Approach to Chronic kidney disease

1. D R . S E G E N E T B I Z U N E H
A S S I S T A N T P R O F E S S O R O F I N T E R N A L
M E D I C I N E
U N I V E R S I T Y O F G O N D A R
10/13/2021
1
Chronic kidney disease

2. Objectives
10/13/2021
2
Define chronic kidney disease (CKD)
Identify risk factors for progression and co-morbid
conditions
Discuss how early intervention improves outcomes
during CKD progression
Review measurements of kidney disease

3. Current definition of CKD
10/13/2021
3
CKD: is defined as the presence of kidney damage or
GFR < 60 mL/min/1.73 m2 for ≥ 3 months, irrespective
of cause. With implication of the health.
Kidney failure: is defined as either:
 (a) GFR < 15 mL/min/1.73 m2 usually with uremia. OR
 (b) A need to start kidney replacement therapy.
ESRD: Kidney failure is not synonymous with ESRD.
 The term ESRD does not include patients with kidney failure
who are not treated with dialysis and transplantation.

4. Cont…
10/13/2021
4

5. Diagnosis of CKD alone is not enough
10/13/2021
5
CKD care is directed by:
Specific therapy VS non-specific therapies.
If CKD is diagnosed, the cause should be sought,
and Classification should be done on the basis of
eGFR and albuminuria levels (CGA).
Cause of CKD
Levels of eGFR
Levels of albuminuria

6. Categorization of CKD based on CGA
10/13/2021
6

7. Classification of CKD Based on GFR and
Albuminuria Categories: “Heat Map”
10/13/2021
7
Kidney Disease: Improving Global Outcomes
(KDIGO) CKD Work Group. Kidney Int Suppls.
2013;3:1-150.

8. Audience Response :
10/13/2021
8
Cause eGFR
Category
Albumineuria
Category
Criterion for CKD
Diabetic kidney
disease
G5 A3
Idopatic focal
sclerosis
G2 A3
Kidney transplant
reciplant
G2 A1
Polycystic Kidny
disease
G2 A1
Vesicouretral
Reflex
G2 A1
Distal tubular
acidosis
G1 A1
Decreased GFR, Albominuria
Albominuria
History of Kidney T
Imaging abnormality
Imaging abnormality
Electrolyte abnormality

9. 10/13/2021
9
GFR
measurements
Endogenous
Creatinine
Cystatin-C
Estimated GFR
CG
MDRD
CKD-EPI
Exogenous
Inulin
Isothalamate
Iohexal
Measured GFR
Equation GFR < 60 GFR > 60 Prevalence
of CKD
Risk
prediction
MDRD Accurate Underestimate High Less accurate
CKD-EPI Accurate Accurate Low More
accurate

10. Inker LA et al. N Engl J Med 2012;367:20-29.
Performance of Three Equations for Estimating Glomerular Filtration
Rate (GFR).

11. The caveats of using serum creatinine to
“guess” level of renal function
24-yo
Black Man
63-yo
White Man
59-yo
White Woman
SCr 1.3 mg/dL 1.3 mg/dL 1.3 mg/dL
GFR as
estimated
by MDRD
Study
equation
≥60
mL/min/1.73 m2
45
mL/min/1.73 m2
59
mL/min/1.73 m2

12. Use These Equations Cautiously, if at
all in ….
10/13/2021
12
Patients who have/are:
 Poor nutrition/loss of muscle mass
 Amputation
 Chronic illness
 Not African American or Caucasian
 Changing serum creatinine
 Obese
 Very elderly, young

13. Epidemiology and Etiology of CKD
10/13/2021
13

14. Incident ESRD patients; rates adjusted for age & gender.
Incidence varies widely by
race and ethnicity
Rate
per
million
population
Af Am
N Am
Hispanic
Asian
White
Non-Hispanic
USRDS ADR, 2007

15. Cont…
10/13/2021
15
Some explanations of the variation are:
 Extrinsic to the population studied :
 Variation in diagnostic and CKD staging
 Creatinine assay standardization and
 GFR estimating equations, as well as the threshold for renal replacement
therapy (RRT)
 Intrinsic to the population studied :
 The age distribution
 The frequency of high-risk genetic alleles
 Such as those in polycystic kidney disease (PKD)
 Apolipoprotein 1 (APOL1)
 The burden of chronic conditions such as diabetes and hypertension

16. 10/13/2021
16
April 24, 2014

17. ESRD, end stage renal disease
USRDS ADR, 2007
Diabetes and hypertension are
leading causes of kidney failure
Incident ESRD rates, by primary diagnosis, adjusted for age, gender, & race.
10/13/2021
17

18. Pathophysiology of Progression
10/13/2021
18

19. CKD Screening and Evaluation
10/13/2021
19

20. Gaps in CKD Diagnosis
10/13/2021
20
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).
0
10
20
30
40
50
60
Not Appropriately Tested Appropriately tested - no diagnosis Appropriately tested - accurate diagnosis
CKD Screening in Primary Care
(% of patients)
% of Patients

21. Renal Risk Scores for developing
CKD
10/13/2021
21

22. Clinical Evaluation of Patients with
CKD
10/13/2021
22
Blood pressure
HbA1c
Serum creatinine
 Use a GFR estimating equation or clearance measurement; don’t rely
on serum creatinine concentration alone.
 Be attentive to changes in creatinine over time--even in “normal” range
Urinalysis
 Urine sediment
 Spot urine for protein/creatinine or albumin/creatinine ratio
Albuminuria/Proteinuria
Electrolytes, blood glucose, CBC

23. Cont..
10/13/2021
23
 Depending on stage: albumin, phosphate, calcium, PTH
 Renal imaging
 Depending on age and H & P
 Light chain assay, serum or urine protein electrophoresis
(SPEP, UPEP)
 HIV, HCV, HBV tests
 Complements, other serologies—limited role unless specific
reason

24. Assess for evidence of progression
10/13/2021
24
100
90
80
70
60
50
40
30
20
10
Years
Stage 2
Stage 3
Stage 4
Stage 5 (Dialysis)
GFR
0 1 2 3 4 5 6 7

25. Predictors for progression to ESRD
10/13/2021
25
 Incorporated into
clinical decision-
making
 Age
 HTN
 DM
 Male gender?
 Proteinuria
 Lower GFR
 Chicken and egg
 Marker of progression vs
marker of severity
 Hyperphosphatemia,
hyperurecimea,
dyslipidymiea and acidosis
 NT-Pro-BNP & Troponin
 Marker of oxidative stress,
inflammation & fibrosis
 ADMA, TGF-B & IL-6

26. Early treatment can make a difference
10/13/2021
26
100
10
0
No Treatment
Current Treatment
Early Treatment
4 7 9 11
Time (years)
Kidney Failure
GFR
(mL/min/1.73
2
)

27. Management of progression and complication
of CKD
10/13/2021
27
Prevention of CKD
progression
 BP and RAAS
interruption
 Glycemic control
 Hyperuricemia
 Salt intake
Complication
associated with CKD
 Anemia
 CKD-MBD
 Acidosis, Nutrition…

28. Slowing Progression of CKD
10/13/2021
28

29. Management of Hypertension CKD
10/13/2021
29
Blood pressure goal
Pharmacological treatment
Non-pharmacological treatment

30. Arterial Hypertension in Chronic Kidney Disease
10/13/2021
30

31. Prevalence of Hypertension in Renal Parenchymal
Disease
10/13/2021
31
Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4

32. Current Blood Pressure and CKD Progression
10/13/2021
32

33. Target BP: JNC 8
10/13/2021
33
CKD
SBP <140 mmHg DBP <90 mmHg
ACEI/ARB alone or in
combination with
other drug class

34. Target BP: ESH/ESC
10/13/2021
34
CKD
SBP <140 mmHg DBP <90 mmHg

35. 10/13/2021
35

36. Postural Hypotension
10/13/2021
36

37. Lifestyle Measures: KDIGO
10/13/2021
37
 Weight: maintain BMI 20-25 kg/m²
 Salt: < 2 g sodium (5 g salt) per day unless
contraindicated
 Exercise: At least 30 minutes 5 times per week
 Alcohol: Limit to maximum of 2 standard drinks
per day
 Smoking: No direct effect on long-term BP but
cessation reduces CV risk
 Protein 0.8 g/Kg/day, Avoid High protein
>1.3g/Kg/day

38. Pharmacological Treatment
Often Combination Therapy will be Required
10/13/2021
38

39. ACEIs and ARBs
10/13/2021
39
 Generalised arterial vasodilatation: Reduction of blood
pressure
 Vasodilatation particularly of the efferent glomerular
arteriole:
 Reduction of glomerular pressure
 Reduction of proteinuria
 Long-term renoprotection
 Reduction of adrenal aldosterone secretion:
But note aldosterone breakthrough

40. ACEIs and ARBs
10/13/2021
40
Indicated in all hypertensive patients with CKD,
especially in proteinuric diabetic and non-diabetic
CKD.
Will lead to deterioration of renal function in short
term but then to slower progression of renal failure
in longer term.

41. Short-term GFR Reduction vs Long-term
Protection
10/13/2021
41
Patients in whom GFR did not fall after start of treatment
Patients who initially showed a distinct fall in GFR Apperloo AJ et al. Kidney Int
1997

42. Stopping ACEI/ARB in Advanced CKD?
10/13/2021
42

43. Combination ACEI and ARB
10/13/2021
43

44. Side Effects
10/13/2021
44
 Hyperkalaemia
 Higher risk of hyperkalaemia in combination with potassium-
sparing diuretics.
 ACEI: mainly renal excretion (except fosinopril, trandolapril)
 ARB: mainly hepatic excretion, therefore reduce dose (stop?)
at GFR <15 mL/min
 Other treatment strategies in Hyperkalaemia:
 Dietary advice
 Furosemide
 Dose reduction of ACEI/ARB

45. Side Effects cont..
10/13/2021
45
AKI, especially in:
 Bilateral renal
stenosis
 Diabetes and
sepsis
 Combination with
NSAIDs
 State of volume
depletion
(diarrhoea/
vomiting)

46. Aldosterone Antagonists
10/13/2021
46

47. Aldosterone Antagonists
10/13/2021
47
It is premature to draw a definite conclusion as
to whether aldosterone antagonists— through
their anti-albuminuric, anti-hypertensive, or anti-
fibrotic effects —reduce the rate of decline in
kidney function in the long term.
This is an area for future research

48. Diuretics
10/13/2021
48
 Thiazide diuretics: e.g. Hydrochlorothiazide, Bendroflumethiazide
 Thiazide-like diuretics: e.g. Chlorthalidone, Indapamide
 Loop diuretics: e.g. Furosemide, Torasemide
 Widely used as patients with CKD are characterised by sodium and
water retention.
 For antihypertensive therapy:
 GFR >50 mL/min: Thiazides alone or in combination with distal
diuretics (e.g. spironolactone)
 GFR <30 mL/min: Loop diuretics. Avoid distal (potassium sparing).

49. Calcium Channel Blockers  Beta-Blockers
10/13/2021
 Antihypertensive action.
S/E Oedema and fluid retention
and proteinuria.
 Dihydropyridines
predominantly dilate the
afferent arteriole and thereby
increase GFR but also the
glomerular pressure.
 Non-DHPs seem not to have
this effect.
 Beta-blockers reduce
increased sympathetic
activity in CKD.
 Indication in heart failure.
 Often combined with
diuretics in RCTs but
no reason why not
combine with others.
 No robust evidence for
superiority of certain beta-
blockers.
49
Calcium and Beta blockers

50. Hyperglycemia
10/13/2021
50
Collins et al. Kidney Int. 2003;64(suppl 87):S24-S31.
+ DM,
- CKD
- DM,
+CKD
+ DM,
+ CKD
Medical Cohort
Patients
(%)
0
20
40
60
80
100
84.0
67.6 61.6
No Events
29.5
15.7
32.3
Death
ESRD, CKD Stage 5
0.3
2.9
6.1

51. Intensive Vs Conventional Glycemic controle
10/13/2021
51

52. Managing Hyperglycemia
10/13/2021
52
 Hyperglycemia is a fundamental cause of vascular
complications, including CKD.
 Poor glycemic control has been associated with albuminuria
in type 2 diabetes.
 Risk of hypoglycemia increases as kidney function
becomes impaired.
 Declining kidney function may necessitate changes to
diabetes medications and renally-cleared drugs.
 Target HbA1c ~7.0%
 Can be extended above 7.0% with comorbidities or limited
life expectancy, and risk of hypoglycemia.
NKF KDOQI. Diabetes and CKD: 2012 Update.
Am J Kidney Dis. 2012 60:850-856.

53. Lipid Disorders in CKD
10/13/2021
53
 In ESRD, LDL-C >130 mg/dL are present in 10–45% of non-nephrotic
patients.
 TG levels are >200 mg/dL in 40–50% of these individuals.
 Increased IDL-C and reduced HDL-C
 No consistent effect on LDL-C and total cholesterol.

54. 4D study AURORA
10/13/2021
 The first powered RCT to address
the issue: Do statins prevent CV
events in dialysis patients?
 1255 German patients with type 2
DM on hemodialysis.
 Compared atorvastatin 20mg
daily with placebo.
 Composite outcome of death
from cardiac causes,
nonfatal MI and stroke.
 RCT, double blind, 2776
patients aged 50-80 yrs on
hemodialysis
 Compared rosuvastatin
10mg daily with placebo
 Primary end point:
time to major CV
events (death from CV
causes, nonfatal MI or
nonfatal stroke)
 Secondary endpoints
included change in lipids
and CRP levels.
54
Statin study comments
Four year
later

55. SHARP: Rationale SHARP: Eligibility
10/13/2021
 Risk of vascular events is
high among patients with
chronic kidney disease.
 Lack of clear association between
cholesterol level and vascular
disease risk.
 Pattern of vascular disease is
atypical, with a large proportion
being non-atherosclerotic.
 Previous trials of LDL-
lowering therapy in chronic
kidney disease are
inconclusive.
 History of chronic kidney disease
 Not on dialysis: elevated creatinine
on 2 occasions.
 Men: ≥1.7 mg/dL (150 µmol/L)
 Women: ≥1.5 mg/dL (130 µmol/L)
 On dialysis: haemodialysis or
peritoneal dialysis.
 Age ≥40 years
 No history of myocardial infarction
or coronary revascularization
 Uncertainty: LDL-lowering
treatment not definitely indicated
or contraindicated.
55
Clearing the ambiguity

56. SHARP: Conclusions
10/13/2021
56
 A 32% reduction in LDL17% reduction in primary outcome
(nonfatal MI, coronary death, non hemorrhagic stroke, arterial
revascularization)
No reduction in CKD progression, overall or CAD mortality
 Similar proportional reductions in all subgroups (including among dialysis
and non-dialysis patients)
Baigent C, et al. Study of Heart and Renal
Protection (SHARP). Lancet. 2011;11:60739-

57. Management of Lipid Disorders in
CKD
10/13/2021
57
 Use statin alone or statin + ezetimibe in adults > 50 yrs with
GFR < 60ml or CKD 3-5(ND and NT).
 Use statin alone in adults > 50 yrs with GFR >=60 or CKD 1-2.
 In adults < 50 yrs use statin alone if history of known CAD,
MI, DM, stroke or 10yr CVD death >10%.
 Treat according to a “fire and forget” rather than “treat
to target” strategy.
 There is no direct evidence that routine follow-up of lipid levels
improves clinical outcomes.
NICE guideline: Increase the dose if non –HDL-C is < 40%
Statin dosage reduction is not necessary to reduce dosage by
> 50%.

58. Complications of CKD Start in Stage 3 and
Progress
10/13/2021
58
Kidney Failure
Malnutrition
Bone Disease
Brittle bones
And fractures
Anemia/blood loss
Decrease production
Of red blood cells
Fluid overload
Water overload Acid Base Imbalance
Acidic Blood
Electrolyte Abnormalities
Hypertension
Cardiac Disease
Vascular Disease

59. CARDIOVASCULAR ABNORMALITIES
10/13/2021
59

60. Traditional risk factors CKD related risk factors
10/13/2021
 HTN
 Dyslipdimea
 Volume overload
 Sympathetic overactivity
 Hyperhomocystemia
 Anemia
 Hyperphosphatemia
 Hyperparathyroidism
 Sleep apnea
 Inflammation
60
CARDIOVASCULAR ABNORMALITIES

61. Cardiovascular complication of CKD
10/13/2021
61
Acute coronary syndrome.
HF with low pressure pulmonary edema.
LVH(concentric) early in the course of CKD…S4 gallop.
Systolic dysfunction(eccentric hypertrophy)…S3 gallop.
AF
Sudden cardiac death (1 death per 1000 subject years)
Mx: Addressing both traditional and CKD related risk
factors.

62. Anemia in CKD
10/13/2021
62

63. Pathogenesis of renal anemia
10/13/2021
63
Reduced erythropoietin production.
Reduced red cell lifespan
 Shortened to 60–90 days
Uraemic inhibitors of erythropoiesis
 Spermine, Spermidine, putrescine, PTH
Blood loss-annual blood loss 1-4 l/yr
Iron and folate deficiency- negative iron balance.
Aluminium toxicity
 Dialysate and aluminium-containing phosphate binders.

64. 10/13/2021
64

65. Anemia workup in CKD
10/13/2021
65
Regardless of age and CKD stage:
CBC: which should include Hb concentration, red
cell indices, white blood cell count and differential,
and platelet count
Absolute reticulocyte count
Serum ferritin level
Serum transferrin saturation (TSAT)
Serum vitamin B12 and folate levels

66. Erythropoietins Adverse effect
10/13/2021
1. Recombinant human
erythropoietins (t1/2 6–8
h)
epoetin alfa and epoetin beta
2. Erythropoiesis-
stimulating agents(ESAs)
Darbepoetin alfa (t1/2 25h)
Micera ( t1/2 130h)
3. Erythropoietin-mimetic
peptide
 Peginesatide- for Tx of
PRCA due to anti-
erythropoietin antibodie
66
Management of Anemia in CKD

67. Unresponsiveness to Eop
10/13/2021
67

68. Detection of iron deficiency
10/13/2021
68

69. Iron supplementation
10/13/2021
69
3–4 g
200 mg
125 mg
Newer iron products
Ferric
carboxymaltose
Iron iso-maltoside

70. Target hemoglobin in CKD
10/13/2021
70
 Initiate iron therapy if TSAT ≤ 30% and ferritin ≤ 500
ng/mL (IV iron for dialysis, Oral for non-dialysis CKD)
 Individualize ESA therapy – Start ESA if Hb <10 g/dl, and
maintain Hb <11.5 g/dl. Ensure adequate Fe stores.
 Appropriate iron supplementation is needed for ESA to
be effective
 Important to avoid transfusion in transplant candidates
 If transfused use leukocyte filter to reduce HLA
sensitization
Guidelines Target Hg
UK-NICE 10-12 g/dl
KDIGO 10-11.5 g/dl
FDA More focused on avoiding
transfusion than Hg targat

71. DISORDERS OF CALCIUM AND
PHOSPHATE METABOLISM
 PTH
Bone Disease
Fractures
Bone pain
Marrow fibrosis
Erythropoietin resistance
 Serum P
1,25D
Calcitriol
Renal Failure
 PTH
Systemic Toxicity
CVD
Hypertension
Inflammation
Calcification
Immunological
25D
 Ca++
Decreased Vitamin D Receptors
and Ca-Sensing Receptors
© 2005 The Johns Hopkins University School of
Medicine.

72. High bone turnover Low bone turnover
10/13/2021
Osteitis fibrosa cystica
Secondary
hyperparathyroidism
Adynamic bone disease
Osteomalacia
Role of DEXA
 Are not able to discriminate
between the histological or
microarchitectural
abnormalities seen in CKD.
 Doesn’t predict fracture
risk in CKD 3-5.
72
Bone Manifestations of CKD

73. CKD-MBD Testing
10/13/2021
73
Use CKD progression, presence or absence of abnormalities,
treatment response and side effects to guide testing frequency.
CKD Stage
Calcium,
Phosphorus
PTH & ALP
25(OH)D
Stage 3
Every 6-12
months
Once then based
on CKD
progression
Once, then based
on level and
treatments
Stage 4 Every 3-6 months
Every 6-12
months
Stage 5 Every 1-3 months Every 3-6 months

74. Controle of
hyperphosphataemia
Correction of
hypocalcaemia
10/13/2021
Diet
P binders
 Aluminium hydroxide
 Ca carbonate, Ca acetate
 Sevelamer
 Also decrease LDL-C
 P removal with dialysis
 Vitamin D sterols
 Calcitriol – natural form
 Paricalcitol- Analogus
 Decrease other effect of vitamin
D sterols( hypercalcemia and
hyperphosphataemia)
 Calcimimetics
Cinacalcet
 Parathyroidectomy
74
CKD-MBD Treatment

75. Metabolic Acidosis
10/13/2021
75
 Often becomes apparent at GFR < 25-30 ml/min
• More severe with higher protein intake
 May contribute to bone disease, protein catabolism, and
progression of CKD
Maintain serum bicarbonate > 22
mmol/L
Correction of metabolic acidosis
may slow CKD progression and
improve patients functional status.
1) Mahajan, et al. Kidney Int. 2010;78:303-309.
2) de Brito-Ashurst I, et al. J Am Soc Nephrol.
2009;20:2075-2084.

76. Risk Factors Vaccination in CKD
10/13/2021
 Advanced age
 High burden of coexisting
illnesses (e.g., diabetes)
 Hypoalbuminuria
 Immunosuppressive therapy
 Nephrotic syndrome
 Uremia
 Anemia and malnutrition
 High prevalence of
functional disabilities
 Annual influenza
vaccine for all adults
with CKD, unless
contraindicated.
 Polyvalent
pneumococcal vaccine
and Hepatitis B
immunization when
eGFR < 30
ml/min/1.73m2 and at
high risk of pneumococcal
infection.
76
Infection in People with CKD

77. Referral to specialist
10/13/2021
77
1. AKI or abrupt fall in GFR
2. GFR < 30 ml ( G4-G5)
3. Albuminuria (A3)
4. Progression of CKD
5. RBC case/HPF sustained with no explanation
6. CKD and HTN refractory for >= 4 antihypertive
7. Persistent hyperkalemia
8. Recurrent or extensive nephrolithiasis
9. Hereditary Kidney disease

78. TIMING THE INITIATION OF RRT
10/13/2021
78
when one or more of the following are present:
uremic symptoms
 Serositis, acidbase or electrolyte abnormalities, pruritus
 Inability to control volume status or blood pressure
A progressive deterioration in nutritional status refractory
to dietary intervention or
Cognitive impairment
Living donor preemptive renal transplantation:
 Should be considered when the GFR is <20 ml/min/1.73
m2, and there is evidence of progressive and irreversible
CKD over the preceding 6-12 months.

79. 10/13/2021
79