Prediction Of Renal Prognosis In Chinese Patients With Autosomal Dominant Polycystic Kidney Disease By Refining Genotype-Phenotype Correlation

BackgroundAutosomal dominant polycystic kidney disease(ADPKD)is the most common inherited kidney disease.About 50%of patients progress to end-stage renal disease in middle age.Previous studies have shown that the prognosis of ADPKD is related to its genotype,mutation type and mutation location.Clarifying the ADPKD related gene information of patients is helpful to improve the clinical diagnosis,guide the treatment of ADPKD and evaluate renal prognosis.However,the current reports on ADPKD-related gene mutations and clinical phenotypes are mainly from Western countries,and there are few genotype-phenotype studies in Asian ADPKD populations.Based on the above background,we analyzed the differences of renal prognosis in Chinese ADPKD population from the perspective of genotype,mutation type and mutation location.MethodsWe retrospectively detected PKD1 and PKD2 mutations in 115 patients with ADPKD(proband)recorded in the outpatient and inpatient systems of the Nanfang Hospital of Southern Medical University(Guangzhou,China)betweenNovember 2017 and July 2018 using NGS-targeted exome sequencing and LR-PCR.Data were collected including baseline demographic data(date of birth,sex),age at diagnosis of ESRD and initiation of renal replacement therapy(RRT),and family history of ESRD/ADPKD.We collected the peripheral blood of probands and detected ADPKD-related mutations by next-generation sequencing(NGS)targeted exon sequencing and long-range polymerase chain reaction(LR-PCR).genetic information,including genotype(PKD1 and PKD2 mutations),mutation type(truncating mutations:nonsense,frameshift,splice mutations;non truncating mutations:Missense,in-frame,synonymous,atypical splicing mutations)and mutation location.The correlation between them and renal prognosis of ADPKD patients was analyzed.ResultsAmong the 115 probands,76.52%(88/115)carried PKD1 mutations,12.17%(14/115)carried PKD2 mutations,and 11.30%(13/115)had no PKD1/PKD2 mutation detected.In the PKD1 cohort,62.50%(55/88)were truncating mutations(PKD1-T),and 69.3%(61/88)were novel mutations;In the PKD2 cohort,92.85%(13/14)were truncating mutations(PKD2-T),and 21.4%(3/14)were novel mutations.69.6%(80/115)of probands developed ESRD and had undergone RRT,and 66.09%(76/115)of probands had a family history of ADPKD.In the gene-phenotype correlation study,the comparison of the renal survival curves of PKD1 mutation carriers and PKD2 mutation carriers showed that the prognosis of PKD1 mutation carrers was significantly lower than that of PKD2 mutation carriers(median age at initiation of RRT,54 versus 58 years,respectively)(P=0.0208).A detailed assessment of mutation types revealed that ADPKD probands with nonsense mutations in PKD1 truncating mutations had significantly worse renal survival than non-PKD1 nonsense mutation carriers,with a median age at initiation of RRT of 49,56(among non-PKD1 nonsense mutation carriers in the entire cohort),55 years(among non-PKD1 nonsense mutation carriers in the PKD1 cohort)(P1=0.0055;P2=0.0283).While gender and mutation location did not significantly affect renal prognosis in ADPKD patients.Two thirds of patients with PKD2 mutations required renal replacement therapy before the age of 58 years.Simultaneous univariate Cox regression analysis in the entire cohort revealed that PKD1 and PKD1 nonsense mutations were risk factors for renal outcomes in patients with ADPKD(P<0.05).ConclusionsIn summary,we found that in the Chinese population,different types of mutations in PKD1 and PKD2 were associated with different renal prognosis.In the entire cohort,PKD1 mutation carriers had poor renal prognosis;Among PKD1 truncating mutation carriers,nonsense mutations have a poor renal prognosis.The study also confirmed that the Chinese ADPKD population appears to enter ESRD earlier than the international ADPKD patient,and it was also confirmed that renal prognosis was not always favorable in patients with PKD2 mutations.Detailed assessment of mutation type may help predict renal prognosis in ADPKD patients.Although ADPKD is still diagnosed based on its imaging criteria and family history,genetic diagnosis of ADPKD patients can help to stratify the ADPKD population,which is helpful to predict the progression of the disease,and timely intervene and guide treatment.It is of great significance to achieve the personalization of patient treatment and care.