive for less than a year. During hemodialysis therapy, major problems contributing to a high mortality are an unexplained malnutrition and a wasting phenomenon, whether or not an underlying malignancy and/or an opportunistic infection are present. This "failure to thrive" syndrome
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
in AIDS patients during maintenance hemodialysis does not respond to nutritional support by hyperalimentation. Death usually results from cachexia superimposed on opportunistic or other intercurrent infections. Some HIVAN patients with ESRD but not yet manifesting the signs and symptoms of A RC/AIDS tolerate maintenance dialysis well and survive for prolonged periods. Whether or not prolonged AZT therapy can improve the current dismal results remains to be seen. Renal transplantation has been performed in some asymptomatic HIV seropositive subjects with chronic uremia. Such patients are few in number and a general recommendation is not possible with the available data. I n view of the need for immunosuppressive therapy following allografting, most centers avoid transplantation in HIV patients. A few centers have also documented transmission of HIV through renal transplantation. The strict screening for HIV in donors and the exclusion of high-risk donors will effectively stop this mode of spread of HIV to organ recipients. In summary, HIV disease is associated with both incidental and unusual forms of renal complications. Coincidental acute reversible renal disorders are potentially preventable and in many patients carry a good prognosis. HIVAN, a disease predominantly of young black men, has unique features and offers many challenges for future investigations. Understanding the pathogenesis of HIVAN through animal models and human disease may lead to a better knowledge of the role of viruses in general in the genesis of other primary (idiopathic) kidney diseases. In the coming decade it is hoped that newer therapeutic antiviral agents might prevent or allow more effective treatment of HIVAN, which at present is an inexorable form of irreversible renal failure.
Literature Cited I. Lifson, A. R., Rutherford, G. W., Jaffe, H. W. 1988. The natural history of
human immunodeficiency virus infec tion. J. Infect. Dis. 158(6): 1360-67 2. Rao, T. K. S., Filippone, E. J., Nicastri, A. D., Landesman, S. H., Frank, E. et
al. 1984. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N. Engl. J. Med. 310: 669�73 3. Rao, T. K. S., Friedman, E. A., Nicastri, A. D. 1987. The types of renal disease in
HIV-ASSOCIATED NEPHROPATHY
4.
5.
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
6.
7.
8.
the Acquired Immunodeficiency Syn drome. N. Engl. J. Med. 316: 1062-68 Rao, T. K. S., Friedman, E. A. 1989. AIDS (HIV) associated nephropathy; does it exist? An in-depth review. Am. J. Nephro/, 9: 441-53 Bourgoignie, J. J., Meneses, R., Ortiz, C., Jaffe, D., Pardo, V. 1988. The clinical spectrum of renal disease associated with human immunodeficiency virus. Am. J. Kidney Dis. 12(2): 131-37 Bourgoignie, J. J., Ortiz, C., Green, D. F., Roth, D. 1989. Race a cofactor in HIV-I associated nephropathy. Trans. Proc. 21: (6) 3899-3901 Langs, C, Gallo, G. R., Schacht, R. G., Sidhu, G., Baldwin, D. S. 1990. Rapid renal failure in AIDS-associated focal glomerulosclerosis. Arch. Intern. Med. 150: 287-92 Carbone, L., D'Agati, V., Suh, J. I.,
401
Cheng, 1. T., Appel, G. 1989. Course and prognosis of human immunodeficiency virus associated nephropathy. Am. J. Med. 87: 389-95 9. Chander, P., Soni, A., Suri, A., Bhagwat, R., Yoo, J" Treser, G. 1987, Renal ultrastructural markers in AIDS associated nephropathy. Am. J. Palhol. 126: 513-26 10. Chander, P., Agarwal, A., Soni, A., Kim, K., Trcser, G. 1988. Renal cyto membranous inclusions in idiopathic renal disease as predictive markers for the acquired immunodeficiency syn drome. Hum. Palhol. 19: 1060--64 II. D'Agati, V., Suh, J. I., Carbone, L., Cheng, J. T., Appel, G. 1989. Pathology of HIV-associated nephropathy: a detailed morphologic and comparative study. Kidney Int. 35: 1358-70
Annu. Rev. Med. 1991. 42.·391-4!J1 Copyright © 1991 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
HUMAN IMMUNODEFICIENCY VIRUS (HIV) ASSOCIATED
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
NEPHROPATHY T. K. Sreepada Rao, M.D., F.A.C.P. Department of Medicine, S UNY Health Science Center at Brooklyn, Brooklyn, New York KEY
WORDS:
11203-2098
focal and segmental glomerulosclerosis, end-stage renal disease, nephrotic syndrome, acute renal failure, hemodialysis
ABSTRACT
Patients with HIV infection can manifest a spectrum of potentially revers ible forms of acute renal failure and a unique form of nephropathy clin ically characterized by nephrotic syndrome, a rapid progression to irre versible uremia in weeks, and a poor prognosis despite maintenance dialysis therapy. Typical histologic features consist of focal and segmental glomerulosclerosis, with some distinct and unusual e lectron microscopic features in the kidney. HIV-associated nephropathy ( HIVAN) is pre dominantly a disease of young black men; about half are intravenous drug addicts and the remaining half belong to various groups at risk for HIV infection. Evidence points to a viral etiology in the pathogenesis of HIVAN. Currently, no effective forms of therapy are available for HIV associated nephropathy. It is hoped that the newer antiviral agents given early and for·prolonged periods may change the natural history of HIV AN, which at present is a fulminant form of irreversible renal syndrome.
INTRODUCTION Acquired immunodeficiency syndrome (AIDS) is an infectious disease caused by the human immunodeficiency virus ( HIV), a retrovirus with special trophism for the T helper lymphocytes. AIDS is primarily a dis order of cellu lar immunity consequent to depietion of circulating CD4 lymphocytes by HIV; thus it predisposes affected patients to develop
391 0066-4219/91/0401-0391$02.00
392
RAO
unusual life-threatening infections and malignancies. HIV is acquired through needle sharing by intravenous drug addicts, contaminated blood transfusions, intercourse (either homosexual or heterosexual) with infected persons, and transplacentally by fetuses from their infected mothers. In certain areas of the United States, notably in Brooklyn, New York, and in Miami, Florida, there is an increased incidence of HIV infection in persons who have recently immigrated from Haiti, but who have no history of homosexuality or needle sharing; here the mode of viral transmission is unclear.
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
In the early stages of the disease, patients are generally asymptomatic carriers of the virus, and can be identified by HIV seropositivity ( E LISA screening with Western Blot confirmation) and viral cultures. With time, patients develop nonspecific clinical signs and symptoms such as prolonged fever, weight loss, persistent diarrhea, and generalized lymphadenopathy; this is referred to as AIDS-related complex (ARC). As the disease advances and more CD4 lymphocytes are affected, clinical AIDS results
(1).
As
defined by the Centers for Disease Control (CDC), AIDS is characterized by the occurrence of conventional as well as opportunistic infections and by unusual malignancies (lymphomas, and Kaposi's sarcoma). The devel
opment of opportunistic infections in patients with HJV infection (onset of clinical AIDS) generally signifies a poor prognosis whether or not functional impairment of other organs is present. Because HIV preferentially depletes the CD4 lymphocytes, infectious complications and malignancies dominate the clinical picture in patients with AIDS. However, it is increasingly evident that HIV infection can also result in a multisystem disease involving various organs, even those lacking specific receptors to CD4 cells. One such sequela, renal involvement sec ondary to HIV, was first reported from New York area about three years after the initial description of AIDS (2). As the HIV -infected patient pool expands worldwide, renal syndromes are being recognized with increasing frequency not only in various parts of the United States, but in many other countries as well. For the primary physician, nephrological problems offer unique challenges in diagnosis and management. The existence of prior renal disease also greatly influences the physician'S choice of which drug (of the rapidly increasing number currently employed or being tested) to use in the treatment of patients with AIDS (HIV infection). Many of the drugs can themselves induce renal disease and contribute to morbidity and mortality in patients. It is therefore necessary for physicians caring for patients with HIV disease to familiarize themselves with various renal manifestations encountered in such subjects, so as to minimize any adverse effects that may result from therapeutic interventions. Both a coincidental and an unusual (specific?) fulminant form of HIV-
393
HIV-ASSOCIATED NEPHROPATHY Table 1
Renal syndromes in patients with HIV infection
I. Coincidental rcnal disorders A. Potentially reversible acute renal failure
B. Acid-base and fluid-electrolyte derangements C. Infections in the kidney (bacterial, fungal, viral) D. Infiltrations in the kidney II. Specific(?) renal disorder; HIV-associated nephropathy A. Focal and segmental glomerulosclerosis
Annu. Rev. Med. 1991.42:391-401. Downloaded from www.annualreviews.org Access provided by University of Bristol on 01/22/15. For personal use only.
B. Other forms of glomerulonephritis III. Renal disease occurring in HIV seropositive patients A. Heroin-associated nephropathy
B. Diabetic glomerulosclerosis, polycystic kidney disease, etc C. Obstructive uropathy IV. Superimposed HIV infection in those with renal replacement therapy A. Maintenance dialysis patients acquiring HIV from blood transfusions, intravenous drug abuse, and sexual contacts
B. Renal transplant recipients developing HIV infection through renal allograft, blood transfusions, intravenous drug abuse, and sexual contacts
associated nephropathy (HIVAN) have been reported in AIDS patients. Also, patients suffering from end-stage renal disease (ESRD) from various other unrelated causes may acquire HIV during the course ofrenal replace ment therapy (either maintenance dialysis or renal transplantation)
(3).
From a review ofthe available studies (4,5), the spectrum ofrenal disorders in patients with HIV disease can be classified as shown in Table
1.
This
chapter deals primarily with a specific renal syndrome referred to as HIV associated nephropathy, with brief references to various forms of coinci dental renal diseases observed in AIDS patients and to other issues relevant to renal physicians.
COINCIDENTAL RENAL DISORDERS IN HIV Coincidental renal lesions refers to those disorders that are not directly attributable to HIV infection but that are also encountered in the usual nephrologic practice. In Table
2,
a detailed classification of coincidental
renal disorders reported in patients with HIV is tabulated. Commonest of these problems seen in AIDS patients are acute renal failure (ARF) from a variety of causes, and fluid-electrolyte and acid-base derangements. While a multitude of systemic infectious complications and malignancies domi nate the clinical manifestations in patients with AIDS during life, kidney infections secondary to fungal, mycobacterial, and viral agents, and
394 Table 2
RAO Co-incidental renal syndromes and HIV
Acute renal failurc (ARF) Acute tubular necrosis from hypovolemic, anoxic, and toxic injuries AlIergic interstitial nephritis from drugs Azotemia from nonsteroidal antiinflammatory drugs Renal failure from massive proteinuria and severe hypoalbuminemia (intrarenal edema) Postinfectious immune complex glomerulonephritis Sulfadiazine and acyclovir crystal induced renal failure Plasmacytic interstitial nephritis
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Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura Acid-base and fluid-electrolyte derangements Hypo- and hypernatremia Inappropriate secretion of antidiuretic hormone (ADH) Hypo- and hyperkalemia Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) Metabolic alkalosis Hypomagnesemia Hypouricemia Infections in the kidney Microabscesses from bacterial infections
(Staphylococcus aureus)
Tuberculosis of the kidney (both typical and atypical mycobacterium) Cytomegalovirus infection Candida, cryptococcal, aspergillus and other fungal infections Infiltrations in the kidney Lymphoma of the kidney Kaposi's sarcoma Amyloidosis of the kidney Calcifications of the kidney
renal infiltrative lesions such as lymphoma and Kaposi's sarcoma are usually incidental findings recognized only during autopsy. For clinicians, the most significant life-threatening renal problem found in AIDS is a spectrum of potentially reversible acute kidney failure, similar to that observed in patients severely ill from any other cause. Acute tubular necrosis (A TN), a fairly common occurrence in hospi talized AIDS patients, results from ischemic insult sustained by the kidneys secondary to septicemia or to extracellular fluid depletion from vomiting, diarrhea, and hypotension. Contributing factors include hyponatremia, systemic acidosis, varying degrees of respiratory insufficiency, and the use of radiocontrast agents and/or nephrotoxic antibiotics. Usual therapeutic agents that cause A TN in AIDS patients are aminoglycoside antibiotics, pentamidine, amphotericin, and some antineoplastic drugs. Considering the nature of the clinical setting-severely ill AIDS patients hospitalized
HIV-ASSOCIATED NEPHROPATHY
395
for multiple infections with compromised hemodynamic status and exposed to ischemic and toxic renal injuries-it is not surprising to find an increased incidence of A TN. Both oliguric and nonoliguric forms of ATN are seen, with a triad of high fractional excretion of sodium (urine sodium concentration of > 20 meq/liter); isosthenuria (urine to plasma osmolality ratio of close to one); and rising concentrations of serum cre atinine, blood urea nitrogen ( BUN), and other nitrogenous products. ATN in AIDS patients follows the usual pattern of azotemic (oliguric) phase, followed by diuresis in days or weeks, with a return of kidney function if
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the patient survives the primary illness. In many patients, renal failure is mild to moderate in severity, and with conservative therapy alone (cor rection of volume depletion and acidosis) and removal of the offending nephrotoxic agent, the disease is self-limiting. In others, ATN is a terminal morbid event and all heroic measures, including intensive dialysis, fail to alter thc mortality from overwhelming infections and respiratory failure. Another cause of acute renal failure in AIDS patients is allergic inter stitial nephritis (AIN) caused by a hypersensitivity to the therapeutic agents used, such as trimethoprim sulphamethaxazole, or phenytoin. Allergic nephritis (also referred to as hypersensitive nephropathy) usually manifests as an abrupt onset of azotemia in patients who have received the offending drug while lacking an obvious ischemic renal insult. AIN is accompanied by fever, oliguria, azotemia with mild proteinuria, and benign urinary sediment (absence of red cell casts in the urine), generalized skin rash with eosinophilia, and eosinophiluria (in about 50% of patients). Renal histology reveals normal glomeruli and renal tubules, and diffuse inter stitial edema with infiltration by lymphocytes, plasma cells, and eosino phils. Stopping administration of the offending agent and instituting sup portive care, including dialysis when indicated, usually restore renal function in a few days. Severe but reversible renal failure is occasionally seen in a volume depleted AIDS patient receiving nonsteroidal antiinflammatory drugs. The failure is attributed to renal prostaglandin inhibition and unopposed renal vasoconstriction. On rare occasions, massive proteinuria and severe hypoalbuminemia (secondary to HIV-associated nephropathy, described below) may result in acute renal insufficiency, probably secondary to severe intrarenal (interstitial) edema. Renal function in these patients improves after a brief period of dialysis, though many of them progress to irreversible uremia. An increasing number of recent reports of poorly understood entities, thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome with irreversible ARF, along with a generally poor patient prognosis, suggests a possible role for HIV infection in causing these disorders.
396
RAO
Irrespective of etiology, ARF adds significantly to the morbidity and mortality in patients with AIDS. Renal failure is a terminal event in many who suffer a combination of sepsis and multiorgan failure. The majority of such patients are hemodynamically unstable and all measures, including dialysis support, fail to improve the prognosis. Ncvertheless, it is important to recognize that ARF is potentially reversible and is a manageable com plication in many AIDS patients. With a coordinated approach including correction of fluid-electrolyte and acid-base abnormalities, early dialysis intervention, and nutritional supplementation (essential amino acids),
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renal recovery is likely, which then gives the physician more time to treat the surviving patient with newer antiviral agents. Physicians caring for acutely ill AIDS patients should therefore take steps to minimize this renal complication. Preventive measures include avoiding renal injury whenever possible, a careful assessment of renal functional status before and during the administration of nephrotoxic drugs (primarily antibiotics and radiocontrast agents), monitoring drug levels of antibiotics, main taining good hydration, and an appropriate management of acid-base and fluid-electrolyte derangements. Consequently, an approach integrating both conservative and aggressive dialytic support is indicated for patients
with AIDS and ARF.
HIV-ASSOCIATED NEPHROPATHY In the early years, prior to the introduction of serological markers (ELISA and Western Blot tests) to detect HIV infection, the Centers for Disease Control (CDC) established clinical criteria for diagnosing patients with AIDS. Consequently, in 1984 the initial descriptions of a renal syndrome then referred to as AIDS-associated nephropathy included only those patients in whom CDC-defined guidelines for clinical AIDS were met. With a better understanding of HIV disease, however, and an expansion of serological testing to diagnose viral infection even in asymptomatic subjects, it became obvious that nephropathy may predate clinical ARC/AIDS in many patients by several months. Appropriately, the ter minology was then changed to HIV-associated nephropathy ( HIVAN), a comprehensive label that includes renal disease in individuals with HIV disease, irrespective of the clinical stage of their illness. Studies indicate that more than half the patients with nephrotic syn drome ( HIVAN) may be either asymptomatic, seropositive carriers of the virus or those with ARC. Although initial descriptions of HIVAN originated from New York and Miami, reports have since appeared from many centers in the US and from several other countries, including Brazil,
HIV-ASSOCIATED NEPHROPATHY
397
Canada, France, Mexico, Spain, Trinidad, and the United Kingdom. The number of cases of HIVAN seen at institutions in New York, Miami, and other urban centers in the US is also increasing. Approximately half the patients with HIVAN are intravenous drug addicts; others are gay men, recent immigrants to US from Haiti, who deny intravenous drug use or homosexuality (mostly in Brooklyn and Miami areas), recipients of contaminated blood or blood products, sexual partners of HIV-infected persons, and children born to infected mothers. HIVAN is a disease primarily of young black men (less than 10% in published reports are
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Caucasians). About 80 cases of renal disease in HIV-afflicted children have also been reported
(4-6).
Massivc protcinuria, discovered either through routine urine exam ination during a clinic visit or while investigating patients with generalized edema, is the commonest clinical manifestation of HIVAN. Proteinuria is usually a component of the nephrotic syndrome (greater than 3.5 grams in a 24-hour urine sample), accompanied by hypoalbuminemia (serum albumin of less than 2.5 g/dl), along with edema and hyperlipidemia. Elevated lipid levels in the blood occur less often in HIVAN than in other primary glomerulopathies. Nephrotic range proteinuria may be associated with normal glomerular filtration rate (Ccr) or varying degrees of azotemia. Of our patients, 90% presented with nephrotic syndrome along with nor mal to impaired Ccr; only 10% had mild to moderate azotemia with hematuria (gross or microscopic) and proteinuria of less than 2 grams per day. The onset of edema with massive proteinuria and renal insufficiency can sometimes be very abrupt. Such was the finding in many of our patients followed in the HIV clinic, with no evidence of prior renal disease but who presented with an explosive onset of edema and/or severe azotemia during routine follow-up visits. Investigations fail to reveal known sec ondary or other systemic causes for the renal disease. The serum com plement levels are normal, and diffuse elevation in the concentrations of IgG and IgM in the blood are detectable. All these patients are seropositive to HIV antibody, and the absolute levels of circulating CD4 cells are low; in addition the ratio of T4 to T8 cells is reversed (even in asymptomatic individuals with the nephrotic syndrome). Ultrasound studies reveal large echogenic kidneys during the nephrotic phase of the illness. With progression to ESRD, the renal size still remains large. An important clinical finding in patients with HIVAN is the notable absence of hypertension during both early and late stages of the disease (despite severe renal failure). One of the distinctive features of the syn drome is its malignant nature, as seen in the rapidity with which renal function is lost in the absence of additional anoxic and nephrotoxic injuries. In most studies, ESRD developed in 4-6 months from the initial discovery
39 8
RAO
of proteinuria, although wide variations in time course to renal deterio ration are observed
(7, 8).
In our experience, the mean duration from
proteinuria to irreversible renal failure was 16 weeks. This finding is in distinct contrast to that in other common disorders in these young black men, namely heroin-associated nephropathy (HAN) and idiopathic focal and segmental glomerulosclerosis, in which progression to ESRD occurs over several months to years. The reasons for the rapid deterioration in renal function in HIVAN are unclear. Some have speculated that direct HIV invasion of the kidneys per se is responsible, and that HIVAN
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is a unique disease of combined glomerular, tubular, and interstitial involvement. The most frequently encountered renal pathology in HIVAN is focal and segmental glomerulosclerosis (FSGS). Other uncommonly reported renal histologic findings include minimal change disease, glomerular mesangial changes, and membranous and membranoproliferative glo merulonephritis. If the mesangial lesions represent an early change before evolution to focal sclerosis, then FSGS accounts for about 95% of all renal histological changes described in HIVAN. In the early stages of the disease, the visceral epith elial cells are enlarged, with coarse cytoplasmic
vacuoles, and underlying capillary walls collapse. Later, there is pro nounced obliteration of capillary lumen, with an increase in the mesangial matrix and advanced glomerular sclerosis. The proximal renal tubular cells contain numerous protein absorption droplets. But the most striking feature is the dilatation of renal tubular lumen with pale staining casts, referred to as "microcystic dilatation." These changes are present through out the cortex and medulla. Interstitial fibrosis, renal tubular atrophy, and vascular changes of arteriolosclerosis are minimally present or strikingly absent. There is usually only a sparse infiltration of interstitium by lym phocytes and other mononuclear cells. Immunofluorescent studies reveal intraglomerular deposition of IgM, C l q, and C3, and rarely IgG in the mesangium and sclerotic areas, the nature of which is unknown. They may represent deposited immune complexes or nonspecific trapping of immunoglobulins in the mesangium and in the sclerotic areas. Ultrastructural renal changes consist of fusion of epithelial foot processes, increase in mesangial matrix, and detachment of epithelial cells from the basement membrane, plus electron dense deposits in the mesan gium. Most notable is the presence of abundant tubuloreticular structures in the endothelium of glomerular and peritubular capillaries, interstitial cells, and leukocytes. Other distinctive ultrastructural changes in HIVAN include peculiar nuclear cell bodies in the tubular and interstitial cells, a granulofibrillary transformation of tubular and interstitial cell chromatin, and the presence of intracytoplasmic and intranuclear inclusions of test-
HIV-ASSOCIATED NEPHROPATHY
399
tube- and ring-shaped forms in different renal cells (9- 1 1). These findings favor a viral etiology for HIVAN. Recent in situ hybridization studies employing cDNA probes demonstrated the localization of proviral HTV nucleic acid in the glomerular and renal tubular epithelium. These studies offer strong support for direct HIV infection as the cause of HIVAN. The clinical and some pathological features of HIVAN are similar to those seen in heroin-associated nephropathy (HAN), which is also a disease commonly seen in young black addicts. In some patients this distinction may be impossible, yet the two diseases can generally be distinguished by
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some unusual characteristics, as described below. As compared to heroin related, idiopathic, or other forms of focal sclerosis, the differentiating features in HIV-associated FSGS include a greater percentage of "col lapsed" glomeruli, greater degree of tubular degeneration, and microcystic dilatation of renal tubules. Ultrastructurally, there is an abundance of tubuloreticular inclusions in the glomerular endothelial cells in HIVAN, which arc distinctively rare or absent in other forms of FSGS. Another distinction is that children, Haitian immigrants, and gay men constitute about 50% of patients with HIV AN, while HAN by definition includes only intravenous drug addicts. A fulminant clinical course of ESRD devclops in 3-4 months, kidney size is large, and normotension persists despite severe uremia in HIVAN. In contrast, patients with HAN have azotemia accompanied by severe hypertension, small shrunken kidneys along with global glomerulosclerosis, severe arteriolosclerosis, tubular atrophy, and marked interstitial fibrosis. The pathogenesis of HIVAN is poorly understood, and the role (if any) of presumed immune complexes
(IgM, C3,
and
IgG
seen on immu
nofluorescent studies) in the development of glomerulosclerosis remains speculative. These immune globulins may represent deposited immune complexes, or merely a nonspecific trapping in the injured glomerulus. Attempts to localize
HIV antigens in the glomeruli have been unsuccessful.
Nevertheless, the electron microscopic features and the in situ hybrid ization studies strongly support a direct role for HIV in the initiation and possibly in the progression of renal disease. At present, the exact mechanisms of HIV-induced renal injury, in the absence of CD4 receptors in various target cells in the kidney are unknown. No specific treatment is available for HIV-associated nephropathy other than alleviating the symptoms of edema and hypoalbuminemia through salt restriction, diuretics, and protein supplementation. Neither short- nor long-term use of corticosteroids or other immunosuppressive agents has been tested because of the risk of further compromising the immune system and precipitating lethal infectious complications. Isolated case reports indicating beneficial effects of zidovudine (AZT) in the treatment of some
400
RAO
patients with HIVAN offer hope for the future. These preliminary results need to be confirmed by large-scale studies. The survival and rehabilitation of patients with clinical AIDS and chronic uremia who are treated by maintenance dialysis are dismal. Despite renal replacement therapy, the majority of AIDS patients with ESRD survive for less than a year. During hemodialysis therapy, major problems contributing to a high mortality are an unexplained malnutrition and a wasting phenomenon, whether or not an underlying malignancy and/or an opportunistic infection are present. This "failure to thrive" syndrome
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in AIDS patients during maintenance hemodialysis does not respond to nutritional support by hyperalimentation. Death usually results from cachexia superimposed on opportunistic or other intercurrent infections. Some HIVAN patients with ESRD but not yet manifesting the signs and symptoms of A RC/AIDS tolerate maintenance dialysis well and survive for prolonged periods. Whether or not prolonged AZT therapy can improve the current dismal results remains to be seen. Renal transplantation has been performed in some asymptomatic HIV seropositive subjects with chronic uremia. Such patients are few in number and a general recommendation is not possible with the available data. I n view of the need for immunosuppressive therapy following allografting, most centers avoid transplantation in HIV patients. A few centers have also documented transmission of HIV through renal transplantation. The strict screening for HIV in donors and the exclusion of high-risk donors will effectively stop this mode of spread of HIV to organ recipients. In summary, HIV disease is associated with both incidental and unusual forms of renal complications. Coincidental acute reversible renal disorders are potentially preventable and in many patients carry a good prognosis. HIVAN, a disease predominantly of young black men, has unique features and offers many challenges for future investigations. Understanding the pathogenesis of HIVAN through animal models and human disease may lead to a better knowledge of the role of viruses in general in the genesis of other primary (idiopathic) kidney diseases. In the coming decade it is hoped that newer therapeutic antiviral agents might prevent or allow more effective treatment of HIVAN, which at present is an inexorable form of irreversible renal failure.
Literature Cited I. Lifson, A. R., Rutherford, G. W., Jaffe, H. W. 1988. The natural history of
human immunodeficiency virus infec tion. J. Infect. Dis. 158(6): 1360-67 2. Rao, T. K. S., Filippone, E. J., Nicastri, A. D., Landesman, S. H., Frank, E. et
al. 1984. Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N. Engl. J. Med. 310: 669�73 3. Rao, T. K. S., Friedman, E. A., Nicastri, A. D. 1987. The types of renal disease in
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the Acquired Immunodeficiency Syn drome. N. Engl. J. Med. 316: 1062-68 Rao, T. K. S., Friedman, E. A. 1989. AIDS (HIV) associated nephropathy; does it exist? An in-depth review. Am. J. Nephro/, 9: 441-53 Bourgoignie, J. J., Meneses, R., Ortiz, C., Jaffe, D., Pardo, V. 1988. The clinical spectrum of renal disease associated with human immunodeficiency virus. Am. J. Kidney Dis. 12(2): 131-37 Bourgoignie, J. J., Ortiz, C., Green, D. F., Roth, D. 1989. Race a cofactor in HIV-I associated nephropathy. Trans. Proc. 21: (6) 3899-3901 Langs, C, Gallo, G. R., Schacht, R. G., Sidhu, G., Baldwin, D. S. 1990. Rapid renal failure in AIDS-associated focal glomerulosclerosis. Arch. Intern. Med. 150: 287-92 Carbone, L., D'Agati, V., Suh, J. I.,
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Cheng, 1. T., Appel, G. 1989. Course and prognosis of human immunodeficiency virus associated nephropathy. Am. J. Med. 87: 389-95 9. Chander, P., Soni, A., Suri, A., Bhagwat, R., Yoo, J" Treser, G. 1987, Renal ultrastructural markers in AIDS associated nephropathy. Am. J. Palhol. 126: 513-26 10. Chander, P., Agarwal, A., Soni, A., Kim, K., Trcser, G. 1988. Renal cyto membranous inclusions in idiopathic renal disease as predictive markers for the acquired immunodeficiency syn drome. Hum. Palhol. 19: 1060--64 II. D'Agati, V., Suh, J. I., Carbone, L., Cheng, J. T., Appel, G. 1989. Pathology of HIV-associated nephropathy: a detailed morphologic and comparative study. Kidney Int. 35: 1358-70
