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.
DEFINIȚIE

• Anomalii renale structurale sau funcționale, prezente mai mult de 3 luni

DEFINIȚIE

• Ce este RFG?

RFG =

cantitatea de filtrat glomerular format

în toți nefronii în ambii rinichi/min
DEFINIȚIE

Estimarea/Măsurarea RFG

Markeri exogeni ai filtrării Markeri endogeni ai filtrării

Inulină, EDTA, iohexol, Clearance de creatinină Ecuații eGFR

acid dietilen-triamin- (CrCl) (vârstă, sex, rasă, etc)
pentaacetic
DEFINIȚIE

• Evaluarea RFG
CLASIFICARE
• În funcție de cauză, RFG și albuminurie
Epidemiology of CKD
 Epidemiology of CKD 2015

Data Source: National Health and Nutrition Examination Survey (NHANES), 1988–1994, 1999-2004 & 2007–2012
participants aged 20 & older. Note: CKD is defined as eGFR <60 or ACR ≥30.
Vol 1, CKD, Ch 1 10
PREVALENȚĂ – în creștere

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, 5–14; 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 36th leading 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 ml/min
IMPACTUL BCR – eGFR și 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 cauză și de cauză cardiovasculară
• 1357/3291 (41%) decese, din care 510
(15.5%) de cauză cardiovasculară

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 One - In press (2014).
 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 practica…adresare 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
Importanța problemei:

Mortalitatea de cauză renală la pacienții cu BCR este scăzută.

Patologia cardiovasculară = factor principal de morbiditate si
mortalitate la pacienții cu BCR.
PROGRESIA BOLII CRONICE DE RINICHI
Atenționări !!!:

Declinul eGFR - interpretată diferit în funcție de gradul inițial

al afectării renale cronice

Rata de progresie - diferită, în funcție de etiologie!!!

- rată mai mare de progresie – în nefropatia interstițială si nefropatia diabetică;

- rată medie de progresie în GN non-diabetice;

- rată scăzută de progresie in nefropatia hipertensivă și ADPKD;

PROGRESIA BOLII CRONICE DE RINICHI
Importanța problemei:

Mortalitatea de cauză renală la pacienții cu BCR este scăzută.

Patologia cardiovasculară = factor principal de morbiditate si mortalitate
la pacienții cu BCR
(ÎNAINTE DE INIȚIEREA TERAPIEI DE SUPLEERE A FUNCȚIEI RENALE)

TRATAMENTUL BOLII CRONICE DE RINICHI

=
ÎNCETINIREA PROGRESIEI BCR CĂTRE STADIUL
TERMINAL!!!!!!!!
PROGRESIA BOLII CRONICE DE RINICHI
Factori de risc ai progresiei BCR:
Factori de risc nemodificabili Factori de rsic modificabili
Genetici Proteinuria
Sexul masculin HTA
Vârsta Controlul glicemic
Greutatea mică la naștere 3 factori majori ai progresiei BCR!!! :
Acidoza metabolică
Dislipidemia
•Activitatea bolii de bază
Hiperuricemia asimptomatică
•Modificările
Aldosteronul adaptative la nivelul rinichiului

• Reteneția
Sechelele de fosfați
locale + sistemice ale bolii renale
Greutatea corporală
Fumatul; Nivelul socio-economic redus
Drogurile
Consumul cronic de AINS/analgezice
Hiperhomocisteinemia
Anemia
Hipoxia tubulară cronică
IRA!!!
Mecanismele progresiei
 Avoid insults…DO NOT HARM !

Patient Safety Following

CKD detection

Improved diagnosis creates opportunity for strategic preservation

of kidney function

Fink et al. Am J Kidney Dis. 2009,53:681-668

 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 3–4 patients

Intensive blood-pressure control had NO EFFECT on CKD progression.

there may be differential effects of intensive BP control in patients with and those
without baseline proteinuria.
 3) Proteinuria si progresia BCR

6
RR

5
Meta-analiză a 11 RCTs
4 4685 de date cu BCR non-diabetică

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 după 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 therapy

Prescription upon discharge 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

Hyperkalaemia =
inherent risk in the
Angiotensinogen treatment with
Renin Inhibitors RAAS Inhibitors

Angiotensin I

ACE Inhibitors K Retention

Angiotensin II Na/Water
Uptake
ARBs Mineralcorticoid Receptor

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 level 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 37.4±12.1 ml/min ; 68.6% - stage 3 CKD and 53 (31.3%), stage 4 CKD

The eGFR decreased by a 2.1±0.4 ml/min in pts UAE - mean percentage increase of 5.7% in the
treated with PTF versus 6.5±0.4 ml/min in the control group versus a mean percentage reduction
control group - mean difference of 4.3 ml/min of −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 ESRD
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 50±13 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 examined subgroups,
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 2014

Geriatrizarea medicinei
TA la varstnicul cu CKD
 DO WE have studies in patients with
hypertension and CKD???

‘Renal failure’ 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: 1.065–1.600) and
41% higher CV mortality (1.412: 1.052–1.892).
Adjusted mortality rate in ESRD and DM: HbA1c
The Cochrane Library 2011, Issue 6
The Cochrane Library 2011, Issue 6
Comprehensive risk analysis:

FRAILTY or ONE of the following: yes

• Risk for hypoglycaemia (see figure) ≤ 8.5 %
• Poor motivation and attitude of patient
• Decreased general life expectancy
• Cardiovascular disease
• Micro-vascular complications

no

Patient on therapy wth

Lifestyle only yes
or ≤7%
therapy with low or absent hypoglycaemia risk *

no

Diabetes duration < 10 yes

years ≤8%

no ≤ 7.5 %
 Conclusions from EBM

• First concern: avoid hypoglycemia

• If no hypoglycemia’s and HbA1c > 8%: try to

intensify hypoglycemic treatment

• Take into consideration comorbidity and age of

patients
Sharp trial
Măsuri 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%
ERYTHROPOIETIN
Anemia in CKD
Hematinic
deficiency
Pathogenesis
Decrease RBCs life span, blood
sampling, blood loss during
haemodialysis

Erythropoietin
deficiency
Hipoxia

•BM fibrosis( PTH)

•BM affected by
90% 10% retained toxins

ERYTHROPOIETIN
Anemia in CKD-Management
General Steps

Step 1:
Step 2:
Iron status & 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?

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

Administrare po vs iv?

Pacientii in predializa Pacientii dializati

Fe po Obligatoriu Fe 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 2009

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

Hypertension

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 Axis Bone pain
Marrow Fibrosis
Eryyhropoiethin
resistance

2ry hyperPTH

Calcitriol Decrease
1,25(OH)2-D serum Ca

Alfa-1 hydroxylase Increase

serum Pi

Increase Ca
Reabsorbtion

Increase Pi
excrection
Mineral & Bone Disorder (MBD)
Lab Abnormalities
ALK
PTH Ca Pi Phosphatase
Secondary
Hyperparathyroidism
Mineral & Bone Disorder (MBD)
Bone Abnormalities –Renal Osteodystrophy
High turn Over- Osteitis Fibrosa Cystica
Mineral & Bone Disorder (MBD)
Bone Abnormalities –Renal Osteodystrophy

High turn Over- Osteitis Fibrosa 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

Serum P p<0.02 vs intervention group
Available and new phosphate binders

Calcium-based Calcium-free phosphate binders

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

Calcium-containing • Magnesium-OH / Magnesium carbonate

phosphate binders • Colestilan

• CaMg • Niacin / Nicotinamide*

• PA21, ferric citrate

*Phosphate transport inhibitor (not a binder)

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 GI
to
tolerability
calcification
by calcium Reduced Ca content,
Highly Avoiding Al Improving overload
effective P toxicity efficacy Mg benefits
binder
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;65:728-36

Iron based phosphate binders

Block GA et al, AJKD 2015;65:728-36

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