Genetic, Environmental & Histologic Basis for Kidney Disease Risk among Persons Living with HIV

摘要 美国有超过110万人携带人类免疫缺陷病毒(HIV) 感染，估计有30%的艾滋病毒携带者(PLWH)有慢性肾脏疾病的证据 (CKD)。与普通人群相比，PLWH中终末期肾病(ESRD)的发生率为 透析死亡率增加10倍，死亡率增加19倍。PLWH中CKD的贡献者包括共病 与未感染的人群、艾滋病毒特异性因子和基因变异共享；然而， 这些不同的决定因素仍然没有完全被理解。PLWH现有CKD风险预测工具 对临床决策敏感度低，阳性预测值不足。冒险的能力- 对PLWH进行分层，并区分CKD未来发展的高危人群和低风险人群 对于优化护理和患者结果至关重要。高危PLWH可作为延缓CKD的干预措施 进展和提高存活率，包括及早建立肾病护理和转诊 移植；虽然识别低风险的人可以发展活体捐赠者选择 PLWH特有的框架，有效地将艾滋病毒+对艾滋病毒+的移植扩大到包括活体捐赠者。我们 假设艾滋病毒对慢性肾脏病风险的影响因共病条件、艾滋病毒和其他疾病的相互作用而异。 存在高、低CKD风险的PLWH的相关因素、遗传变异和不同的表型。至 更好地理解这种关系，我们将利用艾滋病中心的综合研究网络 临床系统(CNICs)，一个独特的预期临床队列，有34,000名参与者，并将解决 以下是独特的目标：(1)探索独特的艾滋病毒相关过程和临床之间的联系 CKD的风险特征；(2)探讨基因变异与CKD风险的关系； 将组织学发现与遗传风险相关联；以及(3)开发一种预测PLWH中CKD风险的工具。 按风险分层对慢性肾脏病的未来发展至关重要，以确定哪些PLWH风险最高， 将受益于移植和风险最低的患者的早期肾脏护理和转诊 有资格获得活体肾脏捐赠。利用代表美国艾滋病毒人群的PLWH现有队列， 对于时变的数据和用于基因分型的DNA，通知CKD风险预测是必要的、实用的和 小说。我们的发现将有助于对艾滋病毒与肾脏疾病风险之间的关系提供新的见解。

SUMMARY More than 1.1 million people in the United States (US) are living with human immunodeficiency virus (HIV) infection, and an estimated 30% of people living with HIV (PLWH) have evidence of chronic kidney disease (CKD). Compared to the general population, the rate of end-stage renal disease (ESRD) among PLWH is tenfold greater and mortality on dialysis is 19-fold higher. Contributors to CKD in PLWH include comorbidities shared with the uninfected population, HIV-specific factors, and genetic variants; however, the interplay of these various determinants remains incompletely understood. Existing CKD risk prediction tools for PLWH have low sensitivity and insufficient positive predictive value for clinical decision-making. The ability to risk- stratify PLWH and distinguish those at highest risk for future development of CKD from those at low risk is critical to optimize care and patient outcomes. PLWH at high risk can be targeted for interventions to slow CKD progression and improve survival, including earlier establishment of nephrology care and referral for transplantation; while identification of those at low risk allows for the development of a living donor selection framework specific to PLWH, effectively expanding HIV+ to HIV+ transplantation to include living donors. We hypothesize that the impact of HIV on CKD risk varies by the interplay between comorbid conditions, HIV- related factors, and genetic variants, and distinct phenotypes of PLWH with high and low CKD risk exist. To better understand this relationship, we will leverage the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a unique prospective clinical cohort with > 34,000 participants, and will address the following unique aims: (1) to explore the association of unique HIV-related processes and clinical characteristics with risk for CKD; (2) to explore the association of genetic variants with risk for CKD and correlate histologic findings with genetic risk; and (3) develop a tool for predicting CKD risk among PLWH. Stratification by risk for future development of CKD is critical for identifying those PLWH at highest risk that would benefit from early nephrology care and referral for transplantation and those at lowest risk that could be eligible for living kidney donation. Using an existing cohort of PLWH representative of the US HIV population, with time varying data and DNA for genotyping, to inform CKD risk prediction is necessary, practical, and novel. Our findings will contribute new insights into the relationship between HIV and risk for kidney disease.