Review Article

Early Diagnosis of Ckd and Its Prevention

MS Amaresan*, R Geetha**

Abstract
Chronic kidney disease is associated with increased mortality and morbidity especially due to cardiovascular
disease and imposes a huge economic burden to the family and health care delivery system. In both developing
and developed countries, diabetes mellitus and hypertension are the leading causes of CKD. While dialysis
and transplantation are excellent options for end stage kidney disease, they are costly. Renal transplant is
again limited by organ shortage. The better strategy to tackle CKD will be early identification of the disease
and adopt measures to slow its progression to ESRD. A comprehensive approach to the prevention of CKD
and retarding its progression is outlined. ©

INTRODUCTION on the prevention of CKD. Early diagnosis of CKD

and its prevention involves measures to 1) screen for
C hronic Kidney Disease (CKD) is emerging as a Public
Health problem in both developed and developing
countries. Besides causing premature mortality and
CKD 2) evaluate and estimate the progression of CKD
and 3) measures to prevent the progression of CKD.
This involves early identification of patients at risk for
morbidity and lowering quality of life it is a disease,
CKD. Patients with diabetes, hypertension, subjects
which imposes a huge economic burden on not only the
above the age of 60 years, close relatives of patients
patients and their families but also on the health care
with nephropathy caused by diabetes, hypertension
system and society. It is a disease associated with multiple
and glomerulonephritis should be primary targets for
comorbid conditions – especially cardiovascular disease
screening to detect clinically silent kidney disease.
(CVD). The incidence of CVD in CKD is 10 to 30 times
more than in those without kidney disease.1 The size of
the dialysis population is expanding at a rate of 7%per
SCREENING FOR EARLY EVIDENCE OF
year. The aggregate cost of treating ESRD in the coming CHRONIC KIDNEY DISEASE (CKD)
decade will exceed $1 trillion.1 Renal transplantation The simplest screening test for CKD is the detection of
is limited by organ shortage. One important reason proteinuria and microsopic hematuria through standard
for the existing alarming state of the disease is that it dipstick testing. The presence of albumin in the urine
has been underdiagnosed and undertreated. One in 20 predicts both cardiovascular and non cardiovascular
in our population has more than 1.4 mgs/dl of serum morbidity as it reflects a generalized endothelial
creatinine. The benefits of diagnosing early kidney dysfunction. Estimation of the glomerular filtration
disease extends beyond the kidney itself. Appropriate rate (GFR) is the best overall indicator of the level of
management of the comorbid conditions reduces kidney function. Estimates of GFR can be made using the
not only the overall and cardiovascular mortality modification of diet in renal disease (MDRD) formula
but improves the quality of life itself, reduces the or the Cockroft- Gault equation.3 However there is a
economic burden and provides adequate time for the need to validate these formulas based on ethnicities in
psychological, medical and economic preparation for different parts of the world. Serum creatinine alone should
renal replacement therapy (RRT).Glomerulonephritis not be used to assess the level of kidney function.
and chronic interstitial nephritis which appeared to be
the common causes of CKD in developing countries RISK FACTORS FOR PROGRESSION OF
earlier is now replaced by diseases like diabetes mellitus CKD
(DM) 41% and hypertension (HT) 23%.2 India, the
second most populous country has the most diabetics The risk factors for progression of kidney disease
in the world. It is high time that we revise our strategies include (i) persistent activity of the disease responsible
in the management of CKD and focus our attention for CKD, example SLE, PAN, and other primary
or secondary glomerular disease; (ii) suboptimal
prevention and treatment of DM and HT; (iii) persistent
*Head; **Sr. Clinical Professor, Department of Nephrology, Tamil
Nadu Medical Service, Chennai.
proteinuria; (iv) high protein intake in the diet; (v)

© JAPI • VOL. 56 • JANUARY 2008 www.japi.org 41

 enzyme inhibitors (ACEIs) and angiotensin receptor
blockers (ARBs) are highly effective in controlling
glomerular HT and thereby retarding the disease
progression. This is reflected by reduction in proteinuria
and glomerulorsclerosis, whereas, the same is not
achieved by other antihypertensives like hydralazine,
reserpine and diuretics, despite equivalent systemic
blood pressure lowering.6
Angiotensin II emerged as a central mediator of
glomerular hemodynamic changes and progression
of renal injury (Fig. 1). Soon they have found that
angiotensin II had several non-hemodynamic effects
in mediating renal disease progression. These include
Fig. 1 : RAAS in CKD oxidant stress, aldosterone induced injury, increased
filtration of plasma proteins, and co-ordinated nuclear
urinary tract infection, reflux nephropathy or systemic factor-kappa B (NF-kB) induced up-regulation of
infection; (vi) marked reduction in nephron number, cytokines, chemokines, transforming growth factor β
either congenital or acquired; (vii) anemia; (viii) (TGF-β), connective tissues to growth factor (CTGF)
hyperlipidemia; (ix) cigarette smoking; and (x) obesity and chemotactic and cell adhesion molecule expression,
(metabolic syndrome). all of which in-turn lead to mesangial cell proliferation,
Thus all patients with CKD should be screened for increased synthesis of extra-cellular matrix proteins,
traditional risk factors- smoking history, blood pressure stimulation of plasminogen activation inhibitor-1
measurement, body weight, body mass index, fasting production by endothelial and vascular smooth muscle
blood glucose, fasting lipid profile, serum uric acid cells, and macrophage activation and infiltration. 7
level and 12 lead electrocardiogram. Though standard All these factors together promote focal and global
formulas are available to estimate the GFR, a 24 hour glomerulosclerosis and tubulointerstitial fibrosis,
urine sample is advisable in individuals on a vegetarian culminating in further nephron loss and a vicious
diet and those with reduced muscle mass (amputation, cycle.
gross malnutrition)
PREVENTING OR RETARDING THE
MECHANISM OF PROGRESSION OF CKD PROGRESSION OF CKD
Quite early, what we see as renal failure is only a tip Dietary Protein restriction
of the iceberg. With decrease in glomerular filtration
Brenner’s experimental models showed that dietary
rate (GFR) below about one-half of the normal, further
protein restriction abrogates the adaptive rise in
loss of function occurs even if the original disease
glomerular pressure and slows the tendency to renal
becomes inactive. Surviving nephrons undergo
disease progression. The National Institute of Health
adaptation in structure and function that raise single
Modification of Diet in Renal Disease (NIH-MDRD)
nephron GFR to meet excretory demands. These
trial.5 Although ambiguous in early stages, subsequent
hemodynamic adaptations leading to glomerular HT
sub-group analysis by Levey et al provided clear
and hyperfiltration initiate and perpetuate glomerular
evidence of benefit from dietary protein restrictions.
injury, causing detrimental effects of acquired nephron
The meta analysis of 10 randomized controlled studies
loss 5. Inborn deficits in total number of nephrons in
of the effects of protein restriction on the progression of
association with low birth weight contribute to HT,
diabetic and non-diabetic renal disease by Pedrini et al
glomerulorsclerosis and CKD.4
determined that the overall relative risk of renal failure
Among a variety of measures that slow progression or death was indeed reduced with protein restriction
of experimental renal disease, alleviation of glomerular as compared with non-restricted protein intake.8.9
capillary hypertension has been found to be the common The benefits are obvious that GFR between 12.5 and
denominator. Due to nephron loss and thus raising 55 ml/mt. slows the progression of fall in GFR by 0.5
the single nephron GFR leads to hyperfiltration if ml/mt/year. Protein restriction should be initiated in
dietary protein intake is not controlled. Dietary protein the early stage itself when the GFR is 60 ml/mt. The
restriction reduces glomerular pressure and ameliorates recommended protein intake is 0.8 g/kg/day when
renal structure injury.5 Glomerular HT is maintained GFR is 25 to 55 ml/mt and 0.6 g/kg/day if less than
largely by angiotensin-dependent mechanisms, via 25 ml/mt. More than 50% of the calculated protein
increased systemic blood pressure and efferent arteriolar should be of high biological value. A meta-analysis of
vasoconstriction. In addition to their potent systemic five small studies of diabetics showed that the relative
antihypertensive actions, angiotensin-converting risk of progression in protein restricted patients was

42 www.japi.org © JAPI • VOL. 56 • JANUARY 2008

almost 50% less than that of diabetics on a more liberal of blood pressure. Among patients with proteinuria
protein intake.9 of atleast 3gms/day at baseline, a significantly lower
Reduction of Proteinuria rate of GFR was seen after 2 years in patients receiving
ramipril (- 0.44 vs. – 0.81 ml/min/month with non-ACE
Proteinuria has been considered as a marker
conventional therapy). In the extension phase of the
of glomerular barrier integrity and the massive
study, patients who received placebo were switched to
proteinuria indicates glomerular disease severity.
ACE inhibitors, and those already on ACE inhibitors
Besides, proteinuria perse also contributes to progressive
continued the treatment. Consistent with the findings
renal injury. Proteinuria stimulates protein uptake by
of the first 2-year phase of the study, ramipril treatment
promimal tubular cells through megalin and cubulin
enjoyed a significant reduction in the rate of decline of
dependant transport processes. Increased protein
GFR, while patients continuing on the ACE inhibitor
traffic causes tubular cell dysfunction through various
enjoyed a further rate in the reduction of GFR decline
mechanisms, including complement-dependant
to level to those similar with non-ACE inhibitors. In
pathways and generation of oxidative stress, catalysed
36 to 54 months of follow up, no patients in the latter
by iron containing proteins. Excessive endocytosis of
group reached the ESRD, and a small number actually
proteins induces local production of pro-inflammatory
experienced a rise in GFR. In Angiotensin-Converting
and pro-fibrogenic cytokines. Proteinuria also activates
Enzyme Inhibition in Progressive Renal Insufficiency
the local tubular renin angiotensin system (RAS).
(AIPRI) trial,11 Machio et al studies 583 patients with
The REIN study demonstrated that higher baseline
renal disease of diverse etiologies to treatment with
proteinuria was associated with more rapid decline in
benazepril or placebo. After 3 years of follow-up, the
GFR.10 The MDRD study demonstrated that reduction
study found a 53% of reduction with ACE inhibitors in
in proteinuria; independent of blood pressure was
the combined risk of doubling of the base-line serum
associated with slower progression of renal disease.
creatinine or need for dialysis.
Control of Hypertension
In the AIPRI data study based on 11 randomized
Hypertension in CKD results in left ventricular ACE inhibitors versus placebo-treatment trials, Jafar et
hypertrophy, cardiac dilatation, heart failure, ischemic al concluded that ACEIs are more effective than other
coronary changes, worsening of atherosclerosis and antihypertensive treatment in slowing renal progression
contributes to increased cardiovascular morbidity and and reducing proteinuria.12 Significantly lower values
mortality. Both systolic and diastolic blood pressures were seen with ACEIs for several outcome measures
are important. High systolic pressures increase the including level of proteinuria and incidence of ESRD.
myocardial work, while low diastolic pressure reduces A similar conclusion emerged from the AASK trial in
myocardial circulation and increase the myocardial hypertensive African Americans, in which ramipril
ischemia. A pulse pressure of more than 50 mmHg is a proved more renoprotective than that of the comparator
marker of increased cardiovascular morbidity. The target drugs, amlodipine or metaprolol.13
BP is below 130/80 mmHg in all patients with CKD. It
Most diabetic patients who develop ESRD suffer
should be less than 120/75 mmHg in proteinuric renal
from Type II diabetes, reflecting its approximately 20-
disease.11
fold greater prevalence over type 1 diabetes. Type 2
Use of ACEI and ARB diabetic patients develop glomerular hyperfiltration,
The antihypertensive drug of choice in CKD is ACEI, proteinuria and progressive decline in GFR, much as
ARB or their combination, besides adding on long acting in type 1 diabetes. Since 1995, ARBs have also been
channel blockers or beta blockers and diuretics wherever available to inhibit the RAS by blocking angiotensin II
it is indicated. subtype 1 (AT1) receptors. Thus, whereas ACEIs depress
ACE inhibitors retard the development of glomerular ACE-dependent angiotensin II production, ARBs block
lesions of experimental diabetic nephropathy. This the effects of angiotensin II from any source at the
motivated several small clinical studies performed receptor level. The alternative pathway of angiotensin
to assess the effects of antihypertensive treatment in II production can be by chymase, cathepsin, tPa and
general and ACE inhibitors in particular on the rate of PAI-1. Two large prospective randomized trials showed
progression of diabetic nephropathy. When captopril was that the interruption of the RAS with ARBs in type 2
compared with placebo in 407 diabetic nephropathies, diabetic patients with overt nephropathy delays the
patients with proteinuria > 500 mgs/day on captopril progression of renal disease. The Irbesartan Type 2
treatment were associated with a 50% reduction in the Diabetic Nephropathy Trial (IDNT)14 evaluated the
combined risk of ESRD or death.4 This was in Type effects of the ARB, irbesartan on renal versus the effects
I diabetes nephropathy. In the more recent Ramipril of conventional therapy amlodipine or placebo group,
Efficacy in Nephropathy (REIN) study, 352 patients with in 1715 subjects. The primary composite end point of
non-diabetic renal disease, randomly assigned to receive the study was doubling of baseline serum creatinine,
either ACE inhibitor or placebo, achieved similar control ESRD or death from any cause. For subjects receiving

© JAPI • VOL. 56 • JANUARY 2008 www.japi.org 43

irbesartan, the adjusted relative risk of reaching the release. It induces mitochondrial superoxide production
primary composite end point was 20% lower than and increases the oxidative stress. The inflammatory
for those receiving placebo and 23% lower than for and oxidative processes alter lipoprotein metabolism
those receiving amlodipine. There was no significant and results in a highly atherogenic environment. A tight
difference between placebo and amlodipine for the glycemic control will halt these effects. Tight glycemic
primary composite end point. The relative risk of control aims at fasting blood sugar < 100 mgs/dl, 2
ESRD in the irbesartan group was 17% lower than hours post prandial sugar < 130 mgs/dl and Hb A1c
that of placebo group and 24% lower than that in the < 6.5 %. The tight glycemic control will be an ideal
amlodipine group. Proteinuria was reduced an average mode to prevent secondary prevention of progression
of 23% in the irbesartan arm, compared with 6% and 10% of kidney injury in diabetics. It will also be useful in
in the amlodipine and placebo arms respectively. The tertiary prevention.
more favourable renal outcomes were in excess of effects Correction of Anemia in CKD
directly attributable to blood pressure control.
Renal anemia starts early in the course of renal
The Reduction of End Points in NIDDM with ACEI disease due to decreased production of erythropoietin.
losartan (RENAAL) study was undertaken to determine The resultant hypoxia stimulates progression of renal
whether ARB, losartan reduces the number of patients interstitial fibrosis and compromise post glomerular
with type 2 diabetes doubling in serum creatinine, ESRD capillary circulation. The hemodynamic effects of
or death, as compared with placebo-treated subjects. anemia are a burden on the heart and vascular system
The primary and secondary end points of the study already affected by uremia and hypertension. It results
were similar to those of IDNT study but treatment was in mal-adaptive left ventricular growth, cardiac failure,
of longer average duration in the RENAAL study (3.6 exacerbation of coronary ischemia and death.19 Current
vs. 2.6 years). Losartan lowered the risk of doubling of guidelines target a hemoglobin level > 12 gm/dl and a
serum creatinine by 25%, ESRD by 28% and death by hematocrit > 36% to prevent the continuing onslaught
20% when compared to placebo. Proteinuria declined on the heart, and vascular system. In the nutritionally
by 35% in the losartan arm and increased slightly in the deprived population like ours and with the associated
placebo group.15 Besides reno-protective effects of ACE causes of gastrointestinal bleeding or other blood
inhibitor treatment, the Heart Outcomes Prevention loss, iron supplementation may be required besides
Evaluation (HOPE)16 and Losartan Intervention for End erythropoietin administration. Blood transfusions
Point Reduction in Hypertension Study (LIFE)17 trials are preferably avoided for the known problems of
reported substantial reduction in all cause mortality transmitting infections. Sensitisation to foreign antigens
cardiac and stroke events in patients receiving ramipril could interfere with donor selection while preparing
or losartan respectively. Cardiovascular Disease (CVD) for renal transplant. Correction of anemia also gives an
is the single largest cause of morbidity and mortality overall sense of well-being to the patient and improves
among patients with even mild CKD. The HOPE and the quality of life, an important factor in management
LIFE trials provide a further compelling argument of any chronic kidney disease.
for use of drugs that interrupt patients with kidney
Management of Hyperlipidemia:
diseases.
CKD is commonly associated with abnormalities of
One important advantage of ARBs over ACE
plasma lipids, elevated levels of triglycerides, VLDL
inhibitors is their more favourable side effects profile
and LDL and reduced levels of HDL. This is probably
as ARBs are seldom associated with cough that may
secondary to the reduced lipoprotein lipase activity
occur in up to 40% of patients receiving ACE inhibitors.
evident with GFR < 50 ml/mt. Besides increasing the
Finally, the differing effects of ACEIs and ARBs on the
cardiovascular morbidity and mortality, these lipid
RAS imply that in combination, they may have additive
abnormalities might accelerate the progression of renal
or even synergistic effects, and early evidence appears
disease by stimulation of mesangial cell proliferation,
to support this contention. In the largest combination
cytokine expression, extra-cellular matrix synthesis
trial, the COOPERATE trial18 involving 336 patients
and oxidation of LDL to form reactive oxygen species.20
with non-diabetic renal disease treated for 3 years with
The MDRD study revealed low serum HDL to be
maximally effective doses of ACEI, trandolapril or the
an independent predictor of a more rapid decline in
ARB, losartan, alone or in combination, the combination
GFR.
clearly was more effective in lowering the progression
and urinary protein excretion than either drug alone. The aim of treatment is to keep LDL cholesterol <
100 mg/dl. Statins have revolutionized the therapy by
Tight Glycemic Control
their effects not only on lowering LDL and increasing
The pathophysiology of diabetic nephropathy centers HDL but also with their benefits extending beyond
on hyperglycemia. Hyperglycemia induces the polyol lipid control. They are anticytokine and block NF-kb
pathway, activates protein kinase C, increases advanced activation. Their anti-inflammatory effect retards renal
glycation end products (AGE) leading to cytokine disease progression. They reduce peripheral arterial
44 www.japi.org © JAPI • VOL. 56 • JANUARY 2008
resistance and enable better control of hypertension.
Intervention Therapeutic goal
They also reduce the severity of proteinuria.21
Specific renoprotective therapy Proteinuria < 0.5 g/day
Treatment of the Underlying Disease ACEI or ARB Or combination GFR decline < 2 ml/mt/year
Often the diagnosis of CKD shifts the focus of Adjunctive Cardiorenal protective therapy
the treating physician to the supportive measures,
Antihypertensive therapy BP < 130/80 mmHg
reducing the aggressiveness to treat the underlying,
Dietary protein restriction 0.6 to 0.8 g/kg/day
usually glomerular disease. In diseases like SLE,
Dietary salt restriction 3 to 5 g/day
immunosuppressive therapy even in the presence of renal Tight glycemic control HbA1c < 6.5 %
failure may be rewarding with reversal of renal failure. Reduce elevated Ca* P product < 50 mg2/dl2
The advent of newer effective immunosuppressives like Lipid lowering therapy LDL < 100 mg/dl
mycophenolate mofetil has enabled better management Antiplatelet therapy thrombosis prophylaxis
of glomerular diseases, not responsive to steroids or Correction of anemia Hb > 12 gm/dl
cyclophosphamide, e.g. MGN, FGS, resistant MCN and Smoking cessation Abstinence
Weight control Ideal body weight
IgA Nephropathy.
Treatment of Infection education assists the patients in the choice of dialysis
CKD itself is a chronic inflammatory state with modality, preparatory creation of permanent vascular
reduced renal clearance of cytokines, accumulation access, improves their compliance to the treatment plan,
of AGE and persistent infection aggravated by the co- reduces hospitalizations and promotes psychological
existent malnutrition. Early identification of infection, well being too. Patients with serum creatinine > 1.5
adequate and appropriate management with attention mg/dl, creatinine clearance less than 60ml/min/1.73m2
on the dosing modifications required according to the should be referred for specialist management. Earlier
severity of CKD will prevent worsening of the kidney referral is indicated in hypertensives diabetics and in
failure. patients with significant proteinuria more than 1 g/
Relief of Obstruction day.
Enlarged prostate in the old, urethral strictures in
middle age, post urethral valves in the young are some
A Comprehensive Strategy for
examples wherein correction of the obstructive cause Renoprotection in Patients with
will improve renal function or prevent worsening of the CKD
renal disease due to continued insult by backpressure
There is a strong case for prescribing ACEIs, ARBs
effect and increased risk of infection.
or both in any patient with kidney disease in doses
Lifestyle Modifications and Treatment of Obesity sufficient to achieve reduced proteinuria to less than
Life Style Modification is an essential step towards 0.5gm/day and to show by at least twice yearly checks
renoprotection and should be recommended to all that some reliable estimate that GFR is falling by no
patients with CKD. Weight reduction is no longer for more than 2 ml/mt/year. Besides, these adjunctive
cosmetic purpose. Obesity perse causes proteinuric treatments should be given to prevent the cardiovascular
microalbuminuria, secondary focal segmental disease that exists in all patients with kidney disease.
glomerulosclerosis due to hyperfiltration and volume These include additional antihypertensive drugs
overload and results in progression of renal failure.22 to target the blood pressure of < 130/80 mmHg.
Weight reduction should be aimed to their ideal weight We should also recommend protein restriction, salt
and a BMI < 23. Dietary salt intake should also be restriction, tight glycemic control in diabetics, statins,
modified. Regular exercises, adequate nutrition and aspirin, erythropoietin and measures to reduce calcium
a healthy positive outlook enable better reserve for phosphorus products, excess body weight, tobacco use,
braving the illness and retard the onslaught. exposure to nephro-toxic drugs including many herbal
Smoking should be completely stopped. It causes remedies and dietary supplements. This aggressive and
constriction in the renal vascular bed, accelerates comprehensive strategy may add to the costs of the
atherosclerosis, induces progression of renal disease treatment, but it will translate into reduced morbidity
and also causes systemic hypertension.23 and mortality from cardiovascular disease and fewer
patients may need expensive renal replacement
Early Referral to Nephrologist
therapy. There are many newer drugs in the pipeline
Early referral to nephrologist provides the opportunity to add to the effects of ACEIs and ARBs. One such is
to identify the reversible causes of renal function the vaso-peptidase inhibitor (VPIs). Recently, one such
deterioration and to implement Renoprotective dual ACE inhibitor Omapatrilat has been introduced
measures. It also enables patients and their families which reduces high grade proteinuria, reduces the
to receive sufficient information and education about blood pressure and gives rise to great reno-protection,
the disease and the options for treatment. Predialysis particularly when it is combined with ACEI. Many other

© JAPI • VOL. 56 • JANUARY 2008 www.japi.org 45

drugs such as renin inhibitors, endothelium receptor 10. Ruggenenti P, Perna Agherardi G, et al. Renoprotective properties
blockers, are in the phase III trials. Stem cell therapy is of ACE Inhibition in Non Diabetic Nephropathies with Non
Nephrotic Proteinuria. Lancet 1999;354:359-64.
yet another field in which the destroyed nephrons can
11. Foley RN, et al. Impact of hypertension on cardiomyopathy,
be replaced by new nephrons and thus the renal function morbidity and mortality in End stage renal disease. Kidney Int
can be restored towards the normal side, which will be 1996;49:1379-85.
available in the next few years. 12 . Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, et al. The Effect
Successful management of CKD and its prevention of angiotensin Converting enzyme Inhibition on Diabetic
Nephropathy. The Collaborative Study Group. N Engl J of
demands a multidisciplinary approach. A comprehensive Medicine 1993;329:1456-62.
effort will require patient education, professional 13. Wright JT. Effect of blood Pressure lowering and antihypertensive
education, and the involvement of payers (Medicare, drug class on Progression of Hypertensive Kidney Disease.
Medicaid, and the health insurance industry). The Results from the AASK Trial. JAMA 2002;288:2421-31.
involvement or cooperation of business, the community, 14. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective Effects
and government will be required at local, state and of the angiotensin receptor Antagonist Irbesartan in patients with
nephropathy due to Type2 Diabetes. N Engl J Med 2001;345: 851-
national levels. More research efforts will be needed to
60.
measure and track the CKD burden, identify populations
15. Brenner BM, Coffee ME, et al. Effects of Losartan on renal and
at risk, and target program efforts. cardiovascular outcomes in patients with type2 Diabetes and
Nephropathy. N Engl J of Medicine 2001;345: 861-69.
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Announcement
7th Asian-Pacific Congress of Hypertention 2009, Nov. 19th-22nd, 2009.

Contact : Dr Azhari Rosman, APCH Secretariat: 50490 Kuala Lumpur, Malaysia.

Email : apchkl@msh.org.my     website : www.msh.org.my

46 www.japi.org © JAPI • VOL. 56 • JANUARY 2008