1. 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

2. 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

3. 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

4. THE PREVALENCE OF CKD IN THE WORLD

5. 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.

6. Importance of the problem
Renal factors of cardiovascular risk:
albuminuria / proteinuria
systemic inflammation
oxidative stress
anemia
hyperhomocysteinemia
Smirnov A. et al., 2005

7. FREQUENCY OF CARDIOVASCULAR DISEASE IN
CHRONIC KIDNEY DISEASE
(per 100 patients / year)
kidney
diseases
infarction
disturbance
of cerebral
blood flow
peripheral
vasculopathy
atheroscler
osis
cardiovascul
ar 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

8. FREQUENCY OF CARDIOVASCULAR DISEASE IN
PATIENTS IN RELATION TO GLOMERULAR
FILTRATION RATE
the estimated frequency
GFR – glomerular filtration rate
Matthew R., 2005

9. The structure of mortality (%) in patients with ESRD by age
(Russian Register of renal replacement therapy, 1998-2007)
CVD – cardiovascular disease

10. The main markers of kidney damage,
suggestive of the presence of CKD
marker
Albuminuria / proteinuria
notes
persistent increasing in urinary albumin
excretion greater than 10 mg/day (10 mg
albumin/g creatinine) –
see recommendation
hematuria, cylindruria, leykotsituriya (piura)
Persistent changes of the urinary
sediment
Changes of renal imaging studies anomalies of the kidney cysts,
hydronephrosis, resizing kidneys, etc.
Changes of of blood and urine
composition
Persistent decrease of GFR less
than 60 mL/min/1,73m2
Morphological changes of the
lifetime nephrobiopsy
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.)
in the absence of other markers of kidney
damage
should be taken into account the signs of
“chronization” (sclerotic changes of kidneys,
changes of membranes, etc.)

11. 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.

12. 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

13. 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

14. 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

15. 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

16. CKD-EPI formula (modification of 2011 year)
race
gender
Serum
creatinine
mg/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

17. 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

18. 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 chargeselectivity);
- 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

19. Stage of albuminuria/proteinuria
(Levey A.S. et al., 2010 )
urea albumine
(mg/creatinine, g)
Stage
Kidney function
А0
optimum
А1
increased
А2
high
А3
very high
<10
10-29
30-299
300-1999
А4
nephrotic
≥2000

20. The stage of CKD should be indicated in the
diagnosis after the nosologic form of renal disease
Examples 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.

21. Classification and characteristic of main risk factors of
CKD
type
definition
description
increase susceptibility of
factors increasing
susceptibility to CKD 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

22. Risk factors of CKD
nonmodifiable
modifiable
older 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

23. Factors of progression of CKD
nonmodifiable
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

24. 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

25. RISK FACTORS OF CARDIOVASCULAR DISEASE IN
PATIENTS WITH CKD
nonmodifiable:
• gender,
• age,
• race,
• genetic predisposition
common modifiable:
• blood hypertension
• metabolic factors
• endothelial dysfunction
nephrogenic modifiable:
• chronic inflammation
• anemia
• metabolic acidosis
• hyperparathyroidism
• hyperhomocysteinemia
atherosclerosis
heart disease

26. The incidence of arterial hypertension in patients with chronic
kidney disease
(Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow,
Russia)
%
100
90
80
70
60
BH by Korotkov method
BH by ABPM
50
40
30
20
10
0
SRNS
AS
Aspr
ADPKD
TMAP
(HUS)
RN
SRNS – steroid resistant nephrotic syndrome
AS – Alport syndrome
ТМАP (HUS) – thrombotic microangiopathy (hemolytic uremic syndrome)
AD PKD – autosomal-dominant polycystic kidney disease
RN – reflux nephropathy

27. PECULIARITIES OF RENAL ARTERIAL
HYPERTENSION
(Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow, Russia)
RN
RN
TM
AP
AD
(H
PK
U
S)
D
TMAP
(HUS)
ADPKD
AS
AS
SR
N
S
SRNS
0%
50%
nightly / daily BH
100%
daily BP
0%
50%
100%
diastolic / systolo-diastolic HP
systolic HP
SRNS – steroid resistant nephrotic syndrome
AS – Alport syndrome
ТМАP (HUS) – thrombotic microangiopathy (hemolytic uremic syndrome)
AD PKD – autosomal-dominant polycystic kidney disease
RN – reflux nephropathy

28. FREQUENCY OF COMPLICATIONS OF ARTERIAL HYPERTENSION
IN PATIENTS WITH PROGRESSIVE KIDNEY DISEASE
(Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow, Russia)
100
80
60
62,5
40
44,4
20
0
40,0
30,4
17,4
SRNS
angiopathy
33,3
28,6
23,1
4,5
11,8
AS
Aspr
ADPKD
TMAP (HUS)
RN
left ventricular hypertrophy
SRNS – steroid resistant nephrotic syndrome
AS – Alport syndrome
AD PKD – autosomal-dominant polycystic kidney disease
ТМАP (HUS) – thrombotic microangiopathy (hemolytic uremic syndrome)
RN – reflux nephropathy

29. 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

30. 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.

31. Secondary prevention of CKD
• slowing the progression of CKD (renoprotection)
• preventing the development of cardiovascular disease
(cardioprotection)

32. 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

33. Common approaches of primary and
secondary prevention of CKD
stage
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

34. Nephroprotective and cardioprotective therapy
•
•
•
•
ACE inhibitors
AT1-receptor blockers
calcium channel blockers
statins, etc.

35. Treatment of blood hypertension in patients with chronic
kidney disease
medicines with nephroprotective
effect
• inhibitors of angiotensinconverting enzyme
• blockers of ATII receptor type 1
• calcium channel blockers (nondihydropyridine)?
medicines without nephroprotective
effect
• beta-blockers
• diuretics
• calcium channel blockers
(dihydropyridine)

36. 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)

37. 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

38. The hypotensive effectiveness of RAAS inhibitors in
children with progressive kidney disease
(Nephrology department of Research Institute of Pediatrics & Children surgery,
Moscow, Russia)
100
80
75,0
60
71,4
66,7
63,6
58,3
40
20
0
37,5
SRNS
SA
SRNS – steroid resistant nephrotic syndrome
AS – Alport syndrome
AD PKD – autosomal-dominant polycystic kidney disease
Sapr
ADPKD
TMAP(HUS)
RN
ТМАP (HUS) – thrombotic microangiopathy (hemolytic uremic syndrome)
RN – reflux nephropathy

39. 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

40. 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)
12,5%
28,6%
7,1%
50%
50%
37,5%
14,3%
- decreased proteinuria
- proteinuria didn’t increase
- deceleration of the rate of increasing of proteinuria
- stable proteinuria
- increased proteinuria
Конькова Н..Е., 2011

41. 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%
22,2%
33,3%
without ACE-inhibitors
(n = 3)
100%
11,1%
- increasing of GFR
- stable GFR
- deceleration of the rate of reduction of GFR
- reduction of GFR
Конькова Н.Е, 2011

42. Frequency of blood hypertension in children with
SRNS receiving different immunosuppressive
therapy
(Nephrology department of Research Institute of Pediatrics & Children surgery, Moscow,
Russia)
Prograf+Pred
Prograf
Cyph+Pred
MMF+Pred
MMF
CsA+Pred
CsA
Pred maxD
Pred
0
20
40
60
80
100

43. 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)
100
90
80
70
60
50
40
30
20
10
0
1 medicine
2 medicines
hypotensive effect
3 medicines

44. Principles of antihypertensive therapy in kidney
diseases in children
BH
MONOTHERAPY
(ACE-inibitors, calcium channel blockers, BRA II)
CHRONOTHERAPY
COMBINATION THERAPY
ACE-inibitors + diuretics, ACE-inibitors + calcium channel blockers, ACEinibitors + beta-adrenoblockers, calcium channel blockers + diuretics, etc.

45. 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

46. 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

47. 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)
100
90
80
70
60
50
40
30
20
10
0
deterioration
no changes
improvement
2 weeks
4 weeks
6 weeks
8 weeks
Burgall А., 2002

48. Burgall А., 2002

49. Conclusion
Preventing 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

50. Thank you for your
attention!