The underlying etiologies of CKD in persons with HIV can be categorized as follows: (1) HIV-associated nephropathy (HIVAN), (2) HIV-related glomerular diseases that are not HIVAN including immunodeficiency renal diseases, (3) drug-induced nephrotoxicity, and (4) CKD related to non-HIV comorbidities such as diabetes mellitus or hypertension [33]. The first account of kidney disease associated with HIV was in 1984 as a description of what is known today as focal segmental glomerulonephritis [34, 35]. Regardless of etiology, persons with kidney disease have a greater risk of death and cardiovascular events when compared with the community-based population without CKD, a phenomena that still applies in the HIV-infected community with CKD [21, 36].

HIVAN was first described on renal biopsy as collapsing focal glomerulosclerosis [34, 35]. However, in the largest biopsy series of HIV-infected patients of African descent, it has more recently been defined as a histological spectrum, a “constellation of glomerular, interstitial, and tubular abnormalities,” albeit with a glomerular predominance [37]. Table 13.1 describes the changes that can be seen in the nephron which correspond to a histological diagnosis of HIVAN, including tubular microcysts, mesangial hyperplasia, interstitial fibrosis, and lymphocytic infiltrates [6, 37]. HIVAN has been traditionally reported as a late manifestation of HIV but has occasionally been described earlier in the disease [6]. Clinically, it is characterized by variable proteinuria, renal failure, large echogenic kidneys, and absence of peripheral edema and can rapidly progress to ESRD [6, 7]. The progression of HIVAN to ESRD can be significantly slowed but not completely prevented by HAART therapy [6]. In addition to ethnicity, risk factors for the progression of HIVAN likely include lower CD4+ T cell count (<200 cells/μL), higher HIV RNA level, and severe renal failure on presentation [5, 38]. There are also genetic associations that have been explored earlier in this chapter. In the study by Wearne et al. [37], without antiretroviral therapy, the expected median survival after biopsy confirmed HIVAN was approximately 4.5 months, with the “fetal variant” having the worst prognosis [37].

While biopsy studies suggest that HIVAN represents approximately one-third of the glomerular disease among African Americans with lower CD4+ T cell counts, it should be emphasized that it is uncommon in Caucasians and Asians; thus there must be other HIV-related glomerular disease seen more often in these ethnic groups and those with higher CD4+ T cell counts [11, 17, 21]. These include HIV-immune complex disease like membranoproliferative glomerulonephritis (MPGN; including hepatitis C associated), lupus-like glomerulonephritis, IgA nephropathy, membranous nephropathy (MN), and HIV-thrombotic microangiopathies [6, 11, 17]. The HIV-immune complex renal disease involves the deposition of circulating immune complexes containing HIV antigens with B cell lymphocytic infiltrates (compared to T cell infiltrates in HIVAN), inflammation, and scarring [6]. It has been reported in up to 80 % of Caucasians with HIV and glomerular disease [5]. The benefit of HAART therapy on slowing the progression of the HIV-immune complex kidney disease is less clear compared to that seen in HIVAN. While some studies of IgA nephropathy demonstrate that HIV antigens may play an important and causative role [39] in the pathogenesis of these lesions, the definitive evidence linking HIV to these lesions is not available. The HIV-related lupus-like glomerulonephritis involves the subendothelial deposition of multiple immune complexes including IgA, IgG, IgM, C3, and C1q in the absence of serologic and clinical diagnosis of systemic lupus erythematosus (SLE) [40]. HIV-thrombotic microangiopathy (hemolytic uremic syndrome or thrombotic thrombocytopenic purpura) is rare but, when identified, predominates among Caucasians; like its non-HIV-associated counterparts, histological features include the deposition of microthrombi in the glomerular capillaries, fibrinoid necrosis, and onion skinning [6].

Anti-neutrophil cytoplasmic antibodies (ANCA) have been noted in the sera of HIV-infected individuals with varying frequency (18–41.0 %) in the absence of clinical features suggestive of a vasculitis [41–43]. A review of the literature finds only two case reports of persons with HIV who developed an active ANCA-positive vasculitis [42, 44, 45]. Similarly, only one case report of anti-GBM disease in a patient with HIV has been published [46]. The finding of these two autoantibodies in the absence of kidney disease suggests that their pathophysiologic effects may be modified in the presence of HIV infection. Positive tests for these antibodies should be interpreted with caution and should not be used to decide on empiric therapy in the absence of a kidney biopsy to confirm histology.

While the treatment of HIV with antiretroviral medications has therapeutic benefit in HIVAN, the medications can also result in acute kidney injury (AKI) due to acute tubular necrosis, allergic interstitial nephritis, and obstructive uropathy [21, 36]. Table 13.2 lists common HIV medications and their potential renal toxic effects. Tenofovir, indinavir, and atazanavir are the most frequently described as having nephrotoxic effects. Tenofovir is a nucleoside reverse transcriptase inhibitor, and while early clinical trials did not reveal appreciable nephrotoxicity, there have been numerous post-marketing reports describing renal tubular injury with this agent [47]. Tenofovir is actively secreted into the tubules and damages the proximal tubules by a direct cytotoxic effect; this eventually causes a Fanconi syndrome and potential renal tubular acidosis [48]. These phenomena have been seen more frequently in cases where tenofovir was administered as part of a regimen containing HIV protease inhibitors such as ritonavir or lopinavir as these increase the maximum serum concentration of tenofovir by >30 % [6, 49]. Tenofovir nephrotoxicity is largely reversible with the removal of the offending drug. The HIV protease inhibitor indinavir causes nephrotoxicity by inducing crystal formation in approximately 20 % of patients receiving it; this subsequently leads to obstructive uropathy and drug-induced interstitial nephritis [6, 50]. Indinavir also reduces the production of nitric oxide which is a potent vasodilator. A reduced amount of this molecule in the kidney vessels therefore leads to vasoconstriction and subsequent ischemia, which is another proposed mechanism of indinavir-mediated renal injury [51]. Patients can be asymptomatic or present with classic symptoms of dysuria and flank pain and the urinalysis will reveal crystalluria and pyuria; renal ultrasound may reveal signs of obstruction, but indinavir stones are radiolucent and are usually not visualized on imaging [6]. Similar events have been described with atazanavir [32, 33]. Additionally, many of the antimicrobials used for prophylaxis of opportunistic infections can also exert nephrotoxic effects such as renal tubular acidosis, acute interstitial nephritis (AIN), and acute tubular necrosis (ATN) (Table 13.3). Trimethoprim-sulfamethoxazole can also cause an isolated elevation in serum creatinine without significant change to renal function [6].

The epidemiology of HIV infection has changed significantly with the advent of effective HIV suppression using HAART. With the improved survival come an increase in the mean age of those living with HIV/AIDS and an increase in the number of comorbidities such as diabetes, hypertension, and atherosclerosis [8, 11, 52]. A review of kidney tissues contained within the Manhattan HIV Brain Bank obtained from patients who had consented to postmortem organ donation for scientific study reveals that nearly one third of 89 deceased individuals had CKD [53]. Notably, while HIVAN was present in some subjects, vascular diseases including arteriolar nephrosclerosis and diabetic nephropathy were also seen, as well as pyelonephritis, interstitial nephritis, fungal infection, and amyloidosis [53]. Other non-HIV glomerular pathology include postinfectious glomerulonephritis, classic FSGS again most commonly seen in African-Americans, and hepatitis B- and C-related glomerulopathies (discussed elsewhere in this chapter) [32].

Renal disease associated with HIV is multifactorial and can affect any part of the nephron, from the well-described direct viral effect causing HIVAN to nephrotoxic effects of antiretroviral drugs. The presence of certain chromosomal foci may increase the risk of developing renal disease among HIV-infected patients of African descent. Due to the current effectiveness of HAART therapy, HIV-infected patients now have improved life expectancies that may lead to the development of chronic kidney disease secondary to both HIV and non-HIV-related causes. Renal biopsy could provide definitive histologic diagnosis but may not be readily available or even necessary for diagnosis and treatment. Appropriate therapy for HIV-related renal disease includes HAART initiation or adjustment and the use of ACEIs and ARBs.

If proteinuria and serum creatinine fail to improve or at least stabilize in the short term after initiation of treatment, renal biopsy should be considered at that time if not previously performed, to further define the renal disease and allow for more aggressive and tailored therapy. Kidney transplant is a viable therapeutic option for end-stage renal disease in HIV patients and is becoming more accepted as HAART can effectively keep the HIV viral load low and CD4+ T cell count high.