BOALA CRONICA DE RINICHI

Cateva
reflectii
despre
medicina

de la un
prieten
 Content

Definitie. epidemiologie
Major cost driver for health-care systems
Associated with an increase in CV mortality and
is a risk multiplier in patients with diabetes and
HTN;
Early detection and treatment
can be implemented at minimal cost
will reduce the burden of ESRD and morbidity and
mortality from NCDs.
DEFINIIE

Anomalii renale structurale sau funcionale, prezente

mai mult de 3 luni
DEFINIIE
Ce este RFG?

RFG =

cantitatea de filtrat
glomerular format n toi
nefronii n ambii
rinichi/min
DEFINIIE

Estimarea/Msurarea
RFG

Markeri exogeni ai Markeri endogeni ai

filtrrii filtrrii

Clearance de Ecuaii eGFR

Inulin, EDTA,
creatinin (vrst, sex,
iohexol, acid
(CrCl) ras, etc)
dietilen-triamin-
pentaacetic
DEFINIIE
Evaluarea RFG
CLASIFICARE
n funcie de cauz, RFG i albuminurie
Epidemiology of CKD
 Epidemiology of CKD 2015

Data Source: National Health and Nutrition Examination Survey (NHANES), 19881994,
1999-2004 & 20072012 participants aged 20 & older. Note: CKD is defined as eGFR <60 or
ACR 30. Vol 1, CKD, Ch 1 10
PREVALEN n cretere

http://www.usrds.org/2012
EPIDEMIOLOGIE

Andrew S
Levey
Josef Coresh

The Lancet
2012
 CKD in the adult population of Iasi, based on the results of a national
general health screening program from 2007 to 2008. The patients were
tested for CKD with serum creatinine and urinary dipstick.

The global prevalence of CKD was found to be 6.69% by the

MDRD formula and 7.32% when using the CKD-EPI equation
Romania
CKD: care is costly
 CKD: care is costly
USRDS 2015:

CKD
- Costs for CKD patients - 20.1% of all Medicare
spending.

ESRD $30,900
7.1%

Higher costs for CKD not on dialysis

ESRD increasing problem
 HTN and diabetes: most frequent
causes of ESRD
USRDS 2015:

Trends in annual number of ESRD incident cases (in thousands),

by primary cause of ESRD, in the U.S. population, 1996-2013

ETIOLOGIE
http://www.usrds.org/2015

2013
 ESRD: disease of the elderly
USRDS 2015:
 Content

Increasing incidence and prevalence

major cost driver for health-care
systems
associated with an increase in CV
mortality and is a risk multiplier in
patients with diabetes and HTN;
CKD - classification and prognosis
(KDIGO)

Kidney International Supplements (2013) 3, 514; doi:10.1038/kisup.2012.77

 Multiplicative impact of eGFR and Proteinuria
on mortality in general population
Matsushita et al. Chronic Kidney Disease Prognosis Consortium Lancet
2010

ACR: <30 [black], 30-299 [green], and

300 [red]
Death more common than
dialysis in CKD
 Age-standardized mortality 15.8 deaths per
100,000 in 2013,
the 19th leading global cause of years of life lost
(compared with the 36thleading cause in 1990)
Ce fel de mortalitate?
 GFR and the risk for
CV events
Zocalli...Covic et al.

the risk for CV death increases gradually - 3.4 times higher in

patients with kidney failure than in individuals with GFR > 60
IMPACTUL BCR eGFR i evenimentele
cardiovasculare
o- a median follow-up
of 8.3 years
o- 3291 older adults
in the Cardiovascular
Health Study

Rifkin et al. NDT

2010
IMPACTUL BCR mortalitatea
CHS cardiovascular
health study
8 ani de follow-up pt
mortalitate de orice cauz i
de cauz cardiovascular
1357/3291 (41%) decese,
din care 510 (15.5%) de
cauz cardiovascular

Rifkin et al. NDT 2010

 Short term CHANGES
in eGFR
and risk of CV events
27%
N - 526 388 participants,
76.1% (n=400 560) had stable
2.6% (n=13 668) had a certain
drop
3.3% (n=17 499) had a certain
rise in eGFR

51%
adjusted for covariates including
eGFR at the first measurement

20%

Turin T C et al. J Am Heart Assoc 2014;3:e000997

 Content

Increasing incidence and prevalence

major cost driver for health-care
systems
associated with an increase in CV
mortality and is a risk multiplier in
patients with diabetes and HTN;
Detectia precoceand treatment
can be implemented at minimal cost
will reduce the burden of ESR and
morbidity and mortality from NCDs.
Early CKD treatment preserve
renal function
 CKD complications
evolution and acceleration by
stage
Gaps in CKD Diagnosis

Szczech, Lynda A, et al. "Primary Care Detection of Chronic Kidney Disease

in Adults with Type-2 Diabetes: The ADD-CKD Study (Awareness, Detection
and Drug Therapy in Type-2 Diabetes and Chronic Kidney Disease)." PLOS
 CKD still under recognized
problem
Patients unaware:
Only 13 % of pts with eGFR <60 ml/min or +1
dipstick proteinuria aware of their CKD
Only 8% of pts with known CKD aware of their
CKD, despite recent physician visit;

Only 10 % of patients with diabetes receive

annual albuminuria test;

Less than 1/3 of hospitalized patients with

proteinuria are prescribed at ACEi at
discharge
In practicaadresare tardiva la
nefrolog
 Screening si preventie

Populatie cu risc
crescut:

Diabet

Hipertensiune;

Sindrom metabolic;

Rude de grad I cu
CKD;
Detectia pacientilor cu risc crescut
CKD PREVENTION

CKD
PROGRESIA BOLII CRONICE DE
RINICHI Importana problemei:

Mortalitatea de cauz renal la pacienii cu BCR

este sczut.
Patologia cardiovascular = factor principal de
morbiditate si mortalitate la pacienii cu
BCR.
PROGRESIA BOLII CRONICE DE
RINICHI
Atenionri !!!:

Declinul eGFR - interpretat diferit n

funcie de gradul iniial al afectrii renale cronice

Rata de progresie - diferit, n funcie de

etiologie!!!

- rat mai mare de progresie n nefropatia interstiial si

nefropatia diabetic;

- rat medie de progresie n GN non-diabetice;

- rat sczut de progresie in nefropatia hipertensiv i

PROGRESIA BOLII CRONICE DE
RINICHI Importana problemei:

Mortalitatea de cauz renal la pacienii cu BCR este

sczut.
Patologia cardiovascular = factor principal de
morbiditate si mortalitate la pacienii cu BCR
(NAINTE DE INIIEREA TERAPIEI DE SUPLEERE A FUNCIEI
RENALE)

TRATAMENTUL BOLII CRONICE DE RINICHI

=
NCETINIREA PROGRESIEI BCR CTRE STADIUL
TERMINAL!!!!!!!!
PROGRESIA BOLII CRONICE DE
RINICHI
Factori de risc ai progresiei BCR:

3 factori majori ai progresiei

BCR!!! :
Activitatea bolii de baz
Modificrile adaptative la nivelul rinichiului
Sechelele locale + sistemice ale bolii renale
Mecanismele progresiei
Avoid insultsDO NOT HARM !

Patient Safety
Following
CKD detection

Improved diagnosis creates opportunity for

strategic preservation of kidney function

Fink et al. Am J Kidney Dis. 2009,53:681-66

 1) AKI

AKI often preventable;

AKI-produces residual kidney damage;
CKD pts at higher risk for AKI
2) HTN - an important independent risk
factor for
renal-disease progression
2,144 CKD stage 34 patients

Intensive blood-pressure control had NO EFFECT on CKD

progression.
there may be differential effects of intensive BP control in
 3) Proteinuria si progresia BCR

6
RR
5
Meta-analiz a 11 RCTs
4 4685 de date cu BCR non-diabetic

0
<0.5 0.5-0.9 1.0-1.4 1.5-1.9 2.0-2.9 3.0-3.9 4.0-4.9 5.0-5.9 6.0+

Proteinuria (g/24 ore)

Adaptat dup Jafar et al Ann Intern Med 2003;139:244-252

3) RAAS blockade a central role in
nephroprotection
Age, Worsening renal function (WRF)
and hyper-K:
3 major drivers of non-optimal
Prescription upon discharge therapy
are
hardly changed 1 year after
discharge

Zannad et al. EPICAL, JACC 1999, Am H J 2000

 Treatment with RAAS Inhibitors
Reduce Water and Sodium, Increase
Potassium
Hyperkalaemi
a = inherent
risk in the
Angiotensinogen treatment
Renin Inhibitors with RAAS
Inhibitors
Angiotensin I
K
ACE Inhibitors Retention
Angiotensin II Na/Water
Uptake
Mineralcorticoid Receptor
ARBs

AT1 Receptor
MRAs
Aldosterone Production
 Treatment with patiromer was associated
with a reduction from baseline in elevated K
level
N = 243 patients. First phase = a 4-week single-group, single-blind initial treatment
phase
All patients received treatment with patiromer;
Primary efficacy end point was the mean change in the serum potassium lev
from baseline to week 4

At week 4, 76% of the patients had reached the target

potassium level
(3.8 to <5.1 mmol per liter)
Weir, N Engl J Med 2015; 372:211-221
 second phase = the randomized withdrawal phase
107 patients were randomly assigned to patiromer (55 patients) or placebo (52 patients

the incidence of recurrent

hyperkalemia (when defined as a
potassium level 5.5 mmol per
liter) was 4 times as high in the
placebo group as in the
patiromer group (60% vs. 15%),
with hyperkalemia recurring
more rapidly in the placebo group

Weir, N Engl J Med 2015; 372:211-221

 PENTOXIFYLLINE
SILYMARIN

Activation of the Nrf2 pathway

Endotheline 1 antagonists
Targeting renal fibrosis:
Pirfedinone
Tranilast
Cisteamine bitartrat
 Predian study
169 diabetic patients were randomly assigned to a control or a treatment
group.
The mean baseline eGFR was 37.412.1 ml/min ; 68.6% - stage 3 CKD and
53 (31.3%), stage 4 CKD

The eGFR decreased by a 2.10.4 UAE - mean percentage increase of

ml/min in pts treated with PTF versus 5.7% in the control group versus a
6.50.4 ml/min in the control group - mean percentage reduction of
mean difference of 4.3 ml/min 14.9% in patients treated with PTF
 Addition of Silymarin to RAAS Inhibitors on
Proteinuria in Type 2 DM with overt
proteinuria
60 patients with type 2 DM with macroalbuminuria despite treatment with
the maximum dose of a RAASinhibitor for more than 6 months and eGFR>30
mL/min/1.73

Silymarin reduces urinary excretion of albumin, TNF-

alpha, and MDA in patients with diabetic nephropathy

Fallahzadeh, AJKD 2012

 Content

Increasing incidence and prevalence

major cost driver for health-care
systems
associated with an increase in CV
mortality and is a risk multiplier in
patients with diabetes and HTN;
Early detection and treatment
can be implemented at minimal cost
Managementul de rutina al complicatiilor
 Reducerea riscului CV

Controlul TA;

Control glicemic adecvat;

Utilizarea blocantilor SRAA/betablocanti;

Utilizarea statinelor

Corectia sdr anemic

 15 trials including a total of 37,348 participants five (n= 6,960) enrolled only patients with
diabetes and six specifically recruited participants with CKD (n= 2,734).On average there was
a 7.5/4.5-mmHg BP difference.

Intensive BP lowering achieved RR reductions of 11% for major CV

events, 13% for myocardial infarction , 24% for stroke, and 11% for
9361 pts with a sBP of 130 mm Hg or higher and an increased CV risk,
but without diabetes, to sBP target of less than 120 mm Hg (intensive
treatment) or a target of less than 140 mm Hg (standard treatment)
Lower rates of fatal and nonfatal major
CV events and death from any cause

lower rate of the primary composite outcome and

death in the intensive-treatment group
 Primary and Secondary Outcomes and
Renal Outcomes.

Among participants who had CKD at baseline, no significant

difference in the composite outcome of a decrease in the eGFR of
50% or more or the development of ESRD was noted
Decrease in the eGFR of 30% or more to a value of less than
60 ml/min per was higher in the intensive-treatment
group in patients without CKD at baseline
 Rates of serious adverse events of hypotension, syncope,
electrolyte abnormalities, and acute kidney injury or failure, were
higher in the intensive-treatment group
 Controlul TA
(organoprotectie si
supravietuire) la CKD
Cu ce medicamente?
A logistic regression analysis was used to calculate the
propensity of ACEI/ARB initiation in 141,413 U.S. veterans with
nondialysis CKD who were previously unexposed to ACEI/ARB
treatment.
mean estimated GFR (eGFR) was 5013 ml/min/1.73m2
ACEI/ARB administration was associated with a
significantly lower risk of mortality
This lower risk of mortality was present in all
examinedsubgroups, including HF, HTN,
diabetes, CKD stages
 Beta-Blockers Beat ACE Inhibitors in
Dialysis Patients
Open label Lisinopril (n = 100) sau Atenolol (n = 100) x3/sapt
dupa HD

Terapia bazata pe Atenolol ar putea fi superioara celei cu

Lisinopril in prevenirea morbiditatii cardiovasculare si
spitalizarilor de orice cauza
Agarwal, NDT 20
Geriatrizarea medici
TA la varstnicul cu C
 DO WE have studies in patients
with hypertension and CKD???

Renalfailure or a designated upper limit for the

SCr
concentration have been an exclusion criterion in
many
studies, reducing the applicability of the data to
CKD patients.
3260 Japanese participants aged 70 to 84 years, with systolic BP 160 mm Hg

CV events

more- vs. less-intensive BP lowering were unable to

observe benefits by lowering average SBP to 136
and 137 mmHg rather than 145 and 142 mmHg

Ogihara T et al. Hypertension. 2010;56:196-202

 Reducerea riscului CV

Controlul TA;

Control glicemic adecvat;

Utilizarea blocantilor SRAA/betablocanti;

Utilizarea statinelor

Corectia sdr anemic

 Questions

Is intensive glycemic control (as

measured by HbA1c) advantageous in
diabetic patients with CKD 3b-5d?

Is an aggressive treatment strategy

(in number of injections and controls
and follow-up) superior to a more
relaxed treatment strategy in
patients with diabetes and CKD
using insulin?
Targets for glycemic control in
predialysis CKD
Targets for glycemic control in
predialysis CKD

In patients with CKD, intensive glucose lowering - significantly

associated with:
31% higher all-cause mortality (1.306: 1.0651.600) and
Adjusted mortality rate in ESRD
and DM: HbA1c
The Cochrane Library 2011, Issue 6
The Cochrane Library 2011, Issue 6
 Conclusions from EBM

First concern: avoid hypoglycemia

If no hypoglycemias and HbA1c >

8%: try to intensify hypoglycemic
treatment

Take into consideration

comorbidity and age of patients
Sharp trial
Msuri clasice nespecifice
Statinele utile in BCR ???
N = 31 trials providing data for 48 429 patients with CKD, including 6690 major
cardiovascular events and 6653 deaths

Statins useful in CKD ???

Statin therapy produced a reduction for major

cardiovascular events in CKD stage 2-4 but not in CKD
stage 5
Fara efecte semnificative in AVC (21%, 12 to 44) si efecte
incerte in BCR (5%, 1 to 10)
Anemia in CKD

Back to basics Erythropoietin

Hormone

Hipoxia

90% 10%
Anemia in CKD Hemati
nic
deficien
Pathogenesis
Decrease RBCs life span,
cy

blood sampling, blood

loss during
haemodialysis

Erythropoi
etin Hipoxia
deficiency

BM
fibrosis( PTH)
BM affected
90% 10%
by retained
toxins
ERYTHROPOIETIN
Anemia in CKD-Management
General Steps

Step 1:
Iron status & Step 2:
Initial ESA Therapy
Evaluation
Anemia in CKD-Management
Step 1: Iron status & Initial Evaluation
Anemia in CKD-Management
Step 1: Iron status & Initial Evaluation

ANEMIA IN CKD?

Normochromic
Normocytic

Hypochromic
Microcytic

Normochromic
Macrocytic
Presence of other type of
anemia may point to another
cause rather than CKD
Anemia in CKD-Management
Step 1: Iron Therapy

When to start?

TSAT < Ferritin<

30% 500ng/ml
Anemia in CKD-Management
Pasul 1: Terapia cu Fe

Administrare po vs iv?

Pacientii
Pacientii in
dializati
predializa
Obligatoriu Fe
Fe po
iv
Iron - Highly Efficacious in Anemic
Hemodialysis Patients - DRIVE
study

Changes in weekly hemoglobin (SE) in the intravenous iron group (solid line) and the control group
(dashed line) from baseline to week 6.

Daniel W. Coyne et al. JASN 2007;18:975-984

Significantly lower epoetin dose
following iron administration

Kapoian, JASN 200

Anemia in CKD-Management
Terapia cu EPO

Hb tinta
10 11.5
g/dl

Individualizarea
(Unii pacienti au o
calitate a vietii mai
buna cu Hb>11,5g/dl)

La adult
Hb<13g.dl
Anemia in CKD-Management
Terapia cu EPO

Efectele secundare ale EPO

Hypertens
ion
Pure red
cell aplasia
(PCR)
Anemia treatment in CKD:
a balance between patient
safety
and Hb target
Mineral & Bone Disorder (MBD)
Mineral & Bone Disorder
(MBD)
Lab Abnormalities Bone Disease
Fractures
PTH Vit D Ca Pi Bone pain
Marrow Fibrosis
Axis Eryyhropoiethin
resistance

2ry
hyperPTH

Calcitriol
Decrease
1,25(OH)
serum Ca
2-D
Alfa-1
Increase
hydroxylase
serum Pi
Increase
Ca
Reabsorbti
on
Increase Pi
excrection
Mineral & Bone Disorder
(MBD)
Lab Abnormalities
ALK
PTH Ca Pi Phosphat
ase
Secondary
Hyperparathyroi
dism
Mineral & Bone Disorder
(MBD)
Bone Abnormalities Renal
High turn Over-
Osteodystrophy
Osteitis Fibrosa
Cystica
Mineral & Bone Disorder
(MBD)
Bone Abnormalities Renal
High turn Over- Osteitis Fibrosa
Osteodystrophy
Cystica
Clinic
Fracturi osoase
Dureri osase si
discomfort
Calcificari
metastatice
Mineral & Bone Disorder
(MBD)
Bone Abnormalities Renal
Osteodystrophy
1.Dieta

2.Chelatorii de Fosfor

3.Vit D si Analogi de Vit

D

4.Cinacalcet
From: Effect of Food Additives on Hyperphosphatemia Among Patients With End-stage Renal Disease: A
Randomized Controlled Trial
JAMA. 2009;301(6):629-635. doi:10.1001/jama.2009.96

0 vs 3 months 2.32 2mmol/L 2.30

2.17 mmol/L
Available and new phosphate binders

Calcium-free phosphate binders

Calcium-based
phosphate Aluminum-HCl / Aluminum-OH
Sevelamer-HCl / Sevelamercarbonat
binders Lanthanum carbonate

Magnesium-OH / Magnesium carbonate

Colestilan
Calcium carbonate
Niacin / Nicotinamide*
Calcium acetate PA21, ferric citrate

*Phosphate transport inhibitor (not a binder)

Calcium-containing
phosphate
binders

CaMg
Timeline of various
phosphate binders
Over the course of 5 decades, the properties of phosphate
binders have been steadily improved.

Avoiding
Avoiding
acidosis,
contribution
improving
to
GI
calcification
tolerability
by calcium
Highly Avoiding Improving Reduced Ca
overload
effective P Al toxicity efficacy content, Mg
binder benefits

CaMg

Sevelamer HCl Sevelamer Carbonate

Aluminum-
based Calcium acetate
binders
Calcium Lanthanum carbonate
carbonate

1970s 1980s 1990s 2000s 2010s

 Phosphate binders for the
treatment
of hyperphosphatemia in CKD

Iron-based phosphate binders

Sucroferric oxyhydroxide (PA21 [Velphoro])
Ferric citrate (JTT-751, Zerenex)
Iron-Mg hydroxycarbonate (Alpharen, Fermagate)
Iron based phosphate binders

Block GA et al, AJKD 2015;65:7

Iron based phosphate binders

Block GA et al, AJKD 2015;65:7

Mineral & Bone Disorder
(MBD)
Management
Indicatii de Paratiroidectomie
Hiperparatiroidism sever
cu hiperfosfatemie severa
Care nu raspunde la tratamentul cu Ca si Calcitriol
cu hipercalcemie
la pacientii candidati pt transplant renal
cu calcificari metastatice
Calcifilaxia asociata hiperparatirodismului

Prurit sever asociat hiperparatirodismului