1

CHRONIC KIDNEY DISEASE (CKD)

ETIOLOGY

PATHOPHYSIOLOGY

CLINIC

2

Background

• CKD is a worldwide public health problem

• There is a rising incidence and prevalence of kidney failure with poor outcomes and high costs

• Adverse outcomes of CKD can be prevented or delayed

• Earlier stages od CKD can be detected through lab testing

3

CKD is often under-diagnosed and under-treated resulting in

lost opportunities for prevention

4

CKD – former definition

• Irreversible, in most cases progresses slowly without visible symptoms until kidneys lose their ability of functioning

• Leads to changes in volume and quality of fluids in human body, also causes an impairment of other organs and systems

• It is diagnosed when persistently 3 months GFR value is < 90 ml/min

5

CKD – new definition

1. Kidney damage for > 3 months with or without decreased GFR, as manifest by either:

• Pathological abnormalities, or

• Markers of kidney damage (composition of the blood, urine, imaging tests)

2. GFR < 90 ml/min/1,73 m2 for > 3 months with or without kidney damage

6

CKD - etiology

•Primary glomerulonephritis 23,75 %•Diabetic nephropathy 19,8 %•Interstitial nephritis 15,4 % (bacterial and non-bacterial)•Hypertonic Nephropathy 10,2 %•ADPKD 8 %•Systemic disaese 2,64 %•Amyloidosis (secondary) 1,85 %•Urinary tract neoplasms 1,19 %•Myeloma mult. 0,59 %•Gout 0,56 %

7

Diabetes:The Most Common Cause of ESRD

Primary Diagnosis for Patients Who Start Dialysis

Diabetes50.1%

Hypertension27%

Glomerulonephritis

13%

Other

10%

United States Renal Data System. Annual data report. 2000.

No. of patientsProjection95% CI

1984 1988 1992 1996 2000 2004 20080

100

200

300

400

500

600

700

r2=99.8%243,524

281,355520,240

No

. o

f d

ialy

sis

pat

ien

ts

(th

ou

san

ds)

8

CKD czy ARF- how to differentiate?

• An interview- how long does it last?• Symptoms :

-nocturia, polyuria, polydypsia

-itching

-sexual problems / irregular periods

-bone pains, signs of secondary parathyroiditism• Tolerance of high urea and creatinine concentrations• Previously diagnosed renal impairment • Anaemia• Small kidneys in ultrasonography

9

CKD – laboratory evaluation

• Urea / creatinine serum concentration

• Assessment of glomerular filtration – GFR -clearance methods -C-G formula -MDRD formula

Cystatine C

10

CKD-evaluation

• creatininecreatinine

- derives from muscles (phosphocreatine)

- concentration dependent on body muscle mass i physical activity

- production varies in the daytime- lower at night

- excretion during glomerular filtration, it is not metabolized in kidney, 15% secretion in proximal tubule

- according to the loss of kidney functioning this secretion increases (if GFR 40-80 ml/min, it is > 50%); and excretion of creatinine in bowels enhances (> 6 mg%)

- tubular secretion is inhibited by Cimetidin, Trimetoprime, Amiloride

11

CKD - evaluation

• ureaurea

-end product in metabolism of aminoacids

-concentration dependent on glomerular filtration and reabsorption in proximal tubule (due to sodium and water resorption) = 40% in excesive diuresis i 70% in heart failure and dehydration

- dependent on protein intake, high catabolism, heamorrage from digestive tract, drugs, low sodium level, bilirubin level, liver failure

12

Stages of CKD

I stage – kidney damage with normal or high GFR GFR 90ml/min proteinuria

II stage - kidney damage with mild decrease of GFR GFR 89 i GFR > 60 ml/min

III stage – moderate decrease of GFR GFR 59 i GFR > 30 ml/min

IV stage – severe decrease of GFR GFR 29 i GFR 15 ml/min

V kidney failure GFR <15 ml/min dialysis

13

0,6

2,6

4,6

6,6

8,6

10,6

12,6

14,6

16,6

120 110 100 90 80 70 60 50 40 30 20 10 0

-100%

-0%

TIME – months? years?

GFR

Pcr

II s. mild

III s. moderate

IV s. severe

KF

I stage

14

Pathogenesis

Number of nephrons decreases – a rise in concetration of waste from protein

and purine metabolism, phosphate retention, acidosis, uremia toxins.

15

Pathogenesis

Glomerular injury and injury of tubules always coexist in advanced stages of disease giving a reduce in filtration and an impairment of reabsorption – we have a lot of metabolic disturbances (impairment of excretory and regualtory function of kidney).

16

Pathogenesis - CKD

Impaired endocrine function: erythropoietin 1,25- dihydroksy D3 prostaglandins natriuretic factor kinins

Impaired metabolic function: diminishion of gluconeogenesis prolonged T 0,5 for insulin

17

Hormonal disturbances

Secondary parathyreoiditism Hiperinsulinaemia Lack of erythropoietin Lack of active vitamin D3 Hiperprolactinaemia Excess of endorfines Enhanced secretion of somatothropine, calcitonine, gastrine, glukagon Hipogonadism Hiperleptynaemia

RAA system (renin-angiotensin-aldosterone) ADH, natriuretic factors (BNP, ANP)

18

0,6

2,6

4,6

6,6

8,6

10,6

12,6

14,6

16,6

120 110 100 90 80 70 60 50 40 30 20 10 0

-100%

-0%

Time- months? Years?

GFR

Pcr

kidney injury

Impaired urine concentration

Hypertension

Dyslipidaemia

mild CKD

19

II stage GFR 60 – 89 ml/min

Often subclinical (may remain asymptomatic)!

Prevalence of symptoms of primary kidney disease

20

Stage II GFR 60 – 89 ml/min

Impaired urine concentrationIsostenuriaPolyuria and nocturia

DehydrationFluid intake restriction, fever, vomitus,diarrhoea

Fluid accumulationhyponatremia

Heart failure

Decrease in glomerular filtration

21

Stage IIGFR 60 – 89 ml/min

Arterial hypertension

• possible in each kidney disease

• frequency of occuring HA increases with progressive loss of glomerular filtration – stage II - 30 – 50% patients, stage V - 90% patients

22

Stage IIGFR 60 – 89 ml/min

Factors contributing to hypertension in kidney diseases

• the type of renal disease• GFR value• sex• age• obesity• metabolic abnormalities of carbohydrates and lipids• excessive supplementation of sodium chloride

23

Stage II GFR 60 – 89 ml/min

Factors which take place in pathogenesis of HA in patientswith impaired renal function

• salt and water retention• inadequate activation of renin – angiotensin system• activation of symphatetic system• lack of vasodilatating factors• small activity of NO synthetase (ADMA)• circulating inhibitors of Na, K-ATPase • increase of calcium conc. in cells • increase of ET excretion• hyperleptinaemia

24

Arterial Hypertension

Renal impairment

Progression of kidney failure depends on:

• increase of HT (specifically systolic and pulse pressure)• lack of decrase of blood pressure at night (nondippers)

25

DYSLIPIDAEMIA

TG; CH(LDL) HDL

CKD, HDCH (LDL); TG

HDL

Prot., Per.D, KTx

26

0,6

2,6

4,6

6,6

8,6

10,6

12,6

14,6

16,6

120 110 100 90 80 70 60 50 40 30 20 10 0

-100%

-0%

Time-months? years?

GFR

Pcr

Renal impairment

Arterial hypertension

Dyslipidaemia

II stage mild III stage moderate

Anaemia

Abnormalities in Ca – Pi balance

Impaired urine concentration

Nutrition disturbances

27

III stageGFR 30 – 59 ml/min

Anaemia

• appears, when glomerular filtration comes to 25 – 30 ml/min• 85 – 87% patients with GFR< 25 ml/min have Hb < 12 – 13 g/dl, but 25% patients with GFR> 60ml/min have Hb< 12 – 13 g/dl• 85% patients starting dialysis treatment have Hb< 10g/dl

• normochromic, normocytic usually

28

III stageGFR 30 – 59 ml/min

Causes of anaemia • shorter time of erythrocytes life uremic toxins impaired resistance, deformities of cells hipersplenism• chronic losses of blood• impairment in erythropoiesis lack of erythropoietin production iron deficit advanced secondary parathyroiditism coexisting inflammation inefficient dose of dialysis• hemodilution

29

Patophysiological consequences of anaemia

• impaired transport and utilization of oxygen in tissues• heart hypertrophy• low exercise tolerance, weakness of muscles• deteriorating of CNS function• disturbances in immune system• hormonal disturbances

30

Stage IIIGFR 30 – 59 ml/min

Abnormalities in Ca-P metabolism

• occur when GFR falls below 50 ml/min• can cause changes in bone structure – renal osteodystrophy• manifest as secondary pararthyreoiditism PTH is one of very important uremic toxins !• are main factors of cardiovascular complications in kidney failure

31

Renal Osteodystrophy

• osteitis fibrosa• osteosklerosis• osteomalacia

2 forms of renal osteodystrophy with high bone turnover with low bone turnover

32

Stage IIIGFR 30 – 59 ml/min

Changes of nutrition

• when GFR is about 50 ml/min patient spontaneusly starts to reduce protein and callories intake• metabolism of proteins changes• malnutrition gradually develops loss of adipose tissue loss of muscle mass decrease in concentrations of protein, albumin, prealbumin, transferin

33

Protein-Calorie Malnutrition

• is an independent prognostic factor in patients with CKD • is one of the parts of MIA syndrome (Malnutrition, Inflammation, Atherosclerosis)

34

0,6

2,6

4,6

6,6

8,6

10,6

12,6

14,6

16,6

120 110 100 90 80 70 60 50 40 30 20 10 0

-100%

-0%

Time – months? years?

GFR

Pcr

Renal injury

Hypertension

Dyslipidaemia

s. II mild

S.III moderate

Anaemia

Disturbances of Ca – Pi balance

Impaired urine concentration

Changes in nutrition

S.IV severe

S.V

Metabolic acidosis

35

Stage IVGFR 15 – 29 ml/min

Metabolic acidosis

• is caused by low excretion of hydrogen ions• has varied impact on systems enhances proteolysis and reduces protein synthesis (leads to malnutrition) enhances resistance to insulin changes metabolism of bones – impaires function of osteoblasts, enhances function of osteoclasts, enhances release of PTH enhances production and release of 2-microglobulin enhances hypertrigliceridaemia

36

Stage IV GFR 15 – 29 ml/min

Signs – cardiovascular complications

•Left ventricle hypertrophy 85% chorych•Left ventricle systolic insufficiency 16% chorych•Left ventricle concetric hypertrophy 41% chorych•Left ventricle distension 28% chorych•normal echocardiography 16% chorych•IHD (young without DM) 24% chorych (aged with DM) 85% chorych •Arteriosclerosis obliterans in lower extremities (DM 1) 30% chorych (DM 2) 40% chorych

37

Stage IVGFR 15 – 29 ml/min

Symptoms and signs• severe anaemia• bad controlled HA• overhydration• lack of appetite, nausea, vomitus, malnutrition• weakness, drowsiness• hyperkaliemia, hypocalcemia, hyperphosphatemia

38

Kidney failure GFR < 15 ml/min

SYSTEMIC SYMPTOMS AND SIGNS OF UREMIA +SYSTEMIC COMPLICATIONS OF KIDNEY FAILURE

General symptoms• weakness, fatigue• insomnia• malnutrition, cachexia• changes in diuresis• dehydration, overhydration• itching

39

Kidney failure

GFR < 15 ml/min

Cardiovascular system• HA• heart failure• IHD• arrhythmias and heart blocks• pericarditis

Respiratory system• Kussmaul breathing• pleuritis• „uremic lung”

40

Kidney failure

GFR < 15 ml/min

Gastrointerstinal tract• nausea, vomitus• anorexia• abdominal pain• gastroenteritis (inflammation of mucosa)• haemorrage from digestive tract

Haematologic disorders • anaemia• thrombopathy• bleeding tendecy

41

Kidney failure

GFR < 15 ml/min

Nervous s.• headache• peripheral neuropathy

Psychical State• apathy• depression• deterioration of memory, thinking, association

Motoric s.• pain in bones and joints• pathologic fractures• weakness of muscles, muscles atrophy

42

Kidney failure

GFR < 15 ml/min

Genital s.• irregular menstruation• fertility• impotence• low libido

Skin• dryness• pallor• scratches, excoriations• ecchymoses• mousy colour