The Impact of Kidney Development on the Life Course: A Consensus Document for Action

The Impact of Kidney Development on the Life Course: A Consensus Document for Action

Hypertension and chronic kidney disease (CKD) have a significant impact on global morbidity and mortality. The Low Birth Weight and Nephron Number Working Group has prepared a consensus document aimed to address the relatively neglected issue for the developmental programming of hypertension and CKD. It emerged from a workshop held on April 2, 2016, including eminent internationally recognized experts in the field of obstetrics, neonatology, and nephrology. Through multidisciplinary engagement, the goal of the workshop was to highlight the association between fetal and childhood development and an increased risk of adult diseases, focusing on hypertension and CKD, and to suggest possible practical solutions for the future. The recommendations for action of the consensus workshop are the results of combined clinical experience, shared research expertise, and a review of the literature. They highlight the need to act early to prevent CKD and other related noncommunicable diseases later in life by reducing low birth weight, small for gestational age, prematurity, and low nephron numbers at birth through coordinated interventions. Meeting the current unmet needs would help to define the most cost-effective strategies and to optimize interventions to limit or interrupt the developmental programming cycle of CKD later in life, especially in the poorest part of the world.

This consensus document aims to address the relatively neglected issue of the developmental programming of hypertension and chronic kidney disease (CKD). It emerged from a workshop, entitled The Fault Is Not in Our Stars but May Be in Our Embryos – Glomerular Number in Low Birth Weight Babies, held at the Clinical Research Center for Rare Diseases Aldo e Cele Daccò, IRCCS – Mario Negri Institute for Pharmacological Research, Bergamo, Italy, on April 2, 2016, including eminent internationally recognized experts in the field of obstetrics, neonatology, and nephrology (see Appendix). The goal of the workshop through multidisciplinary engagement was to highlight the association between fetal and childhood development and an increased risk of adult diseases, focusing on hypertension and CKD, and to suggest possible practical solutions for the future. Low birth weight (LBW), growth restriction, and preterm birth are the most consistent clinical surrogates for low nephron numbers and are associated with an increased risk of hypertension, proteinuria, and kidney disease later in life. This relationship is amplified by the development of acute kidney injury (AKI) in preterm infants, which may further reduce nephron numbers soon after birth, as well as by rapid catch-up growth or overfeeding during infancy or childhood in children born small, which may further augment the risk of hypertension and CKD and predispose to obesity and type 2 diabetes later in life. Many questions about the developmental origins of chronic renal disease, possible nutritional and pharmacologic interventions, as well as strategies for optimal follow-up and management of vascular, metabolic, and renal functions remain unanswered. The working group has discussed in depth how to raise awareness about developmental programming and renal disease risk later in life, and practical, locally adaptable preemptive strategies were suggested that could have long-term benefits in terms of future kidney health and cost saving worldwide. The discussion ended with the consensus recommendations presented here. This document is well aligned with the recent emphasis on a “life course” approach outlined by the World Health Organization (WHO) in the Minsk Declaration and the Global Action Plan for the Prevention and Control of Noncommunicable Diseases (NCD) [1, 2]. In both documents, the need to begin to prevent later-life chronic disease even before conception is emphasized, but specific recommendations beyond general nutritional interventions have not yet been made [3]. In turn, the life course approach aligns with the targets proposed by the United Nations 2030 Agenda for Sustainable Development, where a much broader approach is advocated to maintain health, and many goals are highly relevant to renal development and kidney disease [4].

The WHO endorsed the Global NCD Action Plan in 2008 in response to growing recognition that NCD have replaced communicable diseases as the predominant causes of premature mortality worldwide [2]. Nevertheless, the global burden of NCD has been relatively neglected by policy makers, major aid donors, and academics until recently, given the global push to address communicable diseases over the past decade which diverted funds from NCD [5]. The NCD Action Plan aims to reduce premature mortality from cardiovascular disease (CVD), diabetes, cancer, and chronic lung disease by 25% by 2020 and emphasizes prevention as a crucial strategy to reduce NCD [2]. A “life course approach” is suggested as 1 of 9 overarching approaches for the prevention of NCD and has been highlighted in the recent Minsk Declaration, reflecting the increasing realization that early development is a determinant of later-life health and disease [1, 2]. Optimizing early development provides the chance for true primary prevention of NCD with major potential multiplier effects on overall health and well- being throughout life [4].

The worldwide prevalence of chronic diseases is projected to increase substantially over the next few decades [6]. For example, according to the International Diabetes Federation, the worldwide prevalence of diabetes is predicted to rise from 415 to 642 million between 2015 and 2040 [7]. In addition, by 2025, more than 75% of the world's diabetic population will reside in low- and middle-income countries (LMIC) [8]. Similarly, the prevalence of ischemic heart disease has almost doubled globally between 1990 and 2013 [9]. Although age-standardized mortality rates attributed to NCD have fallen worldwide, NCD remain the leading cause of death in the world, as shown by the 42% increase in the number of NCD-related deaths from 27 to 39.8 million between 1990 and 2015 [10]. Thus, the social, economic, and public health consequences of the expected increase in most NCD could have devastating consequences especially for LMIC.

CKD is a key determinant of poor health outcomes for major NCD and has a risk-multiplier effect on CVD [11]. Recent findings from the Global Burden of Disease Study have highlighted CKD as an important cause of global mortality [10]. The number of reported deaths due to CKD was estimated to be 1.2 million, a 32% increase from 2005, with deaths from diabetic and hypertensive kidney disease comprising over 75% of these deaths [10]. The prevalence of end-stage kidney disease (ESKD) patients receiving renal replacement therapy (RRT) with maintenance dialysis has increased 1.7 times from 165 patients per million population in 1990 to 284 patients per million population worldwide in 2010 [12]. The number of people who will receive RRT (dialysis or transplantation) worldwide has been projected to more than double from 2.6 to 5.4 million from 2010 to 2030 [13]. Notably, it has been estimated that between 2.3 and 7.1 million people who could have been kept alive with RRT in 2010 died prematurely because they did not have access to the treatment [13]. Most of these deaths occurred in Asia, Africa, and Latin America, where RRT remains unaffordable [11]. With a population that is aging, steep increases in the worldwide incidence of type 2 diabetes mellitus and hypertension are driving the growth in the CKD burden, putting an enormous pressure on health care resources [11]. ESKD is only the tip of the iceberg. CKD occurs in approximately 10% of the population [11]. While the true prevalence of CKD in many LMIC countries remains ill defined [14], in industrialized countries CKD affects more disadvantaged populations and ethnic minorities and, therefore, causes a disproportionate burden on the poor [11]. Kidney disease is, therefore, a global public health priority. Given the very high individual and societal costs of treatment, prevention is the most effective strategy to sustainably address the growing global burden of kidney disease.

The large individual variability in susceptibility to kidney disease and other NCD remains unexplained. Genetic predisposition and environmental exposures are contributory factors, but increasingly it is being recognized that fetal development is also an important modulator of the NCD risk. The quality and quantity of nutrition received during fetal life, exposure to pollutants, drugs, and infections during gestation, as well as the mother's health while she is pregnant, all impact fetal kidney development [15]. Perinatal exposures and nutrition as well as early childhood growth are also important. Since the first observations that adults who were born with LBW (defined as a birth weight