Cilnidipine in hypertension

1. Antiprotenuric
Antihypertensives
Dr Mukesh Shete
Consultant Nephrologist
Navnath Health Care,Jupiter Hospital

2. Hypertensio
n is a major
public
health issue
and one of
the most
common
lifestyle dis
eases
About 1 in 3
adults have
high blood
pressure,
but many
are unaware
of it -
”silent
killer ”
Globally
cardiovascul
ar disease
accounts for
approximate
ly 17 million
deaths
(1/3rd of the
total
death)/year.
Hypertensio
n is
responsible
for at least
45% of
deaths due
to heart
disease, and
51% of
deaths due
to stroke.
In India-
number of
hypertensiv
e individuals
is
anticipated
to nearly
double from
118 million
in 2000 to
214 million
by 2025.
Heart India, Vol 2 / Issue 4 / Oct-Dec 2014: World Health Organization 2013:
Hypertension – Global and Indian Scenario

3. 39%
15% 13%
33%
Incidence of ESRD by Cause
Primary Diagnosis for Patients Who Start Dialysis
Hypertension
Other
Diabetic
Nephropathy
Diabetic Nephropathy
+
Hypertension

5. Culprit
• Diabetic renal disease
• Chronic pyelonephritis
• Renovascular hypertension
• obstructive nephropathy
• Renal parenchymal disease
• Renin secreting tumours
• Genetic renal tubular disorder
• Page kidney

6. CKD
Impaired autoregulation
Systemic HT
Glomerular HT
proteinuria
Glomerular
hypertrophy
Pro inflammatory
Cytokines and
inflammatory mediators
Nephron loss and glomerulosclerosis

7. Victim
• Progression of renal disease
• Hypertensive nephrosclerosis
• Malignant nephrosclerosis

8. Effects of High BP on Renal Function
With Advancing Age
Phase II
Phase III
Phase IV
Phase V
 in RVR due to functional disturbance of renal vasculature: ? active vasoresponse to
endogenous angiotensin II, norepinephrine
Further  in RVR; both functional and structural disturbance in renal vasculature;
preservation of GFR (glomeruli may be ischemic);  in FF; microalbuminuria
Further  in RVR; structural disturbance involving both renal vasculature and glomeruli
(arteriolar nephrosclerosis);  in perfusion disproportionately greater than filtration;
sustained  in FF; proteinuria
Critical  in renal mass;  in RVR ( in afferent arteriolar resistance);  in PGC; progressive
 in GFR; nephrosclerosis, glomerulosclerosis
Chronic renal insufficiency  end-stage renal disease
BP=blood pressure, FF=filtration fraction, GFR=glomerular filtration rate, PGC =glomerular capillary pressure,
RVR=renal vascular resistance.
Adapted from Bauer JH, Reams GP. Am J Hypertens 1989; 2: 173S-178S.
Age (y)
(20-30)
(30-40)
(40-50)
(50+)
Phase I

9. Hypertension due CKD due to Hyper-
to CKD tension
(i) Common (i) Less Common
(ii) H/O Kidney disease (ii) H/O Hypertension prec-
Preceeds hypertension eeds Kidney disease
(iii) Cardiomegaly, HT (iii) Cardiomegaly, HT
retinopathy less common retinopathy more common
(iv) USG: Kidneys contr- (iv) Less contracted>9 cms
acted <9cm. CMD lost CMD preserved
(v) Prognosis: Worse (v) Good

10. Progression of CKD
BP CONTROL
PROTEINURIA
CONTROL

12. Blood Pressure Is a Major Risk Factor for Renal Death
An Analysis of 560 352 Participants From the Asia-Pacific Region
O'Seaghdha CM, et al. Hypertens 2009; 54:509-515.

13. Lower BP Slows Decline in GFR
95 98 101 104 107 110 113 116 119
MAP (mmHg)
GFR
(mL/min/year)
130/85 140/90
Untreated
HTN
0
-2
-4
-6
-8
-10
-12
-14
Bakris GL, et al. Am J Kidney Dis. 2000
But newer studies suggest there
may be other dangers down here

14. Multiple antihypertensive agents are
required to achieve target BP
Majority of the patients require more > 2 drugs to
achieve goal BP
Bakris G et al. AJKD. 2000;36:646-61.Brenner BM et al. NEJM. 2001;345:861-9.Lewis EJ et al. 2001;345:851:60.

16. Morbidity and Mortality Along the
Renal Continuum
Risk Factors
Diabetes
Hypertension
Endothelial
Dysfunction
Micro-
albuminuria
Macro-
proteinuria
Nephrotic
Proteinuria
End-Stage
Renal Disease
CVD
Death

18. GLOMERULUS
GLOMERULUS
AFF
EFF
AFF
EFF
TUBULES TUBULES
Afferent arteriolar dilatation by amlodepine
andhydrallazine leading to increase
intraglomerular(glmP)
Pressure and more proteinuria.
glmP
proteins
glmP
Efferent arteriolar dilatation by ACEIs, ARBs
&,cilnidipine leading to drop in
intraglomerular pressure and no proteinuria
with renoprotection
decrease
increase

19. In the MDRD study, for each 1 g/day reduction in protein
excretion during the first four months, the rate of decline in
GFR fell by 0.9 to 1.3 mL/min per year
The fall in proteinuria was related to the blood pressure,
being more prominent in those with more
aggressive blood pressure control.
●Among patients with protein excretion ≥3 g/day in the REIN
trial, the rate of decline in GFR correlated inversely with the
degree of proteinuria reduction and the magnitude of benefit
seemed to exceed that expected for the degree of blood
pressure lowering .

20. eGFR, UAE and relative risk : Heat map
Categories
Rank Color
Levey A, de Jong P, Coresh J et al. KDIGO. Kidney Int. 2011;80:17-28
No risk/ CKD
Moderate risk
High risk
Very high risk
Composite ranking for
relative risk by GFR and
albuminuria (KDIQO
2009)

21. Association of Kidney Function and
Albuminuria
• ARIC study showed that even mildly increased ACR
(9.14-14.0 mg/g) was associated significantly with
incident hypertension
• Other studies also have shown that higher
normoalbuminuria (ACR >5 or 8.5) also can decline
GFR and increase ESRD and CVD risk
Huan g et al. Am J Kidney Dis. 2015;65(1):58-66.
Hallan SI et al. J AM Soc Nephrol. 2009;20(5):1069:77.
Antihypertensives with anti-albuminuric effect may
have a preference over other antihypertensives with no
anti-albuminuric effect?
The Atherosclerosis Risk in Communities (ARIC) Study with 4,378 participants (45.6%) with prevalent
hypertension at baseline and 2,175 incident hypertension cases during a median follow-up of 9.8 years

22. Targets for blood pressure control in
CKD
Regardless of the cause of CKD antihypertensive treatment should be
initiated to achieve BP goal
Target population Goal BP
CKD (Diabetic/ nondiabetic)
and AER (or ACR) <30 (A1)
≤140/90 mm Hg
CKD (Diabetic/ nondiabetic)
and AER (or ACR) >30 (A2 or A3)
≤130/80 mmHg
Kidney transplant recipients ≤130/80 mmHg
Children with CKD 90th percentile for age, sex,
height
50th percentile for age, sex,
height with any proteinuria
Elderly with CKD Individualize (consider a higher goal,
especially for age >80 y)

23. Drugs That Can Reduce Proteinuria
 ALL ACEs/ARBs
 NONDIHYDROPYRIDINES (CCBs)
 PENTOXYPHYLLINE
 SPIRONOLACTONE, INDAPAMIDE
 LACINIDEPINE - Not very marked
 It takes about 2-3 months for
significant proteinuria
reduction and all act through
reducing PGC

24. RAAS blockade as Initial choice of
therapy?
• Multiple trials powered for kidney outcomes
demonstrate an advantage of RAAS blockade for
slowing progression of CKD and reducing
proteinuria in patients with diabetes and
consequent nephropathy
• But, all of the appropriately powered trials
that demonstrate this effect are in
individuals with advanced Stage 3 CKD who
also had proteinuria > 500 mg/day
Brenner BM et al .N Engl J Med. 2001;345:861-869 , Lewis EJ et al . N Engl J Med.
2001;345:851-860, Lewis EJ et al. N Engl J Med. 1993;329:1456-1462

25. Reduction in
renal
function
Lower Ang-II
level reduces
efferent
vasomotor
tone
resulting in
reduced GFR
and renal
function
Hypotension
Suppression
of Ang-II in
patients
with
circulatory
failure may
cause severe
hypotension
Hyperkalemia
ACE-i
decrease
aldosteron
e levels
This blunts
renal
potassium
excretion
Elevated
bradykinin
ACE-i leads to
accumulation
of bradykinin
and other
pro-
inflammatory
peptides

26. What about CKD with ACR < 30
mg/gm, without diabetes?
No clear drug preference including
RAAS blockers
Treat similar to normal hypertensives
NICE 2014 guidelines

27. Non dihydropyridine calcium channel blocker
The non-dihydropyridine calcium channel blockers, such
as diltiazem and verapamil, have significant
antiproteinuric effects in patients with proteinuria. By
comparison, the dihydropyridines, such
as amlodipine and nifedipine, have a variable effect on
proteinuria, ranging from an increase to no effect to a
fall in protein excretion.
The mechanisms underlying this varied effect on
proteinuria may include preferential afferent arteriolar
dilatation with dihydropyridines,which allows more of
the aortic pressure to be transmitted to the glomerulus,
and differential abilities of the non-dihydropyridine and
dihydropyridine calcium channel blockers to alter renal
autoregulation, the permeability of the glomerulus, and
perhaps other factors.

28. Differences between non-dihydropyridine and
dihydropyridine calcium channel blockers were
illustrated in a systematic review of 23 studies
that adjusted for sample size, study length, and
baseline values.Based upon an analysis of
monotherapy in 510 patients,
non-dihydropyridines decreased mean
proteinuria by 30 percent and dihydropyridines
increased proteinuria by 2 percent.
Bakris GL, Weir MR, Secic M, et al. Differential effects of calcium
antagonist subclasses on markers of nephropathy progression.
Kidney Int 2004; 65:1991.

29. Slowing Down CKD
Progression – Where
are we now?
Blood pressure reduction
RAS Inhibition
Low Protein Diet
SGLT2 Inhibitors
GLP-1 Agonist
MRAs
Statins
Anemia Correction
Smoking Cessation
Vitamin D ?

31. L – type = Long lasting
 L-type currents are long lasting (slow inactivation rate)
and are blocked by all CCBs
 They are found in Cardiac & Vascular tissues
 They are absent in Renal tissues
T – type = Transiently activated
 T-type currents are transient (fast inactivation)
 They are present in Renal tissue
N – type = Neuronal
 The N-type currents are found primarily in neurons
where they initiate
neurotransmission by releasing norepinephrine from
peripheral sympathetic nerve endings
 They are also present in Renal tissue
P or Q-type
 They are neuronal type of Calcium channels
 They were recently detected in Arterioles

33. Sympathetic
nerve
activity
(N-type Ca++ channels)
Leptin
Obesity
Increased Insulin resistance
H
Y
P
E
R
T
E
N
S
I
O
N
Stress
Heart
Peripheral artery
Kidney
Skeletal muscle
Leads to increase in :
• Cardiac output
 Vascular resistance
 Na+ retention
 Renin-Angiotensin System
Cardiovascular Therapeutics 27 (2009) 124–139

34. Cardioprotective Effect
Renoprotective Effect
Neuroprotective Effect
Metabolic Syndrome
Other Benefits

35. RSSDI
Recommendations
for Management of
Hypertension in
Patients with
Diabetes Mellitus
2022
35
● Dietary & Lifestyle
Recommendations
● Goal BP & Initial Drug
Therapy
● Individual Drug classes and
their benefits
● Pharmacotherapy for HTN management
in Diabetes - Recommendations
RSSDI

36. 36
Pharmacotherapeutic recommendations in diabetic
hypertension
Individual profile of the patient and their response to the treatment
must be evaluated for the selection of the most suitable treatment
agent for hypertensive management (grade A)
ARBs, either alone or in combination with CCBs, can be used for BP
control in diabetic patients (grade A)
Combination therapy of ARB and CCB is recommended to be
initiated in hypertensive patients for better BP control, reducing
risks of complications, and better patient adherence (grade B)
ARBs must be preferred over ACEi in diabetic patients with
hypertension, telmisartan or azilsartan being selected as the first-
line agent (grade B)

37. 37
Pharmacotherapeutic recommendations in diabetic
hypertension
In patients at the risk of CVDs, renal disorders, or cerebrovascular disorders,
combination therapy must be preferred for the reduction of patient mortality (grade
B)
CCBs must be preferred over BB and thiazides in combination therapy with ARBs.
Cilnidipine is a comparatively more effective and safer novel molecule as compared
to conventional CCBs for Indian diabetic hypertensive patients (grade A)
The use of BB and thiazide diuretics must be avoided in patients with DM and
hypertension because of their potential to cause cardiovascular events and
hyperglycaemia, respectively (grade A)
Monitoring of electrolyte levels, serum potassium, and creatinine levels, as well as
regular evaluation of kidney function, is recommended for patients with diabetic
hypertension based on the choice of treatment agents and their risk profile (grade B)

38. 38
Summary of
Recommendations

39. Reno-protective and antioxidant effects of cilnidipine
in hypertensive patients
The urinary albumin, 8-hydroxy-
20-deoxyguanosine (OHdG) and
liver-type fatty-acid-binding
protein (L-FABP) to creatinine
ratios significantly decreased in
the cilnidipine group compared
with those in the amlodipine
group.
The reductions in urinary
albumin, 8-OHdG and L-FABP
were not correlated with the
change in systolic BP.
Cilnidipine, but not amlodipine, ameliorated urinary albumin excretion and
decreased urinary 8-OHdG and L-FABP in the hypertensive patients. Cilnidipine
probably exerts a greater reno-protective effect through its antioxidative properties
Hypertension Research (2012) 35, 1058–1062; doi:10.1038/hr.2012.96; published online 5 July 2012

40. Cilnidipine – Reduction of Proteinuria
CARTER
Study
• Cilnidipine was more beneficial than amlodipine as additional medication for
hypertensive patients who had kidney disease associated with significant
proteinuria
• Combination therapy with cilnidipine and an ARB ameliorated urinary albumin
excretion more potently than ARB monotherapy
• It is suggested that cilnidipine rather than an amlodipine should be recommended
Conclusion