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

Progression of Chronic Kidney Disease: Mechanismsand Interventions in Retardation.

Review Article

Progression of chronic kidney disease: Mechanismsand 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

The incidenceofchronickidneydisease (CKD) is increasingworldwideand isbecomingamajor

concern for thehealthcare.Approximately 1.8millionpeople,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-

trializednations,while availability ofRRT is scarce in developing countries. It is estimated that

more than 150 permillion 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

postulated to result fromaself-perpetuatingvicious cycleoffibrosis activatedafter initial 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-

gressiverenal injuryandan inexorabledecline inrenal function.

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

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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 effectswith RAAS blockade. with

either ACEI or AT1RA treatment.11e15

1.2.1. Effect of mechanical stress on various glomerular cellsExperiments in isolated perfused rat glomeruli showed that

increased perfusion pressures cause increases in wall tension

andglomerular volumewhich result in stretchingof 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.

Thismay 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 indetachment and exposure of thebasement

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,21and 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-bTGF-b is associatedwith 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 IIAngiotensin 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.


1.3.3. AldosteroneMechanisms 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. EndothelinsEndothelins 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 SNGFRwas unchanged

or 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 glomerular

hydraulic 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 with

renal mass ablation seems to be effect of vasodilators out-

weighing the vasoconstrictors.

1.3.7. Oxidative stressCKD is associated with increased oxidative stress that likely

contributes to the progression of renal damage and the patho-

genesisof theassociatedcardiovasculardisease.39 Following5/6

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 9e2 8 21

(enzyme for removal) were observed in the liver and kidneys

resulting in increase in superoxide.40 Adverse consequences of

oxidative stress thatmay contribute toCKDprogression 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. AcidosisAcidosis 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 factors1.3.9.1. 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-

ciationwith increased expression ofmatrixmetalloproteinase

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.


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 thesemolecules 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 ofchronic 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 aldosteroneblockade

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/dayat baseline, a significantly lower rate of decline

in GFR was seen after 2 years in patients receiving ramipril

(�0.44 vs. �0.81 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

monthsof follow-up,nopatients in the lattergroup 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 endpointwas 20% lower than for those receivingplacebo

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 reducedanaverageof 23% in the irbesartanarm, 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 studywere 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%


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 causedmore 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 associatedwith 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%, bloodpressure byapproximately 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

TheModification 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 outcomehas 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 withmore rapid declines

in GFR and reduction of proteinuria over 3 or 6 months, in-

dependent of reduction in blood pressure, was associatedwith

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


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 lowprotein 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.

5.93mL/min/1.73m2) 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 animalmodels 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.


r e f e r e n c e s

1. Remuzzi G, Weening JJ. Albuminuria as a test for vasculardisease. Lancet. 2005 Feb 12e18;365(9459):556e557.

2. Xue JL, Ma JZ, Louis TA, Collins AJ. Forecast of the number ofpatients with end-stage renal disease in the United States tothe year 2010. J Am Soc Nephrol. 2001 Dec;12(12):2753e2758.

3. Kher V. End-stage renal disease in developing countries.Kidney Int. 2002;62:350e362.

4. Modi GK, Jha V. The incidence of end-stage renal disease inIndia: a population-based study. Kidney Int. 2006;70:2131e2133.

5. Mani MK. Treating renal disease in India’s poor-the art of thepossible. Semin Nephrol. 2010;30:74e80.

6. Mani MK. Nephrologists sans frontiers: preventing CKD ona shoestring. Kidney Int. 2006;70:821e823.

7. Mani MK. Experience with a programme for prevention ofchronic failure in India. Kidney Int Suppl. 2005;94:S75eS78.

8. Hostetter TH, Olson JL, Rennke HG, et al. Hyperfiltration inremnant nephrons: a potentially adverse response to renalablation. J Am Soc Nephrol. 2001;12:1315e1325.

9. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intakeand the progressive nature of kidney disease: the role ofhemodynamically mediated glomerular injury in thepathogenesis of progressive glomerular sclerosis in aging,renal ablation and intrinsic renal disease. N Engl J Med.1982;307:652e659. 213.

10. Malcolm JB, Bagrodia A, Derweesh IH, et al. Comparison ofrates and risk factors for developing chronic renalinsufficiency, proteinuria and metabolic acidosis after radicalor partial nephrectomy. BJU Int. 2009;104:476e481.

11. Anderson S, Rennke HG, Brenner BM. Therapeutic advantageof converting enzyme inhibitors in arresting progressive renaldisease associated with systemic hypertension in the rat. JClin Invest. 1986;77:1993e2000.

12. Lafayette RA, Mayer G, Park SK, Meyer TW. Angiotensin IIreceptor blockade limits glomerular injury in rats withreduced renal mass. J Clin Invest. 1992;90:766e771.

13. Taal MW, Chertow GM, Rennke HR, et al. Mechanismsunderlying renoprotection during renin-angiotensin systemblockade. Am J Phys. 2001;280:F343eF355.

14. Anderson S, Rennke HG, Garcia DL, et al. Short- and long-term effects of antihypertensive therapy in the diabetic rat.Kidney Int. 1989;36:526e536.

15. Fujihara CK, Padilha RM, Zatz R. Glomerular abnormalities inlong-term experimental diabetes. Role of hemodynamic andnonhemodynamic factors and effects of antihypertensivetherapy. Diabetes. 1992;41:286e293.

16. Cortes P, Zhao X, Riser BL, et al. Regulation of glomerularvolume in normal and partially nephrectomized rats. Am JPhysiol. 1996;270:F356eF370.

17. Hostetter TH. Progression of renal disease and renalhypertrophy. Annu Rev Physiol. 1995;57:263e278.

18. Brooks AR, Lelkes PI, Rubanyi GM. Gene expression profilingof vascular endothelial cells exposed to fluid mechanicalforces: relevance for focal susceptibility to atherosclerosis.Endothelium. 2004;11:45e57. 241.

19. Nagel T, Resnick N, AtkinsonWJ, et al. Shear stress selectivelyupregulates intercellular adhesion molecule-1 expression incultured human vascular endothelial cells. J Clin Invest.1994;94:885e891.

20. Ingram AJ, Ly H, Thai K, et al. Activation of mesangial cellsignaling cascades in response to mechanical strain. KidneyInt. 1999;55:476e485.

21. Riser BL, Cortes P, Zhao X, et al. Intraglomerular pressure andmesangial stretching stimulate extracellular matrixformation in the rat. J Clin Invest. 1992;90:1932e1943.

22. RiserBL,CortesP,HeiligC,etal.Cyclicstretching forceselectivelyup-regulates transforming growth factor-beta isoforms incultured rat mesangial cells. Am J Pathol. 1996;148:1915e1923.

23. Becker BN, Yasuda T, Kondo S, et al. Mechanical stretch/relaxation stimulates a cellular renin-angiotensin system incultured rat mesangial cells. Exp Nephrol. 1998;6:57e66.

24. Durvasula RV, Shankland SJ. Podocyte injury and targetingtherapy: an update. Curr Opin Nephrol Hypertens. 2006;15:1e7.

25. Yu D, Petermann A, Kunter U, et al. Urinary podocyte loss isa more specific marker of ongoing glomerular damage thanproteinuria. J Am Soc Nephrol. 2005;16:1733e1741.

26. Durvasula RV, Petermann AT, Hiromura K, et al. Activation ofa local tissue angiotensin system in podocytes by mechanicalstrain. Kidney Int. 2004;65:30e39.

27. Border WA, Noble NA. Fibrosis linked to TGF-beta in yetanother disease. J Clin Invest. 1995;96:655e656.

28. Ketteler M, Noble NA, Border WA. Transforming growthfactor-beta and angiotensin II: the missing link fromglomerular hyperfiltration to glomerulosclerosis? Annu RevPhysiol. 1995;57:279e295.

29. Niemir ZI, Stein H, Noronha IL, et al. PDGF and TGF-betacontribute to the natural course of human IgAglomerulonephritis. Kidney Int. 1995;48:1530e1541.

30. Yamamoto T, Noble NA, Cohen AH, et al. Expression oftransforming growth factor-beta isoforms in humanglomerular diseases. Kidney Int. 1996;49:461e469.

31. Yamamoto T, Noble NA, Miller DE, et al. Increased levels oftransforming growth factor-beta in HIV-associatednephropathy. Kidney Int. 1999;55:579e592.

32. Yamamoto T, Nakamura T, Noble NA, et al. Expression oftransforming growth factor beta is elevated in human andexperimental diabetic nephropathy. Proc Natl Acad Sci U S A.1993;90:1814e1818.

33. Chan LY, Leung JC, Tang SC, et al. Tubular expression ofangiotensin II receptors and their regulation in IgAnephropathy. J Am Soc Nephrol. 2005;16:2306e2317.

34. Lapinski R, Perico N, Remuzzi A, et al. Angiotensin IImodulates glomerular capillary permselectivity in rat isolatedperfused kidney. J Am Soc Nephrol. 1996;7:653e660.

35. Hoffmann S, Podlich D, Hahnel B, et al. Angiotensin II type 1receptor overexpression in podocytes inducesglomerulosclerosis in transgenic rats. J Am Soc Nephrol.2004;15:1475e1487.

36. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates theexpression of plasminogen activator inhibitor-1 in culturedendothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest.1995;95:995e1001.

37. Feener EP, Northrup JM, Aiello LP, et al. Angiotensin II inducesplasminogen activator inhibitor-1 and -2 expression invascular endothelial and smooth muscle cells. J Clin Invest.1995;95:1353e1362.

38. Gomez-Garre D, Largo R, Tejera N, et al. Activation of NF-kappaB in tubular epithelial cells of rats with intenseproteinuria: role of angiotensin II and endothelin-1.Hypertension. 2001;37:1171e1178.

39. Himmelfarb J, Stenvinkel P, Ikizler TA, et al. The elephant inuremia: oxidant stress as a unifying concept of cardiovasculardisease in uremia. Kidney Int. 2002;62:1524e1538.

40. Vaziri ND, Dicus M, Ho ND, et al. Oxidative stress anddysregulation of superoxide dismutase and NADPH oxidasein renal insufficiency. Kidney Int. 2003;63:179e185.

41. Kim HJ, Vaziri ND. Contribution of impaired Nrf2-Keap1pathway to oxidative stress and inflammation in chronicrenal failure. Am J Physiol Renal Physiol. 2009;298:F662eF671.

42. Vaziri ND. Roles of oxidative stress and antioxidant therapyin chronic kidney disease and hypertension. Curr Opin NephrolHypertens. 2004;13:93e99.


43. Vaziri ND, Oveisi F, Ding Y. Role of increased oxygen freeradical activity in the pathogenesis of uremic hypertension.Kidney Int. 1998;53:1748e1754.

44. Whaley-Connell AT, Chowdhury NA, Hayden MR, et al.Oxidative stress and glomerular filtration barrier injury: roleof the renin-angiotensin system in the Ren2 transgenic rat.Am J Physiol Renal Physiol. 2006;291:F1308eF1314.

45. Guan YouFei, Breyer Matthew D. Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renaldisease. Kidney Int. 2001 Jul;60(1):14e30.

46. Guan Y, Breyer MD, Olson JL, et al. Altered glomerularpermselectivity and progressive sclerosis following extremeablation of renal mass. Kidney Int. 1982;22:112e126.

47. Miceli I, Burt D, Tarabra E, et al. Stretch reduces nephrinexpression via an angiotensin II-AT (1)-dependentmechanism in human podocytes: effect of rosiglitazone. Am JPhysiol Renal Physiol. 2009;298:F381eF390.

48. Erkan E, De Leon M, Devarajan P. Albumin overload inducesapoptosis in LLC-PK (1) cells. Am J Physiol Renal Physiol.2001;280:1107e1114.

49. Morais C, Westhuyzen J, Metharom P, et al. High molecularweight plasma proteins induce apoptosis and Fas/FasLexpression in human proximal tubular cells. Nephrol DialTransplant. 2005;20:50e58.

50. Kshirsagar AV, Joy MS, Hogan SL, Falk RJ, Colindres RE. Effectof ACE inhibitors in diabetic and nondiabetic chronic renaldisease: a systematic overview of randomized placebo-controlled trials. Am J Kidney Dis. 2000;35:695e707.

51. Lewis EJ, Hunsicker LG, ClarkeWR, et al. Renoprotective effectof the angiotensin-receptor antagonist irbesartan in patientswith nephropathy due to type 2 diabetes. N Engl J Med.2001;345:851e860.

52. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartanon renal and cardiovascular outcomes in patients with type 2diabetes and nephropathy. N Engl J Med. 2001;20(345):861e869.

53. Chiurchiu C, Remuzzi G, Ruggenenti P. Angiotensin-converting enzyme inhibition and renal protection innondiabetic patients: the data of the meta-analyses. J Am SocNephrol. 2005;16(suppl 1):S58eS63.

54. Schrier RW, Estacio RO. The effect of angiotensin-convertingenzyme inhibitors on the progression of nondiabetic renaldisease: a pooled analysis of individual-patient data from 11randomized, controlled trials. Ann Intern Med.2001;135:138e139.

55. Jafar TH, Stark PC, Schmid CH, , et al, AIPRD Study Group.Progression of chronic kidney disease: the role of bloodpressure control, proteinuria, and angiotensin-convertingenzyme inhibition: a patient-level meta-analysis. Ann InternMed. 2003;39:244e252.

56. Ruggenenti P, Perna A, Remuzzi G, Gruppo Italiano di StudiEpidemiologici in Nefrologia. ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never tostop: a post hoc analysis of the REIN trial results. Ramiprilefficacy in nephropathy. J Am Soc Nephrol. 2001;12:2832e2837.

57. The GISEN Group (Gruppo Italiano di Studi Epidemiologici inNefrologia). Randomized placebo-controlled trial of effect oframipril on decline in glomerular filtration rate and risk ofterminal renal failure in proteinuric, non-diabeticnephropathy. Lancet. 1997;349:1857e1863.

58. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R,Remuzzi G. Renal function and requirement for dialysis inchronic nephropathy patients on long-term ramipril: REINfollow-up trial. Gruppo Italiano di Studi Epidemiologici inNefrologia (GISEN). Ramipril efficacy in nephropathy. Lancet.1998;352:1252e1256.

59. Brenner BM, Coffee ME, et al. Effects of Losartan on renal andcardiovascular outcomes in patients with type2 diabetes andnephropathy (RENAAL study). N Engl J Med. 2001;345:861e869.

60. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconvertingenzyme inhibitor, ramipril, oncardiovasculareventsinhigh riskpatients. TheHeart outcomespreventionEvaluationstudy Investigators (HOPE). N Engl J Med. 2000;342:145e153.

61. Dahlof B, Devereux R, Siedldsen S, et al. Cardiovascularmorbidity and mortality in the Losartan intervention forendpoint reduction in hypertension study ( LIFE ). Arandomized trial against atenolol. Lancet. 2002;359:995e1003.

62. Mani MK. Semin Nephrol. January 2010;30(1):74e80.63. Hou FF, Xie D, Zhang X, et al. Renoprotection of optimal

antiproteinuric doses (ROAD) study: a randomized controlledstudy of benazepril and losartan in chronic renalinsufficiency. J Am Soc Nephrol. 2007;18:1889e1898.

64. Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety ofbenazepril for advanced chronic renal insufficiency. N Engl JMed. 2006;354:131e140.

65. Ruggenenti P, Perna A, Zoccali C, et al. Chronic proteinuricnephropathies. II. Outcomes and response to treatment ina prospective cohort of 352 patients: differences betweenwomen and men in relation to the ACE gene polymorphism.Gruppo Italiano di Studi Epidemologici in Nefrologia (GISEN). JAm Soc Nephrol. 2000;11:88e96.

66. Mitchell HC, Smith RD, Cutler RE, et al. Racial differences inthe renal response to blood pressure lowering during chronicangiotensin-converting enzyme inhibition: a prospectivedouble-blind randomized comparison of fosinopril andlisinopril in older hypertensive patients with chronic renalinsufficiency. Am J Kidney Dis. 1997;29:897e906.

67. Burgess E, Muirhead N, Rene de Cotret P, et al. Supramaximaldose of candesartan in proteinuric renal disease. J Am SocNephrol. 2009;20:893e900.

68. Rossing K, Schjoedt KJ, Jensen BR, Boomsma F, Parving HH.Enhanced renoprotective effects of ultrahigh doses ofirbesartan in patients with type-2 diabetes andmicroalbuminuria. Kidney Int. 2005;68:1190e1198.

69. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis:effect of monotherapy and combination therapy withinhibitors of the renin angiotensin system on proteinuria inrenal disease. Ann Intern Med. 2008;148:30e48.

70. Catapano F, Chiodini P, De Nicola L, et al. Antiproteinuricresponse to dual blockade of the renin-angiotensin system inprimary glomerulonephritis:meta-analysis andmetaregression.Am J Kidney Dis. 2008;52:475e485 [PUBMED] [FULLTEXT].

71. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T,Ideura T. Combination treatment of angiotensin-II receptorblocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomized controlledtrial. Lancet. 2003;361:117e124 [PUBMED] [FULLTEXT].

72. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomeswith telmisartan, ramipril, or both, in people at high vascularrisk (the ONTARGET study): a multicentre, randomized,double-blind, controlled trial. Lancet. 2008;372:547e553.

73. Lambers Heerspink HJ, de Zeeuw D. Dual RAS therapy not ontarget, but fully alive. Nephron Clin Pract. 2010;116:c137ec142.

74. MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J,Clark HD. Combination therapy with an angiotensin receptorblocker and an ACE inhibitor in proteinuric renal disease:a systematic review of the efficacy and safety data. Am JKidney Dis. 2006;48:8e20.

75. Limesh M, Annigeri RA, Mani MK, et al. Retarding theprogression of chronic kidney disease with renin angiotensinsystem blockade. Indian J Nephrol. 2012;22(2):108e115.

76. Iseki K, Iseki C, Ikemiya Y, et al. Risk of developing end-stagerenal disease in a cohort of mass screening. Kidney Int.1996;49:800e805.

77. Perry Jr HM, Miller P, Fornoff JR, et al. Early predictors of 15-year end-stage renal disease in hypertensive patients.Hypertension. 1995;25(4 Pt 1):587e594.


78. Haroun MK, Jaar BG, Hoffman SC, et al. Risk factors forchronic kidney disease: a prospective study of 23,534 menand women in Washington County, Maryland. J Am SocNephrol. 2003;14:2934e2941.

79. Fox CS, Larson MG, Leip EP, et al. Predictors of new-onsetkidney disease in a community-based population. JAMA.2004;291:844e850.

80. Klag MJ, Whelton PK, Randall BL, et al. Blood pressure andend-stage renal disease in men. N Engl J Med. 1996;334:13e18.

81. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control,proteinuria, and the progression of renal disease. Themodification of diet in renal disease study. Ann Intern Med.1995;123:754e762.

82. Perna A, Remuzzi G. Abnormal permeability to proteins andglomerular lesions: a meta-analysis of experimental andhuman studies. Am J Kidney Dis. 1996;27:34e41.

83. Kidney disease: improving global outcomes (KDIGO)guidelines. Kidney Int Suppl. 2012;2(5).

84. Bjorck S, Mulec H, Johnsen SA, Norden G, Aurell M. Renalprotective effect of enalapril in diabetic nephropathy. BMJ.1992;304:339.

85. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary proteinrestriction and blood-pressure control on the progression ofchronic renal disease. Modification of Diet in Renal DiseaseStudy Group. N Engl J Med. 1994;330:877e884.

86. Jafar TH, Stark PC, Schmid CH, et al. Proteinuria asa modifiable risk factor for the progression of non-diabeticrenal disease. Kidney Int. 2001;60:1131e1140.

87. Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitorsof the renin-angiotensin system and other antihypertensivedrugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005;366:2026e2033.

88. Menon V, Kopple JD, Wang X, et al. Effect of a very low-protein diet on outcomes: long-term follow-up of theModification of Diet in Renal Disease (MDRD) Study. Am JKidney Dis. 2009;53:208e217.

89. Pedrini MT, Levey AS, Lau J, et al. The effect of dietary proteinrestriction on the progression of diabetic and nondiabetic renaldiseases: a meta-analysis. Ann Intern Med. 1996;124:627e632.

90. Fouque D, Wang P, Laville M, et al. Low protein diets delayend-stage renal disease in non-diabetic adults with chronicrenal failure. Nephrol Dial Transplant. 2000;15:1986e1992.

91. Kasiske BL, Lakatua JD, Ma JZ, et al. A meta-analysis of theeffects of dietary protein restriction on the rate of decline inrenal function. Am J Kidney Dis. 1998;31:954e961.

92. Mitch WE, Remuzzi G. Diets for patients with chronic kidneydisease, still worth prescribing. J Am Soc Nephrol.2004;15:234e237.

93. Menon V, Tighiouart H, Vaughn NS, et al. Serum bicarbonateand long-term outcomes in CKD. Am J Kidney Dis.2010;56:907e914. Epub June 3, 2010.

94. Shah SN, Abramowitz M, Hostetter TH, et al. Serumbicarbonate levels and the progression of kidney disease:a cohort study. Am J Kidney Dis. 2009;54:270e277.

95. de Brito-Ashurst I, Varagunam M, Raftery MJ, et al.Bicarbonate supplementation slows progression of CKD andimproves nutritional status. J Am Soc Nephrol.2009;20:2075e2084.

96. Mahajan A, Simoni J, Sheather SJ, et al. Daily oral sodiumbicarbonate preserves glomerular filtration rate by slowing itsdecline in early hypertensive nephropathy. Kidney Int.2010;78:303e309.

97. Dahly AJ, Hoagland KM, Flasch AK, et al. Antihypertensiveeffects of chronic anti-TGF-beta antibody therapy in Dahl Srats.Am J Physiol Regul Integr Comp Physiol. 2002;283:R757eR767.

98. Kelly DJ, Zhang Y, Gow R, et al. Tranilast attenuates structuraland functional aspects of renal injury in the remnant kidneymodel.

99. Bolton WK, Cattran DC, Williams ME, et al. Randomized trialof an inhibitor of formation of advanced glycation endproducts in diabetic nephropathy. J Am Soc Nephrol.2004;15:2619e2629.


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

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