8-1. progression of ckd to crf. vladimir dlin (eng)
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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!
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