APOL1 risk alleles and renal transplant function: time for Mission APOLLO

APOL1 is the newest addition to the list of CKD risk factors- possibly never before in the history of nephrology has a gene associated with such a high odds ratio with disease - above 7 for hypertensive CKD & >10 for FSGS. A gene that confers heterozygous survival advantage when present as a single variant allele, but two variants lead to high CKD risk - APOL1 on chromosome 22. A similar picture of the survival advantage is seen with sickle cell disease. For more on the fascinating story of APOL1 itself, see this open access review, NephMadness coverage from 2015, and the NephJC coverage of a more recent research.

A recent study has shown increased risk of CKD and subsequent ESKD in a population of black kidney donors with high risk APOL1 genotype. High risk is defined as presence of two variants (G1 and G2 – so any combination G1/G1, G1/G2 or G2/G2 is high risk) and was associated with faster progression of renal dysfunction and lower pre- and post-donation eGFR (pre-eGFR 98 versus 108; p= 0.03 and post-eGFR 58 versus 68; p=0.01) over a median follow up of 12 years. The second part of the study involved comparison between these donors and non donors from the CARDIA cohort (Coronary Artery Risk Development in Young Adults), based on APOL1 genotype status. After median 11 years, there was no difference in eGFR decline between the two groups when segregated based on genotype status, indicating that it was the genotype which influenced the eGFR decline and not the donation. Other salient features in the study were:

• 2 donors in the high risk group developed ESRD at 10 and 18 years of donation (11 %, but there were only 19 in this group).
• 78% of the donors were first degree relatives of the recipients. So the fact that a substantial percentage of donors were at risk of subsequent renal disease in this study does raises some valid concerns. Should all black donors be genotyped before transplantation?

An original article published in the Annals of Surgery recently studied eligible kidney donors (n=3438) from the CARDIA cohort of 1985-86 and deduced some risk scores based on the clinical and genetic profile of this population. They projected the 25 year pre-donation risk of CKD (eGFR <60ml/min) or microalbuminuria or macroalbuminuria in an 18 year old and a 30 year old potential donor. This risk is for people with no clinical risk factors (family history/pre-hypertension/diabetes). The risk increases significantly if any of these risk factors are present. See the table for some examples (EA – European American; AA – African American):

How about the risk to the recipients? Case reports have shown development of post transplant FSGS in siblings and monozygotic twins, both in the donor and in the recipient. Data from other studies have shown increased risk of allograft failure in recipients if the donor has a high risk genotype. All these data clearly point to the risk of CKD and subsequent ESKD in AA individuals (both donors & recipients) following transplantation. This brings us back to the most pertinent question, should people of African ancestry be genotyped for APOL1 prior to transplantation? The present studies are not well equipped to answer this question. Though it may seem that one obviously should screen (‘11% of donors with high risk variants develop ESRD!’ ‘High risk variants increase graft failure in recipients!’), lets pause and consider this. We know that live donor transplantation is the modality that offers the best survival. We also know that minorities, in US as well as in UK and elsewhere, have a lower rate of live donor transplantation (see NephJC coverage of a recent JAMA study and the ATTOM study, as well as the NephMadness coverage from 2017 on disparities in transplantation). So, would genotyping worsen the disparity? Is our fate inextricably written in our genes? Enter APOLLO.

APOLLO, APOL1 Long-Term Kidney Transplantation Outcomes Network, is a prospective study aimed at  genotyping donors and recipients in transplants involving recent African ancestry in United States and monitoring long term follow up. This will shed more light on this question and even might have a decisive influence on the present KDRI (kidney risk donor index), replacing the race column with APOL1 genotype. We await this important piece of work with interest.

Post by Sriram Sriperumbuduri

Mexican transplant program: All that glitters is not gold

"All that glitters is not gold" is a typical saying that alludes to the difference between appearance and evidence; it is undoubtedly one of the most common sayings by Mexicans and one of the ideas present when citing the Mexican National Transplant Program.

I am about to start my third year of training in Nephrology in a high specialty center in Mexico City and I have faced the daily practice of applying protocols of the Mexican transplant system which has gone through multiple changes in its structure and organization due to the alarming reports of incidence of chronic kidney disease in the country. Unravelling the data of a national kidney transplant program is complicated given the fact that success rates depend on multiple aspects as it can even be so diverse in different entities within the same nation. So, what are the most relevant aspects in the Mexican National Transplant System? I have considered the following 4 aspects as the most transcendental: 1) The Mexican health insurance and the history of the current national transplant program, 2) The number of candidates on the waiting list and the waiting time for kidney transplant, 3) The total number of kidney transplants, which includes living-donor and deceased-donor kidney transplant recipients and 4) The differences associated with the institutions that provide healthcare to the Mexican population, as well as national data about graft and patient survival.

Health insurance and historical review of the Mexican transplant program. 
In Mexico, social security and health insurance have had multiple changes in recent decades. The first and largest social security institution in Mexico and even in Latin America, The Mexican Institute of Social Security (IMSS by its acronym in Spanish) was created in 1943. The IMSS currently covers approximately 30.42% of the Mexican population; it shares this responsibility with other institutions such as the Social Security Institute for Service of State Workers (ISSSTE) and the National Defense Department health care system, similar to the VA system in the USA. Another national organization that provides health coverage is the program of the Ministry of Health called "Popular Insurance", in which the coverage is based on socioeconomic status, lowering the cost of health services through a federal subsidy. It covers approximately 36.55% of the population. Private health services covers a little less than 1% of the population. It has been reported that 25.4% of the Mexican population are uninsured or not affiliated to any of these institutions.

During the creation of the Mexican Transplant Program in 1976, the National Registry of Transplantation was designed as well. This program was implemented a few years after the first Mexican kidney transplant was performed in 1963. Subsequently, the National Transplant Center (CENATRA by its acronym in Spanish) was founded in the year 2000. Prior to 2000, no organization was overseeing the statistical data and activity of organ donation and transplantation.According to CENATRA, as of June 2017, there are 248 authorized transplantation programs, however, it only monitors the activity of 120 of them, because not all programs have an active license.

Number of recipients on the waiting list and waiting time for kidney transplant 
According to the latest report by the National Registry of Transplants, there are 21 686 patients on the national transplant waiting list, 13 956 candidates (64.3%) waiting for a kidney transplant. Concerning the combined transplant, there are 4 candidates on the kidney-pancreas transplant waiting list, 3 candidates on the kidney-liver transplant waiting list and 1 candidate on the kidney-lung transplant waiting list. In 2016, a total of 3,028 kidney transplants were performed in Mexico, with an average waiting time for kidney transplant (both living and deceased donor kidney transplant) of 11.63 months. Furthermore, the average waiting time in the deceased donor kidney transplant list is 29.86 months.

Data on living donor kidney and deceased donor kidney transplant. 
From 1963 to June 2017, 46,492 transplants have been performed in Mexico. However, in view of the relatively recent creation of the National Transplant System in 2000, data became more readily available. In addition to the 2016 national annual report data, we can review the following analysis: 

This proportion contrasts with statistics from other countries. Living-donor and deceased-donor kidney transplant donation programs are necessary to achieve adequate coverage for kidney transplant recipients; However, the need for organ donation continues to surpass the supply. In countries with organ donation systems based on deceased donors, kidney transplantation from a living donor is considered a complementary activity to their programs, since it represents only 10% of the total percentage of transplantation. It also contrasts with the national report of the USRDS where approximately one third of the total transplant is a living donor. 

According to the last CENATRA report from 2016, the following kidney transplant rates have been reported:

In recent years, organ donation campaigns have increased to promote kidney transplantation; however coupled with the uncertainty of health insurance coverage organ donation rates have not improved. In some instances, cultural factors represent barriers to living donation. For instance, a small percentage of the Mexican population, refuse organ donation due to concerns of body mutilation representing approximately 40% of the cases. . Will our Mexican ancestral beliefs about death be a barrier to improve organ donation? So far we do not have national data on dissemination or impact of the use of promotional campaigns.

Kidney Transplant among the different health institutions in Mexico 
One of the most interesting findings is the discrepancy of results among the medical institutions that perform kidney transplantation. In 2016, the IMSS had 13,731 potential kidney transplant recipients in the waiting list, private health insurance 2,541 candidates, and popular health insurance had 1,053 candidates. Although IMSS covers approximately 30% the Mexican population, it has the largest kidney transplant waiting list that includes around the 71 % out of all cases and the highest kidney transplant rate which reached 55% of the total of transplants performed in Mexico.

As of September 2017, of the 33 states of the country and of the 795 kidney transplants performed, 46% (368) of the transplants had been performed in two of the country's largests cities, Guadalajara and Mexico City. Although these statistics may correspond to the population rate of these cities, it shows the disproportion of specialized centers that have a multidisciplinary team to perform a kidney transplant, so that people living far from these areas are less likely to be able to benefit from the programs.. Undoubtedly, it will be of interest and public benefit to have specialized centers in all the entities together to look for alternatives such as the application of telemedicine.

Although at present, according to national data reports, there is no information on graft and recipient survival, there is available data from a transplant center with the highest transplant rate at the National Medical Center, part of the IMSS, where 1,185 patients were followed up for 12 months post-transplant and patient survival was 97.2% and graft survival rate was 95.5% during the first year. In the cohort, graft loss was defined as serum creatinine >4.0 mg/dL. Even though kidney transplantation may be limited, a model to perform kidney transplantation in the uninsured low-resource population has been implemented in a single center in Mexico, which a financial mechanism sharing public, patient, and private foundations funds. Long-term results are expected.

In conclusion we have so many barriers for transplantation and much remains to be done, such as accurate statistics of kidney transplant outcomes, promote kidney transplantation with emphasis on potential cadaveric donors and decentralize the access to health care.

Angel Ortiz, MD
Nephrology Fellow
UNAM (National Autonomous University of Mexico)
NSMC Intern 2018