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.

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

2. 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

3. 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.
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4. 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

5. (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

6. 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

7. 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

8. 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.
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