1st International Congress of Chinese Nephrologists (ICCN 2015) –Importance of Hypertension and Proteinuria Management in Type 2 Diabetes

Reduction of proteinuria and impact on renal outcomes
Professor Enyu Imai
Director, Nakayamadera Imai Clinic
Professor, Fujita Health University School of Medicine
KDIGO Councilor
Hyogo, JapanA

recent lunch symposium held during the
1st International Congress of Chinese
Nephrologists focused on the intimate relationshipbetween proteinuria and hypertension, and their
management in diabetic patients. This reporthighlights key points from the symposium, featuring
renowned nephrologist Professor Enyu Imai.
Blood pressure (BP) and proteinuria control may have positiveeffects on cardiovascular and renal outcomes in diabetic patientswith hypertension and chronic kidney disease (CKD).1 Bothhypertension and CKD are frequently comorbid in patientswith type 2 diabetes mellitus (T2DM).2 Diabetic nephropathy,
characterized by hypertension, progressive albuminuria,
glomerulosclerosis, and decline in glomerular filtration rate (GFR)(Table), is the leading cause of end-stage renal disease (ESRD)
worldwide.2-4 Landmark studies have confirmed that treatmentof hypertension with angiotensin II receptor blockers (ARBs) inpatients with comorbid T2DM also reduces proteinuria, thusslowing the rate of renal function decline.4

Proteinuria is strongly linked to the progression of CKD. A post
hoc analysis of the Olmesartan Reducing Incidence of Endstage
Renal Disease in Diabetic Nephropathy Trial (ORIENT) – ORIENTproteinuria – which involved Asian T2DM patients with overt
nephropathy, determined that either >30% reduction of urine
protein/creatinine ratio (UPCR) or remission of nephropathy,
defined as UPCR <1.0 g/gCr, predicted significant renoprotection,
while patients with residual UPCR ≥1.0 g/gCr were at a higher
risk of renal outcomes. These results suggest that UPCR is
an independent predictor of CKD risk, and may be used as atherapeutic target in the prevention of further nephropathyin T2DM patients with microalbuminuria.4 A meta-regression
analysis of 21 clinical trials revealed that, for every 30% reduction
in albuminuria, the risk of ESRD decreased by 23.7% (p=0.001)(Figure 1).5 Another meta-analysis of nine randomized clinical
trials also showed that, in 98% of patients, short-term reductionsin proteinuria strongly correlated with long-term improvements
in renal outcomes.6

Target BP in diabetic patients with CKD
Although high BP has been associated with increased rates ofpremature mortality, cardiovascular diseases and progressive
loss of kidney function in patients with T2DM and CKD, thetarget BP for these patients remains controversial; publishedrecommendations are also largely based on data from white andblack populations and might not be applicable to Asian patients. Ina post hoc analysis of ORIENT, conducted to explore the optimal
systolic BP (SBP) level for prevention of renal and cardiovascularoutcomes in 566 T2DM patients from Japan and Hong Kong withTable. Diabetic nephropathy stages: Cutoff values of urine albumin for diagnosis and main clinical characteristics3Albuminuria
cutoff values

Microalbuminuria

20-199 μg/min
30-299 mg/24 h30-299 mg/g*Albuminuria
cutoff values

Clinical characteristics
Abnormal nocturnal decrease ofBP and increased BP levels
Increased triglycerides, total andLDL-cholesterol, and saturated
fatty acids
Increased frequency of metabolic
syndrome components
Endothelial dysfunction
Association with diabetic
retinopathy, amputation, andcardiovascular disease
Increased cardiovascular mortality
Stable GFR*Spot urine sample
BP, blood pressure; GFR, glomerular filtration rate; LDL, low-density lipoprotein

Proteinuria≥200 μg/min≥300 mg/24 h>300 mg/g*

Clinical characteristics
Hypertension
Increased triglycerides andtotal and LDL-cholesterol
Asymptomatic myocardialischemia
Progress GFR decline

Figure 1. Treatment effects on albuminuria significantly correlated with the treatment effects on ESRD5

Relative risk of ESRD

N-2
REITE
GET
ITU NTAR
ALTO

ENT

ORI

1.0

RI

AIP

T

AAL IDNB

MDKAASDFIEL

Hou SCEND
N
TRA
CSG
0.6

RP

SHA

RD-REN0.8

cro-ma

SUN

E
ANC
ADV

1.3

ON
PHR PE
A
ESC

NE
VA-

Intervention:
ACEIs
ARBs
Dual RAAS blockade
Dietary protein restriction
Intensive BP lowering
Statins or ﬁbrates
Glycosaminoglycan

A
RD-MD

N

REI

0.5

D
ROA-40-30-20-100Albuminuria difference between randomized groups (%)
Different colors indicate different types of interventions. The size of each circle is inversely proportional to the standard error of mean of the treatment effect on ESRD.
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BP, blood pressure; ESRD, end-stage renal disease; RAAS, renin-angiotensin-aldosterone system

First-line treatment of hypertension inpatients with T2DM and macroalbuminuria
should include ARBs, which are effective
in reducing proteinuria.
Role of ARBs in the management of hypertension andnephropathy in T2DM patients
Landmark trials have established that first-line treatment ofhypertension in patients with T2DM and macroalbuminuria
should include ARBs, which are effective in reducing proteinuria.4
In ORIENT, an ARB effectively managed BP level, proteinuria
and the rate of change of reciprocal serum creatinine, with thesebeneficial effects being especially prominent in patients whoachieved SBP of ≤130 mmHg.1,9 In other trials, ARBs were able todemonstrate superiority to calcium channel blockers in protecting
against nephropathy progression due to T2DM, independent of
the reduction in BP, as well as confer significant renal benefits inpatients with T2DM beyond that attributed to BP control.10-12

Proteinuria and BP control are strongly linked to the progressionof kidney function loss in diabetic patients with CKD andhypertension. In such patients, reductions in these parameters,
which can be effectively achieved with the use of ARBs, can havepositive effects on renal outcomes, ultimately lowering the riskof ESRD. In particular, Asian patients with diabetic nephropathy
should look into treatment with ARBs that can effectively enable
them to achieve BP and UPCR goals.
Figure 2. SBP was linearly associated with increased riskof renal events and renal function decline180≥1 g/gCr<1 g/gCr

70
60
50
40
30
20
100120124

128132136

140

144

148

152

156

160

SBP (mmHg)
SBP, systolic blood pressure

References:
1. Imai E, et al. Nephrol Dial Transplant 2016;34:447-454. 2. Van Buren PN, Toto R. Adv Chronic
Kidney Dis 2011;18:28-41. 3. Gross JL, et al. Diabetes Care 2005;28:164-176. 4. Imai E, et al. Nephrol
Dial Transplant 2013;28:2526-2534. 5. Heerspink HJL, et al. J Am Soc Nephrol 2015;26:20552064. 6. Ruggenenti P, et al. The Lancet 2001;357:1601-1608. 7. Kidney Disease: Improving
Global Outcomes (KDIGO) Acute Kidney Injury Work Group. Kidney Inter Suppl 2012;2:1-138.
8. Ninomiya T, et al. J Am Soc Nephrol 2007;18:2135-2142. 9. Imai E, et al. Diabetologia
2011;54:2978-2986. 10. Lewis EJ, et al. N Engl J Med 2001;345:851-860. 11. Brenner BM, et al.
N Engl J Med 2001;345:861-869. 12. Chan JCN, et al. Diabetes Care 2004;27:874-879.

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OLM16001P/MAR

The presence of proteinuria is an important factor for determining
the BP goal. For example, in high-risk patients with proteinuria,
intensive SBP control may be beneficial and a target BP of<130/80 mmHg is recommended; in patients without
proteinuria, however, target BP can be less aggressively set at<140/90 mmHg.1,7 Interestingly, the Hisayama study, whichlooked at autopsy samples that did not receive hypertension
treatment before death, showed that not only hypertension,
but also prehypertension, was significantly associated with renalarteriosclerosis, regardless of the presence or absence of target
organ damage.8

Summary

Renal composite outcome (%)

overt nephropathy (ORIENT-blood pressure), follow-up SBP wasfound to be linearly associated with increased risk of renal eventsand renal function decline; reduction of SBP to ≤130 mmHg
reduced renal risk, especially in patients with proteinuria≥1 g/gCr (Figure 2), while SBP of ≥140 mmHg was associatedwith an increased incidence of cardiovascular disease in patients
without any prior history. Physicians may, therefore, consider
reducing SBP to 130 mmHg or lower to achieve renoprotection
in patients with T2DM.1