Progression of Chronic Kidney Disease: Mechanisms and Interventions in Retardation.
 

Progression of Chronic Kidney Disease: Mechanisms and Interventions in Retardation.

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The incidence ofchronickidneydisease (CKD) is increasingworldwideandisbecoming a major concern for the healthcare. Approximately 1.8 million people, worldwide, are currently treated with renal ...

The incidence ofchronickidneydisease (CKD) is increasingworldwideandisbecoming a major concern for the healthcare. Approximately 1.8 million people, worldwide, are currently treated with renal replacement therapy (RRT), which consists primarily of kidney transplantation,
hemodialysis, and peritoneal dialysis.

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Progression of Chronic Kidney Disease: Mechanisms and Interventions in Retardation. Progression of Chronic Kidney Disease: Mechanisms and Interventions in Retardation. Document Transcript

  • Progression of Chronic Kidney Disease: Mechanisms and Interventions in Retardation.
  • Review Article Progression of chronic kidney disease: Mechanisms and interventions in retardation S. Balasubramanian* Department of Nephrology, Apollo Hospitals, Chennai 600006, India a r t i c l e i n f o Article history: Received 6 January 2013 Accepted 15 January 2013 Available online 1 February 2013 Keywords: Chronic kidney disease (CKD) Retardation Renin angiotensin aldosterone blockade (RASB) a b s t r a c t Theincidenceofchronickidneydisease(CKD)isincreasingworldwideandisbecomingamajor concern for the healthcare. Approximately 1.8 million people, worldwide, are currently treated with renal replacement therapy (RRT), which consists primarily of kidney transplantation, hemodialysis, and peritoneal dialysis.1,2 More than 90% of these individuals live in indus- trialized nations, while availability of RRT is scarce in developing countries. It is estimated that more than 150 per million develop end-stage renal disease (ESRD) per year in India.3,4 The vast majority of these patients cannot afford renal replacement therapy on reaching ESRD and hence ESRD is equivalent to death in them.3,5 Primary prevention programs are very few compared to the burden of CKD,6,7 hence it is imperative to retard progression of CKD. Regardless of the underlying cause, CKD is characterized by relentless progression, which is postulatedto result from a self-perpetuatingvicious cycle of fibrosis activated afterinitial injury. This article discusses the mechanisms of progression, viz, hemodynamic factors, role of pro- teinuria,systemichypertensionandtheroleofvariouscytokinesandgrowthfactorswithspecial emphasis on renin angiotension system and the evidence based interventions to retard it. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Mechanisms of progression of CKD 1.1. Long-term adverse consequences of (Mal) adaptations to nephron loss Nephron loss causes various functional and structural adapta- tions, which are regarded as a beneficial response that mini- mizes the resultant loss of total GFR. They ultimately produce complex series of adverse effects that eventually leads to pro- gressiverenalinjuryandaninexorabledeclineinrenalfunction. In the 5/6 nephrectomy model that has been extensively studied,the rats subjected to partial nephrectomy subse- quently develop hypertension, albuminuria, and progressive renal failure. Histopathological studies in rat remnant kidneys after 5/6 nephrectomy revealed progressive mesangial accu- mulation of hyaline material encroaching the capillary lumina, obliterating Bowman’s space and finally causing global sclerosis of the glomerulus. Similar finding of sclerosed glomeruli in human CKD of diverse etiologies, led to the hy- pothesis that glomerular hyperfiltration ultimately results in damage to remaining glomeruli and contributes to a vicious cycle of progressive nephron loss.8 1.2. Role of hemodynamic factors Various animal models of CKD including the 5/6 nephrectomy and diabetic nephropathy showed that renal mass ablation produced glomerular hyperfiltration and glomerular capillary * Tel.: þ91 9840534220. E-mail address: nephbala@yahoo.com. Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.01.009
  • hypertension. Brenner and colleagues proposed that the he- modynamic adaptations following renal mass ablation initi- ates various processes of glomerular injury that eventually leads to glomerulosclerosis. This further would induce hyperfiltration in remaining, less affected glomeruli, which causes a vicious cycle of progressive nephron loss. This is regarded as a common pathway for irreversible progression of CKD, regardless of the cause of the initial renal injury9 Various interventions in experimental animals like low protein diet, transplantation with isogeneic kidney prevented the hemo- dynamic changes, effectively reversed glomerular hyperten- sion and hyperfiltration and minimize the structural lesions.9 Direct evidence for the importance of renal mass in humans is further shown by an observational study of 749 patients who underwent either radical nephrectomy or nephron-sparing surgery for removal of a renal mass. Those who had nephron-sparing surgery evidenced a significantly lower incidence of reduced GFR (16.0% vs. 44.7%) and pro- teinuria (13.2% vs. 22.2%).10 The importance of glomerular hemodynamic factors in the development of progressive renal injury was further demon- strated by various experimental and clinical studies that reported dramatic protective effects with RAAS blockade. with either ACEI or AT1RA treatment.11e15 1.2.1. Effect of mechanical stress on various glomerular cells Experiments in isolated perfused rat glomeruli showed that increased perfusion pressures cause increases in wall tension and glomerular volume which result in stretching of glomerular cells.16 The cellular responses to mechanical stress leading to glomerulosclerosis through various complex pathways causing proinflammatory and profibrotic state have been studied.17 1.2.1.1. Endothelial cells. The vascular endothelium acts as a dynamic barrier to leukocytes and plasma proteins, and se- cretes various vasoactive factors (prostacyclin, nitric oxide, and endothelin). They bear receptors which detect changes in mechanical stress that result from glomerular hyperperfusion. This may stimulate expression of genes involved in production of proinflammatory cytokines18 cell cycle control, apoptosis, thrombosis, oxidative stress conversion of angiotensin I to angiotensin II, and expression of cell adhesion molecules19 After 5/6 nephrectomy, endothelial cells are activated or injured, resulting in detachment and exposure of the basement membrane which may induce platelet aggregation, deposition of fibrin and intracapillary microthrombus formation.8 1.2.1.2. Mesangial cells. Various in vitro studies indicate that subjecting mesangial cells to cyclical stretch or strain has been shown to induce proliferation and synthesis of extrac- ellular matrix constituents,21 and also activates the tran- scription factor, nuclear factor k light-chain enhancer of activated B cells (NF-kB),20 stimulates synthesis of inter- cellular adhesion molecule-1 (ICAM-1), transforming growth factor-b (TGF-b)22 connective tissue growth factor (CTGF) and also activates the RAAS in cultured mesangial cells,23 and angiotensin II, in turn, may induce TGF-b synthesis. 1.2.1.3. Podocytes. It is increasingly evident that podocyte injury in a variety of renal diseases, causes CKD progression.24 In 5/6 nephrectomized rats the number of podocytes corre- lated with the severity of proteinuria, as well as mean arterial blood pressure, suggesting that podocyte loss may contribute to CKD progression25 Detailed in vitro studies have shown cyclical stretching of podocytes was associated with dis- ruption of contractile apparatus, increased production of angiotensin II and TGF-b as well as upregulation of angio- tensin II type 1 (AT1) receptors resulting in increased angio- tensin II-dependent apoptosis26 and also resulted in a 50% reduction of nephrin (a key component of the slit diaphragm). 1.3. Role of nonhemodynamic factors Many nonhemodynamic factors have been identified in recent studies, which contribute to progressive glomerulosclerosis and these may offer new therapeutic targets for future reno- protective interventions. 1.3.1. Transforming growth factor-b TGF-b is associated with chronic fibrotic states throughout the body by overproduction of extracellular matrix, including CKD.27 Its expression is increased in several experimental models including 5/6 nephrectomized rat model, diabetic ne- phropathy, anti-Thy-1 glomerulonephritis28 as well as in human glomerulonephritis,29,30 HIV nephropathy,31 and dia- betic nephropathy.32 Treatment with an ACE Inhibitor or an AT1R antagonist resulted in substantial renal protection and prevented upre- gulation of TGF-b and correlated closely with the extent of glomerulosclerosis. 1.3.2. Angiotensin II Angiotensin II is an important factor which plays a key role in the glomerular hemodynamic adaptations observed after renal mass ablation. Angiotensin II subtype 1 receptors are, distributed on many cell types within the kidney including mesangial, glomerular epithelial, endothelial, tubule epi- thelial, and vascular smooth muscle cells suggesting multi- ple potential actions of angiotensin II within the kidney.33 Experimental studies revealed several nonhemodynamic effects of angiotensin II that may be important in CKD pro- gression (Fig. 2). In isolated, perfused kidneys, infusion of angiotensin II results in loss of glomerular size permse- lectivity and proteinuria, an effect that has been attributed to both hemodynamic effects of angiotensin II resulting in elevations in glomerular hydraulic pressure, and a direct effect of angiotensin II on glomerular permselectivity.34 and podocyte injury.35 In vitro, angiotensin II has been shown to stimulate mesangial cell proliferation and induce expression of TGF-b, resulting in increased synthesis of extracellular matrix (ECM). Angiotensin II also stimulates production of PAI-1 by endothelial cells and vascular smooth muscle cells36,37 and may therefore further increase accumulation of ECM through inhibition of ECM breakdown by matrix metalloproteinases. Other reports indicate that angiotensin II may directly induce the transcription of a variety of cell adhesion molecules and cytokines, activate the transcrip- tion factor, NF-kB38 and directly stimulate monocyte acti- vation. which causes interstitial inflammatory cell infiltration. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 820
  • 1.3.3. Aldosterone Mechanisms whereby aldosterone may contribute to renal damage include hemodynamic effects; mesangial cell prolif- eration, apoptosis, hypertrophy, and podocyte injury and apoptosis associated with reduced expression of nephrin and podocin resulting in proteinuria; and increased renal pro- duction of reactive oxygen species, TGF-b, and CTGF. Exper- imental use of, spironolactone alone or in combination with AT1RA various studies found significant amelioration of glo- merulosclerosis in various experimental animals. 1.3.4. Endothelins Endothelins are potent vasoconstrictor peptides that act via atleast two receptor subtypes, ETA and ETB. Renal production of endothelins is increased after 5/6 nephrectomy which in various animal models, showed greater increases in efferent than afferent arteriolar resistance resulting in an increase in glomerular hydraulic pressure. The ultrafiltration coefficient (Kf) was significantly reduced and thus SNGFR was unchanged or was decreased. 1.3.5. Atrial natriuretic peptide (ANP) and other structurally related NP They mediate tubular sodium excretion in 5/6 nephrectom- ized rats and also cause increase in whole-kidney and single- nephron GFR by approximately 20%, by a rise in glomerular hydraulic pressure resulting from significant afferent arte- riolar dilatation and efferent arteriolar constriction. 1.3.6. Eicosanoids Different Eicosanoids exert opposite effects on the renal he- modynamics, but glomerular hyperfiltration associated with renal mass ablation seems to be effect of vasodilators out- weighing the vasoconstrictors. 1.3.7. Oxidative stress CKD is associated with increased oxidative stress that likely contributes to the progression of renal damage and the patho- genesis ofthe associated cardiovasculardisease.39 Following 5/6 nephrectomy significant upregulation of NADPH (enzyme for production) and downregulation of Super oxide dismutase Fig. 1 e Common pathway for hemodynamic and nonhemodynamic factors medicated progression of chronic kidney disease. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8 21
  • (enzyme for removal) were observed in the liver and kidneys resulting in increase in superoxide.40 Adverse consequences of oxidative stress that may contribute to CKD progression include hypertension (caused by inactivation of nitric oxide and oxida- tion of arachidonic acid to generate vasoconstrictive iso- prostanes),43 inflammation (caused by activation of NF-kB),41 fibrosis and apoptosis,42 and glomerular filtration barrier dam- age.44 Inflammation may in turn increase oxidative stress because of ROS generation by activated leukocytes, thus estab- lishing a vicious cycle of oxidative stress and inflammation. 1.3.8. Acidosis Acidosis is present in most patients when GFR falls below 20%e25% of normal. Acidosis may contribute to renal damage after nephron loss include activation of the alternative com- plement pathway by increased ammoniagenesis and induc- tion of endothelin and aldosterone production. 1.3.9. Anti fibrotic factors 1.3.9.1. Hepatocyte growth factor. Several studies have investigated the role of HGF as a potential antifibrotic factor in CKD which offers renoprotection. HGF is upregulated in the remaining kidney after uninephrectomy and may contribute to renoprotection by amelioration of podocyte injury, apop- tosis, and proteinuria; decreased ECM accumulation in asso- ciation with increased expression of matrix metalloproteinase 9 (MMP-9) and suppression of TGF-b 1.3.9.2. Bone morphogenetic protein-7. Bone morphogenetic protein-7 (Bmp7), also termed osteogenic protein-1, is a bone morphogen involved in embryonic development and tissue repair. Preliminary evidence suggests that Bmp7 may also play a role in renal repair by inhibition of proinflammatory cytokines, antagonizing fibrogenic effects of TGF-b in mesangial cells. 1.3.9.3. PPAR-g (peroxisome proliferator activator receptor). PPAR-g modifies numerous cytokines and growth factors, including PAI-1 and TGF-b. PPAR-g is a transcription factor and a member of the steroid superfamily.45 On activation, PPAR-g binds the retinoic acid X receptor, translocates to the nucleus and binds to peroxisome proliferator activator Fig. 2 e Mutiple actions of angiotensin II and its role in progression of CKD. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 822
  • response elements (PPREs) in selected target genes, reducing their expression. PPAR agonists, like thiazolidinediones, have been shown to have anti fibrotic effect in some experimental studies in CKD. 1.4. Role of proteinuria Proteinuria, which has been considered as a marker of glo- merular injury, has also been implicated as an important factor involved in renal disease progression, especially caus- ing tubulointerstitial fibrosis. Proteinuria is the result of altered permselectivity of the glomerular filtration barrier, caused by hemodynamic and nonhemodynamic factors. Sieving studies using dextrans and other macromolecules in rats 7 or 14 days after 5/6 nephrectomy revealed loss of both size and charge-selectivity of the glomerular filtration barrier. This is believed to be the result of detachment of glomerular endothelial cells and visceral epithelial cells from the glo- merular basement membrane and appearance of protein reabsorption droplets seen as blebs in podocytes, observed on ultrastructural examination.46 Recent studies identified decreased nephrin expression in podocytes as a further mechanism contributing to protein- uria after 5/6 nephrectomy.47 Direct role for angiotensin II in modulating glomerular capillary permselectivity is thought to be mediated through its nonhemodynamic effect on the cellular components of the glomerular filtration barrier, resulting in the opening interendothelial junctions and epi- thelial cell disruption and through its hemodynamic effect, principally a reduction in renal perfusion and an increase in filtration fraction. Furthermore, angiotensin II and aldoster- one have been shown to reduce nephrin expression in podocytes and may therefore directly affect glomerular permselectivity.47 A causative association between excessive proteinuria and glomerular and interstitial inflammation was suggested by various in vitro studies. Cellular uptake of these proteins by endocytosis was observed to increase secretion of endothelin- 1, interleukin-8 (IL-8), reactive oxygen species .The liberation of these molecules predominantly from the basolateral aspect of the cells contributes to the development of tubulointer- stitial inflammation and fibrosis. The tubulointerstitial inflammation is also thought to be due to misdirection of protein rich glomerular filtrate into the interstitium due for- mation of adhesion of tuft to the Bowman’s capsule. Preliminary evidence suggests that exposure of tubule cells to albumin may also induce apoptosis.48 Other experi- ments found apoptosis in tubule cells exposed to high- molecular-weight plasma proteins but not smaller proteins. Albumin and transferrin exposure also induced complement activation in tubule cells and reduced binding of factor H, a natural inhibitor of the alternative complement pathway.49 Other filtered molecules like immunoglobulins, free fatty acids bound to albumin, Insulin like growth factor-1(IGF- 1),lipoproteins especially LDL, are also believed to play an important role in provoking proinflammatory response in tubule cells. The net effect of the above described hemodynamic and nonhemodynamic factors cause interstitial inflammatory cellular infiltration and tubulo interstitial fibrosis (Fig. 1). 2. Interventions to retard progression of chronic kidney disease 1. Role of renin angiotensin aldosterone blockade 2. Reduction of proteinuria 3. Effect of hypertension control 4. Role of low protein diet 5. Correction of metabolic acidosis 6. Dyslipidemia management 7. Lifestyle modification, 8. Novel targets for interventions 3. Role of renin angiotensin aldosterone blockade There is enough evidence to show that renin angiotensin system blockade (RASB) using angiotensin converting enzyme inhibitors (ACEI) and/or angiotensin II receptor blockers (ARB) is very effective in retarding progression of CKD87 in protei- nuric diseases such as diabetic nephropathy50e52,84 and glo- merulonephritis,51e58 even when the disease is advanced.64 In the Ramipril Efficacy in Nephropathy (REIN) study, 352 patients with nondiabetic renal disease, randomly assigned to receive either ACE inhibitor or placebo, achieved similar con- trol of blood pressure. Among patients with proteinuria of atleast 3 gm/day at baseline, a significantly lower rate of decline in GFR was seen after 2 years in patients receiving ramipril (À0.44 vs. À0.81 ml/min/month with non-ACE conventional therapy). In the extension phase of the study, patients who received placebo were switched to ACE inhibitors, and those already on ACE inhibitors continued the treatment. In 36e54 months of follow-up, no patients in the latter group reached the ESRD, and a small number actually experienced a rise in GFR. The Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT)51 evaluated the effects of the ARB, irbesartan l versus amlodi- pine or placebo, in 1715 subjects. The primary composite end point of the study was doubling of baseline serum creatinine, ESRD or death from any cause. For subjects receiving irbe- sartan, the adjusted relative risk of reaching the primary com- posite end point was 20% lower than for those receiving placebo and 23% lower than for those receiving amlodipine. There was no significant difference between placebo and amlodipine for the primary composite end point. The relative risk of ESRD in the irbesartan group was 17% lower than that of placebo group and 24% lower than that in the amlodipine group. Proteinuria was reduced an average of 23% in the irbesartan arm, compared with 6% and 10% in the amlodipine and placebo arms respec- tively. The more favorable renal outcomes were in excess of effects directly attributable to blood pressure control. The reduction of end points in NIDDM with losartan (RENAAL) study59 was undertaken to determine whether ARB, losartan reduces the number of patients with type 2 diabetes doubling in serum creatinine, ESRD or death, as compared with placebo-treated subjects. The primary and secondary end points of the study were similar to those of IDNT study but treatment was of longer average duration in the RENAAL study (3.6 vs. 2.6 years). Losartan lowered the risk of doubling of serum creatinine by 25%, ESRD by 28% and death by 20% a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8 23
  • when compared to placebo. Proteinuria declined by 35% in the losartan arm and increased slightly in the placebo group. Besides reno-protective effects of ACE inhibitor treatment, the Heart Outcomes Prevention Evaluation (HOPE)60 and Los- artan Intervention for End Point Reduction in Hypertension Study (LIFE)61 trials reported substantial reduction in all cause mortality cardiac and stroke events in patients receiving ramipril or losartan respectively. Study by Mani MK,62 from our unit showed that by increasing the dose of angiotensin converting enzyme inhi- bition to the maximum, the rate of decline of estimated glo- merular filtration rate in diabetic nephropathy has decreased from 16 mL/min/y in 1993 to 2.7 mL/min/y in 2008, and in chronic glomerulonephritis from 28 to 2.8, respectively. In the entire group of patients with renal failure of all causes, the projected increase in time to reach the end stage from a glo- merular filtration rate of 50 mL/min is 26 years, which is 17 years longer than the controls. It is well-recognized that the efficacy of RASB varies in in- dividual patients and race as well as gender have an influence on their efficacy.65,66 The efficacy and safety of combination of ARB and ACEI or supramaximal doses (doses above the max- imum recommended for control of hypertension) remains a subject of much debate. Supramaximal doses of ACEI or ARB have an additive effect in reducing proteinuria and dual blockade also has similar effect.67e70 The effect of combina- tion therapy on progression of renal disease is conflicting. The only major study (COOPERATE),71 which showed benefit with combination therapy on renal outcome, has recently been retracted by the publisher, due to irregularities found in the conduct of the study. A recently published ONTARGET study72 reported that combination of ARB and ACEI caused more rapid decline in glomerular filtration rate (GFR) in patients with high cardiovascular risk compared to either of the agents used alone, causing widespread concern over the use of combina- tion therapy. However, the validity of the design and inter- pretation of results of the ONTARGET study has been questioned for several reasons.73 A recent meta-analysis showed that combination therapy and monotherapy were associated with a similar rate of decline in GFR.74 We studied the effect of increasing RASB to the maximum tolerated using multiple agents in supramaximal doses and showed that, with careful monitoring, it can be achieved safely in the majority of CKD patients. Such an intervention was associated with significantly better renoprotection in CKD patients of diverse etiology including nonproteinuric diseases and the effect appeared to be dose dependent.75 Several small clinical trials reported additional reduction of proteinuria by 15%e54%, blood pressure by approximately 40%, and GFR by approximately 25%, when aldosterone receptor blockers were added to ACEI or AT1RA treatment, but large randomized trials are required to fully assess the potential benefits of these treatments in CKD, and their use in CKD is currently limited by the associated risk of hyperkalemia. 4. Treatment of hypertension Several population-based studies have shown an increased risk of developing progressive renal failure with higher levels of blood pressure,76e79 and is exemplified by findings from the Multiple Risk Factor Intervention Trial (MRFIT).80 Even small increases in blood pressure, below the threshold usually used to define hypertension, are associated with an increased risk of ESRD.76,78 The Modification of Diet in renal disease study supports the concept that proteinuria is an independent risk factor for the progression of renal disease. The authors suggested a target blood pressure of less than 92 mm Hg (125/75 mm Hg) for patients with proteinuria more than 1 g/day and mean pres- sure of less than 98 mm Hg (about 130/80 mm Hg) for pro- teinuria less than a gram per day.81 The KDIGO guidelines 2012, suggest reducing BP to less than 140/90 in nonproteinuric CKD (not yet on dialysis) and a target to less than 13080 mmHg for proteinuric CKD, of any stage (not yet of dialysis) .A J-shaped relationship between achieved BP and outcome has been observed in the elderly and in patients with vascular disease.83 Several recent RCTs have not shown a benefit of lower BP targets in patients without proteinuria. The African American Study of Kidney Disease and Hypertension (AASK) random- ized participants to treatment to a MAP of either 92 mm Hg or 102e107 mm Hg. During the long-term follow-up of partici- pants, there was a benefit associated with the lower BP target among patients with a urine protein/creatinine ratio (PCR) of 4220 mg/g (422 mg/mmol), but not among those with a PCR 220 mg/g (22 mg/mmol). 5. Reduction of proteinuria Several clinical studies have provided evidence to show cause-and-effect relation between proteinuria and renal damage.82 A meta-analysis of 17 clinical studies of CKD revealed a positive correlation between the severity of pro- teinuria and the extent of biopsy-proven glomerulosclerosis.84 Observations from the Modification of Diet in Renal Disease (MDRD) trial also suggest that proteinuria is an independent determinant of CKD progression: Greater levels of baseline proteinuria were strongly associated with more rapid declines in GFR and reduction of proteinuria over 3 or 6 months, in- dependent of reduction in blood pressure, was associated with lesser rates of decline in GFR81 in randomized trials of ACEI or AT1RA treatment in diabetic nephropathy85 and nondiabetic CKD.86 A meta-analysis that included data from 1860 patients with nondiabetic CKD confirmed these findings and showed that during antihypertensive treatment, the current level of proteinuria was a powerful predictor of the combined end- point of doubling of baseline serum creatinine level or onset of end-stage kidney disease (ESKD) (relative risk 5.56 for each 1 g/day of proteinuria).86 The Renoprotection of Opti- mal Antiproteinuric Doses (ROAD) study63 has provided the most direct evidence of the clinical benefit of proteinuria reduction to date. Subjects with proteinuric CKD were ran- domized to standard therapy with an ACEI or AT1RA (sepa- rate groups) or to ACEI or AT1RA therapy titrated to the maximum antiproteinuric dose (two further groups). Despite comparable blood pressure control, subjects in the groups randomized to maximum antiproteinuric doses a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 824
  • evidenced 51% and 53% relative risk reductions in the combined primary endpoint of creatinine level doubling, ESRD or death. The close association between the severity of proteinuria and renal prognosis implies that reduction of proteinuria should be regarded as an important independent therapeutic goal in clinical strategies seeking to slow the rate of progres- sion of CKD. 6. Dietary protein restriction Though the benefits of dietary protein restriction on retarda- tion of CKD has been clearly shown in experimental studies, its confirmation in clinical trials has proved elusive. The large, multicenter, randomized study, the MDRD study,85 was con- ducted with 585 patients with moderate chronic renal failure (GFR at 25e55 mL/min/1.73 m2 ) were randomized to usual (1.3 g/kg/day) or low (0.58 g/kg/day) protein diets (study 1), and 255 patients with severe chronic renal failure (GFR at 13e24 mL/min/1.73 m2 ) were randomized to low (0.58 g/kg/ day) or very low (0.28 g/kg/day) protein diets. All causes of CKD were included, but patients with diabetes mellitus requiring insulin therapy were excluded. Patients were also assigned to different levels of blood pressure control. After a mean of 2.2 years follow-up, the primary analysis revealed no difference in the mean rate of GFR decline in study 1, and only a trend toward a slower rate of decline in the very low protein group in study 2. Long-term follow-up of 255 participants in study 2 of the MDRD trial found no renoprotective benefit associated with randomization to very low protein diet in the original study but did report a higher risk of death in this group (HR, 1.92; CI, 1.15e3.20).88 Despite inconclusive findings in several of the individual studies, three meta-analyses each concluded that dietary protein restriction is associated with a reduced risk of ESKD (odds ratio [OR] of 0.62 and 0.67, respectively),89,90 as well as a modest reduction in the rate of estimated GFR decline (0.53 mL/min/year).91 Though the renoprotective benefit of dietary protein re- striction in humans appears modest, it is associated with other benefits including improvement in acidosis and reduc- tion in phosphorus and potassium load. Thus comprehensive dietary intervention with a moderate restriction in dietary protein intake should remain an important part of the man- agement of patients with CKD.92 7. Management of hyperlipidemia The benefits of lipid lowering in retarding progression of CKD have been elusive. Though some studies showed reduction in proteinuria and cardiovascular end points with statins, they have not shown to retard progression. 8. Correction of metabolic acidosis Observational clinical studies identified acidosis as an inde- pendent risk factor for CKD progression,93,94 but to date only small studies investigated the renoprotective potential of al- kali supplementation in human subjects. In one randomized study95 in adults with creatinine clearance 15e30 mL/min/ 1.73 m2 , randomization to treatment of acidosis (serum bi- carbonate 16e20 mmol/L) with sodium bicarbonate was associated with less decline in creatinine clearance (1.88 vs. 5.93 mL/min/1.73 m2 ) and lower incidence of end-stage kidney disease (6.5% vs. 33%). In another randomized, placebo- controlled trial in subjects with a mean estimated GFR of 75 mL/min/1.73 m2 , treatment with sodium bicarbonate for 5 years was associated with a slower reduction in estimated GFR (derived from plasma cystatin C measurements) than placebo or treatment with sodium chloride.96 Further large randomized studies with more direct measures of GFR are required to adequately evaluate the renoprotective potential of alkali supplementation in human CKD. 9. Life style modifications Cessation of smoking, and achieving ideal body mass index in obese patients have shown to benefit the process of retarda- tion of CKD progression. 10. Novel targets for intervention The following interventions that inhibit the effects of TGF-b have been shown to afford renoprotection in animal models of renal disease: Transfection of the gene for decorin, a naturally occurring inhibitor of TGF-b, into skeletal muscle limited the progression of renal injury in anti-Thy-1 glomerulonephritis97 Administration of anti-TGF-b antibodies to salt-loaded Dahl- salt sensitive rats ameliorated the hypertension, proteinuria, glomerulosclerosis, and interstitial fibrosis typical of this model. Treatment with tranilast (n-[3,4-dimethoxycin- namoyl]anthranilic acid) an inhibitor of TGF-b-induced extracellular matrix production, significantly reduced albu- minuria, macrophage infiltration, glomerulosclerosis, and interstitial fibrosis in 5/6 nephrectomized rats.98 Transfer of an inducible gene for Smad 7, which blocks TGF-b signaling by inhibiting Smad 2/3 activation, inhibited proteinuria, fibrosis, and myofibroblast accumulation after 5/6 nephrectomy. Epithelial Growth Factor receptor-tyrosine kinase in- hibitors prevent inhibition of abnormal increase in collagen I gene expression, decrease proteinuria and improvement in GFR, and prevent the development of renal vascular and glo- merular fibrosis. Advanced glycation end product interacts with receptor, causing intracellular signaling for increased production of TGF b and CTGF production. Pimagedine, an inhibitor of AGE for- mation showed reduction in decline of GFR over 36 months of follow-up 9.8 vs 6.3 ml/min in diabetic nephropathy.99 Conflicts of interest The author has none to declare. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 8 25
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