Progression of chronic kidney diseases:

mechanisms, risk factors, treatment strategies

Dlin V.V., Konkova N.E.Nephrology department of Research

Institute of Pediatrics & Children surgery, Moscow, Russia

History and conception of problem

• The conception was developed at the beginning of XXI century by U.S. National Kidney Foundation (National Kidney Foundation) and published in 2002. It’s development was continued by experts from the European Dialysis and Transplant Association (ERA-EDTA) and KDIGO (Kidney Desease: Improving Global Outcomes)

• The purpose of the conception:

            - early detection of kidney disease            - slowing down the progression of kidney disease            - reduction the risk of cardiovascular complications            - prevention of kidney lesions - the use of common criteria and universal classification             - the use of common terminology

Importance of the problem

The high prevalence of CKD in the world:

  1-5 stage of CKD - 12-15% of the population

3-5 stage of CKD - 6-8 % of the population

THE PREVALENCE OF CKD IN THE WORLD

Importance of the problem

Renal mortality in patients with kidney disease is low.

Cardiovascular pathology as a major factor of patient’s death is ignored.

Importance of the problem

Renal factors of cardiovascular risk:albuminuria / proteinuriasystemic inflammationoxidative stressanemiahyperhomocysteinemia

Smirnov A. et al., 2005

FREQUENCY OF CARDIOVASCULAR DISEASE IN CHRONIC KIDNEY DISEASE

(per 100 patients / year)

kidney diseases infarcti

on

disturbance of

cerebral blood flow

peripheral vasculopat

hy

atherosclerosis

cardiovascular death

CKD - 1,6 7,6 6,9 14,1 5,5

CKD+ 3,9 16,6 19,9 35,7 17,7

CKD – chronic kidney disease

C.R.. Harper, 2008

FREQUENCY OF CARDIOVASCULAR DISEASE IN PATIENTS IN RELATION TO GLOMERULAR

FILTRATION RATE

the estimated

frequency

GFR – glomerular filtration rate Matthew R., 2005

The structure of mortality (%) in patients with ESRD by age (Russian Register of renal

replacement therapy, 1998-2007)

CVD – cardiovascular disease

The main markers of kidney damage, suggestive of the

presence of CKDmarker notes

Albuminuria / proteinuria persistent increasing in urinary albumin excretion greater than 10 mg/day (10 mg albumin/g creatinine) – see recommendation

Persistent changes of the urinary sediment

hematuria, cylindruria, leykotsituriya (piura)

Changes of renal imaging studies

anomalies of the kidney cysts, hydronephrosis, resizing kidneys, etc.

Changes of of blood and urine composition

changes in serum and urinary electrolyte concentration, impaired HGA and others, including the characteristic of the "tubular dysfunction syndrome" (Fanconi's syndrome, renal tubular acidosis, Bartter's syndrome and Gitelman, nephrogenic diabetes insipidus, etc.)

Persistent decrease of GFR less than 60 mL/min/1,73m2

in the absence of other markers of kidney damage

Morphological changes of the lifetime nephrobiopsy

should be taken into account the signs of “chronization” (sclerotic changes of kidneys, changes of membranes, etc.)

Terminology

• CKD - the common notion reflecting the presence of common risk factors of development and progression of different nephropathy.

• The diagnosis of CKD is based on the presence of markers of kidney damage and/or GFR < 60 ml/ min for at least 3 months.

Normal GFR in children and adolescents

Age / Sex The average GFR ± σ

(ml/min/1,73m2)

1 week 41 ± 15

2-8 weeks 66 ± 25

> 8 weeks 96 ± 22

2-12 years 133 ± 27

13-21 years(m) 140 ± 30

13-21 years(f) 126 ± 22

Estimation of GFR

• estimation of GFR in general clinical practice (outpatient) will be based of calculation formulas (eGFR), including gender, age, the patient and the concentration of creatinine in serum

• clearance methods of GFR’s determination will be used at the hospital

Methods of GFR’s estimation

• Simple ways to calculate GFR based on measurements of serum parameters without hour urine collection:

1. Schwart’s formulas 2. Formulas of Cockroft DW., Gault MH.

3. MDRD (Modification of Diet in Renal Disease)4. CKD-EPI method eGFR (the most suitable in the clinical practice)

Levey AS. et al., 2000

eGFR in children on the basis of serum creatinine and growth

(according to Schwartz)

• GFR (ml/min/1,73m2)= [0,0484*х Height (сm)]/Scr (mmol/l)

*k= 0,0616 for boys >13 years

CKD-EPI formula (modification of 2011 year)

race gender

Serum creatininemg/100 ml

formula

White and other

female ≤ 0.7 144*(0.993) Age*Cr/0.7)-

0.328

White and other

female > 0.7 144*(0.993)Age*Cr/0.7)-

1.21

White and other

male ≤ 0.9 141*(0.993) Age*Cr/0.9)-

0.412

Stages of CKD in based on GFR(National Kidney Foundation KD, 2002 in modification of Smirnov

et al., 2008) stages Kidney function GFR

ml/min/1,73 m2

С1 high and optimal >90

С2 slightly decreased 60-89

С3а moderately reduced 45-59

С3б significantly reduced 30-44

С4 drastically reduced 15-29

С5 ESRD <15

Albuminuria

• Albuminuria (normal < 10 mg/day) – integral sign of CKD

[A. Smirnov et al., 2010] and represents: - increased permeability of cell membranes (size-selectivity, the charge-selectivity);

- transport changes in the proximal tubule;- increased hemodynamic burden on the glomerules;- presence of systemic and renal endothelial dysfunction;- the degree of glomerular/interstitial sclerosis due to glomerular and tubular transport protein disturbances and subsequent activation of profibrotic cytokines

• Albuminuria – risk factor of total and cardiovascular mortality, ESRD, acute kidney injury and progression of CKD

Stage of albuminuria/proteinuria

(Levey A.S. et al., 2010 )

Stage Kidney functionurea albumine

(mg/creatinine, g)

А0 optimum <10А1 increased 10-29А2 high 30-299А3 very high 300-1999

А4 nephrotic ≥2000

The stage of CKD should be indicated in the diagnosis after the nosologic

form of renal diseaseExamples of diagnosis:

• Kidney’s anomaly: a partial doubling of right renal pelvis. CKD C1A0

• Hypertensive nephrosclerosis. CKD C3aA1

• Focal segmental glomerulosclerosis. Nephrotic syndrome. CKD С3аА3

• IgA-nephropathy. Isolated urinary syndrome. CKD С1А3.

Classification and characteristic of main risk factors of CKD

type definition description

factors increasing susceptibility to CKD

increase susceptibility of kidney to damage

older age, family history of CKD, low renal weight, low birth weight, racial and ethnic differences

factors of initiation of CKD

cause direct damage of kidneys

diabetes, blood hypertension, autoimmune diseases, systemic infections, urinary tract infections, urinary stones, urinary tract obstruction, drug toxicity, genetic diseases

factors of progression of CKD

promote the progression of renal damage and accelerate the rate of decline in renal function

high level of proteinuria, high blood pressure, poor control of blood glucose level in diabetic patients, dyslipidemia, smoking

factors of ESRD increase morbidity and mortality in patients with ESRD

inadequate dialysis (Kt/V); temporary vascular access, low albumin level, high levels of phosphorus and delayed treatment

Risk factors of CKD

nonmodifiable modifiableolder age diabetes

male sex blood hypertension

low number of nephrons (low birth weight)

autoimmune diseases

racial and ethnic peculiarities

chronic inflammation, systemic infections

hereditary factors (including family history of CKD)

urinary stones, urinary tract infection

urinary tract obstruction

drug toxicity

high protein diet

dyslipidemia

smoking

obesity/metabolic syndrome

hyperhomocysteinemia

pregnancy

Factors of progression of CKDnonmodifiable modifiable

older age persistent activity of the basic renal pathology

male sex high levels:- systemic blood pressure- proteinuria

low number of nephrons (low birth weight)

uncontroled diabetes

racial and ethnic peculiarities

obesity/metabolic syndrome

dyslipidemia

smoking

anemia

metabolic acidosis

pregnancy

disturbed calcium-phosphorus metabolism (hyperparathyroidism)

high protein and sodium diet

CKD as independent risk factor for the development and progression of

cardiovascular disease

Groups of risk for cardiovascular disease:

• group of intermediate risk - CKD stages C1-C2 and albuminuria A1;

• group of high risk - CKD stages C1-C2 and albuminuria A2-A3 or CKD stage C3a, regardless of the level of albuminuria/proteinuria;

• group of very high risk - CKD stages C3B - C5 regardless of the level of albuminuria/proteinuria

RISK FACTORS OF CARDIOVASCULAR DISEASE IN PATIENTS WITH CKD

nephrogenic modifiable:• chronic inflammation• anemia• metabolic acidosis• hyperparathyroidism• hyperhomocysteinemia

nonmodifiable:• gender, • age, • race,• genetic predisposition

common modifiable:• blood hypertension• metabolic factors• endothelial dysfunction

heart disease

atherosclerosis

The incidence of arterial hypertension in patients with chronic kidney disease

(Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow, Russia)

0

10

20

30

40

50

60

70

80

90

100

SRNS AS Aspr ADPKD TMAP(HUS)

RN

BH by Korotkov methodBH by ABPM

%

SRNS – steroid resistant nephrotic syndrome

AS – Alport syndrome

ТМАP (HUS) – thrombotic microangiopathy (hemolytic uremic syndrome)

RN – reflux nephropathy

AD PKD – autosomal-dominant polycystic kidney disease

PECULIARITIES OF RENAL ARTERIAL HYPERTENSION (Nephrology department of Research Institute of Pediatrics & Children

surgery, Moscow, Russia)

0% 50% 100%

SRNS

AS

ADPKD

TMAP(HUS)

RN

nightly / daily BH daily BP0% 50% 100%

SRNS

AS

ADPK

DTMAP

(HUS)

RN

diastolic / systolo-diastolic HP systolic HP

SRNS – steroid resistant nephrotic syndrome

AS – Alport syndrome

ТМАP (HUS) – thrombotic microangiopathy (hemolytic uremic syndrome)

RN – reflux nephropathy

AD PKD – autosomal-dominant polycystic kidney disease

FREQUENCY OF COMPLICATIONS OF ARTERIAL HYPERTENSION IN PATIENTS WITH PROGRESSIVE

KIDNEY DISEASE (Nephrology department of Research Institute of Pediatrics & Children surgery,

Moscow, Russia)

0

20

40

60

80

100

SRNS AS Aspr ADPKD TMAP (HUS) RN

angiopathy left ventricular hypertrophy

17,4

30,4

11,8

44,4

62,5

33,323,1

4,5

40,0

28,6

SRNS – steroid resistant nephrotic syndrome

AS – Alport syndrome ТМАP (HUS) – thrombotic microangiopathy (hemolytic uremic syndrome)

RN – reflux nephropathyAD PKD – autosomal-dominant polycystic kidney disease

The risk of cardiovascular complications in children with steroidresistant nephrotic

syndrome (Nephrology department of Research Institute of Pediatrics & Children

surgery, Moscow, Russia)

data Left ventricular hypertrophy

retinal angiopathy

SRNS ≥ 4 years 2,8 2,7

the severity of blood hypertension

(explicit)

9,7 0,56

systolo-diastolic blood hypertension

2,1 7,2

the lack of antihypertensive

therapy

2,3 9,2

RR>2,0 – high risk of cardiovascular disease

Primary prevention of CKD

is the elimination or minimization of the risk factors for its development:

• clinical supervision of patient from high-risk group;

• the control of modifiable risk factors of development and progression of CKD;

• control of GFR and albuminuria.

Secondary prevention of CKD

• slowing the progression of CKD (renoprotection)

• preventing the development of cardiovascular disease (cardioprotection)

Correction of common risk factors for the development and progression of renal and

cardiovascular disease

• metabolic and hemodynamic changes• glycemia• dyslipidemia• uricemia• blood hypertension• anemia

Common approaches of primary and secondary

prevention of CKDstage recommendations

The presence of risk factors for CKD

Regular screening for CKD, measures for reduction of the risk of development CKD

С1 (normal renal function) Diagnosis and treatment of the kidney disease, correction of common risk factors of progression of CKD. Identification of CVD, correction of therapy, monitoring of risk factors of progression of CVD.

С2 (initial reduction of GFR) previous measures + estimation of the rate of progression CKD, correction therapy

С3 А и В (moderate reduction of GFR)

previous measures + detection, prevention and treatment of systemic complications of renal dysfunction (anemia, dizelektrolitemiya, acidosis, hyperparathyroidism, hyperhomocysteinemia, etc)

С4 (marked reduction of GFR) previous measures + preparations for renal replacement therapy

С5 (ESRD) renal replacement therapy + identification, prevention and treatment of systemic complications of renal dysfunction

Nephroprotective and cardioprotective therapy

• ACE inhibitors• AT1-receptor blockers• calcium channel blockers• statins, etc.

Treatment of blood hypertension in patients with chronic kidney disease

medicines with nephroprotectiveeffect

• inhibitors of angiotensin- converting enzyme• blockers of ATII receptor type 1• calcium channel blockers (non-dihydropyridine)?

medicines without nephroprotective

effect

• beta-blockers• diuretics• calcium channel blockers

(dihydropyridine)

Indications for ACE inhibitors and BRA in

patients with CKD• in patients with blood hypertension

(for achievation of target blood pressure levels)

• in patients with albuminuria / proteinuria A2-A3 (even in the absence of hypertension)

Antihypertensive therapy

• If the target level of blood pressure was not achieved by ACE inhibitors and BRA it’s necessary to add the hypotensive medicine of other pharmacological groups and/or diuretics

The hypotensive effectiveness of RAAS inhibitors in children with progressive

kidney disease (Nephrology department of Research Institute of Pediatrics & Children surgery,

Moscow, Russia)

0

20

40

60

80

100

SRNS SA Sapr ADPKD TMAP(HUS) RN

37,5

58,3

66,7

75,0

63,6

71,4

SRNS – steroid resistant nephrotic syndrome

AS – Alport syndrome ТМАP (HUS) – thrombotic microangiopathy (hemolytic uremic syndrome)

RN – reflux nephropathyAD PKD – autosomal-dominant polycystic kidney disease

Antihypertensive therapy

• Clinical predictor of renoprotective efficacy of the drugs is partial (daily proteinuria <2.5 g / day) or total (daily proteinuria <0.5 g / day) remission of proteinuria in a few weeks or months after starting of treatment

Dynamics of proteinuria in children with

Alport's syndrome (Nephrology department of Research Institute of Pediatrics & Children surgery,

Moscow, Russia)

on the therapy with ACE-

inhibitors (n = 14)

without ACE-inhibitors

(n = 8)

50%

14,3%7,1%

28,6%

12,5%

37,5%50%

Конькова Н..Е., 2011

decreased

proteinuria

-

- proteinuria didn’t increase

- deceleration of the rate of increasing of proteinuria

- stable proteinuria

- increased proteinuria

Dynamics of GFR in children with progressive course

of Alport's syndrome

(Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow, Russia)

on the therapy with ACE-

inhibitors (n = 9)

33,3%

11,1%

33,3%

22,2%

100%

- increasing of GFR

- stable GFR

- deceleration of the rate of reduction of GFR

- reduction of GFR

Конькова Н.Е, 2011

without ACE-inhibitors

(n = 3)

Frequency of blood hypertension in children with SRNS receiving different

immunosuppressive therapy(Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow,

Russia)

0 20 40 60 80 100

Pred

Pred maxD

CsA

CsA+Pred

MMF

MMF+Pred

Cyph+Pred

Prograf

Prograf+Pred

The effectiveness of antihypertensive therapy in children with SRNS in dependence of the number

of antihypertensive drugs(Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow, Russia)

0102030405060708090

100

1 medicine 2 medicines 3 medicines

hypotensive effect

Principles of antihypertensive therapy in kidney diseases in children

BH

MONOTHERAPY(ACE-inibitors, calcium channel blockers, BRA II)

COMBINATION THERAPYACE-inibitors + diuretics, ACE-inibitors + calcium channel blockers, ACE-inibitors + beta-adrenoblockers,

calcium channel blockers + diuretics, etc.

CHRONOTHERAPY

CHRONOTHERAPY

ABPM allows:

to identify the peaks of blood pressure rises

to calculate: Т/Р - duration of antihypertensive action of the drug

N/D - uniformity of drug’s action in the daytime and night hours

    IND - uniformity of drug’s action during a day

to optimize therapy

to reduce the risk of target organ’s damage

CHRONOTHERAPY (Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow, Russia)

• Hypotensive therapy of capoten without individual choice of time giving was effective in 57% of children with glomerulonephritis (n = 13).

• The uniformity of the drug’s action during the daytime and nighttime periods was achieved in 45% of children. The uniformity of drug’s action during the day was seen in <25% and a sufficient duration of antihypertensive action of the drug - in 33% of children.

Burgall А., 2002

Effectivenes of hypotensive therapy individualized on the base of ABPM in

children with glomerulonephritis (Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow, Russia)

010

2030

40

5060

70

8090

100

2 weeks 4 weeks 6 weeks 8 weeks

deteriorationno changesimprovement

Burgall А., 2002

2 weeks 4 weeksuniformity during the day and night0,44 0,65uniformity within a day0,22 0,48sufficient duration of action0,33 0,62

00,10,20,30,40,50,60,7

2 weeks 4 weeks

The value of ABPM in control of uniformity and duration of action of hypotensive therapy

uniformity during the day and night uniformity within a day sufficient duration of action

Burgall А., 2002

ConclusionPreventing initiation and progression of CKD:

• correction of common modifiable risk factors for the development and progression of renal and cardiovascular disease;

• primary and secondary prevention of CKD (factors increasing susceptibility to CKD, factors of initiation of CKD and factors of progression of CKD);

• nephroprotective and cardioprotective early therapy;

• SMBP control

Thank you for your attention!