Table 6.
Controversies, knowledge gaps, and areas for future research
| Renal pathology |
| • What is the spectrum of renal pathology in the setting of HIV infection in the current era and in diverse patient populations? |
| • How do pathologic features correlate with the duration of ART, HIV viral load, racial and geographic origin, and APOL1 risk allele genotype? |
| • What is the relative contribution of de-differentiated podocytes versus parietal epithelial cells to the glomerular epithelial cell hyperplasia seen in HIVAN? |
| • What are the roles of specific HIV transcript expression in promoting proliferation and possible transdifferentiation of podocytes and parietal epithelial cells, and in mediating the tubular phenotype of cell cycle arrest and microcyst formation? |
| • What is the pattern of HIV viral transcript expression in specific renal cell types and tissue compartments in FSGS (NOS) and other non-HIVAN lesions in the setting of HIV? |
| • Is FSGS (NOS) in the setting of HIV representative of attenuated or partially treated HIVAN? |
| • How can immune complex disease that is causally related to HIV infection be distinguished from coincident disease? |
| • Can HIV infection of renal dendritic cells, infiltrating monocyte/macrophages, or intrinsic renal epithelial cells produce a viral reservoir that is capable of reactivation? |
| • What is the composition of the inflammatory infiltrates in HIV-related tubulointerstitial disease? |
| Genetics/ Genomics |
| • What is the prevalence of APOL1 risk alleles among ethnic and tribal populations in Sub-Saharan Africa, particularly in central and southeastern Africa? |
| • What is the prevalence of APOL1 risk alleles in African admixed populations as a consequence of the African diaspora in Central and South America and in the Caribbean? |
| • What other genes or viral or environmental factors cause HIVAN in 30% of individuals with 0 or 1 APOL1 risk alleles? Why isn’t HIVAN observed more frequently in other populations lacking APOL1 risk alleles? |
| • Why do APOL1 gain-of-function variants show recessive inheritance? |
| • Is a single copy of APOL1 G1 or G2 sufficient to cause HIVAN in a setting of HIV infection? |
| • What are the genetic and environmental factors which affect penetrance of APOL1 and does this differ by ethnicity or ancestry? |
| • What is the role of APOL1 in children with HIV infection? |
| • What are the mechanisms by which APOL1 precipitates kidney disease? Do these mechanisms differ in the setting of HIV infection? |
| • Is APOL1 an initiator of HIVAN or a progression factor? |
| • What are the public health implications of APOL1 in resource-limited settings? |
| Antiretroviral therapy and nephrotoxicity |
| • What is the clinical significance of TDF-induced sub-clinical renal tubular dysfunction, and what is the value of monitoring for low-molecular weight proteinuria and reduced phosphate reabsorption in patients on TDF? |
| • What is the rate of TDF nephrotoxicity in individuals without access to regular kidney function monitoring, including HIV-negative individuals taking TDF to prevent HIV infection? |
| • What is the long-term renal safety of TAF in individuals with a history of TDF-associated nephrotoxicity, CKD, or relevant comorbidities? |
| • What is the long-term safety of TAF in children, particularly with respect to bone health? |
| • Would epidemiologic studies linking ritonavir-boosted protease inhibitors to decreased eGFR yield similar results with cystatin C-based eGFR estimates? |
| Management of CKD and ESKD |
| • What are the optimal strategies for assessing and monitoring kidney health among ART-treated adults and children in resource-rich and resource-limited settings? |
| • Are existing CKD risk scores developed in HIV-positive US and European populations valid in other populations? |
| • How well do creatinine-based eGFR estimates predict true GFR in ART-treated individuals, especially those on ART that interferes with creatinine secretion and in sub-Saharan African populations? |
| • What is the role of serum cystatin C, alone or in combination with creatinine, in evaluating kidney function in specific clinical contexts, such as the use of ART that interferes with creatinine secretion? |
| • What is the clinical utility of novel urine biomarkers of kidney injury in assessing and monitoring kidney health? |
| • Are clinical guidelines for diabetes, hypertension, and cardiovascular disease developed in the general populations effective in preventing CKD onset and progression in HIV-positive individuals? |
| • Do ACE inhibitors and ARBs confer similar renoprotective effects among HIV-positive individuals with CKD as in the general population? |
| • What is the impact of tuberculosis co-infection and its treatment on the risks of CKD development and progression among HIV-positive individuals? |
| • What is the role of adjunctive therapy with corticosteroids or immunosuppressive therapy in patients with HIVAN or other kidney disease that may be causally related to HIV infection? |
| • What is the role of HIV infection in immune complex kidney disease, and what is the optimal therapy for specific immune complex diseases in this setting? |
| • Has the epidemiology of acute kidney injury changed in the era of modern ART, and what is the impact on CKD risk in the setting of HIV? |
| • What is the optimal antiviral therapy for HBV or HCV co-infection with regards to efficacy and safety in HIV-positive individuals? |
| • Does treatment of HBV or HCV co-infection impact CKD prognosis? |
| • How does the peritonitis risk among ART-treated HIV-positive patients undergoing peritoneal dialysis |
| compare to that of their HIV-negative counterparts? |
| • Are existing treatment guidelines for catheter-related infections developed in HIV-negative populations effective among HIV-positive patients with ESKD? |
| • What are the optimal strategies for anemia and mineral-bone disease management in the HIV-positive population with CKD or ESKD? |
| Kidney Transplantation |
| • Among HIV-positive patients being considered for kidney transplantation, what is the optimal timing of HBV or HCV treatment relative to kidney transplantation? This is particularly important based on the worse post-transplant outcomes among recipients with HIV-HCV co-infection. |
| • What is the optimal induction therapy for highly sensitized HIV-positive transplant recipients? |
| • What are the optimal ART and immunosuppressive regimens for HIV positive kidney transplant recipients? |
| • What is the optimal strategy for selecting and matching potential HIV-positive organ donors and recipients? |
| • What are the long-term implications of HIV-to-HIV kidney transplantation on patient and allograft outcomes and HIV disease course? |
ACE, angiotensin-converting enzyme; APOL1, apolipoprotein L1; ARB, angiotensin receptor blocker; ART, antiretroviral treatment; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; GFR, glomerular filtration rate; HBV, hepatitis B virus; HCV, hepatitis C C; HIV, human immunodeficiency virus; HIVAN, HIV-associated nephropathy; NOS, not otherwise specified; TDF, tenofovir disoproxil fumarate; US, United States.