Conference Paper

1. 1
Proteinuria, is it a Therapeutic Target or only a Cardiovascular Risk Marker?
Jafar Al-Said, M.B.ChB. MD. FASN. FACP.
During the past decades several studies have proven the strong correlation between
proteinuria, specifically albuminuria, with different cardiovascular diseases. Some studies
have even confirmed the association between reduction in proteinuria and better
cardiovascular and renal outcome. However, during the last 10 year multiple prospective
randomized trials targeting solid cardiovascular end points such as mortality, morbidity and
doubling serum creatinine or ESRD development were published. These studies have shown
that despite the successful reduction in proteinuria there was either no benefit or negative
impact on major cardiovascular and renal outcomes. The review below illustrate on the
current evidence behind therapeutic reducing proteinuria and cardiovascular outcome
depending on major solid end point in view of the recent published trials. The aim is to
demonstrate according to the updated evidence, whether proteinuria per say should be used
as a therapeutic target or it would be only an indication of high cardiovascular risk.
Multiple studies have confirmed the direct positive correlation between the
prevalence of different cardiovascular (CV) risk factors and proteinuria.(1,2) In one
metaanalysis of 39 prospective studies that tested the correlation of proteinuria with major
CV outcome showed that patients with proteinuria have increased hazard ratio for
cardiovascular events by 1.6-5.5, CV mortality by 1.7-5.4 and all-cause mortality by 1.4-2.9.(2)
In patients with diabetes mellitus type II (DM II) and proteinuria, as illustrated in the
Strong heart study, have worse LV function and impaired diastolic filling volume. (3) Patient
with hypertension (HTN) specifically those with reduced kidney function the proteinuria was
a determinant factor for the presence of high blood pressure. (4) Moreover in patients with
an estimated glomerular filtration rate (EGFR) less than 90ml/min. proteinuria was directly
related to the degree of systolic blood pressure. (5) It was also demonstrated that proteinuria
per say is a predictor for developing of HTN. (6)
Publications have also confirmed that proteinuria was associated with 3 times
increased relative risk of stroke. (7,8) The direct correlation between the presence of
proteinuria and coronary calcification was statistically significant. Indicating that among
Diabetics with Chronic kidney disease (CKD) patients high coronary calcium score, more than
400, was more prevalent among patients with proteinuria. (9,10)
Hyperlipidemia was associated with proteinuria. In a metaanalysis of 6 randomized
controlled trials. Furthermore, using Statins in 311 CKD patients was associated with
significant reduction in proteinuria as well as CV events.(11,12)
Studies have illustrated further that increased vascular thrombosis, increased
platelets and Leukocyte adhesion, smooth muscle proliferation, and endothelial dysfunction
were encountered more among patients with Nephrotic range proteinuria. (13, 14, 15, 16, 17).
The RENAAL trial that was published in 2004, studied 1513 individuals having DM II
and Nephropathy. Their serum Creatinine was 1.3-3mg/dl in that trial. Using Losartan versus
placebo was proven to reduce Heart failure hospitalization. However, no difference was found

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in mortality and morbidity. (18) In the same cohort a post hoc analysis showed that reduction
in proteinuria of 30% or more was associated with a 49 % reduction in heart failure, 23% less
non-heart failure CV disease and 34% decreased composite CV end points. (19)
The previously mentioned studies according to the evidence base, would be of class I
recommendation with level B evidence. This indicates that multiple cardiovascular risk and
diseases are correlated positively with proteinuria. It would therefore only prove that with
proteinuria there is a higher possibility of having or developing any of the above mentioned
CV diseases. Evidence is also revealing that there is an association between the level of the
reduction in proteinuria and the decline in some negative CV outcomes. RAAS blocking was
proven very effective in decreasing proteinuria as well as blood pressure. Using RAAS
blockade has been beneficial in decreasing the progression of renal disease and delaying the
need for dialysis mainly among diabetics. It also was associated with decreasing CV morbidity
and mortality. (18, 20) Post hoc analysis of these trials have shown that there was a significant
blood pressure lowering in the Interventional arm. All the above confirms the significance of
RAAS blockade per say and not specifically though proteinuria reduction. An association, but
not a cause and effect relationship were proven. To have a proteinuria reduction as a cause
of improvement of CV outcome we need randomized controlled trials designed to target
reduction in the urine protein and look at the major CV outcomes. Delay renal disease
progression to ESRD or prolonging time to dialysis is not the ultimate better outcome we are
looking for. It is not enough to confirm the superior CV outcome when we already know that
most of the CKD patients will end up dying from CV disease, even before they get to ESRD or
need dialysis. (21)
Over the past decade, within the era of combination RAAS blockade, certain aspects
of this matter have been illustrated as explained from the studies below:
The IDNT, Irbisartan Diabetic Nephropathy renoprotective effect of the ARB Irbisartan
in patients with nephropathy due to type 2 diabetes. In that study 1715 patient having DM
with HTN and proteinuria. Their S. Creatinine was between 1-3 mg/dl. They were followed for
2.6 years. The final outcome was that although Irbisartan succeeded in lowering doubling of
S. Creatinine as well as proteinuria, it failed to show a significant difference in CV mortality,
non-fatal MI, Heart failure, or stroke.(22)
In 2004 the DIAB-HYCAR, Non-Insulin Dependent DM, HTN, Microalbuminuria or
proteinuria CV event and Ramipril have tested 4912 patients. All have DM with Albuminuria
and intact kidney function. S. Cr. was less than 150micmol/l. The question was whether small
dose of Ramipril, 1.25mg, would have a beneficial effect. The result was a successful reduction
in albuminuria by 14%. However, it did not show significant difference in CV outcome such as
death, nonfatal MI, Stroke or Heart failure.(23)
Afterwards, in 2008 came the famous ONTARGET trial with Telmisartan, Ramipril or
both at high risk of vascular event. It revealed that Telmisartan was equivalent to Ramipril in
patients with vascular disease or high risk diabetes. This trial marked the beginning of the
awareness of the harmful effect with RAAS combination.(24) A sub analysis from ONTARGET
looking at renal outcome, including doubling serum creatinine, dialysis and death clearly

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showed that although the ACE inh. and the ARB combination had successfully reduced
proteinuria, but it ended up having worse renal as well as CV outcome.(25)
Within the same time the TRANSCEND, Telmisartan Randomized Assessment Study in
aCE- iNTolerant Subjects with CV disease, came out. Its’ hypothesis tested the benefit of ARB
in reducing the major CV events among high risk patients. Those who were intolerant to ACE
inh. It randomly assigned 2954 patients to Telmisartan against 2972 were given a placebo.
The initial result revealed that Telmisartan modestly reduced CV death, MI and stroke.(26)
When looking at the renal outcome, including dialysis and doubling serum creatinine it
confirmed decrease GFR 12% more with the Telmisartan without a significant CV outcome
noticed although Albuminuria was reduced.(27)
The AASK trial in the second phase, with aggressive BP control among 1094 African
American patient, testing MAP below 92mmHg against a moderate decline between 102-
107mmHg using ACE inh. or ARB versus other medications. The outcome was doubling serum
creatinine, ESRD, and death. The interventional arm showed lower proteinuria but no
statistical difference was encountered on the solid CV end points.(28)
In the ROADMAP Trial, Randomized Olmesartan and diabetes Microalbuminuria
Prevention. This RCT followed a cohort of 2200 patients. The hypothesis was prevention of
Microalbuminuria in HTN and DM II using AT 1 receptor blocker, Olmesartan. The primary
endpoint was the onset of persistent microalbuminuria. The secondary endpoint was CV
event, morbidity, mortality, ESRD and microvascular morbidity. The result illustrated a lower
miroalbuminuria as well as blood pressure in the Olmesartan subgroup, but that group had a
higher cardiovascular death.(29)
The ALTITUDE trial published in 2012. It studied 8561 patients with DM II on ACE inh.
or ARB randomized to receive Aliskiren 300 mg versus placebo. The primary end point was
Time for CV event, cardiac arrest, non-fatal MI, non-fatal stroke, death due to renal failure,
ESRD and the need for renal replacement. Although the urine albumin to Creatinine ratio
decreased significantly from 16% in the combination as compared to only 5% in the placebo
arm, there were no significant evident in the primary, renal or cardiovascular composite
endpoints. Moreover, the study was terminated prematurely because of safety issues. Higher
decline in eGFR, hyperkalemia and hypotension were encountered in the combination
arm.(30)
The VA-NEPHRON-D, Combined Angiotensin inhibition for the treatment of Diabetic
Nephropathy, was published in 2013. In 1448 diabetic patients with urine Alb/Cr ratio more
than 300 mg/gm were randomized to receive losartan 100mg with or without Lisinopril 10-
40mg and followed over a median of 2.2 years. The primary end point was decline in eGFR of
30% for those with eGFR more than 60ml/min or a reduction of eGFR of more than 50% for
those with eGFR less than 60ml/min. The outcome was not statistically different. The study
was stopped prematurely because of more acute renal injury and hyperkalemia in the
combination arm.(31)
In the above major prospective randomized trials an evidence started to show that
decreasing proteinuria and albuminuria was not associated with a better CV outcome. On the

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contrary, this had led to more negative cardiac and renal outcomes. In fact, this was the
reason behind the premature termination of some of these trials.
This could be a light shedding point on the fact to reconsider our belief in the
significance of proteinuria to be only a cardiac risk stratification marker. Indicating that the
patients are having a significantly higher CV risk. This would warrant implementing and
maximizing all the primary CV preventive measures, rather than chasing the levels of the
proteinuria and trying to target a reduction in the proteinuria levels per say.
What would be the benefit of reducing proteinuria in a patient with renal disease
when there is a strong compelling evidence that this could lead to more negative solid CV
outcome? Would reducing the decline in kidney function ordelaying the time to dialysis justify
increasing negative CV outcomes?

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