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Human immunodeficiency virus-1 associated nephropathy (HIVAN): epidemiology, pathogenesis, histology, diagnosis, and medical management.


Recognize human immunodeficiency virus-1 associated nephropathy (HIVAN) as the most common cause of chronic kidney disease in patients who are HIV-seropositive.


1. Discuss epidemiology and incidence of human immunodeficiency virus-1 (HIV-1) and HIVAN.

2. Describe the clinical presentation of HIVAN.

3. List the important components of diagnosis and treatment of HIVAN.

Human immunodeficiency virus-associated nephropathy (HIVAN) is a very distinct, unique, clinico-pathological syndrome and also a structural type of renal failure (Betjes, Weening, & Krediet, 2001; Dellow, Unwin, Miller, William, & Griffiths, 1999; Pardo et al., 1987; Rao, Friedman, & Nicastri, 1987; Szczech, 2001; Tokizawa et al., 2000). More specifically, HIV-associated nephropathy (HIVAN) is the most common cause of chronic renal failure in patients who are HIV-seropositive (Monahan, Tanji, & Klotman, 2001; Sothinathan, Briggs, & Eustace, 2001; Winston, Burns, & Klotman, 2000). Usually, HIVAN is diagnosed when HIV-seropositive patients present with the classic textbook signs and symptoms of the nephrotic syndrome with progressive loss of renal function and also an increased risk of mortality (Betjes et al., 2001; Dellow et al., 1999; Szczech, 2001; Tokizawa et al., 2000). Studies suggest that the HIV genome is ubiquitous in renal tissue of HIV-infected patients regardless of the presence or absence of renal disease, and that the HIV genome itself is probably not enough for the development of sclerosis. Other immunity factors and inflammatory mechanisms are necessary for the induction of the disease. Thus far, the most beneficial combination of treatment is an angiotensin converting enzyme inhibitor and highly active anti-retroviral (HAART) drug regime. Steroids are also a beneficial, yet controversial, treatment for HIVAN.

Pathogenesis of HIVAN

The human immunodeficiency virus-type 1 (HIV-1) is classified as a member of the retroviral family, a subgroup of the Lentiviruses (McCance & Huether, 2002). Over time, the HIV-1 undergoes changes and mutations, and increases its virulence in the same subject at different times, especially in advanced disease. Different strains of the virus are found in different patients (over 1,000 strains have been identified) and in the same patient at different times and even at the same time (McCance & Huether, 2002). Different renal lesions have been reported in patients with HIV infection, including: idiopathic (non-HIVAN) focal and segmental glomerulosclerosis, arterionephrosclerosis, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP, allergic interstitial nephritis, chronic interstitial nephritis from Amphotericin B, immunoglobulin A nephropathy, immunodactoid glomerulonephritis, renal amyloidosis, membranoproliferative glomerulonephritis, and membranous glomerulonephritis (Betjes et al., 2001; Cohen & Nast, 1988; Cosgrove, Abu-Alfa, & Perazella, 2002; Pardo et al., 1987; Rao et al., 1987; Szczech, 2001). Since discussing each unique HIV-connected renal disease would require a great deal of time and depth, the focus of this article is the very unique and specific renal disease entity of HIVAN.

Epidemiology of HIVAN

HIVAN is the most common cause of chronic renal failure in patients who are HIV-seropositive (Monahan et al., 2001; Sothinathan, Briggs, & Eustace, 2001; Winston, Burns, & Klotman, 2000). HIVAN occurs predominantly in African Americans between the ages of 20-64 and is the third leading cause of end stage renal disease (ESRD), ranking only behind hypertension and diabetes mellitus as a cause of ESRD (Betjes et al., 2001; Bruggeman et al., 2000; Cosgrove et al., 2002; Dellow, Unwin, & Miller, 2000; Kimmel, 2000; Martins, Tareen, & Norris, 2002; Monahan et al., 2001; Szczech, 2001; Szczech et al., 2004; U.S. Renal Data Systems, 1999; Wei et al., 2003; Winston, Burns, & Klotman, 2000). In addition, a genetic predisposition exists for concurrent HIVAN in the other affected African American family members (Betjes et al., 2001; Bruggeman et al., 2000; Cosgrove et al., 2002; Dellow et al., 2000; Kimmel, 2000; Martins et al., 2002; Monahan et al., 2001; Pardo et al., 1987; Rao et al., 1987; Szczech, 2001; Winston, Burns, & Klotman, 2000).

Besides the African American genetic predisposition, HIVAN is also strongly associated with intravenous drug use (IVDU) and consequential development of focal segmental glomerulosclerosis (FSGS) from IVDU (Betjes et al., 2001; Bruggeman et al., 2000; Cosgrove et al., 2002; Dellow et al., 2000; Kimmel, 2000; Klotman et al., 2000; Martins et al., 2002; Monahan et al., 2001; Pardo et al., 1987; Rao et al., 1987; Szczech, 2001). HIVAN is 7 to 10 times more common in men than women, and 30% to 60% have a history of IVDU (Pardo et al., 1987; Rao et al., 1987).

In addition, other renal disease lesions may be caused by an HIV-active infection superimposed over viral Hepatitis B and/or C, intravenous drug use, nephrotic syndrome, drug-induced (both prescribed and recreational) interstitial nephritis, renal amyloidosis, or crystal-induced acute renal failure caused by indinavir or acyclovir (Szczech, 2001). During the past decade, patients who were HIV-seropositive developed ESRD began receiving dialysis treatments at a rate that increased by 20% per year (Szczech, 2001). Without treatment, these patients progress to ESRD within weeks to months after the initial diagnosis of HIVAN with the classic nephrotic syndrome presentation (Betjes et al., 2001). In 1999, HIV-related renal disease became the third leading cause of ESRD in this particular demographic group (Betjes et al., 2001). Unfortunately, the prognosis for patients with HIVAN with consequent ESRD is poor, with the mortality rate reaching 50% at 1 year after the initiation of dialysis (Betjes et al., 2001). The rate of incidence continues living with HIVAN and AIDS continues to rise, with the largest proportionate increase occurring among African Americans and among Hispanic women infected through heterosexual contact living in urbanized areas (Dellow et al., 2000; Kimmel, 2000; Monahan et al., 2001; Szczech, 2001).


In 2004 (the most recent data available), the Centers for Disease Control (CDC) estimated that there were 42,514 cases of AIDS diagnosed in the United States, growing the cumulative estimated number of patients living with the AIDS diagnosis in 2004 to 415,193 (CDC, 2006) (see Table 1). In 2004, the most cases occurred in the Black, non-Hispanic population (see Table 2). The most frequent exposure category was male-to-male sexual contact (see Table 3). The highest number if individuals diagnosed with AIDS in 2004 came from New York (7,641), Florida (5,822), California (4,679),and Texas (3,298) (CDC, 2006).


In the actual renal biopsy sections, Bruggeman et al. (2000) assert that "the polymerase chain reaction (PCR) amplification performed for HIV-1 DNA detected the circularized, unintegrated form of the viral DNA [within renal epithelial and parenchymal cells]" (p.6). They also note "this circularized form is a head-to-tail ligation of the long terminal repeats that occurs after reverse transcriptase and nuclear importing of the proviral DNA" (p.6). Besides the long terminal repeats, the extrachromosomal circles have previously demonstrated short-half life in replicating in the renal epithelial and parenchymal cells (Bruggeman et al., 2000). The extrachromosomal circles are now considered a marker for recent viral infection and active replication of the HIV-1 in this very specific renal tissue location (Bruggeman et al., 2000).

Furthermore, Bruggeman et al. (2000) argue that the "DNA in-situ PCR in-situ hybridizations of the human [epithelial and parenchymal] kidney tissues ... amplified the DNA nucleotides 6,827 to 7,367 of the env [envelope proteins gp41 and gp120] genes from NL4-3 (sense: 'TGTC CAAAGGTATCCTTTGAGC CAATTC GAGCCAATTCC'; anti-sense: 'AGTAGAAAAATTCCCCT CCACAATTAA')" (p.3). Fantini et al. (1993) also concur with Bruggeman et al. (2000) concerning the amplified envelope proteins gp120 genes. According to Barisoni, Bruggeman, Mundel, D'Agati, and Klotman (2000), they discovered that glomerular and tubular epithelial cells express the HIV-1 transgene early in the disease process. On the other hand, they postulate that "in glomerular epithelial cells, dedifferentiation occurs with reduced expression of WT-1 and synaptopodin, in association with activation of desmin expression" (p. 173). Barisoni et al. (2000) also theorize that "transgene expression is lost, however, in tubular epithelial cells when they lose their differentiated cuboidal phenotype" (p. 173). In particular, renal epithelial cells undergo apoptosis in response to the HIV-1 gene expression, therefore causing these cells to loosen from the basement membrane and to slough into the lumen of the tubule (Barisoni et al., 2000; Bruggeman et al., 2000).

Continuing the discussion at the DNA level, Bodi, Abraham, and Kimel (1995) propose that "human immunodeficiency virus peptides and peptide-antibody complexes are immunomodulary and are associated with apoptosis in lymphoid cells" (p. 286). Essentially, the HIV-1 pathogenesis causes severe dysregulation of the epithelial cell cycle with increased proliferation, apoptosis, cellular dedifferentiation, and altered cellular polarity (Barisoni et al., 2000). After HIV infection, tubular cells became very susceptible to apoptosis induced through Fas (capsase) stimulation (Conaldi et al., 1998). On the other hand, according to Conaldi et al. (1998), "HIV-1 is a polytropic and not solely lymphotropic pathogen ... and demonstrate that the apoptosis of nonlymphoid cells can be directly induced by HIV-1" (p. 2041). HIV-1 DNA is also detected in the nucleus of the tubular epithelial cells, interstitial cells, and also the cells that line Bowman's capsule within the glomerulus (Bruggeman et al., 2000). The cellular distribution of the viral mRNA primarily observed in the cytoplasm of the infected cells suggest recent transcriptions (Bruggeman et al.,2000). The podocytes located throughout the glomerular tuft were also positive for both HIV-1 DNA and RNA.

Very briefly, the actual development of HIV-1 is also thought to involve the mesangial renal cells (Tokizama et al., 2002). Tokizawa et al. (2000) postulate that "[their] findings suggest that an orphan G protein-coupled receptor, GPR1, is a coreceptor expressed in [renal] mesangial cells ... and that mesangial cells were susceptible to HIV/Simian (S) IV strains that use GPR1 as a coreceptor" (p. 607). In addition, CD4 and GPR1 mRNAs were detected in mesangial cells (Tokizawa et al., 2000). Finally, viral DNA also was detected in biopsies from patients with undetectable viral burdens, suggesting that perhaps the kidney may be a reservoir for HIV-1 infection as the previously identified macrophages and lymph nodes (Tokizawa et al., 2000).

Besides the genetic expression of HIV-1 in both renal epithelial and parenchymal cells, the renal tubular cellular pathology will now be explored. In patient biopsies with renal tubules expressing the HIV-1 mRNA, frequently other tubules in the same section were negative, suggesting focal areas of infection (Bruggeman et al., 2000). Both renal glomerular and tubular epithelial cells contain HIV-1 mRNA and HIV-1 DNA, indicating very active HIV-1 infection (Bruggeman et al., 2000). A very typical pathological feature of HIVAN is the microcystic dilation of the tubules with the presence of both cellular and proteinaceous casts. After HIV infection, tubular cells became very susceptible to apoptosis induced through Fas (capsase) stimulation (Conaldi et al., 1998). Essentially, the HIV-1 pathogenesis causes severe dysregulation of the epithelial cell cycle with increased proliferation, apoptosis, cellular dedifferentiation, and altered cellular polarity (Barisoni et al., 2000; Bruggeman et al., 2000). According to Barisoni et al. (2000), "tubular microcysts also form with mislocation of sodium, potassium, ATPase expression to the lateral and apical cellular membranes" (p. 173).

Immunity Factors in HIVAN

In patients who are HIV-1 seropositive, the interstitium of the tubules is heavily infiltrated with leukocytes, forming microabscesses (Bruggeman et al., 2000). Within the abscesses, the leukocytes revealed levels of HIV-1 DNA and HIV-1 mRNA far exceeding these levels observed in the neighboring infected renal epithelial cells (Bruggeman et al., 2000). Shrivastav et al. (2000) theorize that HIVAN affects the renal parenchymal cells and that "the target cells would be expected to express viral proteins and this could be targets for cytotoxic T lymphocytes" (p.408). Cellular casts were observed in the lumens of infected tubules, and frequently, these particular cellular casts were also positive for HIV-1 mRNA expression (Bruggeman et al., 2000). However, the proteinaceous casts without cells did not demonstrate a positive hybridization signal (Bruggeman et al., 2000).

Infiltrated infected leukocytes harbor more viral mRNA than the renal epithelium, suggesting that effectively targeting the kidneys with anti-retrovirals and corticosteroids may be critical for patients who are seropositive with renal disease, thus a previously unrecognized cellular target for HIV-1 infection (Barisoni et al., 2000). A patient with HIVAN demonstrates the following typical features: microcystic tubular distortion, interstitial fibrosis, immune cell infiltrates, and collapsing focal glomerulosclerosis (Bruggeman et al., 2000). Due to the typical basal position of the nucleus in the tubular cells, the most intense staining appeared in the cytoplasm above the nucleus on the apical side (Bruggeman et al., 2000).

By electron microscope, the pathology slide would picture focal sclerosing glomerulosclerosis with evidence of prominent glomerular tuft collapse, glomerulus with capillary collapse, large dilated microcystic tubules containing hyaline casts, prominent lymphocytic interstitial infiltrates, tubuloreticular structures within the endothelial cells and the presence of nuclear bodies, and interstitial edema, fibrosis, and inflammation (Betjes et al., 2001; Szczech, 2001). The thrombotic microangiopathies--hemolytic uremic syndrome and thrombotic thrombocytopenic purpura--are thought to occur due to endothelial cell dysfunction which is partly mediated by HIV proteins (Kimmel, Barisoni, & Kopp, 2003). According to Kimmel et al. (2003), renal cell apoptosis and inhibition of yon Willebrand factor-cleaving protease may also involve significant roles. The following symptoms are commonly associated with HIV-associated thrombotic microangiopathy: fever, neurologic dysfunction, thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency with hematuria, and high-level proteinuria (uncommon) (Kimmel et al., 2003).

In addition to the epithelial, parenchymal, endothelial, mesangial, and tubular cells affected by HIV-1, the roles of inflammation related to HIVAN will now be explored, particularly chemokine receptors. For background information, chemokine receptors represent a family of structurally and functionally related seven transmembrane-spanning, G protein-coupled receptors (Eitner et al., 2000). Certain chemokine receptors may also facilitate HIV-1 infection by immunodeficiency viruses in a CD4independent manner, and subsequently, these receptors determine viral tropism (Eitner et al., 2000). CXCR4 is a coreceptor for strains of HIV-1 that infect T lymphocyte cell lines (T-tropic strains), and CCR5 serves as a coreceptor for HIV-1 isolates that infect macrophages and activate T-lymphocytes (M-tropic strains) (Eitner et al., 2000). Individuals are homozygous for a mutant allele of the CCR5 gene bearing a 32-nucleotide deletion (CCR5 delta 32) (Eitner et al., 2000). According to Wei et al. (2003), cytokines and growth factors are key players in mediating disease pathogenesis by infiltrating immune or renal cells. Eitner et al. (2000) have observed that "individuals homozygous for a mutation of the only identified CXCR4 ligand, stromal cell-derived factor-l, appear to have some degree of protection against disease progression after HIV infection" (p. 859). In the clinical study performed by Eitner et al. (2000), "the expression of both chemokine receptors CCR5 and CXCR4 was undetectable in intrinsic, tubular, and renovascular cells in all analyzed cases" (p. 856).

Eitner et al. (2000) also noted that CCR5 and CXCR4 expression was localized to both circulating and infiltrating mononuclear leukocytes at the sites of tubulointerstitial inflammation. HIV-1 strains, previously characterized by T-lymphocyte-tropic bind to the chemokine receptor CXCR4 as conditional entry into mammalian cells while macrophage-tropic strains of HIV-1 require the chemokine receptor CCR5 (Eitner et al., 2000). According to Eitner et al. (2000), "HIV-1 protein and HIV RNA were undetectable in renal parenchymal cells in biopsies with features of HIV-associated disease" (p. 860). Increased viral load associated with increased T-cell turnover, increase in Interleukin (IL)-2, IL-4-6, and increase in interferon-alpha may all stimulate renal injury or mesangial and glomerular changes (Dellow et al., 2000). However, the HIV DNA was also present in kidney tissue from patients with HIV but without renal disease.

These studies suggest that the HIV genome is ubiquitous in renal tissue of patients with HIV regardless of the presence or absence of renal disease, and that the HIV genome itself is probably not enough for the development of sclerosis. Other mechanisms are necessary for the induction of the disease. The HIV virus directly affects the glomerular endothelial and mesangial cells, causing cytokines and transforming growth factor beta to inhibit T cell stimulation and down regulation of the CD4 cells (Dellow et al., 1999). Following HIV infection, certain cytokines may mediate the cellular infiltration and sclerosis (Dellow et al., 1999).

Clinical Patient Findings

The prevalent HIVAN-presenting clinical patient case would be an African-American male between the ages of 20-64 with a history of IVDU, who presents with proteinuria due to the nephrotic syndrome; absence of hematuria on urinalysis; rapidly progressive renal insufficiency; normal blood pressure; and large, echogenic kidneys seen on ultrasound (Dellow et al., 1999; Szczech, 2001). For background information, the nephrotic syndrome is the excretion of 3.5 grams or more of protein in the urine per day, and the large amount of urine protein is characteristic of glomerular injury (McCance & Huether, 2002). According to McCance and Huether (2002), "disturbances in the glomerular basement membrane, which may be metabolic, biochemical, or physiochemical, lead to increased [capillary] permeability to protein. Hypoalbuminemia results from urinary loss of albumin combined with a diminished synthesis of replacement albumin by the liver" (p. 1204).

The most common initial signs of HIVAN, as manifested by the initial diagnosis of the nephrotic syndrome are: heavy proteinurea from the nephrotic syndrome, azotemia, hypoalbuminemia, normal blood pressure reading, significant peripheral edema, and absence of hematuria and white blood cells, except the presences of lipid bodies in the urine as seen in the urinalysis results (Dellow et al., 1999; McCance & Huether, 2002; Szczech, 2001). Disturbances in peripheral edema, increased serum cholesterol, phospholipids, and triglycerides along with fat bodies present in the urine are also seen clinically (McCance & Huether, 2002).

In addition, the HIVAN patient presenting with this secondary nephrotic syndrome may also experience a Vitamin D deficiency, low levels of ionized calcium, secondary hyperparathyroidism, and osteomalacia McCance & Huether, 2002). The typical laboratory chemistry values that a practitioner may see in clinical practice include: elevated creatinine (N 3.0-8.0 mmol/L); elevated plasma urea levels (N 50-125 umol/L); gross proteinuria (N 35-53 gin/L); CD4 cell counts dropped to less than 200 [mm.sup.3]; and escalating HIV-1 viral load counts (N greater than 500 copies/ml HIV-1 DNA) (Betjes & Verhagen, 2002; Dellow et al., 1999; Rajvanshi & Gupta, 2001).

Most patients are now first being diagnosed with late-stage HIV-1 infection (Winston, Klotman, & Klotman, 1999), which has huge public health ramifications due to all of the present and past sexual partners that this patient has been in sexual contact with. The city public health department needs to be informed of the HIV-1 case so that the Centers for Disease Control continues to have updated data regarding HIV and AIDS cases in the United States.

Diagnostic Tests and Procedures for HIVAN

The comprehensive diagnostic tests for both HIV and for HIVAN include the following: HIV culture (has the unfortunate high false negative rates), viral polymerase chain reaction (PCR) test; plasma viral RNA (probably the most accurate); viral load of HIV; antigen tests for p17 and p24; enzyme-linked immunosorbant assay (ELISA) test first, then Western Blot next; HIV RNA antibodies; CBC with differential; complete CD cell count; cell lipid panel (to diagnose the nephrotic syndrome); T4: T8 ratio; antibody testing for gp120 and gp41; helper T cell (CD4) count; reverse transcriptase; HIV RNA antibodies; and serum immunoglobulins.

To further assess actual renal function and extent of kidney damage from the HIV-1 virus, other diagnostic tests to order include: electrolyte panel; urinalysis to check for lipids, eosinophils, red and white blood cells, casts, and protein; serum albumin level; ionized calcium; phosphorus; magnesium; analyzed with aspartate aminotransferase (to assess for hepatic injury vs. hepatorenal syndrome); and parathyroid hormone level (to assess for secondary hyperparathyroidism) (Chernecky & Berger, 2004). A 24-hour urine collection to calculate both protein and creatinine clearances is also warranted.

For further investigation of the differential diagnosis, more invasive diagnostic tests may need to be ordered such as: renal biopsy; renal ultrasound to assess renal size, echogenicity, and cortical thickness; plain abdominal film if nephrocalcinosis is suspected; intravenous urogram if obstruction/stones suspected; nuclear medicine scans such as MAG-3 renography for differential function; and DTPA scan for evidence of scarring (Dellow et al., 2000).

These tests will assist the practitioner to rule out the following diagnoses: acute renal failure, diabetes mellitus vs. insipidus, immunotactoid glomerulonephritis, renal amyloidosis, systemic lupus erythematous, Henoch-Schonlein purpura, malignancy, vascular disorders, arterionephrosclerosis, HUS/TTP, allergic interstitial nephritis, membranoproliferative glomerulonephritis, membranous glomerulonephritis, nephritic wasting syndrome, FSGS, IgA nephropathy, glomerulonephritis, Wegener's granulomatosis, cystitis, scleroderma, Goodpasture's disease, nephrotic syndrome, acute tubular necrosis, pyelonephritis, and chronic renal failure.

Medication Management and Other Medical Treatments

First and foremost, the patient's presenting nephrotic syndrome needs to be treated. The second priority is to implement HAART and corticosteroid medication regimes. Care must be taken to observe for hypovolemia, hypokalemia, and potassium toxicity in the presence of this acute renal insufficiency of the nephrotic syndrome as these medical conditions can be life threatening. Commonly, the nephrotic syndrome is treated with a normal-protein, low-saturated fat diet with salt restrictions; loop diuretics in combination with aldactone; corticosteroids; and occasionally albumin replacement if the serum and urine laboratory values warrant this intervention.

HIVAN results in a poor prognosis, emphasizing the need for accurate and timely treatment. The mortality rate varies from a few months without treatment to several years with treatment, depending upon each individual's unique disease processes (Betjes & Verhagen, 2002; Sothinathan, Briggs, & Eustace, 2001).

Decreasing the viral load while preserving renal function is the optimal outcome of medical management A variety of drug regimes and dialysis have been incorporated into treatment. Thus far, the most beneficial combination of treatment is an angiotensin converting enzyme inhibitor and the HAART drug regime. Steroids, particularly prednisone, are frequently added to this regimen with much caution and some controversy. In clinical trials, corticosteroids have demonstrated modest improvement in slowing the progression of HIVAN but also increase the risk of acquiring opportunistic infections, malignancy, and lymphoma.

Improving renal function results from a multi-interventional approach. Findings upon renal biopsy demonstrate collapsing of focal glomerulosclerosis, glomerular epithelial cell hypertrophy, tubulointerstitial infiltration with edema, fibrosis, and microcystic tubule dilation (Betjes & Verhagen, 2002; Rajvanshi & Gupta, 2001; Winston, Klotman & Klotman, 1999), all potential areas to combat with HAART, ACE-inhibitors, and steroids. The worsening manifestations of these laboratory values correlate with increased morbidity and an ultimately poor prognosis.

The viral load of the HIV virus is directly related to the virulence of HIVAN. The devastating effect of cell damage inhibits immune as well as podocyte function. Podocyte damage results from the HIV-regulatory protein, Tat, which affects the glomerular endothelial and mesangial cells, causing cytokines and transforming growth factor beta (TGFB), subsequently inhibiting T cell stimulation and down regulation of CD4 cells (Cosgrove et al., 2002; Dellow et al., 1999). Further proliferation of the HIV-1 gene proteins cause loss of cell-cell or cell-extracellular matrix interactions, causing loss of normal contact inhibition and increase in the number of deregulated podocytes, resulting in the clinical progression of HIVAN (Cosgrove et al., 2002; Schwartz et al., 2001). Controlling the viral load contributes to decreased podocyte damage and improved renal function.

Like the treatment of HIV, the treatment of HIVAN must be individually tailored. Immense advancements in research and pharmacology have contributed to the standardization of treatment of both HIV-1 and HIVAN. Angiotensin converting enzyme (ACE)-inhibitors, HAART, and steroids are the current and most reliable treatment regimes along with hemodialysis. ACE-inhibitors are a viable component of the therapeutic regime responsible for the treatment of HIVAN. According to the research study conducted by Wei et al. (2003), "nephrotic range proteinuria significantly increased the risk of mortality as a confounding variable, suggesting that the survival benefit of ACE inhibition relates to its antiproteinuric effects" (p. 1469). ACE-inhibitors appear to block tumor growth factor (TGF)-beta and other cytokines and may explain the decreased rate of HIVAN disease progression significantly from 160 days to 40 days in one clinical trial study (Dellow et al., 1999). ACE-inhibitors also control the conversion of angiotensin I to angiotensin II, the release of aldosterone, and the expression of TGF and fibroblast growth factor (FGF), both of which are transcriptional regulators (Betjes & Verhagen, 2002; Wei et al., 2003). Necrosis factor-kappa B (NK-kB) is another transcriptional regulator of HIV that may be affected by the renin-angiotensin system (Wei et al., 2003). The pharmacological benefits that result from the inhibition of TGF and FGF truly improve renal function. Hyperkalemia, persistent cough, fatigue, tachycardia, dizziness, and headaches are the most prevalent side effects (Moore, Crosby, & Hamilton, 1994).

HAART is essential in the medical management of HIV-1 and HIVAN. HAART directly affects viral load, and the mortality rate declines when HAART is used in combination with ACE-inhibitors and steroids. In other words, the combinations of HAART, ACE-inhibitors, and steroids have been clinically proven to effectively treat HIVAN.

Medications from the three main classes of antiretroviral drugs are combined to pharmacologically manage HIVAN. Nucleoside reverse transcriptase inhibitors (NRTIs) interfere with VIRAL DNA synthesis by preventing reverse transcriptase and viral HIV-1 RNA from exiting the host cell's protein coat and becoming a part of the cell's DNA strand where it could further potentiate HIV replication (McCance & Huether, 2002; Moore et al., 1994). Zidovudine (AZT), Stavudine (d4T), and Didanosine (ddI) are some of the most researched and manipulated RTIs in the clinical treatment of HIVAN and HIV. The second class of antiretrovirals, the nonnucleoside RTIs, interfere with the catalytic site of the enzyme, thereby inhibiting the insertion of circular DNA in to the noninfected cell (McCance & Huether, 2002). Delavirdine, Efaverenz, and Nevirapine are commonly used from this very specific drug class. The third class of antiretrovirals, the protease inhibitors (PIs), compete with viral protease, preventing protein cleavage and the processing of p160, which ultimately interferes with viral assembly (McCance & Huether, 2002). Amprenavir, Indinavir, and the widely used combination of Lopinavir and ritonavir are the most frequently prescribed PI medications.

The side effects of HAART are consistent with those of standard HIV treatment regimes. Side effects of the RTIs, NRTIs, and PIs include the following signs and symptoms that certainly are not benign: fever, rash, nausea, vomiting, malaise, increase in indirect bilirubin, peripheral neuropathy, acute pancreatitis, lactic acidosis, stomatitis, anemia, neutropenia, headache, confusion, abnormal dreams, agitation, increased transaminase levels, gastrointestinal intolerance, lipid abnormalities, possible fat redistribution, glucose intolerance, diarrhea, taste perversions, asthenia, and major drug-drug interactions (Spach, 2001). Most notably, the NRTI Nevirapine (Viramune) can cause fatal hepatitis and the NRTI didanosine can cause life-threatening pancreatitis (2001). In addition, the NRTI Abacavir (Ziagen) can cause the Stevens-Johnson syndrome (2001). All of the NRTIs can cause a profound lactic acidosis (Spach, 2001). Concerning the PIs, the drug Ritonavir (Norvir) possesses major drug-drug interactions and severe hypersensitivity reactions (Spach, 2001).

A close practitioner-patient relationship can facilitate proper individual treatment, hopefully diminishing the side effect problems, observing the patient early for the severe adverse drug reactions, and improving HAART compliance. Through the decreased viral load, HAART has been clinically established to have profound, significant effects on preventing further damage of podocytes, the major renal cells affected by the detrimental HIVAN.

For ongoing clinical management, the prudent practitioner must monitor the following laboratory chemistries every 3 to 4 months: liver function tests, CBC with differential, electrolyte panel, pH, ionized calcium, triglycerides, phosphorus, magnesium, fasting glucose levels, and a urinalysis. In general, routine follow-up should be scheduled at least every 3 months to properly monitor and manage the patient's clinical condition. The HIV RNA and CD[4.sup.+] count levels should be ordered and drawn pre-HAART and then every 4 weeks thereafter until the viral load drops to less than 50 copies/ml (Spach, 2001). After this period of time, the HIV RNA level and the CD[4.sup.+] T cell count should be monitored every 3 months to assess HAART effectiveness (Spach, 2001). Suppressing HIV levels to less than 50 copies/ml significantly diminishes the number of new HIV virions and this profoundly decreases the chance that resistant strains will develop (Spach, 2001).

Steroids are also a beneficial, yet controversial, treatment for HIVAN. In general, the individualized combinations of the therapeutic HAART, ACE-inhibitors, and steroids have proven to be the most beneficial treatments for HIVAN. Infiltrated infected leukocytes harbor more viral mRNA than the renal epithelium, suggesting that effectively targeting the kidneys with antiretovirals and corticosteroids may be critical for patients who are seropositive with renal disease, thus a previously unrecognized cellular target for HIV-1 infection (Conaldi et al., 1998). If profound renal impairment persists for a brief period of time, tailored steroid regime may be then incorporated as this is considered the third line of treatment for HIVAN. On the other hand, practitioners must weigh the risks and benefits of steroid usage in an already severely immunocompromised patient. Essentially, glucocorticoids interact with the specific glucocorticoid receptor (GR). According to Kino, Kopp, and Chrousos (2000), the "glucocorticoid binds with the GR, dissociating it from the hetero-oligomer of the cytoplasmic heat shock protein and translocates into the nucleus to exert its effects by binding to the glucocorticoid-responsive genes." (p. 283) Also, according to Kino et al. (2000), elements (GREs) in the promoter region of glucocorticoid-responsive genes or to other transcription factors, AP-1 and STAT proteins through direct protein-protein interactions is necessary for loosening or strengthening promoter DNA winding around nucleosomes" (p. 283).

The extensive damage possible with the use of steroids emphasizes the need for close medical monitoring by skilled, competent, and educated medical professionals. Steroids are commonly reserved for the use in opportunistic infections associated with HIV. Although not an opportunistic infection, steroids may augment the treatment of HIVAN. The coactivator Vpr increases the sensitivity of target tissues to glucocorticolds (Kino et al., 2000). Increasing tissue sensitivity is beneficial, yet at the same time, detrimental, to the treatment of both HIV and HIVAN. The timing of steroid initiation and exact length of treatment is widely debated. Research demonstrates a mild stimulatory and moderate inhibitory effect of glucocorticoids of HIV (Kino et al., 2000).

Basically, steroids favorably influence inflammation. Steroid use has been found to decrease inflammatory mediators, resulting in decreased inflammation (Eustace et al., 2000; Szczech et al., 2004). The underlying decrease in inflammation contributes to decreased cellular damage, and caution, close observation, and monitoring have proven that steroid utilization is an acceptable temporary addition to the treatment of both HIV and HIVAN (Eustace et al., 2000; Kino et al., 2000; Szczech et al., 2004). The adjunct of steroids to ACE-inhibitors and adequately prescribed HAART decreases interstitial inflammation by lessening the tubulo-intersfitial mononuclear cell infiltration, therefore improving renal function (Betjes & Verhagen, 2002; Eustace et al., 2000). Szczech et al. (2004) strongly assert that the combined use of ACE-inhibitors and angiotensin receptor blockers (ARBs) is extremely important.

Dialysis is also a standard treatment of both acute and chronic renal failure. In HIVAN treatment, dialysis is considered less desirable than HAART, ACE-inhibitors, and steroids. Patients who have HIV-1 and require dialysis have a higher plasma viraemia level than those who do not have renal impairment from HIV or who have chronic renal failure but do not yet require dialysis (Dellow et al., 1999). By conclusion, these individuals have a higher mortality rate than those with renal failure. Unfortunately, the prognosis for patients with HIVAN with consequent end stage renal disease (ESRD) on dialysis is very poor, as the mortality rate reaches 50% after 1 year after the initiation of dialysis (Betjes et al., 2001; Szczech, 2001). The increased mortality rate combined with the immense support needed from the dialysis community reiterates the need for accurate, effective, and timely HIVAN management.


Through the art and science of individually manipulating and managing these regimens, clinically significant documented cases exist that demonstrate improvements in overall renal function and profoundly decreased HIV-1 DNA viral loads. Eventually, the treatment of HAART, ACE-inhibitors, and steroids will immensely decrease viral loads and the extent of proteinuria, increase CD4 counts, and normalize the following laboratory chemistries: serum creatinine, blood urea nitrogen (BUN), plasma albumin, electrolytes, ionized calcium, phosphorus, and magnesium (Dellow et al., 2000). Overall, in the case studies reviewed, the side effects of the comprehensive HIVAN therapy were manageable by the partnerships between patients and the medical practitioners.

Early referral to a board-certified nephrologist or a certified nephrology family nurse practitioner is essential and very important along with long-term, primary care approach provided jointly by nephrologists and infectious disease specialists. Careful adjustments of prescription doses with regularly scheduled, and at times frequent, laboratory testing will yield optimal health, improve the quality of life, and most importantly, decrease the incidence of morbidity and mortality in those individuals afflicted with both HIV and HIVAN.

Posttest--2.3 Contact Hours

Posttest Questions

(See posttest instructions on the answer form, on page 269.)

1. Which statement is true about the human immunodeficiency virus-type 1 (HIV-1)?

A. HIV-1 does not mutate

B. Only one strain of the HIV-1 is found in a patient at any given


C. HIV-1 may increase in virulence over time

D. HIV-1 is associated with one type of renal lesion

2. You would likely diagnose human immunodeficiency virus-1 associated nephropathy (HIVAN) in which patient?

A. African American, female, ages 18-25, history of intravenous drug use

B. Hispanic, male, ages 20-64, history of male-to-male sexual contact

C. African American, male, ages 20-64, history of intravenous drug use

D. Hispanic female, age 18-25, history of unprotected sexual contact

3. Which renal cell(s) is affected by the HIV-1 ?

A. Epithelial only

B. Epithelial and mesangial only

C. Epithelial, mesangial, and parenchymal only

D. Epithelial, mesangial, parenchymal and tubular cells

4. The patient with HIVAN presents with which clinical symptoms?

A. Hypertension, nephrotic syndome, and absence of edema

B. Hematuria, periperal edema, and hypotension

C. Nephrotic syndomre, peripheral edema, and normal BP

D. Hypoalbuminuria, hematuria and hypertension

5. You are seeing a patient in the CKD clinic. He has risk factors for HIV-1 infection. You suspect he may have HIVAN. Which test is most accurate for HIV?

A. Plasma viral RNA

B. HIV culture

C. Viral polymerase chain reaction (PCR)

D. Enzyme-linked immunosorbant essay (ELISA)

6. Which statement is true about the treatment of HIVAN?

A. Patients with HIVAN when treated aggressively have an excellent prognosis

B. Decreasing the viral load is critical to success of treating HIVAN

C. Corticosteroids have demonstrated improvement in slowing CKD progression without risks

D. Patients with HIVAN are rarely started on hemodialysis

7. Angiotensin converting enzyme (ACE) inhibitors are utilized in treatment of HIVAN because of their

A. antiproteinuric effect only.

B. antiporteinuric effect and tumor growth factor blockade only.

C. antiporteinuric effect, tumor growth factor blockade, and inhibition of fibroblast growth factor only.

D. antiporteinuric effect, tumor growth factor blockade, inhibition of fibroblast growth factor, and potentiation of HAART.

8. You have placed a patient on HARRT to manage HIVAN. Which side effect(s) should you be assessing in your patient?

A. Jaundice only

B. Jaundice and anemia only

C. Jaundice, anemia, and acute abdominal pain only

D. Jaundice, anemia, acute abdominal pain, and hyperkalemia

9. The goal of HARRT is to depress the HIV levels to less than

A. 5 copies/ml.

B. 10 copies/ml.

C. 25 copies/ml.

D. 50 copies/ml.

10. When should steroid treatment be incorporated in treating HIVAN?

A. To further suppress HIV to target levels

B. To treat profound renal failure for a brief time

C. For long-term use with HARRT and ACE inhibitors

D. In patients who have begun renal replacement therapy


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Michelle L. Lochner, MSN, RN, FNP, CNN, is Staff Nurse, Inpatient Dialysis Unit/Division of Nephrology and Hypertension, Mayo Clinic/Mayo Medical Center, Rochester, MN. She is also a Family Nurse Practitioner Intern at the Grand Meadow Family Practice Clinic at the Mayo Health System. She is a member of the Southeast Minnesota Chapter of ANNA.

Andrea Wolf, BSN, RN, is Staff Nurse, Medical/Surgical/Transplant Intensive Care Unit, Rochester Methodist Hospital at the Mayo Medical Center, Rochester, MN.
Table 1
AIDS Incidence 2000-2004

                                         Estimated # of
       Estimated # of   Estimated # of   Persons Living
       AIDS Diagnoses    AIDS Deaths       with AIDS

2000       39,513           17,139          320,177
2001       39,206           17,611          341,773
2002       40,267           17,544          364,496
2003       41,831           17,849          388,477
2004       42,514           15,798          415,193

Source: Centers for Disease Control (2006).

Table 2
Estimated Number of People Diagnosed with AIDS in 2004
By Race or Ethnicity

                                  Estimated # of AIDS Cases

Black, not Hispanic                        20,965
White, not Hispanic                        12,013
Hispanic                                    8,672
Asian/Pacific Islander                        488
American Indian/Alaskan Native                193

Source: Centers for Disease Control (2006).

Table 3
Estimated Number of People Diagnosed with AIDS in 2004
By Gender and Exposure Category

                               Male    Female    Total

Male-to-male sexual contact   17,691        0   17,691
Injection drug use             5,968    3,184    9,152
Male-to-male sexual contact    1,920        0    1,920
  and injection drug use
Heterosexual contact           5,149    7,979   13,128
Other                            298      279      577

Source: Centers for Disease Control (2006).
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Title Annotation:Continuing Education; nephrology nursing research; includes test and statistical tables
Author:Lochner, Michelle L.; Wolf, Andrea
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:May 1, 2006
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