**2. Human Evidence for Developmental Programming of CKD**

The development of the human kidney starts at week 3 and ends at week 36 of gestation [31]. Hence, term neonates are born with a full complement of nephrons. In

each kidney, the average number of nephrons, the basic unit of a kidney, is approximately 1 million with 10-fold interindividual differences [32]. Adverse in utero events could interfere with nephrogenesis, resulting in a reduction of nephron numbers and a wide range of congenital anomalies of the kidney and urinary tract (CAKUT) [33]. Reduced nephron number causes glomerular hyperfiltration and compensatory glomerular hypertrophy, consequently initiating a vicious cycle of further nephron loss [34]. Accordingly, reduced nephron number could act as a first trigger to increase the offspring's vulnerability to CKD throughout their later life.

Strong support for the developmental programming of CKD came from a number of epidemiological studies. Premature birth and low birth weight (LBW) are significant risk factors for CKD in later life [35–38]. A meta-analysis study recruiting more than 2 million babies revealed that LBW babies were 70% more likely to develop CKD in later life than those with normal birth weight [36]. In addition to premature birth and LBW, a case–control study of 1.6 million infants revealed that maternal gestational diabetes, maternal thalassemia/hemochromatosis, male gender, polyhydramnios or oligohydramnios, and first pregnancy are also risk factors for CAKUT [37]. Another case–control study recruiting 2000 CKD children acknowledged several early-life risk factors, such as LBW, prematurity, gestational diabetes, and maternal obesity, showed an increased risk of CKD in adult life [38]. As we reviewed elsewhere, a number of environmental risk factors are related to the developmental programming of CKD, such as maternal illness, nutritional imbalance, environmental chemicals, medication use, substance abuse, infection, and exogenous stress [4]. For example, maternal obesity and diabetes are correlated with an increased risk of kidney disease in adulthood [39,40]. Additionally, deficiencies in maternal total energy [41], folate [42], and vitamin A [43] during pregnancy were associated with detrimental influence on kidney structure and function. Epidemiological studies also showed that maternal exposure to polycyclic aromatic hydrocarbon, per- and polyfluoroalkyl substances, and polycyclic aromatic hydrocarbon, as well as air pollution associated with premature birth and LBW [44–47], are both risk factors for low nephron number. Moreover, a number of drugs administrated to pregnant women have been known to affect kidney development, resulting in CAKUT [48]. These medications include angiotensin converting enzyme inhibitor, angiotensin receptor blockers, aminoglycosides, cyclosporine A, dexamethasone, furosemide, anti-epileptic drugs, cyclophosphamide, etc. [48].

Although the risk of CKD has been evaluated in plenty of human studies, interventions required to prove causation and to elucidate underlying molecular mechanisms remain unknown. Most of our knowledge regarding the critical window of vulnerability for insults, the types of insults driving renal programming, potential core mechanisms behind renal programming, and therapeutic strategy arise out of studies in animal models.
