Heart and Kidney, for better or for worse

P. van Paassen, MD, PhDDept. Nephrology and Clinical ImmunologyMaastricht UMC+

Hartfalen dag Zeist, 29 09 17

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Bedrijfsnamen

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• Honorarium of andere (financiële) vergoeding

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Disclosure potential conflicts of interest

Ronco et al. J Am Coll Cardiol 2008

a double edged sword

Naranjo et al. Dis Mon 2017

GFR measurements

renal function

endogenous, creatinine

creatinine clearance

[CrCl]

MDRD

CKD–EPI

exo–

Inulin/DTPA/iothalamate

𝐶𝑟𝐶𝑙 =𝑈𝐶𝑟 × 𝑉

𝑃𝐶𝑟

U-protS-albumin/urea/Na/KCa/P/PTHTot CO2Hemoglobin/EPO

over– and underestimation of renal function

Webster et al. Lancet 2017

*Cystatin C may be a better marker of renalfunction

“normal” decline in eGFR

CKD N eGFRt=0 follow–up, yr. decline/yr.

Levey et al.J Am Soc Nephrol, 1991 1, 2, 3 28 37.1 [8.7] 1.2 –3.7 [7.6]

4, 5 63 15.0 [4.5] –4.3 [4.7]

Eriksen et al.Kidney Int, 2006 3 3047 55.1 [50.8 – 57.9] 3.7 –1.03

Levin et al.Am J Kidney Dis, 2008 3, 4, 5 4231 33.0 2.6 –2.65

*rapid decline per year if eGFR ≥5 mL/min/1.73m2

CKD and cardiovascular disease [1]

Go et al. N Engl J Med 2004

coronary artery calcification among patients with CKD

Chen et al. JAMA Cardiol 2017

risk of CVD depends on calcification among patients with CKDadjusted for CKD, HbA1c, P, FGF23, etc.

Chen et al. JAMA Cardiol 2017

pathophysiology of the cardiorenal syndrome type 2

heart failure induced kidney damage

the “normal” cardiorenal axis

low cardiac output [CO]genetics

environment

“compensated” kidney

modified from Ronco et al. J Am Coll Cardiol 2008

Kidney “compensation”HF: a syndrome of renal sodium and

water retention

Cardio-renal interactions in volume expansion and congestion in chronic heart failure.

Wayne L. Miller Circ Heart Fail. 2016;9:e002922

Paradigm of interstitial and intravascular volume expansion in chronic heart failure.

Wayne L. Miller Circ Heart Fail. 2016;9:e002922

stable glomerular filtration rate [GFR]

normal GFR during the first weeks,[1]

LAD coronary artery ligation reserve capacity; male[2]

[1]Lekawanvijit et al. Am J Physiol Heart Circ Physiol 2012[2]Levey et al. Ann Int Med 1999

renal autoregulation; constant over MAP 80–170 mmHgvascular smooth muscle cells and tubuloglomerular feedback

blood flow

capillary pressure

arteriolar resistance

Pollak et al. Clin J Am Soc Nephrol 2014

Structure of the renal corpuscle, looking into the Bowman’s capsule at glomerular capillary

tuft.

Martin R. Pollak et al. CJASN 2014;9:1461-1469

©2014 by American Society of Nephrology

2.10*6 nephrons

major determinants of [glomerular] ultrafiltration

Kf, ultrafiltration coefficient

πA, oncotic pressure

P, hydraulic pressure

QA, plasmaflow

Pollak et al. Clin J Am Soc Nephrol 2014SNGFR, single–nephron GFR

low CO

RAS, SNS

IVP

NPs

water

solutes

macula densa

NaCL content determinessecretion of adenosine by MDas marker of GFR, leading tot constriction of v afferent=TGF

Peritubular capillariesCountercurrent Osmolar gradient medulla

RAS in response to decreased renal perfusion

ATII

SNS

intraglomerularpressure

increased GFR,

single nephronlow Na,

low Cl

renin

efferent arterioleRAS

FF=GFR/ERPF

water

solutes

expanding intravascular fluid due to sodium retention

65%

20%

10%

5%

ATII ALDO

↑ ↑

↑

Na, %

hyperfiltration; the other side of the medal?glomerular hyperfiltration and cardiovascular events in 8749 participants

Reboldi et al. Kidney Int 2017

95th percentile

5th percentile

HR 1.6 [95% CI, 1.1 – 2.3]

CVE defined asinfarction,

heart failure,

revascularisation,

sudden cardiac death

type 2, chronic cardiorenal syndrome

chronic hypoperfusionincreased renal vasc. resistance

renal congestion

anemia, hypoxiaRAS[!], SNS[!]

Na, water retentionCa, P

hypertension

sclerosis and fibrosis

modified from Ronco et al. J Am Coll Cardiol 2008

[acute] subtle renal inflammation after LAD coronary artery ligation; ischemia

Lekawanvijit et al. Am J Physiol Heart Circ Physiol 2012

KIM–1*

*kidney injury molecule–1

also, increased macrophage infiltration and IL–6 mRNA

interstitial fibrosis can be found after 4 – 16wks

Lekawanvijit et al. Am J Physiol Heart Circ Physiol 2012

picrosirius red

1wk

ATII causes epithelial mesenchymal differentiation/fibrosis

• ATII stimulates renal Smads phosphorylation and the TGFβ axis

Smad2

Carvajal et al. Kidney Int 2008

HK2

cobblestone spindle-shaped,

fibroblast like

IFTA is common among patients with end-stage HF

Golestaneh et al. J Heart Lung Transplant 2014

male/female 13/1

HF, ischemicHF, non-ischemicHF, amyloidosis

851

eGFR, mL/min 29–55

uProt, gm/d <0.5

IFTA<30%

30-60%>60%

741

PAS

but, it’s not only a “forward” problem –inverse association between eGFR and CVP >5 mmHg

adjusted forage,

sex,

cardiac index

Damman et al. J Am Coll Cardiol 2009

r = -0.212, P <0.0001

HF a state of renal sodium and volume retention

• Osmoregulation (Pna, AVP)

• Volumeregulation (ANGII/Aldo)

• However far more complicated in HF:

• Both hypo-Na and hyper-Na are serious risk factors.

• HF and hypo-Na:

– RAAS-activity increases despite volume overload

– AVP increases

– SNS increases

– Clearance free-water impaired

• HF and hyper-Na

• Elderly, frail

• Diet, Thirst

• Loop diuretics

treatment of heart failure and it’s renal consequences

water

solutes

65%

20%

10%

5%

Na, %

all diuretics but spironolactone

work in the lumen

commonly prescribed diuretics

ter Maaten et al. Nat Rev Cardiol 2015

>30% of HF have “[loop–] diuretic resistance”the so-called braking phenomenon

u[Na]ATII, aldosterone

furosemide,

bumetanide

measureu[Na],u[K]

Braking phenomenon

• Dose more frequently, or add thiazides

how to manage [loop–] diuretic resistance?

ter Maaten et al. Nat Rev Cardiol 2015

IV administration

HCT[!]K+ sparing agents

bumetanide[!]also binds to globulins

Pharmacology (loop-)diuretics

• Equipotent dosing

• Switch classes in case no effect probablyuseless (dosing!)

Pharmacology (loop-)diuretics

NB spironolacton: actieve metabolieten T ½ ca. 1½ uur (spironolacton), 9–12 uur (7α–thiomethylspironolacton), 10–35 uur (canrenon)

(loop-)diuretics

• Effect bumetanide 2.5-3 h

• Effect furosemide 4-5 h

• Remaining time is “rebound” = no net negative effect on Na loss

Particularly in case :

- Diuretic response low (Urine Na 24 /K)

- Medication free interval long

- Salt intake

(loop-)diuretics

• Synchronize intake and drug dosing

• - loop diuretic before meals

Slow release less effective?

(loop-)diuretics - therapy

• GFR 15 mL/min:• Only 10-20% furosemide in tubule: so increase

dose

• IV to oral: • bumetanide identical• furosemide 1-10 times (x ceiling dosis 160-250

mg iv)

• Dosing based on effect!

(loop-)diuretics - therapy

• Normal response on 40 mg furosemide (of equivalent bumetanide):

• 200-250 mmol Natrium & 3-4 L urine in 3-4 h.

• Max. response 20-25% filtered Natrium• In case GFR 15 mL/min, then 25 mmol

Natrium per dose.

• So restrict salt intake• Add thiazide

Loop-diuretics – combi thiazides

• Mild KI: 50-100 mg/daY• Severe KI: 100-200 mg/day

• Loading dose? ( T½)• Once a day (T½)

• Severe KI:– more and more often (NYHA II-III 3-4x)

(loop-)diuretics – intravenous

Diuretics - ¿more? (thiazides)

• Predictive:• Urine low Na- High K: distal reabsorption Natrium::> so

####• Urine low Na-low K: less effect

• Add amiloride in stead of triamterene (conversion lower in congested liver), even in addition to spironolacton/eplerenone

What about kidney function?

• Deterioration often acute and hemodynamically, not structural

• Renal autoregulation

• Treat blood pressure

• Treat heart failure and accept kidney function (to certain extent)

the protective effects of RAS blockade

• improved survival [CONSENSUS, SOLVD]

• anti–fibrotic effects[1]

• improved pressure natriuresis[2]

…[1]

[2]van Paassen et al. J Am Soc Nephrol 2001

what about dual blockade? lessons from the ONTARGETONgoing Telmisartan Alone and combined with Ramipril Global Endpoint Trial

ARB and ACEi combined

• additional 2 – 3 mmHg BP reduction

• less proteinuria

[S]AEs, increased prevalence

• acute kidney injury/doubling SCr

• hyperkalemia

Yusuf et al. N Engl J Med 2008

cardiovascular death

AKI in the setting of RAS blockade

Scherpbier et al. Ned Tijdrschr Geneeskd 2010

dehydration

elderly,

atherosclerosis,

NSAIDs

diarrhea,

fever

check for SCr, K

hyperkalemia among HF patients; particularly when SCr >150 mM

Palmer et al. N Engl J Med 2004

Role of renal replacement therapy?

• UF?

• CAPD?

• Data still unclear

PD in CHF

Rationale:

End-stage congestive heart failure is a serious invalidating condition with a poor prognosis and increasing incidence.

Non-randomized observations showed peritoneal dialysis in these patients to improve clinically from NYHA stadium III-IV to as low as NYHA stadium I-II.

A randomized trial is needed to test whether PD improves symptoms in this condition and to find an optimal scheme.

Groningen trial still running , WMT Janssen (Martini hospital)

Conclusion

• Cardio-renal failure is a fascinating clinical challenge

• There is problably no such thing as a “normal kidney or a normal heart” in this perspective, when checking meticulously organ function and structure.

• It is a systemic disease.

• Even closer cooperation between cardiology and nephrology (and immunology) is warranted

Conclusion

• Treatment needs to be guided by deep understanding of underlying (patho)-physiological mechanisms in order to better maintain volume status, organ perfusion, and inhibit ongoing inflammation and fibrosis