Kidney Transplantation in HIV Positive Patients: Current Practice and Management Strategies

Abstract

Background

HIV positive patients had been successfully transplanted for the last 15 years and the donor pool had successfully been expanded to also include HIV positive donors.

Methods

We aimed to evaluate the effectiveness of transplantation in HIV positive patients and highlight some of the important issues reported in the literature. We pooled clinical data form different cohorts in order to show some of the common issues encountered in HIV positive transplantation. Furthermore we searched MEDLINE via PubMed, EMBASE, Cochrane CENTRAL to create a comprehensive table for current evidence for different issues currently encountered when transplanting HIV positive patients.

Results

We included data from 19 cohort studies and reported on outcomes of the current HIV positive transplant programs. We made recommendations based on personal experience as well as the experience reported in the literature regarding rejection, opportunistic infection and HIV associated nephropathy. Opportunistic infections and malignancies are not a major problem for this population group.

Conclusions

HIV positive patients encounter very specific issues after transplantation, specifically related to drug interactions and higher rejection rates. When utilizing HIV positive donors, the recurrence of HIV Associated nephropathy in the graft kidney is an issue which can be important. Despite some issues with high rejection rates, HIV positive patients have similar results to HIV negative patients post transplantation.

INTRODUCTION

Chronic kidney disease (CKD) secondary to Human Immunodeficiency Virus (HIV) infection is a common problem. HIV-Associated Nephropathy (HIVAN) is most prevalent in patients who receive antiretroviral therapy (ART) late after initial diagnosis, and is a major cause for CKD in developing countries¹. In these patients, high rates of infection-related nephropathies and a limited capacity for secondary prevention result in more rapid progression to organ failure than experienced in high income countries. However, HIV positive patients also suffer from CKD secondary to non-communicable diseases, in particular diabetes and hypertension. HIV-related CKD is likely to be responsible for a significant burden of CKD in the African region – at least 400 cases per million population per year.² It has become the third most common cause of ESRD in young people of African descent in the US.³

Estimating the burden of CKD in HIV-positive patients is important when considering the allocation of resources including dialysis, availability of deceased and living donor organs, and transplantation. It is important to understand the benefits of transplantation in the HIV infected population in the context of : (i) the underlying burden of organ failure and its risk factors, irrespective of current treatment availability or eligibility criteria; (ii) the cost and efficacy of treatment for HIV patients with CKD; and (iii) the current outcomes for HIV patients with different treatment modalities available to them. Because the improved quality of life and better long-term prognosis of a HIV positive patient, the focus for treatment for these patients have moved to transplantation rather than dialysis over the last 10 years.⁴

Pathophysiology of HIV and the kidney and the impact on treatment options

The spectrum of renal pathology in HIV-positive individuals is diverse, including lesions directly related to intrarenal HIV gene expression and lesions related to co-morbidities, drug effects, immune dysregulation, and other co-infections (Table 1).⁵ Podocytopathy or immune complex-mediated glomerular disease are two common manifestations of HIV in the kidney. The podocytopathy can manifest as focal segmental glomerulosclerosis (FSGS) or minimal change disease and diffuse mesangial hypercellularity.^{6, 7} Because of the direct impact of the virus on the kidney as well as the associated immune response, HIV positive patients are more suspectable to CKD than HIV negative patients. This leaves the medical community with a responsibility to address treatment options for this unique population. In South Africa a transplant program utilizing HIV-positive donors was started in 2008.^{8, 9} In the USA transplant programs had been using HIV negative donors for approximately two decades and more recently HIV positive donors had also been utilized as part of the Hope Act.^10–12

Table 1.

Pathological classification of HIV-related kidney diseases

I. Glomerular Dominant* Podocytopathies (all characterized by extensive foot process effacement)** Classic HIVAN FSGS (NOS) in the setting of HIV Minimal change disease in the setting of HIV Diffuse mesangial hypercellularity in the setting of HIV Other podocytopathy in the setting of HIV Immune complex-mediated glomerular disease* IgA nephropathy in the setting of HIV Lupus-like glomerulonephritis in the setting of HIV Lupus nephritis in the setting of HIV Membranous nephropathy in the setting of HIV Indicate whether HBV positive, HCV positive, PLA2R positive (should not preclude workup for other secondary causes) Membranoproliferative pattern glomerulonephritis in the setting of HIV Indicate whether HCV positive (should not preclude workup for other secondary causes) Endocapillary proliferative and exudative glomerulonephritis in the setting of HIV Post-streptococcal, staphylococcal-associated, other Fibrillary or immunotactoid glomerulonephritis in the setting of HIV Other immune complex disease in the setting of HIV

II. Tubulointerstitial Dominant* Tubulointerstitial injury in the setting of classic HIVAN Hyaline droplet tubulopathy Tubular microcysts Tubulointerstitial inflammation Acute tubular injury/ acute tubular necrosis Ischemic Toxic (associated with ART vs other) Drug-induced tubulointerstitial nephritis (other than ART) Antibiotics Proton pump inhibitors NSAIDs Other Direct renal parenchymal infection by pathogens (bacterial, viral, fungal, protozoal, etc.) Immunologic dysfunction-related tubulointerstitial inflammation Diffuse infiltrative lymphocytosis syndrome (DILS) Immune restoration inflammatory syndrome (IRIS) Other tubulointerstitial inflammation in the setting of HIV

III. Vascular Dominant* Thrombotic microangiopathy in the setting of HIV Arteriosclerosis

IV. Other, in the setting of HIV infection Diabetic nephropathy Age-related nephrosclerosis

^*Indicate the likelihood of HIV causality

^**Indicate association with APOL1 risk allele genotype

ART, antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; FSGS, focal segmental glomerulosclerosis; HIV, human immunodeficiency virus; HIVAN, HIV-associated nephropathy; NSAID, nonsteroidal anti-inflammatory drug.

Patient selection for HIV positive transplantation

HIV positive patients should be selected for transplantation according to standard selection criteria, similar to HIV negative transplant recipients. Additional recommendations, specific to HIV, include that the patient should be virally suppressed (undetectable viral load) and be on a stable ART regimen for at least 3 months before the date of the transplant. Ideally the patients must have a CD4 count above 200 cells/mm³, but patients with lower CD4 counts have been transplanted successfully in the past.¹³ The transplantation of recipients with low, but detectable levels of HIV remains a contentious issue. Some programs are moving forward with transplantation in this cohort.¹⁴ The majority of clinicians will accept patients for transplantation with a temporary viral load increase that is less than 200cps/ml. Nonetheless, since this may represent low grade replication, transplantation of HIV positive recipients with viral loads less the 200 cps/ml should be limited to centres with a broad experience in the transplantation and management of the HIV infected recipient.

Only patients with fully treated tuberculosis should be considered for transplantation. For patients who are being treated for a positive purified protein derivative (PPD) skin test, transplantation can move forward prior to completion of therapy, provided that the prophylactic treatment is completed post transplant. Patients with opportunistic infections and neoplasms without effective medical therapy are generally excluded (i.e. progressive multifocal leukoencephalopathy (PML), chronic intestinal cryptosporidiosis). Visceral and systemic Kaposi’s sarcoma are no longer contraindicated, as long as the disease is successfully eradicated with the use rapamycin.¹⁵ All potential recipients should routinely be screened for tuberculosis, syphilis and hepatitis C pre-transplant. Similarly, in places or patients with epidemiologic risk, strongyloidiasis screening may be warranted. Treatment/screening for co-infection for HBV/HCV should be done prior to transplant.

Donor selection for HIV positive patients

Because of excellent long-term outcomes, HIV patients should have access to HIV negative living/deceased donors that become available to them. In the case of using HIV positive deceased donors, specific attention should be given to other infections that occur commonly in these donors and particular attention should be given to the risk of donor derived infections like latent tuberculosis and strongyloidiasis in endemic areas. Screening for sexually transmitted diseases such as syphilis, West Nile Virus and Chagas parasitic disease are important.

Post-transplant infection screening, prophylactic therapy and vaccinations against common infections

Specific infection screening considerations in HIV positive transplantation

Screening considerations for Paediatric transplant patients after transplantation

In paediatric patients who received a positive Epstein-Barr virus (EBV) donor, but tests negative for EBV before the transplant, EBV viral load monitoring should be done post-transplant to prevent an opportunistic EBV infection. This is generally not done in adults.

HPV screening post transplantation

HPV-related cervical and anorectal disease, already accelerated in people with HIV infection, may be exacerbated by post-transplant immunosuppression. It has become apparent that close follow-up with anal and cervical PAP smears is particularly important in the HIV positive recipient, and early detection of atypical cells with aggressive treatment can prevent the need for a major surgical resection.¹⁶

Prophylactic therapy

Prophylaxis against fungal infections, Pneumocystis pneumonia (PCP), and Cytomegalovirus infection (CMV) is similar to regimens used at most centres for HIV negative recipients. A summary of prophylactic therapy is presented in Table 2.

Table 2:

Prophylactic therapy recommended for HIV positive recipients of solid organ transplants

Infection	Recommended prophylactic therapy
Pneumocystis Pneumonia (PCP)	PCP prophylaxis with Co-Trimoxazole should start immediately post-transplant and continued for 1 year at the discretion of the treating physician. An alternative would be Dapsone. If G6PD negative Atovaquone is recommended. Some centres use inhaled Pentamidine monthly as an alternative approach.
Toxoplasmosis	Trimethoprim Sulphamethoxazole (TMP-SMX) prophylaxis should be continued for 1 year at the discretion of the treating physician. An alternative would be Dapsone + Pyrimethamine + Leucovorin if allergic to TMP-SMX.
Cytomegalovirus (CMV)	Prophylaxis should continue for 3–6 months after the transplant. Oral valgancyclovir is recommended for 3–6 months after transplant and should be considered again during the treatment of acute rejection for 1–3 months following completion of acute rejection therapy. Donor positive, recipient negative patients should continue prophylaxis for 6 months. Donor negative recipient negative can get Acyclovir as an alternative.
Candidiasis	Centre-specific approach, but most centres use prophylaxis with fluconazole 100mg once a week or mycostatin swish/swallow for the first 2– 3 months after transplant.
Tuberculosis	In endemic areas all patients receive prophylaxis with INH for 6–12 months after transplant. This can be continued at the discretion of the treating physician.
MAC prophylaxis	Azithromycin is initiated when the CD4 counts drop below 50 cells/mm3 In the general public, if ART is going to be started in a patient with a low CD4 count, clinicians often choose to withhold MAC prophylaxis. In the light of this, a transplant patient with a CD4 count below 50, but with adequate virological control might not need MAC prophylactic therapy.
Coccidioidomycosis	Fluconazole is used in endemic areas for 6 months after transplant

Vaccinations prior to transplant

Pneumococcal Polysaccharide Vaccine (PPSV) and Pneumococcal Conjugate Vaccine (PCV) should be given to all patients on the waiting list pre-transplant. Hepatitis A&B immunity should be checked, and if a patient is not immunized, this vaccine should be given before the transplant. Influenza vaccine should be given once yearly. Herpes Zoster vaccination (Shingrix vaccine) is usually given pre-transplant in selected high-risk patient groups, especially patients over 50 years old. Human Papilloma Virus (HPV) vaccine should be given in selected patients, usually under the age of 45 years. All patients have to be up to date with tetanus, diphtheria, pertussis (DPT) as well as measles, mumps and rubella (MMR) vaccinations before transplantation.

Vaccinations post-transplant

Annual influenza vaccination is recommended. It is usually not recommended to use live virus vaccine post-transplant. Therefore MMR should not be given post-transplant. It is recommended to wait 3 to 6 months after transplant before giving vaccines. When COVID-19 vaccines become available, these should be administered as per guidelines that will be dependent on characteristics of the developing vaccines. If a patient received treatment for rejection, vaccination should be avoided for 6 months following treatment.

Common management issues and condition specific considerations in HIV positive kidney transplant recipients

Loss of HIV control and progression to advanced HIV have not been observed in the larger series of HIV positive patients following transplantation and immunosuppression, provided they had good viral control and were maintained on a stable antiretroviral regimen pre-transplant.¹⁰ Although opportunistic infections have been observed in this cohort, the incidence has not been more frequent than in the HIV negative cohort.¹⁰

Several reports and case studies in the literature highlight both issues/complications as well as excellent outcomes when transplanting HIV positive patients. A summary of clinical outcomes reported in the literature after renal transplantation in HIV positive recipients is depicted in Table 3. In most centres HIV positive patients had been transplanted with HIV negative living and deceased donors. Only one centre had reported longterm outcomes using HIV positive deceased donors with several new centres now embarking on this practice as part of the HOPE act in the USA as well as some centres in Europe.^{10, 12, 17}

Table 3:

Specific clinical outcomes reported in the literature in HIV positive patients receiving solid organ transplants

Organ system or Condition	Assessment/reported outcome
Infections:
Opportunistic infections in general10	This study compared matched HIV negative to HIV positive recipients using SRTR registry data. There were no recurrent opportunistic infections in recipients with a pretransplant history, and opportunistic infection history was not associated with survival. There were five esophageal and one bronchial candidiasis, two Pneumocystis jirovecii pneumonia (PCP) and one cryptosporidiosis. Sixty-nine (55%) liver and 75 (50%) kidney recipients experienced 215 and 197 non-opportunistic infections requiring hospitalization, respectively. Half occurred within 6 months post-transplant. Among cultured liver recipient infections, 81% were bacterial, 7% fungal, 5% viral and 1% protozoal.
Opportunistic infections in general34	The rate of incidence of post-transplant infections was 23.58 and 26.98/100 patient-years, in HIV-infected and HIV-negative groups. In HIV-infected KT recipients, bacterial infections were the most frequent (67.7%), followed by viral (14.7%) and fungal and parasitic infections (8.8%). Similar trends were seen in the control group. Incidence of opportunistic infections was similar in HIV-infected KT recipients and controls (38.2 vs. 26.5%; p = 0.44). There were three post-transplant HIV reactivations in two patients, secondary to poor adherence to medication.
Fungal infection35	Radiologically, HIV patients had significantly more areas of diffuse lung affection (81% HIV vs. 25% RTR; p = 0.02), more ground glass nodules 5–10 mm (69% vs. 4%; p = <0.001) and enlarged hilar lymph nodes were found only in HIV patients (44%).
Fungal infection36	Case study reporting Mucormycosis in HIV-infected patients who underwent SOT.
Tuberculosis37	Central nervous system (CNS) tuberculosis (TB) is a devastating infection with high rates of morbidity and mortality worldwide and may manifest as meningitis, tuberculoma, abscess, or other forms of disease. Immunosuppression, due to either human immunodeficiency virus infection or solid organ transplantation, increases susceptibility for acquiring or reactivating TB and complicates the management of underlying immunosuppression and CNS TB infection. This review summarizes clinical presentation and outcomes in immunocompromised patients with an increased mortality reported for SOT patients (40% versus 13% in non-SOT patients).
Drug interactions and its impact
Drug interactions38	Review article that reports improved results with integrase strand transfer inhibitor-based antiretroviral regimens compared to protease and non-nucleoside reverse transcriptase inhibitors.
Drug interactions39	A review of 332 recipients. PI-based regimens were associated with a 1.8-fold increased risk of allograft loss with the greatest risk observed in the first post transplantation year and a 1.9-fold increased risk of death as compared to non-PI regimens
Drug interaction and impact on rejection40	Single center study reporting biopsy-proven rejection at 38%, 38%, and 40.5% at 1-, 2-, and 3-year time points and 92% of episodes were acute rejection. At these time points, rejection rates were significantly higher with boosted PI HAART regimens compared to other HAART regimens, 59% vs 24%.
Drug interaction and impact on rejection41	Report on 50 patients where cumulative rejection rates at 12 and 36 months were 41% and 54% in the PI group vs 52% and 86% in the non-PI group. At last follow-up, the overall risk of acute rejection in the PI group was 46% lower compared with the non-PI cohort.
Rejection
Rejection rates42	Registry based study looking at 516 HIV-positive SOT patients. HIV SOT patients had a twofold higher risk of AR. HIV-positive patients receiving ATG induction had a 2.6-fold lower risk of AR than those receiving no antibody induction. HIV-positive patients receiving sirolimus-based therapy had a 2.2-fold higher risk of AR than those receiving calcineurin inhibitor-based regimens.
Immunological subsets in HIV positive population43	Compared to nontransplanted patients, HIV-LT displayed significantly increased frequency of T CD8+ cells, lower percentage of T CD4+ cell, and lower number of nonclassic TH1, TH1/17 cells and naive T CD4+ regulatory cells (Tregs). Healthy controls showed increased numbers of B cell subsets and decreased percentage of T effector subpopulations compared to HIV-LT. Compared to HIV-positive patients, healthy controls had higher B cells, NK cells, CD4(+) T cells, naive CD4+ Tregs but lower CD8(+) T cells, effector Tregs, CD8(+) Tregs, and all T effector cell subsets.
Surgical risk factors
Surgical complications44	The rates and outcomes of surgical complications are similar to what has been observed in the non-HIV setting in carefully selected HIV-infected liver and kidney TX recipients.
Malignancy risk
Kaposi sarcoma15	In HIV positive patients on ART the prevalence of Kaposi sarcoma is between 0.18% and 0.46%, in transplanted patients these values increase to 0.50 – 0.66%.
Cancer/Malignancy45	The risk for the development of new cancer cases was higher among people with HIV (SIR=4, IC95% 3.78–4.24) and who received organs (SIR=3.28, IC95% 3.06–3.52) when compared with the general population
Cancer/Malignancy46	The risk of recurrent or de-novo malignancy after solid-organ transplantation in HIV patients is low. HPV-related neoplasia, however, requires further study.
Graft survival
Graft Loss	Compared with HIV-negative controls, HIV-infected recipients had significantly lower 5-year (75.3% versus 69.2%) and 10-year (54.4% versus 49.8%) post-transplant graft survival that persisted when censoring for death.
Patient survival
Patient survival10	Thymoglobulin use within first week following transplant [HR 3.5 (95% CI 1.3, 9.1), P.0.01] and higher age [HR 1.7 (95% CI 1.1, 2.6) per decade, P.0.01] were associated with kidney recipient mortality
Patient survival.47	This study compared the outcomes of HIV-TR recipients with controls identified from the Scientific Registry of Transplant Recipients (SRTR). HIV-positive kidney recipients experienced similar outcomes as their HIV-negative counterparts approximately 5 years posttransplant in all control analyses. HIV/HCV coinfected recipients had worse survival compared with HIV-negative/HCV-infected controls
Patient survival and graft loss24	A total of 150 patients underwent kidney transplantation; survivors were followed for a median period of 1.7 years. Patient survival rates at 1 year and 3 years were 94.6% and 88.2 stocke %, respectively, and the corresponding mean graft-survival rates were 90.4% and 73.7%. In general, these rates fall somewhere between those reported in the national database for older kidney-transplant recipients (>/=65 years) and those reported for all kidney-transplant recipients.
Patient survival and graft loss using HIV positive donors8	The rate of survival among 27 patients was 84% at 1 and years and 74% at 5 years. The corresponding rates of graft survival were 93%, 84%, and 84%. HIV infection remained well controlled, with undetectable virus in blood after the transplantation.
Impact of second viral strain using HIV positive donors
HIV superinfection after using HIV positive donors48	Favourable clinical outcomes, lack of transmitted drug resistance, as well as the lack of evidence for sustained donor-derived superinfection provides support for the use of HIV+ to HIV+ renal transplants as a treatment option.

Immunosuppression and antiretroviral therapy interaction

Because of the interaction between protease and non-nucleoside reverse transcriptase inhibitors with the calcineurin and mTOR inhibitors, it can be challenging to manage patients on these drug combinations. Drug levels vary considerably between patients and often calcineurin inhibitor dosages have to be significantly increased (in the case of patients on non-nucleoside reverse transcriptase inhibitors) or decreased (in the case of patients on protein inhibitors) as a result of these drugs on the cytochrome P450 enzyme.¹⁸ Since this same metabolic pathway is used in the metabolism of CNI and TOR inhibitors, the use of NNRTIs results in the need for slightly higher dosing of those immunosuppressive agents, whereas the use of PIs result in the requirement for significantly lower doses. The most profound effects on dosing the immunosuppressive agents results from the inhibition on the cytochrome P450 system by the protease inhibitors (PIs).

In some studies, superior outcomes had been reported with integrase strand transfer inhibitor-based antiretroviral regimens. As these regimens have no interaction with calcineurin inhibitors, it should be preferred to protease and non-nucleoside reverse transcriptase inhibitors.^{19, 20} It should be pointed out that in some parts of the world, integrase inhibitors are not available. In resource constrained regions, the PIs have been used to decrease the amount of CNI that the HIV positive recipients require, hence saving drug costs. Nonetheless, if integrase inhibitors are available, it greatly simplifies the complex post-transplant management of the HIV positive recipient.

Interestingly, the antiretroviral agent maraviroc, which blocks the CCR5 receptor entry site for the HIV virus into the T-cell, may have a role in blocking the immune response to alloantigen. The use of CCR5 blockade with maraviroc was successful in blocking graft versus host disease following bone marrow transplantation, prompting a US NIH multicenter trial to study the efficacy of maraviroc in blocking the immune response following kidney transplantation in the HIV positive recipient (in progress).²¹

Another serendipitous finding in the US NIH multicenter trial was the retrospective finding that mTOR inhibition was associated with a reduction in the HIV viral reservoir.²² This interesting finding has been studied prospectively, and reduction in the reservoir has been confirmed in recipients with levels of mTOR inhibition that effectively blocked the mTOR pathway (Henrich et al AJT 2020 in press)

Infective complications in HIV positive transplant recipients

In most centers infectious complications had been noted, but not reported as significantly higher than in HIV negative transplant recipients. However, careful consideration should be given to the potential problematic infectious complications that can be seen as a result of aggressive immunosuppression using lymphocyte depleting induction regimens. In the HIV positive patient recipients in South Africa, several early devastating infective complications had been seen.²³ These infections are summarized in Table 4. It is important to note that infections leading to patient death in this patient population included both tuberculosis as well as systemic fungal infection, and that death happened within the first 6 months after transplantation.

Table 4:

Infective complications leading to patient death in the first year after transpalnts in Cape Town, South Africa

Timing after transplant	Reason for patient death
1 month	Respiratory failure secondary to reactivation of tuberculosis
1 month	Acute on chronic pancreatitis, Escherichia coli and Pseudomonas spp (blood culture)
3 months	Recurrent Gram-negative septicemia Recurrent urinary tract infection Carbapenem-resistant Klebsiella Pneumonia (blood culture)
4 months	Rapidly progressive invasive aspergillosis

In the first year after transplant patients are most vulnerable for infective complications. In the US series, a higher rate of infections requiring hospitalization were reported in patients that had received thymoglobulin during the early post-tx period.¹⁰ The use of thymoglobulin should be selective in recipients with a high risk for rejection (i.e highly sensitized). Although there is no question that transplant recipients infected with HIV have a dysregulated immune system and a higher incidence of infection, lymphodepleting induction regimens should be reserved for the higher immunologic risks, and balanced by the higher incidence of infections observed with the more aggressive induction regimens.

Systemic Tuberculosis can be the result of a reactivation of dormant tuberculosis secondary to immunosuppression in the recipient, new infection in the vulnerable immunosuppressed patient or donor derived infection. Most patients who have reactivation or donor-derived tuberculosis will present early after transplant. In South Africa, where tuberculosis is very prevalent, two HIV positive patients were diagnosed with tuberculosis in the first 3 months after transplantation with one person dying and a second having a severe impact on drug levels during the 18-month course of treatment, resulting in marginal graft function.²³ Because of the potentially devastating complications related to reactivation of TB, recipients who are at high risk for tuberculosis should be identified early and if possible, lymphodepleting induction regimens should be avoided. Donors should be carefully tested for tuberculosis and if active tuberculosis is present, donation should be avoided.

Opportunistic neoplasms

There has been ongoing concern regarding the potential for opportunistic neoplasms in the HIV infected recipient, and exacerbation of this potential by the immunosuppression required for successful transplantation. De novo HHV8- mediated Kaposi’s sarcoma (KS) had been reported in some HIV infected transplant recipients, but switching immunosuppressive regimens to include TOR inhibitors generally controlled this. The TOR inhibitors are very effective at suppressing angiogenesis, and pre-transplant KS (systemic or local) is no longer a contraindication to moving forward with transplantation, providing the disease can be eradicated. HPV mediated anal and cervical cancers are problematic in HIV infected people, and atypia and cancers are exacerbated with immunosuppression. In the US series, anal PAP smears were routinely performed, and the screening has yield 2 anal cancers which were successfully resected due to early detection.¹⁶ In addition, progression of atypia observed in this recipient cohort justifies the annual screening of these recipients. Fortunately, EBV mediated lymphoproliferative/lymphomas have not been problematic following transplantation in the HIV infected recipient.

Rejection in HIV positive patients

Rejection remains an important clinical issue in HIV positive patients, despite aggressive induction therapy and immunosuppression. In the South African study all patients received Thymoglobulin induction as the patients were not HLA matched and perceived to be of high immunological risk²³. Acute rejection in the first year dropped because of Thymoglobulin induction therapy (15% at 1 year), but then increased in year 2 and 3 to 20% and 30%. (Figure 1). These rejection rates are similar to what is being seen in the HIV positive patients receiving kidneys from HIV negative donors in the USA.²⁴ One could reason that the use of Thymoglobulin only postponed the first rejection episode in this patient group.

Figure 1.

Rejection rates in patients who received transplants with HIV positive kidneys in South Africa between 2008 and 2020

The reason for high rejection rates in HIV positive patients is still not clear. Many people have speculated that the rejection rates are simply related to the drug interactions affecting the cytochrome P450 enzyme.^{18, 25}

However, a more complex immunological reality might be responsible for high rejection rates in HIV positive patients. Chronic immune activation and inflammation is known to contribute to the risk of cardiovascular diseases in HIV positive patients.²⁶ The exposure to co-pathogens may result in heterologous immunity, leading to immunologic memory for HLA antigen in the absence of direct exposure. Furthermore, the loss of T helper cell function in response to antigens and the critical reduction in CD4+ T cell numbers might be responsible for a dysregulated immune response in HIV positive patients.²⁷

Recurrence of HIVAN

Classic HIVAN, as originally described in the pre-ART era continues to occur among ART-naïve or non-adherent patients, usually of African descent, irrespective of the mode of HIV transmission. Apoliprotein-L1 (APOL1) genetic polymorphism, high viral load and low CD-4 count had been linked to a higher clinical risk for developing HIVAN in the native kidneys of HIV positive patients. Diagnosis is confirmed by a nephrotic range proteinuria, and increased renal echogenicity on ultrasound and a kidney biopsy.²⁸

Pathologically HIVAN is defined by a collapsing glomerulopathy and attendant tubulointerstitial disease, including tubular microcyst formation, interstitial lymphoplasmacytic inflammation, variable acute tubular injury, and endothelial tubuloreticular inclusions by electron microscopy.² Diffuse podocyte foot process effacement and many large endothelial tubuloreticular inclusions (“interferon footprints”) are classic features.

Tubulointerstitial disease is an invariable component of HIVAN and often appears out of proportion to the severity of the glomerular disease. It accounts for marked kidney enlargement and hyperechoic appearance by ultrasound. Typical tubulointerstitial features include “tubular microcysts,” which are dilated tubules (at least 3-fold the diameter of normal tubules) containing glassy proteinaceous casts lined by flattened, simplified epithelium. The microcysts may be focal or diffuse and may involve cortex and medulla, including proximal, distal and collecting tubular segments (Table 1).⁵

In ART-treated patients, a non-collapsing form of FSGS called FSGS (NOS) is more commonly encountered at biopsy.²⁹ Viral burden is generally low and may be undetectable at the time of kidney biopsy. Biopsy findings may be difficult to distinguish from arterionephrosclerosis of hypertension, aging, and APOL1-associated nephropathy.

Numerous forms of immune complex-mediated glomerular disease have been reported in HIV-positive individuals.³⁰ These immune complex-mediated glomerular diseases can include multiple patterns: mesangial proliferative, membranous, membranoproliferative, endocapillary proliferative, and crescentic forms.

In the South African program, 51 patients received 150 biopsies over a 10-year period. Protocol biopsies were performed 1 year after the transplant. All other biopsies were done for clinical indications. Twelve patients had some features of HIVAN on protocol biopsy. This included glomerular, interstitial and tubular findings. The collapsing form of focal segmental glomerular sclerosis (FSGS) was the most common glomerular lesion in HIVAN.⁷ Figure 2 represent a histology sample from one patient with glomerular sclerosis and solidification accompanied by podocyte proliferation. Despite these changes in the kidney, the patient still had excellent graft function and no proteinuria.

Figure 2.

Collapsing glomerulopathy with global sollidification and podocyte proliferation.

An example of a graft with interstitial HIVAN showing significant plasma cell-rich interstitial inflammation and tubular microcysts, is depicted in Figure 3. Another example of ongoing HIVAN is demonstrated in Figure 4. This example shows a collapsing glomerulopathy with podocyte hypertrophy and early microcystic dilatation of an adjacent tubule.

Figure 3.

Interstitial HIVAN with a plasma cell-rich interstitial infiltrate and tubular microcysts in one of the patients who lost a graft.

Figure 4.

An example of segmental glomerulosclerosis with collapse of the glomerular tuft. Podocyte proliferation and prominent hyaline globules are evident.

HIVAN recurrence is a concern in some HIV positive transplant programs.³¹ In the South African group features of HIVAN presented many years after the transplant and had a slow progression having no clinical impact in most cases. In the South African group of 51 transplants, 12 patients were reported to have some HIVAN related changes on biopsy, but only 2 patients lost their grafts as a result. These patients also had episodes of rejection in the first 3 years after transplantation. All patients who had HIVAN recurrence had undetectable viral loads all through the study. No correlation could be found between donor viral load and recurrence of HIVAN in this study group. (p<0.001).

In the USA multicentre trial reporting on more than 150 HIV positive patients, HIVAN was not a clinical issue and was observed in 2/150 positive patients. More detailed assessment of donor and recipient biopsies is in progress, utilizing in situ hybridization and multiplex immunoflourence (miFISH). This technology can be performed from paraffin blocks and will permit a retrospective examination of all biopsies performed as part of the USA multicentre NIH trial.³²

The issue of HIVAN recurrence is an important issue that will need further attention in the future. The exact location of the viral reservoir in the transplanted kidney is important and will be a focus for ongoing research. Canaud et al describe a rapid deterioration in graft function after the diagnosis of HIVAN if the virus is identified in the podocyte rather than in the tubular cell of the transplanted kidney.³¹ The high frequency of HIV infection in the transplanted kidneys noted by Canaud et was not observed in the US trial (ref NEJM), and the reasons for these disparities will be addressed in future studies.

In preliminary data analysis in the South African cohort, patients who had did not have either HIVAN or rejection had a 5 year graft survival rate of 93.5% (95% CI 74.3–98.5%), but estimates dropped to 70.0% (95% CI 38.7–87.5%) in patients with rejection, and 33.3% (95%CI 0.01–77.4%) in patients with defined or possible HIVAN features (Figure 5). This may be related to a flare up of the viral reservoir in the kidney secondary to aggressive immunosuppression to treat an episode of rejection.

Figure 5.

Graft outcomes when patients had both HIVAN and rejection episodes in patients who received transplants with HIV positive kidneys in South Africa between 2008 and 2020

CONCLUSIONS

Kidney transplantation in the HIV infected recipient is moving towards global acceptance and “standard of care” provided good control of HIV with combination antiretroviral therapy. Higher rejection rates noted in this cohort are in part related to drug-drug interactions between the anti-retroviral and immunosuppressive regimens, and these interactions can be minimized by switching potential recipients to integrase inhibitor based regimens prior to transplant if deemed safe by a HIV provider. The use of HIV positive organs in HIV positive recipients has facilitated transplantation in the HIV positive recipients in South Africa, with comparable results to the HIV negative to HIV positive transplants performed in the US³³. Based on the success in South Africa, the US has initiated a similar strategy, and the safety and efficacy of using HIV positive donors is being studied in a NIH multicenter trial (Hope Act).¹² This strategy has decreased waiting times for HIV infected kidney recipients from greater than eight years to less than 1 year in parts of the US, provided the potential recipients have consented to receiving a HIV positive donor. Recurrence of HIV nephropathy was not problematic in the US series, but reports of recurrent disease in France have prompted re-examination of tissue from biopsies from the US multicentre NIH and South African series. Progression of HIV to AIDS has not been an issue provided stable antiretroviral regimens and prophylaxis against opportunistic infections during the early post-transplant period. HPV mediated cancers may be problematic, and HIV positive transplant recipients should undergo screening cervical and anal PAP smears.