Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Abstract

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge of the unique HIV-related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals.

Keywords: APOL1; CKD progression; HIV; antiretroviral therapy; immune complex kidney disease; podocytopathy; renal pathology.

Figure 1. Classic HIVAN and FSGS (NOS) in the setting of HIV

Classic HIVAN (A–E) shows typical global collapse of the glomerular tuft with loss of luminal patency and hypertrophy and hyperplasia of the overlying glomerular epithelial cells, some of which contain intracytoplasmic protein resorption droplets. (A, Jones methenamine silver x400; B, Masson trichrome, x400). The tubulointerstitium shows focal tubular microcysts containing glassy casts, associated with tubular atrophy, interstitial fibrosis and inflammation (C, Masson trichrome, x200). There is marked foot process effacement overlying the collapsed capillaries associated with glomerular epithelial cell hyperplasia forming a pseudocrescent. Some glomerular epithelial cells contain numerous intracytoplasmic protein resorption droplets. No immune type electron dense deposits are seen. (D, electron micrograph x4000). The glomerular endothelial cells contain multiple intracytoplasmic tubuloreticular inclusions (arrows). Foot processes are effaced. (E, electron micrograph, x40,000). FSGS (NOS) in the setting of HIV shows discrete segmental scars with segmental adhesions to Bowman’s capsule. No collapsing features or glomerular epithelial cell hyperplasia are identified. (F, H&E, x400).

Figure 2. Tenofovir nephrotoxicity

Acute tenofovir nephrotoxicity is characterized by irregular proximal tubular profiles with atypical, irregular lining epithelial cells and mild interstitial edema (A, H&E, x200). The atypical proximal tubular cells display loss of brush border, marked irregularity of tubular epithelial height and shape, focal shedding of cytoplasmic fragments, and enlarged atypical nuclei with prominent nucleoli (B, H&E, x400). Chronic nephrotoxicity displays increased separation of the irregular proximal tubules by interstitial fibrosis and mild inflammation with focal tubular atrophy (C, Masson trichrome, x200). The tubules show focal loss and flattening of lining epithelium leaving some desquamated tubular basement membranes, as well as prominent epithelial simplification and irregularity with atypical nuclei. There is intervening interstitial fibrosis and mild inflammation, without tubulitis (D, Masson trichrome, x400). The characteristic features are focal giant mitochondria with few residual peripheral cristae (arrow) within the proximal tubular epithelial cells, as well as cytoplasmic swelling with disruption of brush border, (E, electron micrograph x8000). In some cases, the dysmorphic mitochrondria exhibit irregular size and shape with bizarre patterning of their cristae (F, electron micrograph x12,000).

Figure 3. Recommendations at starting ART

^*if suitable alternatives available ART, antiretroviral therapy; ATV, atazanavir; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate (CKD-EPI, expressed in ml/min/1.73 m²); IDV, indinavir; LPV, lopinavir; TDF, tenofovir disoproxil fumarate; uPCR, urine protein:creatinine ratio (values above are in mg/g; multiply by 0.10 to obtain values in mg/mmol).

Figure 4. Risk factors and underlying etiologies of CKD in HIV-positive individuals

APOL1, apolipoprotein L1; ABCC, ATP-binding cassette transporter proteins; ARV, antiretrovial; CKD, chronic kidney disease; FSGS (NOS), focal segmental glomerulosclerosis, not otherwise specified; GN, glomerulonephritis; HIV, human immunodeficiency virus; HIVAN, HIV-associated nephropathy.

Figure 5. Recommendations for kidney disease screening and monitoring in HIV-positive adults

^*Urinalysis should be performed in all HIV-positive individuals to detect worsening or new onset of proteinuria or hematuria. Where feasible, quantification of proteinuria (spot urine albumin:creatinine or protein:creatinine ratio) should also be performed. ^**More frequent monitoring is recommended in persons who are clinically unstable, severely immunocompromised, or viremic. AKI, acute kidney injury; ART, antiretroviral therapy; CKD, chronic kidney disease; CKD-EPI, CKD Epidemiology Collaboration; GFR, glomerular filtration rate; HIV, human immunodeficiency virus; KDIGO, Kidney Disease: Improving Global Outcomes; TDF, tenofovir disoproxil fumarate.