Malnutrition in Kidney Allograft Recipients Treated with Mycophenolate Mofetil is Associated with IMPDH1 rs2278294 Polymorphism.
Joanna Pazik1, Zbigniew Lewandowski2, Ewa Nowacka-Cieciura1, Monika Ołdak3,4, Marta Podgórska3, Anna Sadowska1, Jacek Malejczyk3, Magdalena Durlik1.
1Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland; 2Department of Epidemiology and Biostatistics, Medical University of Warsaw, Warsaw, Poland; 3Department of Histology and Embryology, Medical University of Warsaw, Warsaw, Poland; 4Department of Genetics, Institute of Physiology and Pathology of Hearing, Warsaw, Poland
Introduction: The exposure to mycophenolic acid (MPA) and drug effects might be due to inosine 5'-monophosphate dehydrogenase (IMPDH1) polymorphisms.
Formation of lipid bodies in adipocytes associates with IMPDH translocation into those structures. In the mouse model of diet-induced obesity, MMF induced loss of body weight and fat content. Our study aims to evaluate whether IMPDH1 polymorphism rs2278294 correlates with malnutrition in kidney recipients treated with mycophenolate mofetil (MMF).
Patients and Methods:
– 240 kidney recipients engrafted 1996-2009, longitudinal observation lasting at least five post-implantation years, treated with mycophenolate mofetil and either tacrolimus (n=100; 42%) or cyclosporine A (n=139; 58%).
– BMI was calculated at 3,6,12, 24 and 60th post-transplant months.
– Minimal BMI within three post-transplant months was regarded as baseline value .
– SNP genetic variants of IMPDH1 (rs2278294) were genotyped by PCR-RFLP method.
– Mixed models for repeated measurements after adjustment for baseline factors were used to test relation between rs2278294 polymorphism of IMPDH1 and BMI in 5 years follow-up (MIXED Procedure of SAS System).
Results: Genotypes frequencies for rs2278294 polymorphism of IMPDH1 were as follow: 27(11%) of AA homozygotes, 91(38%) GA heterozygotes and 122(51%) GG homozygotes
In the subset of recipients with initially normal or diminished BMI(≤25kg/m2) there was a substantial increase of BMI at 6,12, 24 and 60 th post-tx months. Moreover, BMI increase was correlated with rs2278294 polymorphism of IMPDH1.
Among allele G carriers (GG or GA) BMI gain was significantly slower than in AA homozygotes (p<0.0025; interaction effect). Mean values of BMI(kg/m2) at 3,6,12, 24 and 60 th months were as follow: 22.0 vs 22.5; 22.6 vs 23.6; 23.1vs 24.5; 23.6 vs 24.9 and 24,1 vs 24.8 kg/m2 in (GG or GA) and AA carriers, respectively.
In cosequence, among G allele carriers 5% experienced seriously diminished BMI fulfilling malnutrition criteria (18.2, 18.2, 18.8 and 18.8 , 19 kg/m2 at 3,6,12 24 and 60 th post-transplant months).
In G allele carriers mycophenolate mofetil dimunition or withdrawal resulted solely in preserving the subset of patients prone to malnutrition.
Conclusions: Since the effect of rs2278294 on BMI was found at transplantation and persisted until 5th post-implantation year, we hypothesize that the variant of interest influences fat-tissue formation in humans.
