Chronic Kidney Disease: Therapeutic Strategies Targeting the Risk Factors

Chronic kidney disease: An overview

Chronic kidney disease (CKD) is a disorder which is associated with considerable health and economic burden.CKD involves age-related decline in renal function which can be further accelerated by co-associated hypertension,diabetes and obesity. In addition it is an independent risk factor for various comorbidities. Several studies have shown high prevalence of CKD globally; the disorder is known to affect 13·4% of the population. Women are reported to be more commonly affected than men.¹Hill NR, Fatoba ST, Oke JL, et al. Global Prevalence of Chronic Kidney Disease – A Systematic Review and Meta-Analysis. PLoS One. 2016;11(7):e0158765.  The natural history of CKD is known, although it is less well-studied in children.Once significant injury to the kidney occurs, progression towards end-stage renal disease is relentless irrespective of the underlying kidney disorder. Deterioration in renal function occurs at a faster rate in the high risk population compared to those at low risk. Most patients with early CKD remain undiagnosed because of the paucity of symptoms,up until the later stages when signs of uremia and endstage renal disease emerge; CKD also increases risk of cardiovascular morbidity, premature mortality, and/or decreased quality of life.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ³Stringer S, Sharma P, Dutton M, et al. The natural history of, and risk factors for, progressive Chronic Kidney Disease (CKD): the Renal Impairment in Secondary care (RIISC) study; rationale and protocol. BMC Nephrol.2013;14:95.

The CKD severity is stratified based on the GFR and albuminuria, as shown in Figure 1.⁴KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. January 2013. Availabale at: http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf. Accessed on:15-10-2016.  Irrespective of the etiology, the onset of CKD heralds a chain of events which ultimately lead to increased intraglomerular hypertension. Intraglomerular hypertension results in progressive loss of glomeruli, and resultant hypertrophy and hyperfiltration of the remaining nephrons, thereby initiating a vicious cycle which propagates continuous and oftentimes irreversible deterioration in renal functions,and eventually heralds the development of end-stage renal disease. Of note, various hormones and cytokines such as angiotensin II and transforming growth factor beta (TGF-β) also act as contributory factors to the renal function decline. Angiotensin II causes vasoconstriction of the efferent arteriole which in turn aggravates intraglomerular hypertension, and TGF-β results in its fibrosis. The variability of CKD progression among patients suggests that biologically relevant factors may influence the course of CKD.⁵Mallappallil M, Friedman EA, Delano BG, McFarlane SI, Salifu MO. Chronic kidney disease in the elderly: evaluation and management. Clin Pract. 2014;11(5):525-535.  ⁶Staples A, Wong C. Risk Factors for Progression of Chronic Kidney Disease.Curr Opin Pediatr. 2010;22(2):161-169. Figure 2 represents a conceptual model of the course of CKD, which provides a framework for the development of a public health approach towards the disorder.

Risk factors associated with the chronic kidney disease

Over the last few years, several clinical studies have focused on the pathophysiology and risk factors of CKD. There is strong evidence to support the fact that several key players (both modifiable and non-modifiable) are involved in the pathophysiology of CKD and its progression. The non-modifiable risk factors for CKD include: age, gender,ethnicity, genetic factors, degree of initial kidney function,and birth weight; in contrast, modifiable risk factors for CKD include proteinuria, hypertension, poor glycemic control in diabetes, obesity, dyslipidemia, anemia, metabolic factors (Ca/P, uric acid) and use of nephrotoxic drugs (Table 1). Therapeutically addressing the modifiable risk factors appears to reduce the rapidity of progression of CKD.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ⁷Garcia de Vinuesa S. Progression factors for chronic kidney disease.Secondary prevention. Nefrologia. 2008;28 Suppl 3:17-21.  ⁸Levey AS, Eckardt KU, Tsukamoto Y et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67(6):2089-2100.

Hypertension

Hypertension is both an important cause as well as a consequence of CKD. Hypertension is considered an independent risk factor in the progression of renal failure. Systemic hypertension leads to intraglomerular hypertension which further causes glomerular injury and hypertrophy. A rapid deterioration of renal function is noticed in hypertensive subjects when compared to normotensive CKD patients. In fact, the degree of hypertension appears to correlate directly with the severity of the underlying renal disease. Furthermore,an increased prevalence of cardiovascular disease (CVD) is seen in CKD patients and CVD-associated mortality in CKD patients is deemed 10 to 30 times higher than in the general population. There is hence a sound rational for benefits with antihypertensive therapy in CKD patients. Antihypertensive therapy has shown to reduce the rate of renal-failure progression in patients with CKD.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ⁵Mallappallil M, Friedman EA, Delano BG, McFarlane SI, Salifu MO. Chronic kidney disease in the elderly: evaluation and management. Clin Pract. 2014;11(5):525-535.  ⁶Staples A, Wong C. Risk Factors for Progression of Chronic Kidney Disease.Curr Opin Pediatr. 2010;22(2):161-169.

Proteinuria

Proteinuria is considered a marker of kidney damage as it contributes to nephron injury. The damaged tubular basement membrane results in leakage of tubular content into the interstitium, which further prompts infiltration of macrophages. These macrophages produce inflammatory mediators, which trigger an immense inflammatory reaction inside renal interstitium. This process ultimately leads to tubulointerstitial fibrosis that gradually worsens the renal functions (Figure 3). Overall, proteinuria is considered a significant and an independent risk factor for renal disease progression. It is, therefore, important to treat the condition. It has been observed that blockade of the renin-angiotensin system (RAS) in CKD patients reduces proteinuria, which may slow down the CKD progression.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ⁶Staples A, Wong C. Risk Factors for Progression of Chronic Kidney Disease.Curr Opin Pediatr. 2010;22(2):161-169.  ⁹Severity and Stages of Chronic Kidney Disease. Available at: http://cdn.intechopen.com/pdfs-wm/32302.pdf. accessed on:15-10-2016

Dyslipidemia

Epidemiological studies have established that the degree of dyslipidemia corresponds to the extent of renal function impairment. Dyslipidemia may cause damage to glomerular capillary endothelium and mesangial cells as well as podocytes. Stimulation of mesangial cells along with activation of express receptors for low-density lipoprotein (LDL) and oxidized LDL result in mesangial cell proliferation and increased deposition of matrix. This also augments the production of chemokines, cytokines,or growth factors, thereby raising the oxidative stress and deteriorating the renal function. In addition, patients with cholesterol levels >7 mmol/L showed at least three times faster decline in GFR when compared to those with lower cholesterol levels.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ¹⁰Thomas R, Kanso A, Sedor JR. Chronic Kidney Disease and Its Complications. Prim care. 2008;35(2):329-vii.

Diabetes

Diabetic nephropathy, a common microvascular complication of diabetes, is a significant cause of CKD in about 40–50% of patients with diabetes. The accumulation of advanced glycation end products (AGEs) contributes to endothelial dysfunction and as a result, the cardiovascular risk may increase, especially in individuals with CKD. In a large population study, the prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in the year 2000, which is predicted to increase to 4.4% by the year 2030. The aging diabetic population is at risk of developing secondary CKD, which is highly prevalent in geriatric population.³Stringer S, Sharma P, Dutton M, et al. The natural history of, and risk factors for, progressive Chronic Kidney Disease (CKD): the Renal Impairment in Secondary care (RIISC) study; rationale and protocol. BMC Nephrol.2013;14:95.  ⁵Mallappallil M, Friedman EA, Delano BG, McFarlane SI, Salifu MO. Chronic kidney disease in the elderly: evaluation and management. Clin Pract. 2014;11(5):525-535.  ¹¹Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047-1053.

Anemia

Evidence suggests that anemia is an important risk factor for progression of chronic kidney disease. Anemia as a surrogate marker for tissue hypoxia continues to aggravate preexisting renal damage. Hypoxia has the following consequences:

• Increased production of profibrotic molecules such as TGF-βor endothelin-1 by tubular cells
• Increased synthesis of extracellular matrix
• Enhanced production of reactive oxygen species (ROS), which exert an add-on effect in CKD progression.

Erythropoietin (EPO) has been reported to confer renoprotective effects in CKD, as it helps in reducing interstitial fibrosis, tubuloepithelial cell loss, and oxidative stress. In addition, it has a direct protective effect on tubular cells that maintains the integrity of the interstitial capillary network and increases the activity of regenerative progenitor cells.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ¹²Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol. 2002;13:806-816.   ¹³Orphanides C, Fine LG, Norman JT. Hypoxia stimulates proximal tubular cell matrix production via a TGF-ß1-independent mechanism. Kidney Int. 1997;52:637-647.

Oxidative stress

Oxidative stress, an imbalance between levels of reactive oxygen species (ROS) and endogenous antioxidant substances, may be both a cause and an effect of the renal injury. It contributes to endothelial dysfunction and increases the release of proinflammatory and profibrotic molecules. As a result, the production of extracellular matrix by fibroblastic cells gets enhanced. It has been observed that increase in oxidative stress parallels the decline in kidney function in patients with CKD.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ¹⁴Karamouzis I, Sarafidis PA, Karamouzis M, Illiadis S, Haidich A-M, Sioulis A, Triantos A, Vavatsi-Christaki N, Grekas DM. Increase in oxidative stress but not in antioxidant capacity with advancing stages of chronic kidney disease. Am J Nephrol. 2008;28:397-404.

Disorders of calcium-phosphate metabolism

The factors associated with altered calcium-phosphate metabolism in CKD include hyperphosphatemia,hyperparathyroidism, lack of active vitamin D, and possibly an excess of the phosphaturic hormone. It has been established that vitamin D3 attenuates the progression of noninflammatory and inflammatory components in CKD.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716. The mechanistic insights of renal disease progression make a multi-targeted intervention an important step, in order to delay the progression of renal disease and reduce the incidence of associated adverse events.¹Hill NR, Fatoba ST, Oke JL, et al. Global Prevalence of Chronic Kidney Disease – A Systematic Review and Meta-Analysis. PLoS One. 2016;11(7):e0158765.

Management strategies to halt or delay the progression of renal disease

The goal of CKD management is to stop or retard the disease progression, mainly by targeting hypertension and proteinuria- the major factors associated with deterioration of renal function. In addition, the treatment of renal anemia, dyslipidemia, and disorders of mineral metabolism is also clinically important in reducing the renal disease progression. This multifactorial approach (Table 2) also helps to prevent acute exacerbations associated with intercurrent events or inappropriate interventions in CKD patients.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ⁵Mallappallil M, Friedman EA, Delano BG, McFarlane SI, Salifu MO. Chronic kidney disease in the elderly: evaluation and management. Clin Pract. 2014;11(5):525-535.  ¹⁵Laville M, Rognant N.Natural course of chronic kidney disease. Rev Prat.2012 Jan;62(1):30-3.

Management of hypertensionManagement of hypertension

Antagonists of the RAS, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) decrease blood pressure, which subsequently reduces intraglomerular pressure and proteinuria. Moreover, these agents inhibit the release of cytokines and chemokines and block the inflammatory pathways, thereby, attenuating glomerular hypertrophy and tubulointerstitial fibrosis. In addition, oxidative stress is also reduced. Several randomized trials demonstrate a more effective reduction of proteinuria following the use of ACE inhibitors in adults with CKD, usually by 30-40%.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.

Management of dyslipidemia

Statins are considered the front-line therapeutic agents for lowering the lipid levels. These agents inhibit the signaling molecules involved in inflammatory pathways and reduce the overall cardiovascular morbidity and mortality associated with CKD. Furthermore, the evidence is suggestive of the synergistic efficacy of statins and RAS inhibitors in retarding the renal disease progression. In addition, there is also a need to correct the underlying malnutrition, metabolic acidosis, hyperparathyroidism,and anemia, all of which may contribute to dyslipidemia.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ¹⁶Zoja C, Corna D, Rottoli D, Cattaneo D, Zanchi C, Tomasoni S, Abbate M, Remuzzi G. Effect of combining ACE inhibitor and statin in severe experimental nephropathy. Kidney Int. 2002; 61:1635-1645.

Management of anemia

Recombinant human erythropoietin (rhuEPO) is used to treat anemia that acts mainly by reducing the apoptotic cell death. EPO analogs may ameliorate podocyte injury and decrease proteinuria by maintaining podocyte actin cytoskeleton and nephrin expression. This not only reduces morphological damage but also retards renal dysfunction.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.  ¹⁷Sharples EJ, Patel N, Brown P, et al. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol. 2004 Aug; 15(8):2115-24.   In addition to the pharmacological therapy,dietary modification including low-protein diets should be prescribed. Also, vitamin D intake in nonhypercalcemic doses attenuates renal failure progression, possibly due to its immune modulatory and antifibrotic properties.²Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.

Conclusion

Chronic kidney disease (CKD) is a complex disease, which is influenced by a multitude of risk factors and in turn, lays an impact on various systems of the body. Therapeutic strategies to prevent renal disease progression should target blood pressure, proteinuria, and other contributing factors. Of note, early identification of disease followed by appropriate interventions may reduce morbidity and mortality associated with CKD.

References

1. Hill NR, Fatoba ST, Oke JL, et al. Global Prevalence of Chronic Kidney Disease – A Systematic Review and Meta-Analysis. PLoS One. 2016;11(7):e0158765.
2. Wuhl E, Schaefer F. Therapeutic strategies to slow chronic kidney disease progression. Pediatr Nephrol. 2008;23(5):705-716.
3. Stringer S, Sharma P, Dutton M, et al. The natural history of, and risk factors for, progressive Chronic Kidney Disease (CKD): the Renal Impairment in Secondary care (RIISC) study; rationale and protocol. BMC Nephrol.2013;14:95.
4. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. January 2013. Availabale at: http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf. Accessed on:15-10-2016.
5. Mallappallil M, Friedman EA, Delano BG, McFarlane SI, Salifu MO. Chronic kidney disease in the elderly: evaluation and management. Clin Pract. 2014;11(5):525-535.
6. Staples A, Wong C. Risk Factors for Progression of Chronic Kidney Disease.Curr Opin Pediatr. 2010;22(2):161-169.
7. Garcia de Vinuesa S. Progression factors for chronic kidney disease.Secondary prevention. Nefrologia. 2008;28 Suppl 3:17-21.
8. Levey AS, Eckardt KU, Tsukamoto Y et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67(6):2089-2100.
9. Severity and Stages of Chronic Kidney Disease. Available at: http://cdn.intechopen.com/pdfs-wm/32302.pdf. accessed on:15-10-2016
10. Thomas R, Kanso A, Sedor JR. Chronic Kidney Disease and Its Complications. Prim care. 2008;35(2):329-vii.
11. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047-1053.
12. Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol. 2002;13:806-816.
13. Orphanides C, Fine LG, Norman JT. Hypoxia stimulates proximal tubular cell matrix production via a TGF-ß1-independent mechanism. Kidney Int. 1997;52:637-647.
14. Karamouzis I, Sarafidis PA, Karamouzis M, Illiadis S, Haidich A-M, Sioulis A, Triantos A, Vavatsi-Christaki N, Grekas DM. Increase in oxidative stress but not in antioxidant capacity with advancing stages of chronic kidney disease. Am J Nephrol. 2008;28:397-404.
15. Laville M, Rognant N.Natural course of chronic kidney disease. Rev Prat.2012 Jan;62(1):30-3.
16. Zoja C, Corna D, Rottoli D, Cattaneo D, Zanchi C, Tomasoni S, Abbate M, Remuzzi G. Effect of combining ACE inhibitor and statin in severe experimental nephropathy. Kidney Int. 2002; 61:1635-1645.
17. Sharples EJ, Patel N, Brown P, et al. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol. 2004 Aug; 15(8):2115-24.