Recently published epidemiological and outcome analysis studies have brought to our attention the important role played by acute kidney injury (AKI) in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). AKI accelerates progression in patients with CKD; conversely, CKD predisposes patients to AKI. This research gives credence to older, well-thought-out wisdom that recovery from AKI is often not complete and is marked by residual structural damage. It also mirrors older experimental observations showing that unilateral nephrectomy, a surrogate for loss of nephrons by disease, compromises structural recovery and worsens tubulointerstitial fibrosis after ischemic AKI. Moreover, review of a substantial body of work on the relationships among reduced renal mass, hypertension, and pathology associated with these conditions suggests that impaired myogenic autoregulation of blood flow in the setting of hypertension, the arteriolosclerosis that results, and associated recurrent ischemic AKI in microscopic foci play important roles in the development of progressively increasing tubulointerstitial fibrosis. How nutrition, an additional factor that profoundly affects renal disease progression, influences these events needs reevaluation in light of information on the effects of calories vs. protein and animal vs. vegetable protein on injury and progression. Considerations based on published and emerging data suggest that a pathology that develops in regenerating tubules after AKI characterized by failure of differentiation and persistently high signaling activity is the proximate cause that drives downstream events in the interstitium: inflammation, capillary rarefaction, and fibroblast proliferation. In light of this information, we advance a comprehensive hypothesis regarding the pathophysiology of AKI as it relates to the progression of kidney disease. We discuss the implications of this pathophysiology for developing efficient therapeutic strategies to delay progression and avert ESRD.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00017.2010

Acute kidney injury: a springboard for progression in chronic kidney disease

There are many instances in life when the environment plays a critical role in the health outcomes of an individual, yet none more so than those experienced in fetal and neonatal life. One of the most detrimental environmental problems encountered during this critical growth period are changes in nutrition to the growing fetus and newborn. Disturbances in the supply of nutrients and oxygen to the fetus can not only lead to adverse fetal growth patterns, but they have also been associated with the development of features of metabolic syndrome in adult life. This fetal response has been termed developmental programming or the developmental origins of health and disease. The present review focuses on the epidemiological studies that identified this association and the importance that animal models have played in studying this concept. We also address the potential mechanisms that may underpin the developmental programming of future disease. It also highlights (i) how developmental plasticity, although beneficial for short-term survival, can subsequently programme glucose intolerance and insulin resistance in adult life by eliciting changes in key organ structures and the epigenome, and (ii) how aberrant mitochondrial function can potentially lead to the development of Type 2 diabetes and other features of metabolic syndrome.

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Mechanisms involved in the developmental programming of adulthood disease.

Emerging evidence indicates that obesity, even in the absence of diabetes, contributes significantly to the development and progression of chronic kidney disease (CKD). Glomerular hyperfiltration/hypertrophy in response to the increased metabolic needs of obesity are postulated to lead to the development of glomerulosclerosis (GS) in a manner analogous to that in reduced renal mass states. Nevertheless, the individual risk for developing GS with obesity is very low. It is proposed that glomerular hyperfiltration/hypertrophy are per se not pathogenic in the absence of an enhanced glomerular blood pressure (BP) transmission, and the modest preglomerular vasodilation that is likely present in the large majority of obese individuals is not sufficient to result in such increased BP transmission. However, in the small subset of obese individuals who are also born with a substantially reduced nephron number, there is a greater risk of enhanced glomerular BP transmission due to the substantially greater preglomerular vasodilation. Of perhaps greater clinical importance, similar additive deleterious effects of obesity on BP transmission would be expected in individuals with reduced renal mass, either congenital or acquired, or with concurrent renal disease, leading to accelerated progression. Of note, a low birth weight may be a risk factor for not only reduced nephron numbers at birth, but also for obesity and hypertension, resulting in a clustering of risk factors for progressive GS. Therefore, even though the individual risk for developing obesity GS is low, the cumulative impact of obesity on the public health burden of CKD is likely to be large because of its huge prevalence.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00324.2007

Adverse renal consequences of obesity

Significance: Epidemiological and animal studies have demonstrated a close link between maternal nutrition and chronic metabolic disease in children and adults. Compelling experimental results also indicate that adverse effects of intrauterine growth restriction on offspring can be carried forward to subsequent generations through covalent modifications of DNA and core histones. Recent Advances: DNA methylation is catalyzed by S-adenosylmethionine-dependent DNA methyltransferases. Methylation, demethylation, acetylation, and deacetylation of histone proteins are performed by histone methyltransferase, histone demethylase, histone acetyltransferase, and histone deacetyltransferase, respectively. Histone activities are also influenced by phosphorylation, ubiquitination, ADP-ribosylation, sumoylation, and glycosylation. Metabolism of amino acids (glycine, histidine, methionine, and serine) and vitamins (B6, B12, and folate) plays a key role in provision of methyl donors for DNA and protein methylati...

/pdf/nutrition-epigenetics-and-metabolic-syndrome-2hkt1zdezt.pdf

Nutrition, Epigenetics, and Metabolic Syndrome

Metabolic programming and metabolic imprinting describe early life events, which impact upon on later physiological outcomes. Despite the increasing numbers of papers and studies, the distinction between metabolic programming and metabolic imprinting remains confusing. The former can be defined as a dynamic process whose effects are dependent upon a critical window(s) while the latter can be more strictly associated with imprinting at the genomic level. The clinical end points associated with these phenomena can sometimes be mechanistically explicable in terms of gene expression mediated by epigenetics. The predictivity of outcomes depends on determining if there is causality or association in the context of both early dietary exposure and future health parameters. The use of biomarkers is a key aspect of determining the predictability of later outcome, and the strengths of particular types of biomarkers need to be determined. It has become clear that several important health endpoints are impacted upon by metabolic programming/imprinting. These include the link between perinatal nutrition, nutritional epigenetics and programming at an early developmental stage and its link to a range of future health risks such as CVD and diabetes. In some cases, the evidence base remains patchy and associative, while in others, a more direct causality between early nutrition and later health is clear. In addition, it is also essential to acknowledge the communication to consumers, industry, health care providers, policy-making bodies as well as to the scientific community. In this way, both programming and, eventually, reprogramming can become effective tools to improve health through dietary intervention at specific developmental points.

/pdf/metabolic-imprinting-programming-and-epigenetics-a-review-of-4nbxugeuxm.pdf

Metabolic imprinting, programming and epigenetics – a review of present priorities and future opportunities

https://www.kidney-international.org/article/S0085-2538(15)52633-1/pdf

T Stephenson

Papers

Hypertension and impaired renal function accompany juvenile obesity: the effect of prenatal diet.

Hypertension and impaired renal function accompany juvenile obesity : The effect of prenatal diet. Commentary