الفهرس 
Chronic Kidney Disease(CKD)Only 14 pages are availabe for public view
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Abstract
Summary
CKD is an international public health problem affecting 5–10% of the world population (Eknoyanet al., 2004). The incidence and prevalence of CKD is increasing worldwide. As CVD is the principal cause of morbidity and mortality in the CKD population, the primary aims of treatment in patients with CKD are both to slow or prevent progression of CKD and to prevent CVD (Vilayur & Harris, 2009).
The hallmark for treatment of DKD and preservation of kidney function has historically focused on management of hyperglycemia and proteinuria using antihyperglycemic agents, ACE inhibitors, and ARBs(National Kidney Foundation Kidney, 2007).
Since 2000, new treatment strategies have begun to emerge that target the biochemical activity of glucosemolecules on kidney tissues. Various substances have been studied with different degrees of success, ranging from B vitamins to camel’s milk (Shepler et al., 2012).
There are several mechanisms by which medications may be able to inhibit or slow the progression of CKD. Existing medications and entirely new compounds have been studied in human subjects that have antifibrotic and antioxidant effects as well as the ability to bind with and antagonize specific receptors known to contribute to the deleterious effects observed in DKD patients. While most potential new drug therapies remain highly experimental, there is a growing body of data from clinical trials show that many new drugs may eventually lead to new standards for drug treatment in DKD. Potential new drug therapies include antifibrotic agents, antioxidant agents, ET-a receptor antagonists and other compounds with non-specific or multi-faceted mechanisms of action such as paricalcitol, ruboxistaurin (Kania et al.,2013).
The best therapies currently available focus on the control of blood pressure and optimization of RAAS blockade. Several large, RCTs have shown the effectiveness of ARBs and ACE inhibitors, alone or in combination in slowing progression of CKD (Catapano et al. ,2008).
DN is the leading cause of ESRD worldwide. More agents have been tested in human and animal studies in DN than in any other CKD (Vilayur & Harris 2009).
Controlling hyperglycemia and proteinuria is currently the main focus of DKD management (Shepler et al., 2012). Several agents that showed great promise in animal studies have been less effective in humans. To achieve disease regression, such drugs will need to be able to reverse the pathological hallmarks of CKD, including cell proliferation, inflammation, atrophy and fibrosis. Although many strategies are effective at reversing proliferation and inflammation, few are effective at reversing atrophy and fibrosis. In addition, successful drugs will need to be shown to reverse the hard end points such as decline in GFR, need for dialysis and mortality, and not just show beneficial effects on surrogate markers of disease progression such as proteinuria (Vilayur & Harris, 2009).
(1)-ACE Inhibitors, Angiotensin 1 Receptor Blockers (ARB):-
Studies focusing on hypertension and CKD have shown that optimal BP control can slow the progression of renal function impairment, regardless of the underlying kidney disease (Kalra P.A, 2007).
(2)-Antifibrotic Agents: Pirfenidone, and Aliskiren, Tranilast:-
Pirfenidone is an antifibrotic agent that was recently shown to exert its effect through inhibition of TGF-βin animal models.This inhibition can decrease fibrosis in the kidney and may have a renoprotective effect in DKD (Ramachandra et al., 2009).
Aliskiren is a direct renin inhibitor but also exhibits antifibrotic properties exerted through its ability to inhibit the expression of TGFβ (Burney et al., 2009). The drug has also been shown to reduce urinary ACR in some human studies (Kang et al., 2011).
Tranilast, an approved anti-allergic drug with inhibitory effects on profibrotic growth factors and ECM accumulation (Kelly et al., 2004) has also been tested in a small clinical trial. The data suggested that in addition to standard treatment with an ACE inhibitor or an ARB, tranilast can decrease albuminuria in subjects with type 2 diabetes and raised ACR values (Soma et al., 2006).
(3)-Advanced glycation end-products (AGEs) inhibitor:-
One of the key areas of research in treating or at least slowing the progression of DKD in the past decade has focused on halting or interrupting the formation of AGEs (Shepler et al., 2012).
Pyridoxamine is a derivative from the B vitamin family that acts as an AGE inhibitor and has reached Phase II clinical trials (Williams et al., 2007).
Currently, a randomized, double-blind, placebo-controlled trial is being conducted in 300 patients with DKD to further test the effect that pyridoxamine has on decreasing serum creatinine (Turgut & Bolton, 2010).
Benfotiamine, had shown beneficial effects in animal studies, but when tested in 82 patients with DKD (defined by UAE (Alkhalaf et al.,2010).
(4)- Antioxidant Inflammation Modulators:-
Bardoxolone:-
Bardoxolone is classified as an antioxidant inflammation modulator and resembles a cyclopentenone prostaglandin (Pergola et al., 2011).
Pentoxifylline:-
Pentoxifylline is a potential therapeutic agent for DKD because it has anti-inflammatory, antifibrotic, and hemorheological properties (McCormick et al., 2008). :
(5)-Protein Kinase C Inhibitors (Ruboxistaurin):-
Ruboxistaurin is a PKC inhibitor that has been studied for the treatment of DKD and for its potential effects on other micro- and macrovascular parameters (Beckman et al., 2010). Ruboxistaurin has been noted to afford renoprotection by reducing albuminuria, inhibiting the accumulation of ECM protein and decreasing the expression of glomerular TGF-β in diabetic rats with DN (Tuttle & Anderson, 2003). Ruboxistaurin appears to reduce urinary TGF-β concentrations in type 2 DKD patients as well (Gilbert et al., 2007).
(6)- Sulodexide:-
Sulodexide has been studied as a therapeutic tool for reducing urinary protein excretion in experimental models of DN with diverse physiological properties related to renoprotection, including prevention of podocyte apoptosis (Chen et al.,2009).
A recent randomized controlled study failed to prove the renoprotective effect of sulodexide in patients with overt type 2 DN after 1029 person-years of follow-up( Packham et al.,2012).
(7)- Paricalcitol:-
Paricalcitol is used in the CKD and ESRD population as a vitamin D analogue and one of many treatment options for secondary hyperparathyroidism. A vitamin D analogue that also has a clinically significant effect on albuminuria could be quite beneficial to many DKD patients (Shepler et al., 2012).
(8)- Lipid Lowering Agents:-
Several clinical trials have demonstrated that inhibitors of HMG-CoA reductase (statins) are gaining widespread acceptance as a principal therapy for the primary and secondary prevention of atherosclerosis and CVD (Barylski et al.,2013).
(9)- Endothelin antagonists (Avosentan):-
Endothelin-1 has been implicated as an important mediator of progressive renal injury. In diabetic rats with DN, the endothelial type A receptor antagonist, avosentan, when combine with ACE inhibition, significantly reduced proteinuria and reversed the glomerular and tubulointerstitial changes normally seen in this model (Watson et al.,2010). Endothelin type A antagonists reduce albuminuria but currently appear to have a significant side-effect profile that may limit their use in clinical practice (Jandeleit-Dahm & Watson, 2012).
(10)- Vasopressin V2 receptor antagonists:-
The vasopressin V2R antagonist tolvaptan has been found to be efficacious in the treatment of pcy and PKD2ws25/- mice (Wang et al., 2005).
(11)- Somatostatin:-
Somatostatin an analogue octreotide has been found to be effective at inhibiting PKD progression in a group of ADPKD patients. Somatostatin may reduce renal and liver cyst fluid accumulation among patients with PKD (Ruggenenti et al., 2005; Hogan et al., 2010).
(12)- Sirolimus:-
The role of rapamycin has been studied in a large spectrum of kidney diseases, most notably in DN and PKD, the TOR pathway has specific roles in the pathophysiology of these conditions. Derivatives of the TOR inhibitor rapamycin have been approved for treatment of advanced renal carcinoma (Laplante & Sabatini., 2009).
(13)- Erythropoiesis-stimulating agents (ESA):-
Improved quality of life and symptomatic relief of anemia (fatigue, reduced exercise capacity, decreased cognition) with the use of ESAs have been documented in clinical studies (Provenzano et al., 2004).
The potential benefits of reducing blood transfusions and anemia-related symptoms should be balanced against the harm in individual patients (such as stroke, vascular access loss, and hypertension) (KDIGO, 2012).