Metabolic and Physiological Adaptations to Renal Failure - Research Paper Example

?INTRODUCTION Cells need to be at certain specific conditions before they can function normally. Unlike plants or bacteria, animals cell do not have cell walls covering their plasma membranes. Thus, they are more prone to changes in the ionic concentrations of the interstitial fluid bathing them. If ion concentrations in the surrounding fluid are high, water from cells will go extracellularly, and the cells will shrink. In contrast, if they are low compared to that within cells, then water will rush intracellularly, leading to cell rupture. In addition, they have less barrier against toxins present in its surroundings, thus making them more susceptible to the adverse effects of harmful substances present in the body. Thus, humans employ organs that protect the cells by maintaining the ion concentrations within normal levels and removing toxins from the extracellular environment. Both of these functions are done by kidneys. As organisms evolve, the kidneys become more complex, making them more capable of adapting to changes in the body. Although this is beneficial in terms of mitigating the potential of developing CKD, this prevents the early detection of disease since the kidney is still capable of adapting to its condition during the early stages of CKD. This paper summarizes the pathophysiology and symptomatology of chronic kidney disease, as well as the biochemical and physiological adaptations that the body enforce to cope with a dysfunctional kidney. CHRONIC KIDNEY DISEASE (CKD) Pathophysiology Chronic Kidney Disease, according to chronic hypoxia hypothesis, starts with a postglomerular flow obstruction, affecting the associated glomerulus and injuring the peritubular capillary network (Fine and Norman, 2008). Thus, the defective arterial-venous oxygen shunting reduces parenchymal oxygen, facilitating the progress to chronic renal disease (Masaomi, 2006). The resulting hypoxic environment causes the fibrotic response characterizing CKD. In this disease, the extracellular matrix (ECM) accumulates enough to disrupt the normal architecture of renal tissue. Renal fibrosis, specifically glomerulosclerosis and tubulointerstitial fibrosis, is the hallmark of the disease. The latter is characterized by an abundance of inflammatory cell infiltrates, increase in interstitial fibroblasts, and presence of myofibroblasts. The increase in number of fibroblasts is critical in the development of the disease as these cells are the major ECM-producing cells in tubulointerstitium. Specifically, ECM accumulation is caused by increased production and decreased turnover of matrix proteins by fibroblasts and proximal tubular epithelial cells. On the other hand, tubular atrophy is caused by apoptosis and epithelial-mesenchymal transdifferentiation. In summary, the development of fibrosis is associated with increased levels of proinflammatory, vasoconstrictive and profibrotic factors (Fine and Norman, 2008; Deng et al., 2010). Symptomatology CKD clinically manifests as a progressive decrease in glomerular filtration rate (GFR) for at least 3 months duration, usually with albuminuria. As a result, there is a decreased renal phosphate excretion, subsequently increasing serum phosphate levels. In effect, the conversion of vitamin D to active 1, 25-dihydroxyvitamin D is also decreased, depleting intestinal calcium absorption and serum calcium levels. This will then signal the release of parathyroid hormone (Abboud and Henrich, 2010). The loss of calcium levels, in turn, may cause the weight loss and loss of muscle mass seen among uremic patients (Rajan and Mitch, 2008). ADAPTATIONS TO CKD Protein catabolism Protein catabolism is usually seen with among individuals afflicted with CKD, this is because it is induced by inflammation, together with other conditions such as metabolic acidosis, insulin resistance, increased glucocorticoid production, and high serum concentrations of angiotensinogen II. The rapid degradation of proteins allows adaptation to rapid changes in physiological conditions. Such changes can happen in renal diseases, as kidneys are the primary organs, through the renin-angiotensinogen-aldosterone system (RAAS) and its function in regulating ion concentrations in the body, that regulate the entire body’s fluid balance. In effect, these changes in protein catabolism lead to changes in the expression of vasoactive compounds and various hormones (Garibotto et al., 2010). This process has been found by Rajan and Mitch (2008) to be facilitated by the ubiquitin-proteasome system (UPS) and caspase-3. Increasing the cost of sodium reabsorption Oxygen extraction in healthy kidneys is low. However, as in most organs, changes in renal oxygen delivery cause renal oxygen consumption. However, unlike in other tissues in which compromised oxygen delivery decreases the oxygen consumption of the tissue, Deng et al. (2010) has noted that increased kidney oxygen consumption for NaCl reabsorption is seen among individuals with CKD, further worsening CKD. Release of hypoxia inducible factor (HIF) Aside from causing fibrotic changes to the kidney, decreased oxygen concentration stimulates the production of hypoxia inducible factor (HIF) by proximal tubular epithelial cells, which, in turn, causes biochemical changes mitigate the effects of hypoxic conditions by promoting renal cell growth stimulating angiogenesis and reducing inflammation. In particular, HIF induces the release of vascular endothelial growth factor (VEGF), heme-oxygenase-1 (HO-1) and glucose transporter 1 (GLUT1). For VEGF, its anti-hypoxic effects are endothelial cell receptor activation to allow the cells’ proliferation, migration and survival, nitric oxide-mediated vasodilation and vessel formation. On the other hand, GLUT1 inhibits oxidative metabolism, lowering the oxygen consumption of kidneys. Finally, HO-1 catalyzes the production of anti-oxidizing bilirubin, the vasodilating CO and iron. As well, CO and bilirubin reduces oxygen consumption and mitigates inflammation (Deng et al., 2010). However, normal levels of physiologic changes only cause modest beneficial effects. Research efforts thus look into increasing the amounts of HIF in the body as possible treatment options for CKD. Transient increase of Epo mRNA As well, there is a transient increase in angiogenic factor Epo mRNA among patients with CKD. Aside from the factors mentioned above, Epo mRNA is HIF-induced as well. However. the marked increase is followed by the gradual decrease of Epo mRNA levels, since they are degraded by inflammatory cytokines (van der Putten et al., 2008). Epo is important in erythropoiesis, as well as the increased production of other cell types such as renal cells. Changes in the involvement of nephrons Much of the filtration, excretion and reabsorption occurs at the cortex and outer medulla, where the short-looped nephrons are located. These nephrons comprise 70% to 80% of all nephrons, and take the bulk of the excretory function of the kidney (Guyton and Hall, 2006, p. 310). However, tissue perfusion and oxygen consumption throughout the kidney is heterogeneous. The cortex and outer medulla are not as adapted to hypoxic conditions as renal inner medulla, which contains the juxtamedullary nephrons (O’Connor, 2006). This is because the cortex and outer medulla are supplied by the peritubular capillary network, which, as mentioned earlier, is affected by CKD. In contrast, the nephrons in the renal medulla get oxygen and nutrients through the vasa recta coming from the efferent arterioles of the associated glomeruli. What the renal inner medulla lacks in comparison with the other outer parts of the kidney is the thick ascending limbs, where much of sodium, chloride and potassium reabsorption occurs (Guyton and Hall, 2006, p. 310). These functions are thus greatly compromised in CKD. CONCLUSION Chronic kidney disease starts from a decrease in blood supply to the kidney, resulting to hypoxia. This hypoxia, in turn, stimulates many processes, either to support or to mitigate the development of the disease. In particular, the lack of oxygen stimulates the fibrotic changes observed during CKD, but it also induces the production of protective substances such as HIF, VEGF, HO-1 and Epo mRNA. REFERENCES Abboud, H. and Henrich, W. L. Stage IV Chronic Kidney Disease. The New England Journal of Medicine 362: 56-65. 2010. Deng, A., Arndt, M. A. K., Satriano, J., Singh, P., Rieg, T., Thomson, S., Tang, T., and Blantz, R. C. Renal protection in chronic kidney disease: hypoxia-inducible factor activation vs. angiotensin II blockade. American Journal of Physiology - Renal Physiology 299: F1365-F1373. 2010 Fine, L. G. and Norman, J T. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney International 74: 867-872. 2008. Garibotto, G., Sofia, A., Saffioti, S., Bonanni, A., Mannucci, I., and Verzola, D. Amino acid and protein metabolism in the human kidney and in patients with chronic kidney disease. Clinical Nutrition 29: 424-433. 2010. Guyton A. C. and Hall, J .E. Textbook of Medical Physiology 11th ed. Elsevier: Philadelphia/ 2006. p. 310 Masaomi, N. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end stage renal failure. Journal of the American Society of Nephrology. 17: 17-25. 2006. O’Connor, P. M. Renal oxygen delivery: matching delivery to metabolic demand. Clinical and Experimental Pharmacology and Physiology 33: 961-967. 2006 Rajan, V. R. and Mitch, W. E. Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome complex and its clinical impact. Pediatric Nephrology 23: 527-535. 2008. van der Putten, K. Braam, B. Jie, K. E., and Gaillard, C. A. J. M. Mechanisms of disease: erythropoietin resistance in patients with both heart and kidney failure. Nature Clinical Practice Nephrology 4: 47-57. 2008. Read More