Kidney disease in patients with HIV

INTRODUCTION — With dramatic improvements in survival and disease progression in the era of combination antiretroviral therapy (ART), complications such as kidney, liver, and cardiac disease have largely replaced opportunistic infections as the leading causes of mortality in the setting of HIV. Patients with HIV are at risk for both acute kidney injury (AKI) and chronic kidney disease (CKD) secondary to medication nephrotoxicity, HIV-associated nephropathy (HIVAN), and immune complex kidney diseases. In addition, the aging cohort of patients with HIV is at increased risk for comorbid kidney disease related to traditional CKD risk factors including diabetes, hypertension, and obesity, as well as kidney disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection.

This topic will review acute and chronic kidney disease in patients with HIV. HIVAN and issues related to dialysis and kidney transplantation in patients with HIV are discussed separately:

●(See "HIV-associated nephropathy (HIVAN)".)

●(See "Human immunodeficiency virus and dialysis".)

●(See "Kidney transplantation in patients with HIV".)

ACUTE KIDNEY INJURY

Epidemiology and risk factors for AKI — Patients with HIV have an increased risk of developing acute kidney injury (AKI) compared with patients without HIV [1,2]. The incidence of AKI among patients with HIV varies depending upon the population studied and the definition used for AKI and ranges from 5.7 to 9.4 percent among ambulatory patients [3-5] and from 6 to 66 percent among hospitalized patients [1,2,6-11]. Studies have shown that the incidence of severe, dialysis-requiring AKI among hospitalized patients with HIV has been increasing [2,6]. This may be due in part to the increasing prevalence of chronic non-AIDS–related comorbidities as well as the increasing age of people with HIV.

Risk factors for AKI among patients with HIV include risk factors for AKI in the general population, such as older age, diabetes mellitus, preexisting chronic kidney disease (CKD), acute or chronic liver disease, and treatment with nephrotoxic agents [1,2]. In addition, there are risk factors that are specific to HIV, such as low CD4 count, high viral load, and coinfection with hepatitis C virus (HCV) [3,4,6,12].

Causes of acute kidney injury — The most common causes of AKI in patients with HIV are prerenal causes (eg, volume depletion), acute tubular necrosis, and medication toxicity.

General causes — Several of the causes of AKI among patients with HIV are similar to those among the general population, including the following:

●Prerenal causes – Prerenal kidney disease is one of the most common causes of AKI among patients with HIV and often results from volume depletion (due to diarrhea or vomiting) [3,13]. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults", section on 'Causes of prerenal disease'.)

●Acute tubular necrosis – Acute tubular necrosis (ATN) is another common cause of AKI and is typically seen in the setting of sepsis or treatment with one or more nephrotoxic drugs, including aminoglycosides, amphotericin B, acyclovir, cidofovir, foscarnet, and pentamidine. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults", section on 'Causes of acute tubular necrosis'.)

●Acute interstitial nephritis – Acute interstitial nephritis (AIN) can occur in association with certain medications (such as trimethoprim-sulfamethoxazole, rifampin, proton pump inhibitors, and nonsteroidal anti-inflammatory drugs or can be caused by direct kidney parenchymal infection by pathogens such as cytomegalovirus infection. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)

●Medication toxicity – Medication nephrotoxicity can cause different forms of AKI, including ATN, AIN, crystal-induced AKI, or renal tubular disorders (eg, Fanconi syndrome).

Some of the more commonly implicated agents include the following (table 1):

•Tenofovir – Tenofovir is a nucleotide reverse transcriptase inhibitor that is part of many of the commonly used antiretroviral therapy (ART) regimens. There are two formulations of tenofovir, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). TDF is more nephrotoxic than TAF.

TDF is a prodrug of tenofovir that can cause AKI, proximal tubular dysfunction, or both in combination. The use of TDF has also been associated with increased risk of CKD in large observational studies [14-16]. (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir disoproxil fumarate' and 'Antiretroviral therapy nephrotoxicity' below.)

The risk of kidney toxicity with TDF has varied across different studies, with estimates ranging from less than 2 percent to as high as 10 percent in one study [17,18]. Although TDF toxicity can present as severe AKI in individual people with HIV, large observational studies have not shown a significant association between TDF and the risk of hospitalized AKI on a population level [12,19].

TAF, which is also a prodrug, achieves similar antiviral efficacy at much lower plasma concentrations of tenofovir and is associated with less kidney toxicity than TDF [20]. (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir alafenamide'.)

•Protease inhibitors – Atazanavir is a protease inhibitor that can cause crystalluria, nephrolithiasis, and AKI. (See "Crystal-induced acute kidney injury", section on 'Protease inhibitors'.)

•Other antiviral agents – Intravenous acyclovir, foscarnet, and cidofovir are drugs used to treat herpes viruses or cytomegalovirus infection. Each of these agents can be associated with the development of AKI, primarily due to acute tubular injury. (See "Crystal-induced acute kidney injury", section on 'Acyclovir' and "Foscarnet: An overview", section on 'Renal insufficiency' and "Cidofovir: An overview", section on 'Toxicity'.)

●Anti-Pneumocystis drugs – Trimethoprim-sulfamethoxazole and, less commonly, pentamidine are agents used to treat Pneumocystis infection. Trimethoprim-sulfamethoxazole can produce interstitial nephritis, while approximately 25 percent of patients treated with pentamidine develop reversible AKI that is likely due to nephrotoxic ATN [7,21-23]. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Drugs'.)

In addition, several antiretroviral agents can interfere with the tubular secretion of creatinine, producing an increase in serum creatinine (and decline in eGFR) without a true decline in kidney function. The most prominent effect has been observed with the pharmacokinetic boosting agent cobicistat and the integrase inhibitors dolutegravir and bictegravir; the increase in serum creatinine with these drugs occurs early and is typically in the range of 0.05 to 0.2 mg/dL [24,25]. (See "Drugs that elevate the serum creatinine concentration", section on 'Decreased secretion'.)

●Urinary tract obstruction – Urinary obstruction is a less common cause of AKI in patients with HIV. Extrarenal obstruction may be caused by urinary stones, malignancy, or infection (eg, tuberculosis, fungal infection). Intratubular obstruction can be caused by the crystallization of certain drugs, such as acyclovir, protease inhibitors (eg, atazanavir, darunavir), sulfadiazine, and foscarnet. The risk of crystal-induced kidney injury is increased with volume depletion, underlying kidney disease, and metabolic perturbations that change urinary pH. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis" and "Crystal-induced acute kidney injury".)

●Rhabdomyolysis – Rhabdomyolysis has been reported in patients treated with certain antiretroviral agents such as zidovudine or some integrase inhibitors (eg, raltegravir) [26-29]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

HIV-specific causes — A number of causes of AKI are specific to patients with HIV:

●HIV-associated nephropathy (HIVAN) – HIVAN, the classic kidney disease associated with HIV infection, is a collapsing form of focal segmental glomerulosclerosis (FSGS). It can present with AKI and nephrotic-range proteinuria but has become a less common cause of AKI with the use of effective ART regimens. HIVAN is also a cause of CKD. HIVAN is discussed in more detail separately. (See "HIV-associated nephropathy (HIVAN)".)

●Immune complex kidney disease – Immune complex kidney diseases in the setting of HIV may present with AKI or CKD. This is discussed in more detail below. (See 'Immune complex kidney disease' below.)

●HIV-associated thrombotic microangiopathy – While HIV-associated thrombotic microangiopathy (TMA) can present with significant AKI [30,31], results of a large observational cohort study suggest that this is a rare complication of HIV infection with the widespread use of effective ART regimens [32]. (See "HIV-associated cytopenias", section on 'Other 'can't miss' diagnoses (TMAs, HLH, HHV8 disorders)'.)

●Immunologic dysfunction-related tubulointerstitial inflammation – Two rare causes of acute tubulointerstitial injury are related to immunologic dysfunction in the setting of HIV:

•Diffuse infiltrative lymphocytosis syndrome (DILS) – DILS is a rare complication of HIV that is due to a persistent expansion of CD8+ T-cells that can infiltrate and damage multiple organs, most commonly the salivary glands but also the lungs, muscles, peripheral nerves, gastrointestinal tract, liver, and kidneys [33,34]. Kidney involvement occurs in approximately 10 percent of patients and manifests as acute tubulointerstitial nephritis, enlarged kidneys, and mild proteinuria [35]. A kidney biopsy is required to distinguish this entity from other causes of interstitial nephritis.

•Immune reconstitution inflammatory syndrome (IRIS) – IRIS describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of ART in patients with HIV. Case reports of kidney involvement with granulomatous interstitial nephritis have been described [36-38]. Clinically, these patients present with a rise in creatinine several months after ART initiation and immune restoration. IRIS-associated granulomatous interstitial nephritis often occurs in the setting of mycobacterial infection. Definitive diagnosis can only be made by kidney biopsy. (See "Overview of immune reconstitution inflammatory syndromes".)

Evaluation of acute kidney injury — The evaluation of AKI among patients with HIV is similar to that for the general population and includes a thorough history and physical examination, examination of the urinalysis and sediment and urine albumin-to-creatinine ratio, and imaging of the kidneys (algorithm 1). In addition, the evaluation should include an assessment for nephrotoxic medications and HIV-specific causes of AKI. (See 'HIV-specific causes' above.)

HIV-associated thrombotic microangiopathy is a rare cause of AKI in this population. However, if there is high index of clinical suspicion for this diagnosis, we obtain a complete blood and platelet count, review the peripheral blood smear for schistocytes, and check serum markers of hemolysis (lactate dehydrogenase and haptoglobin). (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

In patients with AKI of unclear etiology, despite the evaluation described above, a kidney biopsy may be helpful to establish the diagnosis.

More detailed discussions of the general approach to the evaluation of AKI are presented separately:

●(See "Evaluation of acute kidney injury among hospitalized adult patients".)

●(See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)

●(See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis".)

Management of acute kidney injury — In general, the overall management of AKI among patients with HIV is similar to that for the general population. In most cases, management is primarily supportive, although some patients with severe AKI may require kidney replacement therapy. Early consultation with a nephrologist is advised. (See "Overview of the management of acute kidney injury (AKI) in adults" and "Prevention and management of acute kidney injury in children".)

As with all patients who have AKI, medications should be carefully reviewed for appropriate dose adjustments according to the presumed glomerular filtration rate (see "Overview of the management of acute kidney injury (AKI) in adults", section on 'Dosing'). Patients receiving ART as single coformulated tablets may need to be switched to individual agents that can be appropriately dosed for kidney function. In those receiving a tenofovir-containing regimen, the decision to continue a tenofovir-containing regimen should be individualized depending upon the etiology of the AKI and the need for tenofovir. As an example, in a patient with AKI that is thought to be caused by TDF, we would discontinue TDF and transition to another suitable ART regimen.

Disease-specific management issues in patients with HIV include the following:

●Drug-related nephrotoxicity – In patients with HIV who develop drug-related nephrotoxicity (eg, proximal tubulopathy due to TDF or acute tubular necrosis due to amphotericin), infectious disease should be consulted for guidance on modifying the patient’s treatment regimen. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Reduced kidney function'.)

●HIVAN – Patients with HIVAN who are not already receiving ART should initiate ART as soon as possible. Other therapies for those who have proteinuria and/or hypertension may include an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers. The management of HIVAN in patients with HIV is discussed in separately. (See "HIV-associated nephropathy (HIVAN)", section on 'Treatment'.)

●HIV-associated thrombotic microangiopathy – The management of HIV-associated thrombotic microangiopathy includes ART initiation or optimization. Among patients with HIV-associated thrombotic thrombocytopenic purpura (ie, TMA associated with severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13), the management should also include therapeutic plasma exchange [39]. (See "Immune TTP: Initial treatment", section on 'Therapeutic plasma exchange (TPE)'.)

Prognosis of acute kidney injury — As in the general population, the development of AKI increases the risk of morbidity and mortality in patients with HIV. The following examples illustrate an association with both short- and long-term outcomes:

●Inpatient mortality was significantly more frequent among patients with HIV who had AKI than among patients with HIV without AKI in a 2003 sample of hospitalized patients in New York state (27 versus 4 percent) [1]. Dialysis-requiring AKI was also associated with a significantly increased risk of in-hospital mortality among adults with HIV in a nationally representative sample of United States hospital admissions from 2010 (adjusted odds ratio [OR] 2.64, 95% CI 2.04-3.42) [2].

●Long-term mortality is also higher among individuals with HIV who develop AKI. In a national sample of United States military veterans from 1986 through 2006, 17,325 veterans with HIV were hospitalized and survived for at least 90 days after discharge [7]. AKI occurred in 3060 (18 percent); 334 of these patients with AKI also required dialysis. During an average follow-up of 5.7 years after hospital discharge, the patients with HIV who experienced AKI were significantly more likely to die (56 versus 47 percent). End-stage kidney disease (ESKD) and cardiovascular events were also significantly more common among patients with HIV with AKI.

CHRONIC KIDNEY DISEASE

Epidemiology and risk factors for CKD — The prevalence of chronic kidney disease (CKD) in patients with HIV varies depending upon the geographical location, formula used to estimate kidney function, and definition used to define CKD. In a systematic review of studies from 60 countries worldwide, the overall prevalence of CKD was 6.4 percent using the Modification of Diet in Renal Disease (MDRD) formula and 4.8 percent using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [40]. Africa had the highest MDRD-based prevalence at 7.9 percent. One study reported a CKD prevalence of 44 percent in Cameroon using the CKD-EPI formula [41].

Risk factors for incident or progressive CKD in adults with HIV include hepatitis C virus (HCV) coinfection, low CD4 cell count, longer duration of immunosuppression, high HIV viral load, exposure to tenofovir disoproxil fumarate (TDF) and boosted protease inhibitors, severe acute kidney injury (AKI), and traditional CKD risk factors such as diabetes and hypertension [7,14,16,42-48]. (See 'Antiretroviral therapy nephrotoxicity' below.)

Genetic factors also contribute to the risk of CKD among individuals with HIV, particularly those of African descent. Polymorphisms in the apolipoprotein L1 (APOL1) gene, which are strongly linked with African ancestry, are associated with an increased risk of developing HIV-associated nephropathy (HIVAN) [49-52] and CKD [53]. In addition, APOL1 risk variants are associated with a more rapid progression to end-stage kidney disease (ESKD) among patients with non-HIVAN, HIV-related kidney disease [54]. A more detailed discussion of APOL1 and its association with kidney disease is presented separately. (See "HIV-associated nephropathy (HIVAN)", section on 'Pathogenesis' and "Focal segmental glomerulosclerosis: Genetic causes", section on 'APOL1' and "Epidemiology of chronic kidney disease", section on 'Apolipoprotein L1 in African Americans'.)

Causes of chronic kidney disease — The etiology of CKD in patients with HIV includes both traditional CKD risk factors as well as HIV-related disorders. In addition, individuals with viral hepatitis coinfection are also at risk for glomerulonephritis secondary to hepatitis B virus (HBV) or HCV.

Non-HIV-specific causes — The aging cohort of patients with HIV is at increased risk for comorbid kidney disease related to traditional CKD risk factors including diabetes, hypertension, obesity, and recurrent or severe AKI. A discussion of these risk factors is presented separately. (See "Primary care of adults with HIV", section on 'Glucose intolerance/diabetes mellitus' and "Primary care of adults with HIV", section on 'Hypertension' and "Primary care of adults with HIV", section on 'Weight gain'.)

HIV-associated nephropathy — The classic kidney disease of HIV infection, HIVAN, was first described in 1984 in patients with advanced HIV infection. (See "HIV-associated nephropathy (HIVAN)".)

HIVAN is a collapsing form of focal segmental glomerulosclerosis (FSGS) with associated tubular microcysts and interstitial inflammation. HIVAN classically presents with significant nephrotic-range proteinuria and rapidly progressive kidney disease in the setting of normal blood pressure and normal to enlarged kidneys, although the presentation may be less dramatic in the antiretroviral therapy (ART) era. The pathogenesis, clinical manifestations, diagnosis, and treatment of HIVAN are discussed in detail elsewhere. (See "HIV-associated nephropathy (HIVAN)".)

FSGS (NOS) in the setting of HIV — With the use of effective combination ART, there has been a shift away from the classic presentation of HIVAN to a more indolent presentation of slowly progressive kidney disease. These patients present with a slowly rising creatinine and often have heavy proteinuria. Histologically, this is characterized as noncollapsing FSGS and is more often observed in people with HIV receiving ART, who generally have CD4 counts >200 cells/microL and who have undetectable viral loads [27,55-57]. In contrast with HIVAN, tubulointerstitial disease is generally absent on kidney biopsy, and podocyte effacement is less severe. To distinguish this form of noncollapsing FSGS from classic HIVAN, the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference classified this entity as FSGS (not otherwise specified) in the setting of HIV [58].

The roles of HIV infection and ART in the pathogenesis and treatment, respectively, of noncollapsing FSGS are not known. Some data suggest that noncollapsing FSGS is a milder form of HIVAN that is partially treated with ART, although this has not been proven.

Immune complex kidney disease — A large proportion of patients with HIV who have proteinuric kidney disease and suspected HIVAN will have an alternative diagnosis on biopsy [59]. A number of immune complex kidney diseases have been reported in patients with HIV infection, including membranous nephropathy, membranoproliferative and mesangial proliferative glomerulonephritis, "lupus-like" proliferative glomerulonephritis, and immunoglobulin A (IgA) nephropathy [59-64]. Unlike HIVAN, these immune complex kidney diseases often occur in patients who are receiving ART, are virally suppressed, and have a CD4 count >200 cells/microL [59-64]. In addition, a unique immune complex kidney disease with a characteristic "ball in cup" basement membrane reaction was described in a South African biopsy series [65]. The pathogenic relationship between HIV infection and the development of immune complex kidney diseases has not been extensively studied, although a role for viral antigens in circulating immune complexes and deposits has been suggested [61,66].

The natural history and response of immune complex kidney disease to ART have not been well described; the clinical course may vary depending upon the specific immune complex disease. As examples:

●In a case-control study including 751 patients with HIV, those with immune complex kidney disease were predominantly Black patients, and most had advanced HIV disease [67]. The incidence of ESKD in such patients was 32 percent at two years, much lower than that observed in the patients with HIVAN. ART was not associated with improved kidney disease outcomes in patients with immune complex kidney disease.

●In a small series of four patients with HIV-associated IgA nephropathy, the kidney disease followed a benign course similar to that observed in the absence of HIV [66].

●In a retrospective cohort including 42 patients with biopsy-proven HIVAN and 47 patients with alternative histologic diagnoses, Black patients and those with more advanced HIV infection had a higher risk for HIVAN. In addition, there was no evidence of a beneficial role for ART in non-HIVAN kidney diseases, which were associated with slower progression to ESKD regardless of therapy [68].

●A small retrospective study suggests a more aggressive course in patients with immune complex kidney disease resembling lupus glomerulonephritis [69]. In this cohort, 10 of 14 patients progressed to ESKD within one year.

Because the clinical course and response to ART appear to vary across different types of immune complex kidney disease in the setting of HIV infection, it is recommended that these cases be classified and managed based upon the primary histologic lesion [58]. (See 'Disease-specific considerations' below.)

Glomerulonephritis due to viral coinfection — HCV coinfection has been associated with the development of acute and chronic kidney disease in large cohort studies of patients with HIV [1,3,22,42,44]. However, the histologic patterns of kidney disease have not been studied in large populations of coinfected patients. Membranoproliferative glomerulonephritis (MPGN) is strongly associated with HCV infection in the general population and is a common alternative diagnosis in coinfected patients [59,64,70]. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Overview of kidney disease associated with hepatitis C virus infection".)

Treatment of HCV-associated MPGN in the setting of HIV coinfection has not been rigorously studied. With the availability of effective and well-tolerated direct-acting antiviral therapy for HCV, treatment of the underlying HCV infection is now feasible in these cases. (See "Overview of kidney disease associated with hepatitis C virus infection" and "Mixed cryoglobulinemia syndrome: Treatment and prognosis" and "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)

Antiretroviral therapy nephrotoxicity — Treatment with TDF and boosted protease inhibitors has also been associated with glomerular filtration rate (GFR) decline or decreased GFR in several studies, while ART in general appears to slow the rate of kidney function decline. The following studies provide examples:

●In a prospective cohort of 3329 patients who initiated ART under routine clinical care, ART initiation significantly slowed the rate of estimated GFR (eGFR) decline over a median follow-up of 4.8 years (eGFR loss of 1.4 after versus 2.2 mL/min per 1.73 m² per year before initiation) [42]. The incidence of CKD was 3.2 percent; the risk was higher among Black individuals and those with HCV coinfection, lower CD4 cell count, higher HIV viral load, an AIDS diagnosis, and hypertension. The combination of TDF with a boosted protease inhibitor was also associated with a significant increase in the risk of developing an eGFR below 60 mL/min per 1.73 m² but not below 30 mL/min per 1.73 m².

●Several other large cohort studies have also demonstrated an association between exposure to TDF and/or ritonavir-boosted protease inhibitors and moderately decreased GFR [14-16]. In a large European cohort, use of TDF or ritonavir-boosted atazanavir was associated with an eGFR below 70 mL/min per 1.73 m² but not with an eGFR below 30 mL/min per 1.73 m² [16]. The authors speculated that a high rate of TDF discontinuation among those with low GFR may have prevented further GFR decline. Of note, ritonavir-boosted darunavir, a newer protease inhibitor, does not appear to be associated with an increased risk of CKD [71]. Previous studies have not considered the use of cobicistat as an alternative pharmacoenhancer.

Protease inhibitors (such as ritonavir) and cobicistat raise tenofovir levels in the blood, which may explain why GFR decline is more common among people receiving TDF plus protease inhibitors or cobicistat-containing regimens than among those receiving TDF with non-boosted regimens.

Switching from TDF to tenofovir alafenamide (TAF) has been shown to slow eGFR decline and may improve kidney function in some patients. In a prospective study of 3520 participants with HIV, of whom 2404 were switched from TDF to TAF, switching to TAF was associated with increases in eGFR of 1.5 mL/min/1.73 m² in those with a baseline eGFR of 60 to 89 mL/min/1.73 m² , and 4.1 mL/min/1.73 m² in those with a baseline eGFR <60 mL/min/1.73 m² over 18 months [72]. By contrast, eGFR decreased by 5.8 mL/min/1.73 m² with continued use of TDF in individuals with a baseline eGFR <60 mL/min/1.73 m².

Integrase inhibitors have not been associated with the development of CKD among patients with HIV.

Monitoring for chronic kidney disease — Patients with HIV who have comorbid conditions that are risk factors for kidney disease (eg, diabetes, hypertension) should be monitored for the development of CKD similarly to patients without HIV who have these conditions. (See "Early detection of chronic kidney disease", section on 'Who should be tested?' and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Monitoring for increased urinary albumin excretion'.)

We agree with expert guidelines that recommend monitoring and early identification of CKD in patients with HIV [58,73,74]. Individuals with HIV should have their GFR estimated at least twice yearly and should have either a urinalysis or quantitative assessment of urine protein excretion at least once yearly in order to monitor for the development of kidney disease. Such patients whose eGFR has declined by 25 percent or more to a level below 60 mL/min/1.73 m², or who have protein excretion greater than 300 mg/day, should be referred for nephrology evaluation.

GFR should be estimated using a creatinine-based estimate; available data do not support the use of cystatin C alone to estimate GFR in adults with HIV [75,76]. However, in individuals on medications such as dolutegravir or bictegravir, which raise the serum creatinine level, we often check a cystatin C level when there is uncertainty about whether serum creatinine is accurately reflecting GFR. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) GFR estimates, either based on creatinine alone or creatinine plus cystatin C, are the most accurate for use in adults with HIV on stable ART [75,77], while the Cockcroft-Gault creatinine clearance remains the standard of care for drug dosing. CKD is identified by the presence of proteinuria or by an eGFR less than 60 mL/min/1.73 m² for at least three months. (See "Assessment of kidney function" and "Definition and staging of chronic kidney disease in adults".)

Detailed discussions of monitoring patients with HIV are presented elsewhere:

●(See "Primary care of adults with HIV", section on 'Hematologic, renal, and hepatic toxicity'.)

●(See "Patient monitoring during HIV antiretroviral therapy", section on 'ART-associated toxicity'.)

Evaluation of chronic kidney disease — The evaluation of newly identified CKD among patients with HIV is similar to that for the general population and includes an initial assessment of the duration of kidney disease, followed by an evaluation to identify the cause of CKD (algorithm 2). In patients who have heavy proteinuria or who do not have an identifiable cause of CKD based on the initial evaluation, a kidney biopsy may be warranted. This is discussed in detail separately. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults" and "Chronic kidney disease in children: Clinical manifestations and evaluation".)

Certain medications, such as trimethoprim-sulfamethoxazole or dolutegravir, can interfere with tubular secretion of creatinine and cause an increase in the serum creatinine concentration (and decline in eGFR) without a true decrease in kidney function. In patients receiving such medications, measuring a serum cystatin C level can be helpful in determining if kidney function impairment is present. (See "Assessment of kidney function", section on 'eGFR from cystatin C'.)

For patients receiving a tenofovir-containing regimen, it can be difficult to specifically implicate tenofovir as the cause of CKD. The presence of laboratory findings that suggest proximal tubular dysfunction (eg, normoglycemic glucosuria) may increase the suspicion for tenofovir-related kidney injury. However, there are no laboratory findings that definitively exclude the diagnosis of tenofovir nephrotoxicity.

Management issues

General measures for chronic kidney disease — The approach to management of CKD in patients with HIV is similar to that for patients without HIV, as discussed in detail separately. (See "Overview of the management of chronic kidney disease in adults" and "Chronic kidney disease in children: Overview of management".)

Patients with HIV who have CKD should have at least biannual monitoring of eGFR, with medication dose adjustments as needed. The frequency of monitoring should be increased in patients with mildly reduced eGFR (ie, less than 60 mL/min/1.73 m²) who are taking medications that have potential nephrotoxic effects, including the nucleotide analog tenofovir and boosted protease inhibitors [58,73].

Among patients with HIV who have severely increased albuminuria (ie, >300 mg/g), treatment considerations include renin angiotensin system blockade and sodium glucose cotransporter 2 (SGLT2) inhibitors. This approach is similar to that for patients without HIV who have proteinuric CKD. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria'.)

Early referral to a nephrologist is important to coordinate diagnosis and treatment of CKD in patients with HIV, including discussion of the need for dialysis and the timely placement of dialysis access in patients with progressive disease [58,73].

Disease-specific considerations — All patients with HIV should receive ART. Disease-specific management considerations include the following:

●HIVAN – The management of HIVAN in patients with HIV is presented separately. (See "HIV-associated nephropathy (HIVAN)", section on 'Treatment'.)

●FSGS (NOS) in the setting of HIV – The management of non-HIVAN FSGS in patients with HIV is similar to that for patients with secondary causes of FSGS and should focus on supportive measures such as blood pressure control and reduction of albuminuria. (See "Focal segmental glomerulosclerosis: Treatment and prognosis", section on 'Treatment of secondary FSGS or FSGS of undetermined cause'.)

●Immune complex kidney disease – Patients with immune complex kidney disease in the setting of HIV should be managed based upon the primary histologic lesion seen on kidney biopsy:

•Membranous nephropathy. (See "Membranous nephropathy: Treatment and prognosis".)

•IgA nephropathy. (See "IgA nephropathy: Treatment and prognosis".)

•Membranoproliferative glomerulonephritis. (See "Membranoproliferative glomerulonephritis: Treatment and prognosis".)

●Glomerulonephritis due to HCV coinfection – Patients with kidney disease related to HCV infection should be offered anti-HCV therapy. The management of patients with glomerulonephritis due to HCV coinfection (eg, HCV-associated membranoproliferative glomerulonephritis, mixed cryoglobulinemia) is similar to that for patients without HIV who have glomerulonephritis due to HCV infection. These issues are discussed separately. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment" and "Mixed cryoglobulinemia syndrome: Treatment and prognosis" and "Membranoproliferative glomerulonephritis: Treatment and prognosis", section on 'Infections'.)

Management of antiretroviral therapy — Management of ART in persons with HIV and kidney disease depends in part on whether the patient presents with pre-existing kidney disease when ART is initiated or develops kidney disease on therapy.

●For patients who present with preexisting kidney disease (ie, eGFR <60 mL/min/1.73 m²), TDF and atazanavir should be avoided. Selecting an ART regimen for persons with reduced kidney function is presented separately. (See "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions", section on 'Reduced kidney function'.)

However, if a patient needs to be on a regimen that contains tenofovir (eg, if they have HBV coinfection), a TAF-containing regimen can typically be used. The one exception is patients with severely reduced kidney function who are not on dialysis (eGFR <30 mL/min/1.73m²). Such patients should generally be managed in consultation with an infectious disease specialist. (See "Treatment of chronic hepatitis B in patients with HIV", section on 'If tenofovir should not be used'.)

●Some patients will develop CKD on therapy. If patients develop a decline in eGFR to <60 mL/min/1.73 m², TDF and atazanavir should be changed to alternative medications whenever possible. If tenofovir needs to be included (eg, resistance or chronic HBV), the patient can take a TAF-containing regimen as long as the eGFR is >30 mL/min/1.73 m². In a study of 31 patients who developed proximal tubulopathy on TDF, there was no evidence of recurrence of kidney injury after treatment with TAF for two years [78]. A detailed discussion of switching regimens is presented in a separate topic review. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

Dialysis — Both hemodialysis and peritoneal dialysis can be considered in patients with HIV who develop ESKD. Analyses of data from the United States Renal Data System (USRDS) have demonstrated similar outcomes in patients with HIV and ESKD treated with hemodialysis or peritoneal dialysis, as well as significant improvements in survival in the ART era. Issues relating to HIV and dialysis are discussed in detail separately. (See "Human immunodeficiency virus and dialysis".)

The dosing of ART in patients on dialysis is discussed elsewhere. (See "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions", section on 'Patients on hemodialysis' and "Overview of antiretroviral agents used to treat HIV", section on 'Timing of doses for patients on hemodialysis'.)

Kidney transplantation — Kidney transplantation is a safe alternative to dialysis in patients with preserved immune function and undetectable viral load. Based on promising results from South Africa, several transplant centers in the United States are now investigating the safety of kidney transplantation from donors with HIV [79]. Issues relating to HIV and kidney transplantation are discussed separately. (See "Kidney transplantation in patients with HIV".)

ELECTROLYTE DISORDERS — A variety of electrolyte disorders can occur in patients with HIV, which may be due to HIV-associated complications or medications used to treat HIV or its complications. These issues are discussed in detail elsewhere. (See "Electrolyte disturbances with HIV infection".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Acute kidney injury – Patients with HIV have an increased risk of developing acute kidney injury (AKI) compared with patients without HIV.

•Causes of AKI – In persons with HIV, causes of AKI are often similar to those in the general population, including prerenal kidney disease, acute tubular necrosis, acute interstitial nephritis, medication toxicity, urinary tract obstruction, and rhabdomyolysis.

Causes specific to patients with HIV include HIV-associated nephropathy (HIVAN), immune complex kidney disease, HIV-associated thrombotic microangiopathy, and immunologic dysfunction-related tubulointerstitial inflammation. (See 'Causes of acute kidney injury' above.)

•Evaluation of AKI – The evaluation of AKI among patients with HIV is similar to that for the general population and includes a thorough history and physical examination, examination of the urinalysis and sediment and urine albumin-to-creatinine ratio, and imaging of the kidneys (algorithm 1). In addition, the evaluation should include an assessment for nephrotoxic medications (table 1) and HIV-specific causes of AKI. (See 'Evaluation of acute kidney injury' above.)

•Management of AKI – In most cases, management of AKI is primarily supportive, although some patients with severe AKI may require kidney replacement therapy. Early consultation with a nephrologist is advised. Disease-specific management (eg, the use of ART and angiotensin-converting enzyme inhibitor or angiotensin receptor blockers for people with HIVAN) is discussed above. (See 'Management of acute kidney injury' above.)

●Chronic kidney disease (CKD)

•Causes of CKD – The etiology of CKD in patients with HIV includes both traditional CKD risk factors (diabetes, hypertension, obesity, recurrent or severe AKI) as well as HIV-related disorders, such as HIVAN, noncollapsing focal segmental glomerulosclerosis (FSGS), immune complex kidney disease, glomerulonephritis due to viral coinfection, and antiretroviral therapy (ART) nephrotoxicity (particularly with tenofovir disoproxil fumarate [TDF] and boosted protease inhibitors). (See 'Causes of chronic kidney disease' above.)

•Monitoring for CKD – Patients with HIV who have comorbid conditions that are risk factors for kidney disease (eg, diabetes, hypertension) should be monitored for the development of CKD similarly to patients without HIV who have these conditions. Individuals with HIV should otherwise have their glomerular filtration rate (GFR) estimated at least twice yearly and should have either a urinalysis or quantitative assessment of urine protein excretion at least once yearly in order to monitor for the development of kidney disease. Such patients whose eGFR has declined by 25 percent or more to a level below 60 mL/min/1.73 m², or who have protein excretion greater than 300 mg/day, should be referred for nephrology evaluation. (See 'Monitoring for chronic kidney disease' above.)

•Evaluation for CKD – The evaluation of newly identified CKD among patients with HIV is similar to that for the general population and includes an initial assessment of the duration of kidney disease, followed by an evaluation to identify the cause of CKD (algorithm 2). In patients who have heavy proteinuria or who do not have an identifiable cause of CKD based on the initial evaluation, a kidney biopsy may be warranted. (See 'Evaluation of chronic kidney disease' above.)

•Management issues

-General measures – Management of CKD in patients with HIV is similar to that for patients without HIV. (See "Overview of the management of chronic kidney disease in adults" and "Chronic kidney disease in children: Overview of management".)

Patients with HIV who have CKD should have at least biannual monitoring of eGFR, with medication dose adjustments as needed. The frequency of monitoring should be increased in patients with mildly reduced eGFR (ie, less than 60 mL/min/1.73 m²) who are taking medications that have potential nephrotoxic effects. (See 'General measures for chronic kidney disease' above.)

-Disease-specific considerations – All patients with HIV should receive ART. Disease-specific management considerations are discussed above. (See 'Disease-specific considerations' above.)

-Management of ART – For patients with reduced kidney function, we avoid TDF and atazanavir whenever possible. Selecting an ART regimen for persons with reduced kidney function is presented separately. (See "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions", section on 'Reduced kidney function' and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Reduced kidney function'.)

-Kidney replacement therapy – Both hemodialysis and peritoneal dialysis can be considered in patients with HIV who develop end-stage kidney disease (ESKD). Kidney transplantation is a safe alternative to dialysis in patients with preserved immune function and undetectable viral load. (See 'Dialysis' above and 'Kidney transplantation' above.)

●Electrolyte disorders – A variety of electrolyte disorders can occur in patients with HIV, which may be due to HIV-associated complications or medications used to treat HIV or its complications. (See "Electrolyte disturbances with HIV infection".)