Michael D. Gautreaux

The APOL1 Gene and Allograft Survival after Kidney Transplantation

Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with nephropathy in African Americans (AAs). The effect of transplanting kidneys from AA donors with two APOL1 nephropathy risk variants is unknown. APOL1 risk variants were genotyped in 106 AA deceased organ donors and graft survival assessed in 136 resultant kidney transplants. Cox‐proportional hazard models tested for association between time to graft failure and donor APOL1 genotypes. The mean follow‐up was 26.4 ± 21.8 months. Twenty‐two of 136 transplanted kidneys (16%) were from donors with two APOL1 nephropathy risk variants. Twenty‐five grafts failed; eight (32%) had two APOL1 risk variants. A multivariate model accounting for donor APOL1 genotype, overall African ancestry, expanded criteria donation, recipient age and gender, HLA mismatch, CIT and PRA revealed that graft survival was significantly shorter in donor kidneys with two APOL1 risk variants (hazard ratio [HR] 3.84; p = 0.008) and higher HLA mismatch (HR 1.52; p = 0.03), but not for overall African ancestry excluding APOL1. Kidneys from AA deceased donors harboring two APOL1 risk variants failed more rapidly after renal transplantation than those with zero or one risk variants. If replicated, APOL1 genotyping could improve the donor selection process and maximize long‐term renal allograft survival.

Soluble HLA in human body fluids

There is a growing body of information about the soluble forms of HLA in serum but there are only a few reports discussing sHLA in other body fluids. We quantitated sHLA-I and sHLA-II concentrations in sweat, saliva and tear samples from five normal individuals with known HLA-phenotypes. We also studied sweat samples from an additional 12 normal nonphenotyped subjects, as well as in CSF of 20 subjects with different illnesses, using solid phase enzyme linked immunoassay. Sweat, saliva and tears from normal subjects were found to contain very low or nondetectable amounts of sHLA-I. In contrast, sHLA-II molecules were found in each of these body fluids, although, with considerable variation between individuals. The presence of sHLA-II in saliva was further confirmed by Western-blotting. It was observed that sHLA-II having molecular mass of 43,900 and 18,100 daltons was comparable with that found in serum from normal individuals. In addition, no association of sHLA-II levels with allospecificities in either body fluid or in serum was apparent. The results of CSF sHLA concentrations in different diseases were as follows: (1) High CSF SHLA-I levels were measured during viral encephylitis (n = 3), while none of these patients contained sHLA-II in CSF; (2) The levels of sHLA-II, but not sHLA-I were elevated in CSF of patients during seizure (n = 6) and of patients with neonatal hepatitis (1 of 2) or with connective tissue disease accompanied with viral infection (n = 2); (3) No CSF sHLA-I or sHLA-II could be detected at polyneuropathy (n = 2), or in patients with syphilis (n = 3), or leukemia (n = 2) with evidence of neurologic involvement of central nervous system. Taken together, it may be concluded that the presence of sHLA in several body fluids is physiologically normal. It appears that sHLA-II is the predominant class of HLA molecules present in different body fluids. We propose that the system responsible for sHLA-II production in various body fluids must involve different mechanisms than those responsible for sHLA-I synthesis in serum.

Soluble HLA Class I Antigens in Patients with Type I Diabetes and Their Family Members

Our objective was to study a possible contribution of MHC genes to S-HLA-I secretion in patients with Type I diabetes. Quantitatively, we used a highly sensitive enzyme-linked immunoassay to measure S-HLA-I in the serum of a total of 39 patients with Type I diabetes, as well as 36 kinships of 12 diabetic patients and 82 normal individuals with known HLA-phenotypes. S-HLA-I levels were abnormally elevated in patients or their non-diabetic relatives compared to normal controls (p < 0.0009). No complete HLA-haplotype had been identified to be correlated with high or low S-HLA-I secretion. Only the HLA-A23 or A24 (splits of HLA-A9) positive individuals sera were found to contain high S-HLA-I concentrations in all populations studied. The difference in S-HLA-I levels of HLA-A24 patients (n = 4) or their HLA-A24 positive non-diabetic relatives (n = 10) to the group of HLA-A24 normal controls (n = 15) was statistically highly significant (p < 0.0005 and p < 0.0009, respectively). The results suggests that HLA-A24 may confer additional independent risk for the disease expression in male children but not in female siblings. Nevertheless, the data implies that the patients or their non-diabetic relatives carrying the HLA-A24 have increased risk of developing ICA associated with high S-HLA-I levels compared to HLA-A24 negative probands or their kinships with low levels of S-HLA-I. This effect occurred irrespective to other diabetes related HLA-DR alleles. In summary, the results show a pronounced genetic heterogeneity of Type I diabetes with MHC control of the expression of S-HLA-I and possible involvement of hormonal factors that might potentiate a specific synthesis of S-HLA-I. The findings have implications for identifying individuals with a possible risk for developing the disease.

Hypertension in standard criteria deceased donors is associated with inferior outcomes following kidney transplantation.

Singh RP, Farney AC, Rogers J, Gautreaux M, Reeves‐Daniel A, Hartmann E, Doares W, Iskandar S, Adams P, Stratta RJ. Hypertension in standard criteria deceased donors is associated with inferior outcomes following kidney transplantation.
Clin Transplant 2011: 25: E437–E446.

Deceased Donor Kidney Transplantation in Patients Aged 70 and Older: Is 70 the New 50?

Background: Deceased donor (DD) kidney transplantation (KT) outcomes in patients who are aged 70 years and older are understudied. Methods: We retrospectively reviewed our single center DD KT outcomes in patients aged 70 years and older. All patients received antibody induction with tacrolimus, half-dose mycophenolate, ± steroids. Results: Over 10.75 years, we performed 114 KTs in 112 patients aged 70 and older (mean 73.8, range 70-84 years) including 42 patients who were aged 75 and older. The study group included 60 males/52 females and 79 Caucasians/28 African Americans/5 other with a mean waiting time of 16 months; 75 patients (66%) received kidneys from expanded criteria donors (ECDs) and 14 received dual KTs. Delayed graft function occurred in 27% and influenced graft but not patient survival. With a mean follow-up of 68 months, patient survival was 59% and uncensored kidney graft survival was 47%. Three year and death-censored kidney graft survival rates were 76% and 74%, respectively. Outcomes were similar in patients < or ≥ 75 years. Of 60 graft losses, death with a functioning graft (DWFG) accounted for 41 (68%). Of 46 deaths, 72% were due to cardio/cerebrovascular events, infection, or malignancy. At present, 54 of the 66 surviving patients (81.8%) have functioning grafts. The incidences of acute rejection and major infection were 14% and 45%, respectively. Conclusions: Advanced recipient age has a modest effect on medium-term outcomes in appropriately selected elderly patients using predominantly ECD kidneys, which may not be appropriate for younger patients. However, medium-term outcomes are largely influenced by a higher incidence of DWFGs in the elderly, suggesting that matching strategies for kidney and patient longevity are warranted.