Keywords

Introduction

Renal development is tightly regulated (Challen et al. 2005), and human nephrogenesis starts by the tenth postconceptional week (Quigley 2012). In term-born children, the number of nephrons is determined at birth, whereas in preterm infants, nephron number may still increase postnatally (Sutherland et al. 2011; Fanni et al. 2012). Epidemiologic studies have linked intrauterine and early childhood conditions to unfavorable course of glomerulopathies (Zidar et al. 1998; Sheu and Chen 2001), decreased renal function in adulthood (Hallan et al. 2008), and increased risk of end-stage renal disease (Vikse et al. 2008). Serial ultrasound measurements of the kidney in a cohort of small for gestational age (SGA) infants revealed a marked reduction of renal growth rate compared to controls between 26 and 34 weeks of gestation, which suggests that the third trimester could be a critical period of renal programming (Konje et al. 1996). Although a variety of environmental conditions may influence nephrogenesis, adequate nutrition counts among the key factors ensuring undisturbed renal development (Fanni et al. 2012).

Generally, altered intake of macro- or micronutrients during critical developmental windows may lead to long-lasting effects on organ development, organ function, and susceptibility toward disease. In order to elucidate the mechanisms underlying dietary programming of renal disease, numerous animal models have been developed. Most authors have worked with rats in which kidney development is not completed before the second week of postnatal life (Neiss and Klehn 1981). The effects of dietary influences on renal outcome have been studied in a large variety of experimental settings like low-protein diet during gestation (Zeman 1968; Langley-Evans et al. 1999), calorie restriction during gestation (Bregere et al. 2010), maternal (Yamada-Obara et al. 2016) or postnatal high-fat diet (Aliou et al. 2016), maternal sodium overload (Cardoso et al. 2009), or postnatal hypernutrition (Boubred et al. 2007).

Regarding precise molecular mechanisms, a critical role of the renin-angiotensin system has been established (Woods et al. 2001; Bogdarina et al. 2007). However, programming of renal disease is a very complex process which cannot be explained by single dysregulated genes. The following article gives an overview on current knowledge of dietary programming of renal disease (Figs. 1, 2, 3, 4, and 5).

Fig. 1
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Dietary programming of renal function. Schematic overview presenting the concept of dietary programming of renal function

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Fig. 2
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Important aspects of intrauterine supply. Schematic overview presenting important aspects of intrauterine supply with regard to dietary programming of renal function

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Fig. 3
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Important aspects of postnatal supply. Schematic overview presenting important aspects of postnatal supply with regard to dietary programming of renal function

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Fig. 4
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Mutual interaction between kidney morphology and kidney function in the context of programming. Schematic overview presenting the mutual interaction between kidney morphology and kidney function in the context of programming

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Fig. 5
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Mechanisms contributing to dietary programming of renal function. Schematic overview presenting mechanisms contributing to dietary programming of renal function

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Effects of Dietary Intake During Gestation

Nutrient Deficiency During Gestation

Over the last decades, epidemiologists have studied the effects of exposure to famine during gestation on adult health parameters. Thus, it could be shown that the prevalence of microalbuminuria was elevated in adult persons aged 48–53 years who had been exposed to the Dutch Hunger Winter 1944/1945 during midgestation (Painter et al. 2005). Women born in rural areas during the Chinese famine years of 1959–1961 also had higher levels of proteinuria in their forth decade of life compared to women born before or after the famine (Huang et al. 2014).

Male rat offspring exposed to a multideficient diet in utero showed elevated plasma volume, blood pressure, and parameters of oxidative stress in the kidney (Magalhaes et al. 2006). In a baboon model, calorie restriction (CR) during gestation reduced tubular density (Cox et al. 2006) and altered fetal expression of genes affecting renal mitochondrial energy metabolism (Pereira et al. 2015). However, there is also some evidence for a potential beneficial effect of CR during gestation. A study in sheep suggested that CR in early gestation may provide protective effects against obesity-related nephropathy in the offspring by modulating the inflammatory system (Sharkey et al. 2009).

Low-Protein Diet During Gestation

The specific effect of protein restriction during gestation was tested in animal models. In 1968 already, Frances Zeman subjected rat dams to a casein restriction throughout gestation (6% vs. 24% in controls). Pups were sacrificed immediately after birth, and the kidneys were processed for histological studies. Kidneys from protein-restricted animals were characterized by fewer and less well-differentiated glomeruli, a greater proportion of connective tissue, and relatively fewer collecting tubules. Three decades later, Langley-Evans and colleagues studied different groups of rat offspring exposed to 9% casein restriction either throughout gestation or for single-week periods (days 0–7, 8–14, 15–22 of gestation). Controls were fed a diet containing 18% casein. At birth, nephron number was significantly reduced in offspring exposed to low-protein diet during the second and third weeks of gestation only. This indicates that the impact of protein deficiency depends on the window of exposure (Langley-Evans et al. 1999).

However, low-protein (LP) diet during gestation resulted in reduced nephron numbers in most studies with the exception of protein restriction during early pregnancy only (Jones et al. 2001; Woods et al. 2001, 2004; Siddique et al. 2014). Depending on the exact model and the time point investigated, many studies also demonstrate elevated arterial blood pressure (Langley-Evans et al. 1999; Woods et al. 2004; Black et al. 2015; Lozano et al. 2015) and reduced glomerular filtration rate (Nwagwu et al. 2000; DuBois et al. 2014; Lozano et al. 2015). Microvascular rarefaction, as shown in a sheep model, may contribute to these findings (Lloyd et al. 2012). Further functional restrictions in adult LP rat offspring were demonstrated in a study evaluating the furosemide diuretic response during adulthood. The extent of diuresis was decreased in both male and female LP animals (DuBois et al. 2014) indicating altered tubular function. In addition, low-protein animals may have less regenerative capacities to recover from secondary renal injury (Plank et al. 2006).

High-Salt Diet During Gestation

Human data on kidney function of children exposed to defined amounts of sodium chloride during gestation is not available. Kidney outcome in rat offspring whose mothers were exposed to water containing 1% sodium chloride throughout gestation was studied at the age of 3 months. Interestingly, only urinary protein excretion was increased in the saline group, whereas the number of nephrons, blood pressure, renal hemodynamics, and renal oxidative stress were not different between the groups. If the dams were also maintained on saline during lactation, the effect on the renal phenotype in the offspring was more prominent. These animals also had a reduced glomerular filtration rate, signs of oxidative stress, and an increase in plasma volume (Cardoso et al. 2009). In another study, both low-sodium (0.07% NaCl) and high-sodium (3%) diet throughout gestation and lactation caused reduced glomerular number. In addition, high-salt (3%) offspring developed arterial hypertension (Koleganova et al. 2011). Adult offspring exposed to 4% NaCl diet throughout gestation and lactation developed hypernatremia and elevated plasma levels of corticosterone. Blood pressure was only elevated in male offspring (Gray et al. 2013). In ewes fed a high-salt diet, kidney weight to body weight ratio was reduced in the offspring going along with changes in the renal and systemic renin-angiotensin-aldosterone system (Chadwick et al. 2009, Mao et al. 2013).

Maternal Obesity and High-Fat Diet During Gestation

Epidemiologic studies suggest that there is an association between maternal obesity and elevated systolic blood pressure in midchildhood (Perng et al. 2014). In addition, a preconceptional body mass index of greater than 30 kg/m2 was identified as a risk factor for bilateral renal aplasia/hypoplasia (Slickers et al. 2008).

Consistent with these findings, rat offspring exposed to high-fat diet during gestation and weaned to normal-fat diet developed arterial hypertension. On the molecular level, permanent changes in key RAAS elements were dependent on the exact window of exposure (Guberman et al. 2013). In another study, rat offspring exposed to a lard-rich diet during gestation had reduced renal renin activity and Na+, K+−ATPase enzyme activity at 180 days of age (Armitage et al. 2005). Both in utero and postnatal exposure of rats to high-fat diet induced glomerulosclerosis and tubulointerstitial fibrosis at 17 weeks of age going along with albuminuria (Jackson et al. 2012).

Micronutrient Deficiency During Gestation

Small epidemiologic studies suggest that maternal vitamin A deficiency might be associated with reduced renal volume in the neonate (Goodyer et al. 2007; El-Khashab et al. 2013).

This hypothesis is supported by the observation that vitamin A deprivation during rat gestation induced a nephron deficit in the offspring (Lelievre-Pegorier et al. 1998). A similar effect was demonstrated in rat models of iron and zinc deficiency during gestation. Adult offspring of iron-deficient dams had reduced glomerular density and arterial hypertension (Lisle et al. 2003). Zinc deficiency during gestation and postweaning period caused a nephron deficit, increased systolic blood pressure, and decreased glomerular filtration rate going along with signs of oxidative stress, fibrosis, and increased apoptosis. Postweaning normalization of zinc only partially normalized these findings (Tomat et al. 2008).

Substance Use During Gestation

It is general knowledge that substance use during gestation can have negative influence on the health and well-being of the offspring. Although alterations in organ development and function are often considered as toxic effects in the first line, there is an overlap between toxic and programming effects during critical developmental windows.

In a large human cohort study, maternal smoking showed a dose-dependent effect on fetal kidney volume (Taal et al. 2011). Continued maternal smoking during pregnancy was associated with lower eGFR in school-aged children, whereas smoking during the first trimester was only associated with a higher risk of microalbuminuria (Kooijman et al. 2015). Another epidemiological study demonstrates that smoking during the periconceptional period may increase the risk of bilateral renal aplasia/hypoplasia. The same study also identified binge drinking during the second month of pregnancy as a risk factor for renal agenesis/hypoplasia (Slickers et al. 2008). In animals, ethanol exposure on two occasions during rat gestation induced low nephron number and elevated arterial blood pressure in the offspring (Gray et al. 2010). Rat metanephroi cultured in the presence of ethanol showed less ureteric branching and reduced glomerular numbers. Coculture with retinoic acid ameliorated these findings (Gray et al. 2012). In sheep, repeated alcohol exposure during the second half of gestation similarly reduced nephron numbers in the offspring (Gray et al. 2008).

Rat offspring exposed to 120 mg/kg of caffeine daily during gestation developed significant renal alterations indicative of glomerulosclerosis and interstitial fibrosis. In detail, the authors observed thickening of the glomerular basement membrane, expansion of the mesangium, partial tubular atrophy, and ultrastructural damage of podocytes. On the molecular level, low renal angiotensin II receptor type 2 expression was present in both fetal and adult offspring (Ao et al. 2015).

Effects of Altered Dietary Intake in the Postnatal Period

Early Nutrition

There is growing evidence that early nutrition as represented by early weight gain is an important modulator of adult blood pressure and kidney function.

Epidemiologic data suggest that not only prenatal but also postnatal growth patterns are associated with adult blood pressure (Ben-Shlomo et al. 2008). In a large US multicenter cohort study, pronounced catch-up growth in small for gestational age (SGA) babies resulted in an increased risk of arterial hypertension. Since lack of catch-up growth was associated with an increased risk of infection and low IQ, the authors suggested that rapid catch-up growth to the 30th centile during the first months of life and slower catch-up growth up to the 50th centile might be ideal (Lei et al. 2015). Another SGA cohort study observed that nutrition with a protein-enriched formula during the first months of life was associated with increased diastolic and mean arterial blood pressure values at 6–8 years of age.

In a rat model of placental insufficiency, cross-fostering the restricted offspring to control dams ameliorated both renal morphology and blood pressure in adulthood. Restricted pups raised by their own mothers developed arterial hypertension and reduced nephron number. Cross-fostering restricted pups to control mothers normalized nephron number and prevented the development of arterial hypertension (Wlodek et al. 2007). In another study, offspring exposed to LP diet prenatally and cross-fostered to foster dams receiving standard diet did not develop elevated blood pressure and presented with normal glomerular filtration rate in adulthood (Lozano et al. 2015). Conversely, offspring from standard diet dams cross-fostered to a low-protein foster mother (NP/LP) developed arterial hypertension. On the molecular level, the latter group had increased renal NKCC2 and NCC cotransporter expression which was not present in a LP/LP group. Both NP/LP and LP/LP offspring had elevated plasma renin and angiotensin II levels (Siddique et al. 2014).

However, control rats exposed to early hypernutrition induced by litter-size reduction developed significantly increased systolic blood pressure and proteinuria (Boubred et al. 2007) and decreased glomerular filtration rate (Alcazar et al. 2012). On the morphological level, the number of nephrons was increased, but there was enhanced glomerulosclerosis (Boubred et al. 2007). Mechanistically, this was accompanied by SOCS-3-mediated intrinsic renal leptin resistance (Alcazar et al. 2012). When litter-size reduction was performed in offspring exposed to LP diet in utero, the animals similarly developed arterial hypertension and glomerulosclerosis, but nephron number was reduced (Boubred et al. 2009).

Postnatal Calorie Restriction

In a mouse model, calorie restriction (CR) mitigated the effects of renal aging. Thus, CR mice had decreased glomerular basement membrane thickening and autophagy. Interestingly, a modulation of dietary fat composition had additional beneficial effects (Calvo-Rubio et al. 2016). In another study investigating the effect of calorie restriction on renal ischemia reperfusion injury, CR showed dose-dependent protective effects. Protein restriction (PR) in addition to CR further improved renal outcome. From a mechanistic point of view, the authors provide evidence that altered activation of AMPK and mTORC1 could play a crucial role and that administration of leptin mitigates the beneficial effects of CR/PR (Robertson et al. 2015).

Postnatal High-Salt Diet

In a rat study, challenge with drinking water containing 2% sodium chloride from postnatal week 12 until postnatal week 16 did not alter blood pressure or renal function in control animals. In contrast, former IUGR offspring developed sodium-dependent hypertension, reduced glomerular filtration rate, and albuminuria (Sanders et al. 2005).

Postnatal High-Fat Diet

Adult mice fed a high-fat diet (HFD) for 14 weeks developed significant proteinuria. Renal gene expressions of renin, angiotensin-converting enzyme, and tubular injury markers NGAL and KIM-1 were elevated. Protein expressions of ER stress markers BiP and CHOP were also increased (Li et al. 2016). In another mouse model, long-term HFD for 28 weeks resulted in enhanced mitochondrial damage in podocytes, proximal tubules, and endothelial cells. Furthermore, infiltration with CD68+ macrophages was increased, and proinflammatory markers were upregulated. Treatment with SS-31 which protects mitochondrial cristae structure mitigated all these effects (Szeto et al. 2016). In rats, high-fat diet induced proteinuria and ultrastructural changes in podocyte morphology. On the molecular level, the authors observed changes in the expression of proteins relevant for podocyte function like desmin, nephrin, and CD2AP (Chen et al. 2016).

Postnatal Micronutrient Deficiency

Vitamin D levels are known to be reduced in many different clinical settings. In a population-based cohort study, low plasma 25-hydroxyvitamin D levels were associated with an increased risk of developing albuminuria (Keyzer et al. 2015). However, in another population, these findings could not be confirmed (Guessous et al. 2015). In rodents, it could be shown that 1,25-vitamin D3-deficient animals develop podocyte injury (Sonneveld et al. 2016). In these mice, a slit diaphragm protein expressed by podocytes (TRPC6) was upregulated. Administration of 1,25-D3 brought TRPC6 expression back to normal and normalized podocyte morphology and urinary protein excretion (Sonneveld et al. 2013).

In a lacto-vegetarian population, the role of micronutrient deficiency was studied in the context of arterial hypertension. Data analysis revealed that low intake of vitamin C, folic acid, and zinc may increase the risk of developing arterial hypertension (Chiplonkar et al. 2004).

Molecular Mechanisms of Dietary Renal Programming

Regarding molecular mechanisms of dietary renal programming, there is strong evidence for a critical role of the renin-angiotensin-aldosterone system (RAAS), although study results are partly contradictory.

In newborn low-protein rat pups, renal renin gene and protein expression was significantly suppressed (Woods et al. 2001). In the adrenal gland of neonatal LP rats, gene expression of the angiotensin II receptor type 1b was upregulated (Bogdarina et al. 2007). At 4 weeks of age, male LP rats responded with a greater decrease in glomerular filtration rate when challenged with a bolus of enalapril followed by an infusion of angiotensin II. In the kidney, angiotensin II receptor type I expression was increased (Sahajpal and Ashton 2003). At 4 and 13 weeks of age, plasma angiotensin-converting enzyme (ACE) activity in LP offspring was elevated going along with increased systolic blood pressure. Renin activity in these animals was normal, and plasma angiotensin II concentrations were only slightly elevated (Langley-Evans and Jackson 1995).

High-salt diet (8% NaCl) during the second half of gestation in ewes induced decreased plasma angiotensin II levels in fetal offspring which normalized postnatally. Gene expressions of AGT, AT1, AT2, and ACE were elevated during fetal life and, except for AT2, decreased at postnatal day 90 (Mao et al. 2013). In another sheep study, salt-enriched diet (14% NaCl) or grazing saltbush during gestation decreased basal renin activity in the offspring. Challenged with salt, saltbush offspring still had decreased renin activity, whereas renin activity in high-salt offspring normalized (Chadwick et al. 2009). High-fat diet during gestation, lactation, or postweaning specifically influenced RAAS elements in adipose tissue dependent upon the timing of exposure (Guberman et al. 2013; Li et al. 2016). Treatment of human proximal tubule epithelial cells (HK2) with saturated fatty acid palmitic acid induced an increase in the cellular expression of ER stress markers as well as increased angiotensin II concentrations in cultured medium. RAAS blockade with valsartan or aliskiren protected the cells from the development of ER stress (Li et al. 2016). Caffeine exposure during gestation in rats induced downregulation of the angiotensin II receptor type 2 (Ao et al. 2015).

However, not only RAAS components but also other vasoactive substances and blood pressure-regulating systems are nutrient-sensitive. Thus, maternal LP diet in rats reduced renal 11betaHSD2 expression in adult offspring (Bertram et al. 2001). Other mechanisms involved in dietary programming of renal function are oxidative stress (Magalhaes et al. 2006; Tomat et al. 2008; Costa et al. 2016), mitochondrial energy metabolism (Pereira et al. 2015; Szeto et al. 2016), ER stress (Li et al. 2016), and inflammation (Szeto et al. 2016).

Dietary Interventions

A better knowledge of the mechanisms and principles leading to programming of renal disease bears the opportunity to develop strategies with the aim of modifying the long-term effects of unfavorable environmental conditions (“reprogramming”). In addition, this knowledge can also be used to establish interventional approaches to influence the natural course of “nonprogrammed” pathologic conditions.

Most studies on “nutritional reprogramming” of renal disease have been performed in animals. However, there are a couple of interventional studies in humans. In rural Bangladesh, the effect of early food supplementation (608 kcal/day energy and 18 g/day of vegetable protein) and micronutrient supplementation (containing either iron and folate or multiple micronutrients) during pregnancy was studied. Adjusted analysis provided evidence that there is a small but significant positive effect of food supplementation on blood pressure at age 4.5 years. In addition, high-iron supplement was associated with a higher GFR (Hawkesworth et al. 2013). Nepalese children whose mothers had been supplemented with the daily allowance of 15 vitamins and minerals during pregnancy had a slightly lower blood pressure at age 2.5 years than controls (Vaidya et al. 2008). Maternal supplementation with folic acid or folic acid + iron + zinc reduced the risk of developing albuminuria in 6–8-year-old Nepalese children (Stewart et al. 2009). In an Argentinian study, the effect of additional 2 g calcium per day during pregnancy was studied in 5–9-year-old children. Children whose mothers had been assigned to the calcium group had lower systolic blood pressure values (Belizan et al. 1997). Calcium supplementation in a small group of 11-year-old children also provided a small blood pressure-lowering effect (Gillman et al. 1995). In a small European study, supplementation of infant formula with LCPUFAs reduced blood pressure values at 6 years of age compared to standard formula-fed infants (Forsyth et al. 2003).

In animals, most dietary interventions have been performed in the low-protein model of IUGR. Thus, it is obvious that supplementation of single amino acids might have a positive effect. Indeed, supplementation of a low-protein diet with 3% glycine during gestation prevented the development of arterial hypertension in the offspring (Jackson et al. 2002).

Since oxidative stress may significantly impair nephrogenesis and adequate levels of retinoic acid are crucial for normal kidney development (Lee et al. 2012), several studies have focused on the importance of retinoic acid and other antioxidants. In one study, administration of a single dose of retinoic acid (20 mg/kg) during low-protein gestation at embryonic day 11.5 normalized nephron number in the offspring (Makrakis et al. 2007). However, postnatal treatment with retinoic acid in preterm baboons had neither beneficial nor negative effects on glomerular number or glomerular morphology (Sutherland et al. 2009). Supplementation of lazaroid, a lipid peroxidase inhibitor, throughout LP gestation prevented the development of arterial hypertension. In addition, capillary density normalized and measures of vascular function improved (Cambonie et al. 2007). Administration of ACH09, a grape skin extract with antioxidant properties, normalized nephron numbers in LP offspring (Costa et al. 2016).

A further approach is the administration of food or spices with anti-inflammatory properties. Curcumin has been studied in various settings and exerts both anti-inflammatory and antioxidant effects. In a rat model of postnatal kidney damage induced by unilateral ureteral obstruction, there was evidence for the activation of an antiapoptotic mechanism by increased expression of the TRADD-RIP-TRAF complex (Hashem et al. 2016). Another study could demonstrate that curcumin can alleviate diabetic nephropathy by regulating the Wnt pathway (Ho et al. 2016).

Conclusion

Both macro- and micronutrient deficiency and overload during critical developmental windows may significantly impair nephrogenesis and induce susceptibility toward disease. Defining the adequate amount of macro- and micronutrients which is needed for optimal kidney development remains a challenge for the future.

Mini-dictionary of Terms

  • Blood Pressure – Intravascular pressure. Blood pressure is influenced by cardiac output, vascular resistance and intravascular volume.

  • Gestation – Pregnancy.

  • Glomerular count – Used to estimate nephron number.

  • Glomerular Filtration Rate (GFR) – Blood volume which is filtered by the kidney during a defined time unit. GFR is the most common measure of renal function. In clinical practice, creatinine or cystatin C based calculations are usually used to estimate GFR.

  • High-Fat Diet – Nutrient composition with increased percentage of fat (e.g. 30-60% of calories in rodents).

  • High-Salt Diet – Increased dietary intake of salt.

  • Low-Protein Diet – Reduced intake of protein (e.g. in rodents: 6-9 g protein in 100 g diet).

  • Micronutrient Deficiency – Dietary lack of one or more micronutrients (e.g. vitamins, minerals) essential to an individual’s health.

  • Nephrogenesis – Development of the kidney.

  • Nephron Number – The nephron is the basic structural and functional unit of the kidney. Nephron number considerably varies between individuals. Low nephron number has been linked to an increased risk of cardiovascular and renal disease.

  • Postnatal(ly) – After birth.

  • Proteinuria – Increased excretion of proteins by the kidney resulting in elevated concentrations of proteins in the urine.

  • Renin-angiotensin-aldosterone system (RAAS) – Hormons (renin, angiotensinogen, angiotensin, aldosterone) interacting to regulate blood pressure, intravascular volume and plasma sodium concentration. In addition, local effects like cardiac remodeling are known.

Key Facts of Nephrogenesis

  • Nephrogenesis is a tightly controlled process, and small changes in gene or protein expression during critical timespans may significantly impair renal development.

  • Human nephrogenesis starts by the tenth postconceptional week.

  • The final kidney originates from two embryonic tissues: the ureteric bud forming the collecting duct system of the kidney and the mesonephros which will form the nephrons.

  • In humans, the number of nephrons is fixed at term, but it can vary between three hundred thousand and two millions per kidney

  • There are numerous causes for a reduction in nephron number including ethnicity; prematurity; placental insufficiency; maternal diets deficient in protein, iron, or vitamin A; maternal hyperglycemia; and intrauterine exposure to certain drugs(e.g., COX-2 inhibitors).

  • Reduced nephron number has been linked to the development of arterial hypertension and susceptibility toward renal disease in later life.

Summary Points

  • Adequate nutrition is fundamental to ensure undisturbed renal development.

  • Macro- and micronutrient deficiency as well as energy overload or high-salt intake during gestation may significantly impair nephrogenesis and induce susceptibility toward disease.

  • In addition, there is growing evidence that early nutrition is an important modulator of adult blood pressure and kidney function.

  • The exact renal phenotype strongly depends on the type of dietary influence and the window of exposure.

  • In order to elucidate the mechanisms underlying dietary programming of renal disease, numerous animal models have been developed.

  • Reduced glomerular count, microvascular rarefaction, or increased fibrosis are possible morphological findings.

  • Mechanistically, dysregulation of renin-angiotensin-aldosterone system (RAAS) components and other vasoactive substances, oxidative stress, altered mitochondrial energy metabolism, endoplasmic reticulum stress, and inflammatory processes are key factors.

  • On the functional level, blood pressure levels, urinary protein excretion, and glomerular filtration rate are subject to dietary influences.

  • In interventional studies, the effect of dietary supplementation with vitamin A, iron, folic acid, zinc, calcium, long-chain polyunsaturated fatty acids, or antioxidants has been tested and yielded some beneficial effects.

  • Defining the adequate amount of macro- and micronutrients which is needed for optimal kidney development remains a challenge for the future.