Progression of chronic kidney disease: mechanismsand interventions in retardation


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The incidence of chronic kidney disease (CKD) is increasing worldwide and is becoming 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. More than 90% of these individuals live in industrialized 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. The vast majority of these patients cannot afford renal replacement therapy on reaching ESRD and hence ESRD is equivalent to death in them. Primary prevention programs are very few compared to the burden of CKD, hence it is imperative to retard progression of CKD.

Regardless of the underlying cause, CKD is characterized by relentless progression, which is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. This article discusses the mechanisms of progression, viz, hemodynamic factors, role of proteinuria, systemic hypertension and the role of various cytokines and growth factors with special emphasis on renin angiotension system and the evidence based interventions to retard it.

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Progression of chronic kidney disease: mechanismsand interventions in retardation

  1. 1. Progressionofchronickidneydisease:Mechanismsandinterventionsinretardation
  2. 2. Review ArticleProgression of chronic kidney disease: Mechanismsand interventions in retardationS. Balasubramanian*Department of Nephrology, Apollo Hospitals, Chennai 600006, Indiaa r t i c l e i n f oArticle history:Received 6 January 2013Accepted 15 January 2013Available online 1 February 2013Keywords:Chronic kidney disease (CKD)RetardationRenin angiotensin aldosteroneblockade (RASB)a b s t r a c tTheincidenceofchronickidneydisease(CKD)isincreasingworldwideandisbecomingamajorconcern for the healthcare. Approximately 1.8 million people, worldwide, are currently treatedwith renal replacement therapy (RRT), which consists primarily of kidney transplantation,hemodialysis, and peritoneal dialysis.1,2More than 90% of these individuals live in indus-trialized nations, while availability of RRT is scarce in developing countries. It is estimated thatmore than 150 per million develop end-stage renal disease (ESRD) per year in India.3,4The vastmajority of these patients cannot afford renal replacement therapy on reaching ESRD andhence ESRD is equivalent to death in them.3,5Primary prevention programs are very fewcompared to the burden of CKD,6,7hence it is imperative to retard progression of CKD.Regardless of the underlying cause, CKD is characterized by relentless progression, which ispostulatedto 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,systemichypertensionandtheroleofvariouscytokinesandgrowthfactorswithspecialemphasis 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 CKD1.1. Long-term adverse consequences of (Mal)adaptations to nephron lossNephron 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 producecomplex series of adverse effects that eventually leads to pro-gressiverenalinjuryandaninexorabledeclineinrenalfunction.In the 5/6 nephrectomy model that has been extensivelystudied,the rats subjected to partial nephrectomy subse-quently develop hypertension, albuminuria, and progressiverenal failure. Histopathological studies in rat remnant kidneysafter 5/6 nephrectomy revealed progressive mesangial accu-mulation of hyaline material encroaching the capillarylumina, obliterating Bowman’s space and finally causingglobal sclerosis of the glomerulus. Similar finding of sclerosedglomeruli in human CKD of diverse etiologies, led to the hy-pothesis that glomerular hyperfiltration ultimately results indamage to remaining glomeruli and contributes to a viciouscycle of progressive nephron loss.81.2. Role of hemodynamic factorsVarious animal models of CKD including the 5/6 nephrectomyand diabetic nephropathy showed that renal mass ablationproduced glomerular hyperfiltration and glomerular capillary* Tel.: þ91 9840534220.E-mail address: online at www.sciencedirect.comjournal homepage: p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 80976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
  3. 3. hypertension. Brenner and colleagues proposed that the he-modynamic adaptations following renal mass ablation initi-ates various processes of glomerular injury that eventuallyleads to glomerulosclerosis. This further would inducehyperfiltration in remaining, less affected glomeruli, whichcauses a vicious cycle of progressive nephron loss. This isregarded as a common pathway for irreversible progression ofCKD, regardless of the cause of the initial renal injury9Variousinterventions 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.9Direct evidence for the importance of renal mass inhumans is further shown by an observational study of 749patients who underwent either radical nephrectomy ornephron-sparing surgery for removal of a renal mass. Thosewho had nephron-sparing surgery evidenced a significantlylower incidence of reduced GFR (16.0% vs. 44.7%) and pro-teinuria (13.2% vs. 22.2%).10The importance of glomerular hemodynamic factors in thedevelopment of progressive renal injury was further demon-strated by various experimental and clinical studies thatreported dramatic protective effects with RAAS blockade. witheither ACEI or AT1RA treatment.11e151.2.1. Effect of mechanical stress on various glomerular cellsExperiments in isolated perfused rat glomeruli showed thatincreased perfusion pressures cause increases in wall tensionand glomerular volume which result in stretching of glomerularcells.16The cellular responses to mechanical stress leading toglomerulosclerosis through various complex pathways causingproinflammatory and profibrotic state have been studied. Endothelial cells. The vascular endothelium acts asa dynamic barrier to leukocytes and plasma proteins, and se-cretes various vasoactive factors (prostacyclin, nitric oxide,and endothelin). They bear receptors which detect changes inmechanical stress that result from glomerular hyperperfusion.This may stimulate expression of genes involved in productionof proinflammatory cytokines18cell cycle control, apoptosis,thrombosis, oxidative stress conversion of angiotensin I toangiotensin II, and expression of cell adhesion molecules19After 5/6 nephrectomy, endothelial cells are activated orinjured, resulting in detachment and exposure of the basementmembrane which may induce platelet aggregation, depositionof fibrin and intracapillary microthrombus formation. Mesangial cells. Various in vitro studies indicate thatsubjecting mesangial cells to cyclical stretch or strain hasbeen shown to induce proliferation and synthesis of extrac-ellular matrix constituents,21and also activates the tran-scription factor, nuclear factor k light-chain enhancer ofactivated B cells (NF-kB),20stimulates synthesis of inter-cellular adhesion molecule-1 (ICAM-1), transforming growthfactor-b (TGF-b)22connective tissue growth factor (CTGF) andalso activates the RAAS in cultured mesangial cells,23andangiotensin II, in turn, may induce TGF-b synthesis. Podocytes. It is increasingly evident that podocyteinjury in a variety of renal diseases, causes CKD progression.24In 5/6 nephrectomized rats the number of podocytes corre-lated with the severity of proteinuria, as well as mean arterialblood pressure, suggesting that podocyte loss may contributeto CKD progression25Detailed in vitro studies have showncyclical stretching of podocytes was associated with dis-ruption of contractile apparatus, increased production ofangiotensin II and TGF-b as well as upregulation of angio-tensin II type 1 (AT1) receptors resulting in increased angio-tensin II-dependent apoptosis26and also resulted in a 50%reduction of nephrin (a key component of the slit diaphragm).1.3. Role of nonhemodynamic factorsMany nonhemodynamic factors have been identified in recentstudies, which contribute to progressive glomerulosclerosisand these may offer new therapeutic targets for future reno-protective interventions.1.3.1. Transforming growth factor-bTGF-b is associated with chronic fibrotic states throughout thebody by overproduction of extracellular matrix, includingCKD.27Its expression is increased in several experimentalmodels including 5/6 nephrectomized rat model, diabetic ne-phropathy, anti-Thy-1 glomerulonephritis28as well as inhuman glomerulonephritis,29,30HIV nephropathy,31and dia-betic nephropathy.32Treatment with an ACE Inhibitor or an AT1R antagonistresulted in substantial renal protection and prevented upre-gulation of TGF-b and correlated closely with the extent ofglomerulosclerosis.1.3.2. Angiotensin IIAngiotensin II is an important factor which plays a key rolein the glomerular hemodynamic adaptations observed afterrenal mass ablation. Angiotensin II subtype 1 receptors are,distributed on many cell types within the kidney includingmesangial, glomerular epithelial, endothelial, tubule epi-thelial, and vascular smooth muscle cells suggesting multi-ple potential actions of angiotensin II within the kidney.33Experimental studies revealed several nonhemodynamiceffects of angiotensin II that may be important in CKD pro-gression (Fig. 2). In isolated, perfused kidneys, infusion ofangiotensin II results in loss of glomerular size permse-lectivity and proteinuria, an effect that has been attributedto both hemodynamic effects of angiotensin II resulting inelevations in glomerular hydraulic pressure, and a directeffect of angiotensin II on glomerular permselectivity.34andpodocyte injury.35In vitro, angiotensin II has been shown tostimulate mesangial cell proliferation and induce expressionof TGF-b, resulting in increased synthesis of extracellularmatrix (ECM). Angiotensin II also stimulates production ofPAI-1 by endothelial cells and vascular smooth musclecells36,37and may therefore further increase accumulationof ECM through inhibition of ECM breakdown by matrixmetalloproteinases. Other reports indicate that angiotensinII may directly induce the transcription of a variety of celladhesion molecules and cytokines, activate the transcrip-tion factor, NF-kB38and directly stimulate monocyte acti-vation. which causes interstitial inflammatory cellinfiltration.a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 820
  4. 4. 1.3.3. AldosteroneMechanisms whereby aldosterone may contribute to renaldamage include hemodynamic effects; mesangial cell prolif-eration, apoptosis, hypertrophy, and podocyte injury andapoptosis associated with reduced expression of nephrin andpodocin 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 withAT1RA various studies found significant amelioration of glo-merulosclerosis in various experimental animals.1.3.4. EndothelinsEndothelins are potent vasoconstrictor peptides that act viaatleast two receptor subtypes, ETA and ETB. Renal productionof endothelins is increased after 5/6 nephrectomy which invarious animal models, showed greater increases in efferentthan afferent arteriolar resistance resulting in an increase inglomerular hydraulic pressure. The ultrafiltration coefficient(Kf) was significantly reduced and thus SNGFR was unchangedor was decreased.1.3.5. Atrial natriuretic peptide (ANP) and other structurallyrelated NPThey 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 glomerularhydraulic pressure resulting from significant afferent arte-riolar dilatation and efferent arteriolar constriction.1.3.6. EicosanoidsDifferent Eicosanoids exert opposite effects on the renal he-modynamics, but glomerular hyperfiltration associated withrenal mass ablation seems to be effect of vasodilators out-weighing the vasoconstrictors.1.3.7. Oxidative stressCKD is associated with increased oxidative stress that likelycontributes to the progression of renal damage and the patho-genesis ofthe associated cardiovasculardisease.39Following 5/6nephrectomy significant upregulation of NADPH (enzyme forproduction) and downregulation of Super oxide dismutaseFig. 1 e Common pathway for hemodynamic and nonhemodynamic factors medicated progression of chronic kidneydisease.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
  5. 5. (enzyme for removal) were observed in the liver and kidneysresulting in increase in superoxide.40Adverse consequences ofoxidative stress that may contribute to CKD progression includehypertension (caused by inactivation of nitric oxide and oxida-tion of arachidonic acid to generate vasoconstrictive iso-prostanes),43inflammation (caused by activation of NF-kB),41fibrosis and apoptosis,42and glomerular filtration barrier dam-age.44Inflammation may in turn increase oxidative stressbecause of ROS generation by activated leukocytes, thus estab-lishing a vicious cycle of oxidative stress and inflammation.1.3.8. AcidosisAcidosis is present in most patients when GFR falls below20%e25% of normal. Acidosis may contribute to renal damageafter 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 factors1.3.9.1. Hepatocyte growth factor. Several studies haveinvestigated the role of HGF as a potential antifibrotic factor inCKD which offers renoprotection. HGF is upregulated in theremaining kidney after uninephrectomy and may contributeto renoprotection by amelioration of podocyte injury, apop-tosis, and proteinuria; decreased ECM accumulation in asso-ciation with increased expression of matrix metalloproteinase9 (MMP-9) and suppression of TGF-b1.3.9.2. Bone morphogenetic protein-7. Bone morphogeneticprotein-7 (Bmp7), also termed osteogenic protein-1, is a bonemorphogen involved in embryonic development and tissuerepair. Preliminary evidence suggests that Bmp7 may alsoplay a role in renal repair by inhibition of proinflammatorycytokines, antagonizing fibrogenic effects of TGF-b inmesangial cells. 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 factorand a member of the steroid superfamily.45On activation,PPAR-g binds the retinoic acid X receptor, translocates to thenucleus and binds to peroxisome proliferator activatorFig. 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
  6. 6. response elements (PPREs) in selected target genes, reducingtheir expression. PPAR agonists, like thiazolidinediones, havebeen shown to have anti fibrotic effect in some experimentalstudies in CKD.1.4. Role of proteinuriaProteinuria, which has been considered as a marker of glo-merular injury, has also been implicated as an importantfactor involved in renal disease progression, especially caus-ing tubulointerstitial fibrosis. Proteinuria is the result ofaltered permselectivity of the glomerular filtration barrier,caused by hemodynamic and nonhemodynamic factors.Sieving studies using dextrans and other macromolecules inrats 7 or 14 days after 5/6 nephrectomy revealed loss of bothsize and charge-selectivity of the glomerular filtration barrier.This is believed to be the result of detachment of glomerularendothelial cells and visceral epithelial cells from the glo-merular basement membrane and appearance of proteinreabsorption droplets seen as blebs in podocytes, observed onultrastructural examination.46Recent studies identified decreased nephrin expression inpodocytes as a further mechanism contributing to protein-uria after 5/6 nephrectomy.47Direct role for angiotensin II inmodulating glomerular capillary permselectivity is thoughtto be mediated through its nonhemodynamic effect on thecellular 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 infiltration fraction. Furthermore, angiotensin II and aldoster-one have been shown to reduce nephrin expression inpodocytes and may therefore directly affect glomerularpermselectivity.47A causative association between excessive proteinuria andglomerular and interstitial inflammation was suggested byvarious in vitro studies. Cellular uptake of these proteins byendocytosis was observed to increase secretion of endothelin-1, interleukin-8 (IL-8), reactive oxygen species .The liberationof these molecules predominantly from the basolateral aspectof the cells contributes to the development of tubulointer-stitial inflammation and fibrosis. The tubulointerstitialinflammation is also thought to be due to misdirection ofprotein rich glomerular filtrate into the interstitium due for-mation of adhesion of tuft to the Bowman’s capsule.Preliminary evidence suggests that exposure of tubulecells to albumin may also induce apoptosis.48Other experi-ments found apoptosis in tubule cells exposed to high-molecular-weight plasma proteins but not smaller proteins.Albumin and transferrin exposure also induced complementactivation in tubule cells and reduced binding of factor H,a natural inhibitor of the alternative complement pathway.49Other filtered molecules like immunoglobulins, free fattyacids bound to albumin, Insulin like growth factor-1(IGF-1),lipoproteins especially LDL, are also believed to play animportant role in provoking proinflammatory response intubule cells.The net effect of the above described hemodynamic andnonhemodynamic factors cause interstitial inflammatorycellular infiltration and tubulo interstitial fibrosis (Fig. 1).2. Interventions to retard progression ofchronic kidney disease1. Role of renin angiotensin aldosterone blockade2. Reduction of proteinuria3. Effect of hypertension control4. Role of low protein diet5. Correction of metabolic acidosis6. Dyslipidemia management7. Lifestyle modification,8. Novel targets for interventions3. Role of renin angiotensin aldosteroneblockadeThere is enough evidence to show that renin angiotensinsystem blockade (RASB) using angiotensin converting enzymeinhibitors (ACEI) and/or angiotensin II receptor blockers (ARB)is very effective in retarding progression of CKD87in protei-nuric diseases such as diabetic nephropathy50e52,84and glo-merulonephritis,51e58even when the disease is advanced.64In the Ramipril Efficacy in Nephropathy (REIN) study, 352patients with nondiabetic renal disease, randomly assigned toreceive either ACE inhibitor or placebo, achieved similar con-trol of blood pressure. Among patients with proteinuria ofatleast 3 gm/day at baseline, a significantly lower rate of declinein GFR was seen after 2 years in patients receiving ramipril(À0.44 vs. À0.81 ml/min/month with non-ACE conventionaltherapy). In the extension phase of the study, patients whoreceived placebo were switched to ACE inhibitors, and thosealready on ACE inhibitors continued the treatment. In 36e54months of follow-up, no patients in the latter group reached theESRD, and a small number actually experienced a rise in GFR.The Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT)51evaluated the effects of the ARB, irbesartan l versus amlodi-pine or placebo, in 1715 subjects. The primary composite endpoint 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 placeboand 23% lower than for those receiving amlodipine. There wasno significant difference between placebo and amlodipine forthe primary composite end point. The relative risk of ESRD inthe irbesartan group was 17% lower than that of placebo groupand 24% lower than that in the amlodipine group. Proteinuriawas reduced an average of 23% in the irbesartan arm, comparedwith 6% and 10% in the amlodipine and placebo arms respec-tively. The more favorable renal outcomes were in excess ofeffects directly attributable to blood pressure control.The reduction of end points in NIDDM with losartan(RENAAL) study59was undertaken to determine whether ARB,losartan reduces the number of patients with type 2 diabetesdoubling in serum creatinine, ESRD or death, as comparedwith placebo-treated subjects. The primary and secondaryend points of the study were similar to those of IDNT study buttreatment was of longer average duration in the RENAALstudy (3.6 vs. 2.6 years). Losartan lowered the risk of doublingof 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
  7. 7. when compared to placebo. Proteinuria declined by 35% in thelosartan arm and increased slightly in the placebo group.Besides reno-protective effects of ACE inhibitor treatment,the Heart Outcomes Prevention Evaluation (HOPE)60and Los-artan Intervention for End Point Reduction in HypertensionStudy (LIFE)61trials reported substantial reduction in all causemortality cardiac and stroke events in patients receivingramipril or losartan respectively.Study by Mani MK,62from our unit showed that byincreasing 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 decreasedfrom 16 mL/min/y in 1993 to 2.7 mL/min/y in 2008, and inchronic glomerulonephritis from 28 to 2.8, respectively. In theentire group of patients with renal failure of all causes, theprojected increase in time to reach the end stage from a glo-merular filtration rate of 50 mL/min is 26 years, which is 17years 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 influenceon their efficacy.65,66The efficacy and safety of combination ofARB and ACEI or supramaximal doses (doses above the max-imum recommended for control of hypertension) remainsa subject of much debate. Supramaximal doses of ACEI or ARBhave an additive effect in reducing proteinuria and dualblockade also has similar effect.67e70The effect of combina-tion therapy on progression of renal disease is conflicting. Theonly major study (COOPERATE),71which showed benefit withcombination therapy on renal outcome, has recently beenretracted by the publisher, due to irregularities found in theconduct of the study. A recently published ONTARGET study72reported that combination of ARB and ACEI caused more rapiddecline in glomerular filtration rate (GFR) in patients with highcardiovascular risk compared to either of the agents usedalone, 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 beenquestioned for several reasons.73A recent meta-analysisshowed that combination therapy and monotherapy wereassociated with a similar rate of decline in GFR.74We studied the effect of increasing RASB to the maximumtolerated using multiple agents in supramaximal doses andshowed that, with careful monitoring, it can be achievedsafely in the majority of CKD patients. Such an interventionwas associated with significantly better renoprotection in CKDpatients of diverse etiology including nonproteinuric diseasesand the effect appeared to be dose dependent.75Several small clinical trials reported additional reduction ofproteinuria by 15%e54%, blood pressure by approximately 40%,and GFR by approximately 25%, when aldosterone receptorblockers were added to ACEI or AT1RA treatment, but largerandomized trials are required to fully assess the potentialbenefits of these treatments in CKD, and their use in CKD iscurrently limited by the associated risk of hyperkalemia.4. Treatment of hypertensionSeveral population-based studies have shown an increasedrisk of developing progressive renal failure with higher levelsof blood pressure,76e79and is exemplified by findings from theMultiple Risk Factor Intervention Trial (MRFIT).80Even smallincreases in blood pressure, below the threshold usually usedto define hypertension, are associated with an increased riskof ESRD.76,78The Modification of Diet in renal disease study supports theconcept that proteinuria is an independent risk factor for theprogression of renal disease. The authors suggested a targetblood pressure of less than 92 mm Hg (125/75 mm Hg) forpatients 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.81The KDIGO guidelines 2012, suggest reducing BP to lessthan 140/90 in nonproteinuric CKD (not yet on dialysis) anda target to less than 13080 mmHg for proteinuric CKD, of anystage (not yet of dialysis) .A J-shaped relationship betweenachieved BP and outcome has been observed in the elderly andin patients with vascular disease.83Several recent RCTs have not shown a benefit of lower BPtargets in patients without proteinuria. The African AmericanStudy of Kidney Disease and Hypertension (AASK) random-ized participants to treatment to a MAP of either 92 mm Hg or102e107 mm Hg. During the long-term follow-up of partici-pants, there was a benefit associated with the lower BP targetamong patients with a urine protein/creatinine ratio (PCR) of4220 mg/g (422 mg/mmol), but not among those with a PCR220 mg/g (22 mg/mmol).5. Reduction of proteinuriaSeveral clinical studies have provided evidence to showcause-and-effect relation between proteinuria and renaldamage.82A meta-analysis of 17 clinical studies of CKDrevealed a positive correlation between the severity of pro-teinuria and the extent of biopsy-proven glomerulosclerosis.84Observations from the Modification of Diet in Renal Disease(MDRD) trial also suggest that proteinuria is an independentdeterminant of CKD progression: Greater levels of baselineproteinuria were strongly associated with more rapid declinesin GFR and reduction of proteinuria over 3 or 6 months, in-dependent of reduction in blood pressure, was associated withlesser rates of decline in GFR81in randomized trials of ACEI orAT1RA treatment in diabetic nephropathy85and nondiabeticCKD.86A meta-analysis that included data from 1860 patientswith nondiabetic CKD confirmed these findings and showedthat during antihypertensive treatment, the current level ofproteinuria was a powerful predictor of the combined end-point of doubling of baseline serum creatinine level or onsetof end-stage kidney disease (ESKD) (relative risk 5.56 foreach 1 g/day of proteinuria).86The Renoprotection of Opti-mal Antiproteinuric Doses (ROAD) study63has provided themost direct evidence of the clinical benefit of proteinuriareduction 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 themaximum antiproteinuric dose (two further groups).Despite comparable blood pressure control, subjects in thegroups randomized to maximum antiproteinuric dosesa p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 9 e2 824
  8. 8. evidenced 51% and 53% relative risk reductions in thecombined primary endpoint of creatinine level doubling,ESRD or death.The close association between the severity of proteinuriaand renal prognosis implies that reduction of proteinuriashould be regarded as an important independent therapeuticgoal in clinical strategies seeking to slow the rate of progres-sion of CKD.6. Dietary protein restrictionThough 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,85was 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), and255 patients with severe chronic renal failure (GFR at13e24 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 CKDwere included, but patients with diabetes mellitus requiringinsulin therapy were excluded. Patients were also assigned todifferent levels of blood pressure control. After a mean of 2.2years follow-up, the primary analysis revealed no differencein the mean rate of GFR decline in study 1, and only a trendtoward a slower rate of decline in the very low protein group instudy 2. Long-term follow-up of 255 participants in study 2 ofthe MDRD trial found no renoprotective benefit associatedwith randomization to very low protein diet in the originalstudy but did report a higher risk of death in this group (HR,1.92; CI, 1.15e3.20).88Despite inconclusive findings in several of the individualstudies, three meta-analyses each concluded that dietaryprotein restriction is associated with a reduced risk of ESKD(odds ratio [OR] of 0.62 and 0.67, respectively),89,90as well asa modest reduction in the rate of estimated GFR decline(0.53 mL/min/year).91Though the renoprotective benefit of dietary protein re-striction in humans appears modest, it is associated withother benefits including improvement in acidosis and reduc-tion in phosphorus and potassium load. Thus comprehensivedietary intervention with a moderate restriction in dietaryprotein intake should remain an important part of the man-agement of patients with CKD.927. Management of hyperlipidemiaThe benefits of lipid lowering in retarding progression of CKDhave been elusive. Though some studies showed reduction inproteinuria and cardiovascular end points with statins, theyhave not shown to retard progression.8. Correction of metabolic acidosisObservational clinical studies identified acidosis as an inde-pendent risk factor for CKD progression,93,94but to date onlysmall studies investigated the renoprotective potential of al-kali supplementation in human subjects. In one randomizedstudy95in adults with creatinine clearance 15e30 mL/min/1.73 m2, randomization to treatment of acidosis (serum bi-carbonate 16e20 mmol/L) with sodium bicarbonate wasassociated with less decline in creatinine clearance (1.88 vs.5.93 mL/min/1.73 m2) and lower incidence of end-stage kidneydisease (6.5% vs. 33%). In another randomized, placebo-controlled trial in subjects with a mean estimated GFR of75 mL/min/1.73 m2, treatment with sodium bicarbonate for 5years was associated with a slower reduction in estimatedGFR (derived from plasma cystatin C measurements) thanplacebo or treatment with sodium chloride.96Further largerandomized studies with more direct measures of GFR arerequired to adequately evaluate the renoprotective potentialof alkali supplementation in human CKD.9. Life style modificationsCessation of smoking, and achieving ideal body mass index inobese patients have shown to benefit the process of retarda-tion of CKD progression.10. Novel targets for interventionThe following interventions that inhibit the effects of TGF-bhave been shown to afford renoprotection in animal models ofrenal disease: Transfection of the gene for decorin, a naturallyoccurring inhibitor of TGF-b, into skeletal muscle limited theprogression of renal injury in anti-Thy-1 glomerulonephritis97Administration of anti-TGF-b antibodies to salt-loaded Dahl-salt sensitive rats ameliorated the hypertension, proteinuria,glomerulosclerosis, and interstitial fibrosis typical of thismodel. Treatment with tranilast (n-[3,4-dimethoxycin-namoyl]anthranilic acid) an inhibitor of TGF-b-inducedextracellular matrix production, significantly reduced albu-minuria, macrophage infiltration, glomerulosclerosis, andinterstitial fibrosis in 5/6 nephrectomized rats.98Transfer ofan inducible gene for Smad 7, which blocks TGF-b signaling byinhibiting 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 Igene expression, decrease proteinuria and improvement inGFR, 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 TGFb and CTGF production. Pimagedine, an inhibitor of AGE for-mation showed reduction in decline of GFR over 36 months offollow-up 9.8 vs 6.3 ml/min in diabetic nephropathy.99Conflicts of interestThe 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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