Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Kidney transplant, a treatment option for end-stage renal disease, involves the surgical removal of a kidney from a cadaver, living-related donor, or living-unrelated donor and transplantation into the recipient.

Solid organ transplantation offers a treatment option for patients with different types of end-stage organ failure that can be lifesaving or provide significant improvements to a patient’s quality of life (Black, 2018). Many advances have been made in the last several decades to reduce perioperative complications. Available data supports improvement in long-term survival as well as improved quality of life particularly for liver, kidney, pancreas, heart, and lung transplants. Allograft rejection remains a key early and late complication risk for any organ transplantation. Transplant recipients require life-long immunosuppression to prevent rejection. Patients are prioritized for transplant by mortality risk and severity of illness criteria developed by Organ Procurement and Transplantation Network (OPTN) and United Network of Organ Sharing (UNOS).

In 2021, 41,355 transplants were performed in the United States procured from 34,813 deceased donors and 6,542 living donors (UNOS, 2022). Kidney transplants were the most common procedure with 24,670 transplants performed from both deceased and living donors in 2021. Since 1988, the cumulative number of kidney transplants is 527,427 (OPRN, 2022). Of the cumulative total, 67% of the kidneys came from deceased donors and 33% from living donors.

Kidney transplant, using kidneys from deceased or living donors, is an accepted treatment of end-stage renal disease (ESRD). ESRD refers to the inability of the kidneys to perform their functions (i.e., filtering wastes and excess fluids from the blood). ESRD, which is life-threatening, is also known as chronic kidney disease stage 5 and is defined as a glomerular filtration rate (GFR) less than 15 mL/min/1.73 m2 (National Kidney Foundation, 2020). Patients with advanced chronic kidney disease, mainly stage 4 (GFR 15 to 29 mL/min/1.73 m2) and stage 5 (GFR <15 mL/min/1.73 m2), should be evaluated for transplant (US Department of Health & Human Services, 2015). Being on dialysis is not a requirement to be considered for kidney transplant. Severe non-compliance and substance abuse serve as contraindications to kidney transplantation but even those could be overcome with clinician support and patient motivation. All kidney transplant candidates receive organ allocation points based on waiting time, age, donor-recipient immune system compatibility, prior living donor status, distance from donor hospital, and survival benefit (UNOS, 2020; OPTN, 2020).

Regulatory Status

Solid organ transplants are a surgical procedure and, as such, are not subject to regulation by the U.S. Food and Drug Administration (FDA).

The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation Title 21, parts 1270 and 1271. Solid organs used for transplantation are subject to these regulations.

Effective May 2019

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

*Note: A positive Hepatitis C status of organs for transplant is NOT a contraindication for transplant.

Kidney transplants meet primary coverage criteria that there be scientific evidence of effectiveness for carefully selected candidates with end stage renal disease secondary but not limited to:

Candidates for a kidney transplant need documentation of a progressive or terminal end-stage renal disease who otherwise have no immediate life threatening conditions, psychological impairments, and have a good emotional support system.

Effective Prior to May 2019

Kidney transplants meet primary coverage criteria that there be scientific evidence of effectiveness for carefully selected candidates with end stage renal disease secondary but not limited to:

Kidney transplant has emerged as an accepted treatment of end-stage renal disease due to a variety of etiologies, most commonly diabetic nephropathy. Over the years, there has been interest in expanding the donor pool, both for cadaver and living donors. For example, transplantation with an ABO-incompatible donor organ is considered a donor option. New techniques have also been explored to reduce the morbidity among living donors; laparoscopic live donor nephrectomy has been successfully performed. In addition, new immunosuppressive agents have reduced the number of episodes of rejection, thus improving graft survival.

Kidney transplantation in patients with HIV has long been controversial, due to the long-term prognosis for HIV positivity and the impact of immunosuppression on HIV disease. HIV-positive transplant recipients have been a research interest of some transplant centers, but the minimal data regarding long-term outcome in these patients consist primarily of case reports and abstract presentations. Nevertheless, some transplant surgeons have considered that HIV positivity is no longer an absolute contraindication to transplant due to the advent of highly active antiretroviral therapy (HAART), which has markedly changed the natural history of the disease. Furthermore, United Network for Organ Sharing (UNOS) states that asymptomatic HIV+ patients should not necessarily be excluded for candidacy for organ transplantation, stating, “A potential candidate for organ transplantation whose test for HIV is positive but who is in an asymptomatic state should not necessarily be excluded from candidacy for organ transplantation, but should be advised that he or she may be at increased risk of morbidity and mortality because of immunosuppressive therapy. In 2001, the Clinical Practice Committee of the American Society of Transplantation proposed that the presence of AIDS could be considered a contraindication to kidney transplant unless the following criteria were present.

There is an ongoing multi-institutional prospective study of liver and kidney transplantation in HIV+ recipients. The target enrollment is 150 kidney transplant recipients and 125 liver transplant recipients. The goals of the trial are described as follows:

“Primary aims of the study are to assess the impact of iatrogenic immunosuppression on patient survival and to assess the impact of HIV infection and antiretroviral treatment on graft survival, including in the setting of HBV or HCV co-infection and HIV-associated nephropathy. Secondary aims include assessment of the effect of immunosuppressant therapy on CD 4+ cell counts, HIV RNA levels, and opportunistic complications; exploration of the relationships among disease development, the host immune response and viral evolution with regard to HBC, HCV, CMV, herpes virus-8, and HPV; assessment of the impact of HIV infection on alloimmune response and graft rejection rates; and analysis of pharmacokinetic interactions between immunosuppressant drugs and hepatically metabolized antiretroviral agents. “

A literature search of the MEDLINE database was conducted through June 2012. There was no new literature that would prompt a change in the coverage statement. Several articles of interest were identified and are summarized in this update.

A 2012 review article by Schold and Segev focused on strategies to increase the pool of organs available for kidney transplantation from deceased donors (Schold, 2012). Interventions discussed included an “opt-out” policy in which individuals are presumed to give consent to organ donation unless they specify non-consent, expanded use of donors such as commercial sex workers who are considered to be at increased risk of disease transmission by using rigorous screening and expanded use of donors with documented infections in selected situations e.g. transplantation of organs from HIV-positive donors to HIV-positive recipients. Currently, kidney donation from HIV-positive individuals is against the law in the United States. The authors note that a combination of approaches is needed, as well as a long-term perspective and use of the best available evidence.

Several recent papers report on mortality and long-term survival and long-term renal consequences in live kidney donors. Segev and colleagues analyzed data from a national registry of 80,347 live donors in the U.S who donated organs between April 1, 1994 and March 31, 2009 and compared them with data from 9,364 participants of the National Health and Nutrition Examination Survey (NHANES) (excluding those with contraindications to kidney donation) (Segev, 2010). There were 25 deaths within 90 days of live kidney donation during the study period. Surgical mortality from live kidney donation was 3.1 per 10,000 donors (95% confidence interval [CI]: 2.0-4.6) and did not change during the last 15 years, despite differences in practice and selection. Long-term risk of death was no higher for live donors than for age- and comorbidity-matched NHANES III participants for all patients and also stratified by age, sex, and race.

In 2012, Fournier and colleagues in France reported on long-term follow-up of individuals who had donated a kidney between 1952 and 2008 (Fournier, 2012). Of a total of 398 donors at a single institution, 266 (67%) were alive, 44 (11%) were documented as having died and 88 (22%) were lost to follow-up. Among individuals who were known to have died, death occurred at a mean of 29.6 years after donation. Donor survival did not differ from that of the general population in France. Fifty-nine of 68 (87%) living individuals who had donated a kidney more than 30 years ago responded to a questionnaire. According to questionnaire responses, the mean serum creatinine level was 93.2 +/- 22.5 umol/L, no patient had an estimated GFR less than 30 mL/min per 1.73 m2 and none had ESRD.

A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.

Kidney Retransplant

According to data from the Organ Procurement and Transplantation Network (OPTN), rates of 1-year, 3-year and 5-year survival are similar after a primary kidney transplant and a repeat transplant (OPTN, 2013). For example, for transplants performed between 2002 and 2004, the 1-year survival rate was 95.9% (95% CI: 95.7 to 96.1%) after primary transplantation (n=37,504) and 95.8% (95% CI: 95.3-96.4%) after repeat transplantation (n=4,924). Among patients undergoing transplantation between 1997 and 2000, the 5-year survival rate was 84.8% (95% CI: 84.5% to 85.2%) after primary kidney transplantation (n=29,422) and 85.1% (95% CI: 84.1 to 86.1%) after repeat kidney transplantation (n=3,697).

In 2009, Barocci and colleagues in Italy reported on long-term survival after kidney retransplantation (Barocci, 2009). There were 100 (0.8%) second transplants out of 1,302 kidney transplants performed at a single center between January 1983 and June 2007. Among the second kidney recipients, 1-, 5- and 10-year patient survival was 100%, 96%, and 92%, respectively. Graft survival rates at 1, 5 and 10 years were 85%, 72% and 53%, respectively.

A 2013 study by Johnston and colleagues compared outcomes in 3,509 patients who underwent a preemptive second kidney transplant, defined as transplantation after fewer than 7 days of dialysis following graft failure, to outcomes in 14,075 patients who underwent a non-preemptive second kidney transplant (Johnston, 2013). Data from the U.S. Renal Data System (USRDS) were reviewed. In the first year after retransplantation, there was a significantly lower risk of acute rejection in patients receiving a preemptive second transplant (12%) compared to those with a non-preemptive second transplant (16%), p<0.0001. In a multivariate analysis adjusting for demographic differences between groups, there was a significantly lower risk of allograft failure by any cause including death after preemptive second transplants compared to non-preemptive second transplants (hazard ratio [HR]: 0.88, 95% CI: 0.81 to 0.96).

In inclusion of the above literature, kidney transplant continues to be an accepted treatment of end-stage renal disease in appropriately selected patients and thus may be considered medically necessary. Registry and national survey data suggest that live donors of kidneys for transplantation do not have an increased risk of mortality or ESRD.

Kidney retransplantation after a failed primary transplant may be considered medically necessary, as national data suggest similar survival rates after initial and repeat transplants.

Kidney transplantation is not medically necessary in patients in whom the procedure is expected to be futile due to comorbid disease or in whom post-transplantation care is expected to significantly worsen comorbid conditions. Case series and case-control data indicate that HIV-infection is not an absolute contraindication to kidney transplant; for patients who meet selection criteria, these studies have demonstrated patient and graft survival rates are similar to those in the general population of kidney transplant recipients.

A literature search conducted using the MEDLINE database through June 2016 did not reveal any new information that would prompt a change in the coverage statement.

A literature search was conducted through June 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Potential Contraindications to Kidney Transplant

A 2016 multivariate analysis of the effect of obesity on transplant outcomes by Kwan et al included 191,091 patients from the Scientific Registry of Transplant Recipients database (Kwan, 2016). Covariates in the analysis included age, sex, graft type, ethnicity, diabetes, peripheral vascular disease, dialysis time, and time period of transplantation. Multivariate regression analysis indicated that obese patients had a significantly increased risk of adverse transplant outcomes including delayed graft function, urine protein, acute rejection, and graft failure (p<0.001 for all outcomes). The risk of adverse outcomes of obesity increased with increasing BMI and was independent of the effect of diabetes.

Type 2 Diabetes

Lim et al (2017) evaluated all-cause mortality following kidney transplantation in patients with type 2 diabetes from the Australia and New Zealand Dialysis and Transplant registry (Lim, 2017). Of 10,714 transplant recipients during the study period, 985 (9%) had type 2 diabetes. The 10-year unadjusted overall survival in patients with an intact graft was 53% for individuals who had diabetes compared with 83% for transplant recipients who did not. The adjusted HR for all-cause mortality in patients with diabetes was 1.60 (95% CI, 1.37 to 1.86; p<0.001), with the excess risk of death attributable to both cardiovascular disease and infection. Graft survival rates at 1, 5, and 10 years were 94%, 85%, and 70% in patients with diabetes compared with 95%, 89%, and 78% in transplant recipients without diabetes (p<0.001), respectively.

Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Pestana published a retrospective, single-center analysis of kidney transplants performed between 1998 and 2015 at a hospital in Brazil (Pestana, 2017). Of the 11,436 transplants analyzed, 31% (n=3614) were performed under SCD, while 14% (n=1618) were performed under ECD. The number of ECD recipients increased over time, from 29 transplants in 1998-2000 to 450 transplants from 2013-2014. Patient survival with ECD increased from 1998-2002 to 2011-2014 (from 79.7% to 89.2%, p<0.001); a similar increase was noted in patient survival with SCD over the same time periods (from 73.1% to 85.2%, p<0.001). The study was limited by reliance on limited registry data.

Potential Contraindications to Kidney Transplant

Patients infected with HIV may receive organs from HIV-positive donors under approved research protocols through the HIV Organ Policy Equity Act. As of November 2017, 6 hospitals performed 34 such transplants (23 kidney and 11 liver transplants), involving organs from 14 deceased donors. In a prospective, nonrandomized study, Muller et al (2015) noted that HIV-positive patients transplanted with kidneys from donors testing positive for HIV showed a 5-year survival rate of 74%(Muller, 2015). Researchers noted that the HIV infection remained well-controlled and the virus was undetectable in the blood after transplantation.

Currently Organ Procurement and Transplantation Network policy permits HIV-positive transplant candidates (OPTN, 2018).

The British HIV Association and the British Transplantation Society updated their guidelines on kidney transplantation in patients with HIV disease (Working Party of the British Transplantation Society, 2017).

These criteria may be extrapolated to other organs:

A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Zheng et al performed a meta-analysis of 27 cohort studies, accounting for 1,670 cases, to analyze various outcomes among HIV-positive patients who underwent kidney transplantation (Zheng, 2019). The results revealed 97% (95% CI, 95% to 98%) survival at 1 year and 94% (95% CI, 90% to 97%) survival at 3 years. Other outcomes comprised 91% (95% CI, 88% to 94%) graft survival at 1 year, 81% (95% CI, 74% to 87%) graft survival at 3 years, 33% (95% CI, 28% to 38%) with acute rejections at 1 year, and 41% (95% CI, 34% to 50%) with infectious complications at 1 year.

Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.

Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Chaudhry et al published a systematic review that compared survival for waitlisted patients with kidney failure who received a transplant compared to those who remained on the transplant waitlist (Chaudhry, 2022). A total of 48 observational studies were included in the systematic review, of which 18 studies were suitable for meta-analysis. Results demonstrated a 55% reduction in the risk of mortality in patients who received a transplant compared to those who remained on dialysis (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.39 to 0.54; p<.001).

Kainz et al investigated the association of time on waitlist with survival in patients who received a second transplant versus those who remained on the waitlist (Kainz, 2022). A total of 2346 patients from the Austrian Dialysis and Transplant Registry and Eurotransplant were retrospectively analyzed. Results demonstrated that retransplantation improved survival at 10 years of follow-up compared with remaining on the waitlist (HR for mortality, 0.73; 95% CI, 0.53 to 0.95). For patients with a waitlist time for retransplantation of <1 and 8 years after first graft loss, the mean survival time differences at 10 years were 8.0 life months gained (95% CI, 1.9 to 14.0) and 0.1 life months gained (95% CI, -14.3 to 15.2), respectively.

	Transplant, Kidney

Description:	Kidney transplant, a treatment option for end-stage renal disease, involves the surgical removal of a kidney from a cadaver, living-related donor, or living-unrelated donor and transplantation into the recipient. Solid organ transplantation offers a treatment option for patients with different types of end-stage organ failure that can be lifesaving or provide significant improvements to a patient’s quality of life (Black, 2018). Many advances have been made in the last several decades to reduce perioperative complications. Available data supports improvement in long-term survival as well as improved quality of life particularly for liver, kidney, pancreas, heart, and lung transplants. Allograft rejection remains a key early and late complication risk for any organ transplantation. Transplant recipients require life-long immunosuppression to prevent rejection. Patients are prioritized for transplant by mortality risk and severity of illness criteria developed by Organ Procurement and Transplantation Network (OPTN) and United Network of Organ Sharing (UNOS). In 2021, 41,355 transplants were performed in the United States procured from 34,813 deceased donors and 6,542 living donors (UNOS, 2022). Kidney transplants were the most common procedure with 24,670 transplants performed from both deceased and living donors in 2021. Since 1988, the cumulative number of kidney transplants is 527,427 (OPRN, 2022). Of the cumulative total, 67% of the kidneys came from deceased donors and 33% from living donors. Kidney transplant, using kidneys from deceased or living donors, is an accepted treatment of end-stage renal disease (ESRD). ESRD refers to the inability of the kidneys to perform their functions (i.e., filtering wastes and excess fluids from the blood). ESRD, which is life-threatening, is also known as chronic kidney disease stage 5 and is defined as a glomerular filtration rate (GFR) less than 15 mL/min/1.73 m2 (National Kidney Foundation, 2020). Patients with advanced chronic kidney disease, mainly stage 4 (GFR 15 to 29 mL/min/1.73 m2) and stage 5 (GFR <15 mL/min/1.73 m2), should be evaluated for transplant (US Department of Health & Human Services, 2015). Being on dialysis is not a requirement to be considered for kidney transplant. Severe non-compliance and substance abuse serve as contraindications to kidney transplantation but even those could be overcome with clinician support and patient motivation. All kidney transplant candidates receive organ allocation points based on waiting time, age, donor-recipient immune system compatibility, prior living donor status, distance from donor hospital, and survival benefit (UNOS, 2020; OPTN, 2020). Regulatory Status Solid organ transplants are a surgical procedure and, as such, are not subject to regulation by the U.S. Food and Drug Administration (FDA). The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation Title 21, parts 1270 and 1271. Solid organs used for transplantation are subject to these regulations.

Policy/ Coverage:	Effective May 2019 Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria Note: A positive Hepatitis C status of organs for transplant is NOT* a contraindication for transplant. Kidney transplants meet primary coverage criteria that there be scientific evidence of effectiveness for carefully selected candidates with end stage renal disease secondary but not limited to: Diabetes mellitus Polycystic kidney disease Congenital anomalies of kidney Kidney injury Kidney trauma Poisoning by primarily systemic agents Tuberous sclerosis SLE Multiple myeloma Gouty nephropathy Disorders of calcium metabolism Amyloidosis Hemolytic-uremic syndrome Polyarteritis nodosa Renal vein embolism/thrombosis Acute renal failure Nephrotic syndrome Nephritis Nephropathy. Candidates for a kidney transplant need documentation of a progressive or terminal end-stage renal disease who otherwise have no immediate life threatening conditions, psychological impairments, and have a good emotional support system. Effective Prior to May 2019 Kidney transplants meet primary coverage criteria that there be scientific evidence of effectiveness for carefully selected candidates with end stage renal disease secondary but not limited to: Diabetes mellitus Polycystic kidney disease Congenital anomalies of kidney Kidney injury Kidney trauma Poisoning by primarily systemic agents Tuberous sclerosis SLE Multiple myeloma Gouty nephropathy Disorders of calcium metabolism Amyloidosis Hemolytic-uremic syndrome Polyarteritis nodosa Renal vein embolism/thrombosis Acute renal failure Nephrotic syndrome Nephritis Nephropathy. Candidates for a kidney transplant need documentation of a progressive or terminal end-stage renal disease who otherwise have no immediate life threatening conditions, psychological impairments, and have a good emotional support system.

Rationale:	Kidney transplant has emerged as an accepted treatment of end-stage renal disease due to a variety of etiologies, most commonly diabetic nephropathy. Over the years, there has been interest in expanding the donor pool, both for cadaver and living donors. For example, transplantation with an ABO-incompatible donor organ is considered a donor option. New techniques have also been explored to reduce the morbidity among living donors; laparoscopic live donor nephrectomy has been successfully performed. In addition, new immunosuppressive agents have reduced the number of episodes of rejection, thus improving graft survival. Kidney transplantation in patients with HIV has long been controversial, due to the long-term prognosis for HIV positivity and the impact of immunosuppression on HIV disease. HIV-positive transplant recipients have been a research interest of some transplant centers, but the minimal data regarding long-term outcome in these patients consist primarily of case reports and abstract presentations. Nevertheless, some transplant surgeons have considered that HIV positivity is no longer an absolute contraindication to transplant due to the advent of highly active antiretroviral therapy (HAART), which has markedly changed the natural history of the disease. Furthermore, United Network for Organ Sharing (UNOS) states that asymptomatic HIV+ patients should not necessarily be excluded for candidacy for organ transplantation, stating, “A potential candidate for organ transplantation whose test for HIV is positive but who is in an asymptomatic state should not necessarily be excluded from candidacy for organ transplantation, but should be advised that he or she may be at increased risk of morbidity and mortality because of immunosuppressive therapy. In 2001, the Clinical Practice Committee of the American Society of Transplantation proposed that the presence of AIDS could be considered a contraindication to kidney transplant unless the following criteria were present. CD4 count >200 cells/mm-3 for >6 months HIV-1 RNA undetectable On stable anti-retroviral therapy >3 months No other complications from AIDS (e.g., opportunistic infection, including aspergillus, tuberculosis, coccidioses mycosis, resistant fungal infections, Kaposi’s sarcoma, or other neoplasm). Meeting all other criteria for transplantation. There is an ongoing multi-institutional prospective study of liver and kidney transplantation in HIV+ recipients. The target enrollment is 150 kidney transplant recipients and 125 liver transplant recipients. The goals of the trial are described as follows: “Primary aims of the study are to assess the impact of iatrogenic immunosuppression on patient survival and to assess the impact of HIV infection and antiretroviral treatment on graft survival, including in the setting of HBV or HCV co-infection and HIV-associated nephropathy. Secondary aims include assessment of the effect of immunosuppressant therapy on CD 4+ cell counts, HIV RNA levels, and opportunistic complications; exploration of the relationships among disease development, the host immune response and viral evolution with regard to HBC, HCV, CMV, herpes virus-8, and HPV; assessment of the impact of HIV infection on alloimmune response and graft rejection rates; and analysis of pharmacokinetic interactions between immunosuppressant drugs and hepatically metabolized antiretroviral agents. “ 2012 Update A literature search of the MEDLINE database was conducted through June 2012. There was no new literature that would prompt a change in the coverage statement. Several articles of interest were identified and are summarized in this update. A 2012 review article by Schold and Segev focused on strategies to increase the pool of organs available for kidney transplantation from deceased donors (Schold, 2012). Interventions discussed included an “opt-out” policy in which individuals are presumed to give consent to organ donation unless they specify non-consent, expanded use of donors such as commercial sex workers who are considered to be at increased risk of disease transmission by using rigorous screening and expanded use of donors with documented infections in selected situations e.g. transplantation of organs from HIV-positive donors to HIV-positive recipients. Currently, kidney donation from HIV-positive individuals is against the law in the United States. The authors note that a combination of approaches is needed, as well as a long-term perspective and use of the best available evidence. Several recent papers report on mortality and long-term survival and long-term renal consequences in live kidney donors. Segev and colleagues analyzed data from a national registry of 80,347 live donors in the U.S who donated organs between April 1, 1994 and March 31, 2009 and compared them with data from 9,364 participants of the National Health and Nutrition Examination Survey (NHANES) (excluding those with contraindications to kidney donation) (Segev, 2010). There were 25 deaths within 90 days of live kidney donation during the study period. Surgical mortality from live kidney donation was 3.1 per 10,000 donors (95% confidence interval [CI]: 2.0-4.6) and did not change during the last 15 years, despite differences in practice and selection. Long-term risk of death was no higher for live donors than for age- and comorbidity-matched NHANES III participants for all patients and also stratified by age, sex, and race. In 2012, Fournier and colleagues in France reported on long-term follow-up of individuals who had donated a kidney between 1952 and 2008 (Fournier, 2012). Of a total of 398 donors at a single institution, 266 (67%) were alive, 44 (11%) were documented as having died and 88 (22%) were lost to follow-up. Among individuals who were known to have died, death occurred at a mean of 29.6 years after donation. Donor survival did not differ from that of the general population in France. Fifty-nine of 68 (87%) living individuals who had donated a kidney more than 30 years ago responded to a questionnaire. According to questionnaire responses, the mean serum creatinine level was 93.2 +/- 22.5 umol/L, no patient had an estimated GFR less than 30 mL/min per 1.73 m2 and none had ESRD. 2014 Update A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below. Kidney Retransplant According to data from the Organ Procurement and Transplantation Network (OPTN), rates of 1-year, 3-year and 5-year survival are similar after a primary kidney transplant and a repeat transplant (OPTN, 2013). For example, for transplants performed between 2002 and 2004, the 1-year survival rate was 95.9% (95% CI: 95.7 to 96.1%) after primary transplantation (n=37,504) and 95.8% (95% CI: 95.3-96.4%) after repeat transplantation (n=4,924). Among patients undergoing transplantation between 1997 and 2000, the 5-year survival rate was 84.8% (95% CI: 84.5% to 85.2%) after primary kidney transplantation (n=29,422) and 85.1% (95% CI: 84.1 to 86.1%) after repeat kidney transplantation (n=3,697). In 2009, Barocci and colleagues in Italy reported on long-term survival after kidney retransplantation (Barocci, 2009). There were 100 (0.8%) second transplants out of 1,302 kidney transplants performed at a single center between January 1983 and June 2007. Among the second kidney recipients, 1-, 5- and 10-year patient survival was 100%, 96%, and 92%, respectively. Graft survival rates at 1, 5 and 10 years were 85%, 72% and 53%, respectively. A 2013 study by Johnston and colleagues compared outcomes in 3,509 patients who underwent a preemptive second kidney transplant, defined as transplantation after fewer than 7 days of dialysis following graft failure, to outcomes in 14,075 patients who underwent a non-preemptive second kidney transplant (Johnston, 2013). Data from the U.S. Renal Data System (USRDS) were reviewed. In the first year after retransplantation, there was a significantly lower risk of acute rejection in patients receiving a preemptive second transplant (12%) compared to those with a non-preemptive second transplant (16%), p<0.0001. In a multivariate analysis adjusting for demographic differences between groups, there was a significantly lower risk of allograft failure by any cause including death after preemptive second transplants compared to non-preemptive second transplants (hazard ratio [HR]: 0.88, 95% CI: 0.81 to 0.96). In inclusion of the above literature, kidney transplant continues to be an accepted treatment of end-stage renal disease in appropriately selected patients and thus may be considered medically necessary. Registry and national survey data suggest that live donors of kidneys for transplantation do not have an increased risk of mortality or ESRD. Kidney retransplantation after a failed primary transplant may be considered medically necessary, as national data suggest similar survival rates after initial and repeat transplants. Kidney transplantation is not medically necessary in patients in whom the procedure is expected to be futile due to comorbid disease or in whom post-transplantation care is expected to significantly worsen comorbid conditions. Case series and case-control data indicate that HIV-infection is not an absolute contraindication to kidney transplant; for patients who meet selection criteria, these studies have demonstrated patient and graft survival rates are similar to those in the general population of kidney transplant recipients. 2017 Update A literature search conducted using the MEDLINE database through June 2016 did not reveal any new information that would prompt a change in the coverage statement. 2018 Update A literature search was conducted through June 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below. Potential Contraindications to Kidney Transplant *Obesity* A 2016 multivariate analysis of the effect of obesity on transplant outcomes by Kwan et al included 191,091 patients from the Scientific Registry of Transplant Recipients database (Kwan, 2016). Covariates in the analysis included age, sex, graft type, ethnicity, diabetes, peripheral vascular disease, dialysis time, and time period of transplantation. Multivariate regression analysis indicated that obese patients had a significantly increased risk of adverse transplant outcomes including delayed graft function, urine protein, acute rejection, and graft failure (p<0.001 for all outcomes). The risk of adverse outcomes of obesity increased with increasing BMI and was independent of the effect of diabetes. *Type 2 Diabetes* Lim et al (2017) evaluated all-cause mortality following kidney transplantation in patients with type 2 diabetes from the Australia and New Zealand Dialysis and Transplant registry (Lim, 2017). Of 10,714 transplant recipients during the study period, 985 (9%) had type 2 diabetes. The 10-year unadjusted overall survival in patients with an intact graft was 53% for individuals who had diabetes compared with 83% for transplant recipients who did not. The adjusted HR for all-cause mortality in patients with diabetes was 1.60 (95% CI, 1.37 to 1.86; p<0.001), with the excess risk of death attributable to both cardiovascular disease and infection. Graft survival rates at 1, 5, and 10 years were 94%, 85%, and 70% in patients with diabetes compared with 95%, 89%, and 78% in transplant recipients without diabetes (p<0.001), respectively. 2019 Update Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. Pestana published a retrospective, single-center analysis of kidney transplants performed between 1998 and 2015 at a hospital in Brazil (Pestana, 2017). Of the 11,436 transplants analyzed, 31% (n=3614) were performed under SCD, while 14% (n=1618) were performed under ECD. The number of ECD recipients increased over time, from 29 transplants in 1998-2000 to 450 transplants from 2013-2014. Patient survival with ECD increased from 1998-2002 to 2011-2014 (from 79.7% to 89.2%, p<0.001); a similar increase was noted in patient survival with SCD over the same time periods (from 73.1% to 85.2%, p<0.001). The study was limited by reliance on limited registry data. Potential Contraindications to Kidney Transplant HIV Infection Patients infected with HIV may receive organs from HIV-positive donors under approved research protocols through the HIV Organ Policy Equity Act. As of November 2017, 6 hospitals performed 34 such transplants (23 kidney and 11 liver transplants), involving organs from 14 deceased donors. In a prospective, nonrandomized study, Muller et al (2015) noted that HIV-positive patients transplanted with kidneys from donors testing positive for HIV showed a 5-year survival rate of 74%(Muller, 2015). Researchers noted that the HIV infection remained well-controlled and the virus was undetectable in the blood after transplantation. Currently Organ Procurement and Transplantation Network policy permits HIV-positive transplant candidates (OPTN, 2018). The British HIV Association and the British Transplantation Society updated their guidelines on kidney transplantation in patients with HIV disease (Working Party of the British Transplantation Society, 2017). These criteria may be extrapolated to other organs: Adherent with treatment, particularly antiretroviral therapy Cluster of Differentiation 4 count greater than 100 cells/mL (ideally >200 cells/mL) for at least 3 months Undetectable HIV viremia (<50 HIV-1 RNA copies/mL) for at least 6 months No opportunistic infections for at least 6 months No history of progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, or lymphoma. 2020 Update A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement. 2021 Update Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. Zheng et al performed a meta-analysis of 27 cohort studies, accounting for 1,670 cases, to analyze various outcomes among HIV-positive patients who underwent kidney transplantation (Zheng, 2019). The results revealed 97% (95% CI, 95% to 98%) survival at 1 year and 94% (95% CI, 90% to 97%) survival at 3 years. Other outcomes comprised 91% (95% CI, 88% to 94%) graft survival at 1 year, 81% (95% CI, 74% to 87%) graft survival at 3 years, 33% (95% CI, 28% to 38%) with acute rejections at 1 year, and 41% (95% CI, 34% to 50%) with infectious complications at 1 year. 2022 Update Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. 2023 Update Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below. Chaudhry et al published a systematic review that compared survival for waitlisted patients with kidney failure who received a transplant compared to those who remained on the transplant waitlist (Chaudhry, 2022). A total of 48 observational studies were included in the systematic review, of which 18 studies were suitable for meta-analysis. Results demonstrated a 55% reduction in the risk of mortality in patients who received a transplant compared to those who remained on dialysis (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.39 to 0.54; p<.001). Kainz et al investigated the association of time on waitlist with survival in patients who received a second transplant versus those who remained on the waitlist (Kainz, 2022). A total of 2346 patients from the Austrian Dialysis and Transplant Registry and Eurotransplant were retrospectively analyzed. Results demonstrated that retransplantation improved survival at 10 years of follow-up compared with remaining on the waitlist (HR for mortality, 0.73; 95% CI, 0.53 to 0.95). For patients with a waitlist time for retransplantation of <1 and 8 years after first graft loss, the mean survival time differences at 10 years were 8.0 life months gained (95% CI, 1.9 to 14.0) and 0.1 life months gained (95% CI, -14.3 to 15.2), respectively.

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