chronic kidney disease part 2

1. Chronic Kidney Disease:
An Update
(Part II)
Yassin Ibrahim El-Shahat
Consultant: Nephrology & Hypertension
Chief Medical Officer
Burjeel Hospital, Abu Dhabi

2. Objectives
Upon completion of this talk the attendant will be able to:
 Understand the pathophysiology of Chronic Kidney Disease
 Recognize the signs and symptoms of Chronic Kidney Disease
 Identify the disease progression and treatment interventions

3. Plan
Management of CKD?

4. ESRD
&
death
Stages in Progression of Chronic Kidney
Disease and Therapeutic Strategies
Complications
Screening
for CKD
risk factors
CKD risk
reduction;
Screening for
CKD
Diagnosis
& treatment;
Treat
comorbid
conditions;
Slow
progression
Estimate
progression;
Treat
complications;
Prepare for
replacement
Replacement
by dialysis
& transplant
Normal
Increased
risk
CKDDamage  GFR

5. Natural History of CKD
 Most CKD has a
logarithmic progression
and is predictable

6. Early treatment can make a difference
100
10
0
No Treatment
Current Treatment
Early Treatment
4 7 9 11
Time (years)
Kidney Failure
GFR(mL/min/1.732)

7. CKD is prevalent in CVD
Ix, et al., 2003; Anavekar, et al., 2004; Shlipak, et al., 2004.
0
20
40
60
CAD
GFR ≤60 mL/min
AMI
GFR ≤60 mL/min
CHF
GFR ≤60 mL/min
23%
46%
33%
PatientsWithCKD(%)

8. In addition to ESRD, CKD leads to CVD
Go, et al., 2015
1.0
2.8
3.4
2.0
1.4
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
≥ 60 45-59 30-44 15-29 < 15
AdjustedHazardRatio
eGFR
Adjusted* hazard ratio for CVD events
 Leading cause of
morbidity and mortality in
patients with CKD at all
stages
 Ischemic CAD
 Hypertension and LVH
 Congestive heart failure
 Uremic pericarditis

9. How should clinicians treat
cardiovascular risk factors?

10. Complications of CKD

11.  Intensive glycemic control lessens progression from
microalbuminuria in Type 1 diabetes–goal in Type 2 is less
clear
- DCCT, 1993
- ACCORD, 2008
 Antihypertensive therapy with ACE Inhibitors or ARBs
lessens proteinuria and progression
- Giatras, et al., 1997
- Psait, et al., 2000
- Jafar, et al., 2001
 Blood pressure below 130/80 is beneficial
- Sarnak, et al., 2005
We can have an impact on progression
of CKD

12. Treatments to slow the progression
of CKD

13. Therapeutics in CKD
 Non Pharmacologic
 Risk Factor Modification
 Pharmacologic
 Treatment of complications

14. “Traditional” Risk Factors for CKD
and Associated Interventions

15. What non-drug therapies should
clinicians recommend?
 Quit smoking, and exercise 30 min/d on most days
 Limit alcohol intake
 Maintain BMI within normal range
 Eat a diet high in fruits, vegetables, and whole grains
 DASH diet recommended if GFR >60 mL/min per 1.73 m2
and high normal blood pressure or stage 1 hypertension
 If hypertension present: restrict salt intake <2.0 g/d
 Most patients with CKD should avoid high-protein diets
 Stage 4 or 5: consider low-protein diet (0.6 g/kg/d)

16. Therapeutics in CKD
 Non Pharmacologic
 Risk Factor Modification
 Pharmacologic
 Treatment of complications

17. Parameter Target Agent used
BP 130/80 mmHg or
125/75 in DM and those with
proteinuria.
Start with ACEI or ARBs if proteinuria or DM
microalbuminuria - caution in the elderly and those with
atherosclerosis. Monitor eGFR within 1-2 weeks of initiation,
review if eGFR decreases by ≥15%, stop at ≥25%.
Proteinuria Lowest achievable ACEI/ ARBs
S. Cholesterol Refer to national guidelines
Lifestyle Standard CV risk reduction measures, including salt restriction
Avoid NSAIDs, COX2s and radiocontrast agents
Anaemia Hb 10.5-12.5 g/dl Replace deficiencies
Erythropoietin in CKD stage 4-5
Renal osteodystrophy
(Stages 4 & 5 only)
Ca: 2.2-2.35 mmol/l
PO4 <1.7 mmol/l
Calcium carbonate / Alfacalcidol
Phosphate binders
Acidosis Venous Bicarbonate > 22
mmol/l
Sodium bicarbonate
Undernutrition Adequate calorie & normal protein intake
Infections Chest infections
Hepatitis B
Immunize: influenza & pneumococcus
vaccination (CKD stages 4-5)
CKD management guidelines

18. Pharmacology in CRF
Pharmacokinetics –
drug absorption, distribution,
metabolism & excretion
Pharmacodynamics –
A drug’s mechanism of action
and effect at the target site

19. Alterations in Drug Responses in CRF
 Gastrointestinal impairments affect absorption of
medications
 Volume of distribution (Vd) – the availability of a drug
distributed in body tissues is increased or decreased by
alterations in body composition or protein binding
 Metabolism of medications altered - the kidneys produce
many enzymes involved in drug metabolism including
cytochrome P-450
 Decreased glomerular filtration rate affects drug excretion
Campoy, S, Elwell, R.(2005). Pharmacology & CKD. AJN, 105(9),60-72.

20. Medication Considerations in CKD
 Dilantin – increased Vd related to protein binding
changes and low albumin, increasing risk of drug toxicity
 Digoxin – increased Vd leading to toxicity due to
decreased renal excretion
 Insulin – metabolism of insulin decreases, requiring
dose reduction
 Tylenol and procainamide – liver metabolized drugs
with metabolites that are excreted renally, can
accumulate leading to drug toxicity
Campoy, S, Elwell, R.(2005). Pharmacology &
CKD. AJN, 105(9),60-72.

21. Medication Considerations in CKD (Cont.)
Impaired renal excretion leads to toxic drug
accumulations with:
Diamox
Aminoglycoside antibiotics -
(tobramycin & gentamycin)
Atenolol
Captopril
Lithium
Vancomycin
Metformin
Neurontin
Topamax

22. What is the role of Blood Pressure control
in patients with diabetes and CKD?
 Identify and treat factors associated with
progression of CKD
 HTN
 Proteinuria
 Glucose control

23. Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4
Hypertension in Chronic Kidney Disease

24. Management of Hypertension in CKD
• Investigations into the nature of the patient’s renal disease
• Blood pressure goal
• Non-pharmacological treatment
• Pharmacological treatment

25. What is the role of blood pressure
management?
 To reduce CVD risk, treat to <140/90 mm Hg
 If proteinuria is significant or urine albumin-to-creatinine ratio
>30mg/g: treat to <130/80 mm Hg
 Use ACE inhibitors and ARBs (improve kidney outcomes)
 Combination therapy often needed
 Diuretics reduce extracellular fluid volume, lower BP, and reduce
risk for CVD
 Diuretics also potentiate effects of antihypertensives
 Thiazide-type diuretic if GFR ≥30 mL/min per 1.73 m2
 Loop diuretic if GFR <30 mL/min per 1.73 m2

26. Clinical Practice Guidelines for
Management of Hypertension in CKD
Type of Kidney Disease Blood
Pressure
Target
(mm Hg)
Preferred Agents
for CKD, with or
without
Hypertension
Other Agents
to Reduce CVD Risk
and Reach Blood
Pressure Target
Diabetic Kidney Disease
<130/80
ACE inhibitor
or ARB
Diuretic preferred, then
BB or CCB
Nondiabetic Kidney
Disease with Urine Total
Protein-to-Creatinine
Ratio 200 mg/g
Nondiabetic Kidney
Disease with Spot Urine
Total Protein-to-Creatinine
ratio <200 mg/g None preferred
Diuretic preferred, then
ACE inhibitor, ARB, BB
or CCB
Kidney Disease in Kidney
Transplant Recipient
CCB, diuretic, BB, ACE
inhibitor, ARB

27. Blood Pressure Goals in CKD
Nicholas SB et al. Curr Opin Cardiol 2013
1
2

28. KDIGO Blood Pressure Work Group. Kidney Int Suppl 2012
KDIGO Guidelines
• Non-diabetic adults with CKD:
≤140 mmHg systolic and ≤90 mmHg diastolic if normoalbuminuric
≤130 mmHg systolic and ≤80 mmHg diastolic if micro or macroalbuminuric
• Diabetic adults with non dialysis-dependent CKD:
≤140 mmHg systolic and ≤90 mmHg diastolic if normoalbuminuric
≤130 mmHg systolic and ≤80 mmHg diastolic if micro or macroalbuminuric
• Kidney transplant recipients:
≤130 mmHg systolic and ≤80 mmHg diastolic
• Elderly people with CKD:
probably ≤140 mmHg systolic and ≤90 mmHg diastolic, but set targets after
consideration of co-morbidities

29. Summary
Management of Hypertension in CKD
ESH/ESC 2013
Guidelines
AHA/ACC/CDC
Scientific Advisory
JNC 8 ASH/ISH
Statement
In general <140/90 <140/90 ≥ 60 years:
<150/90
< 60 years:
< 140/90
>140/90
Exception
or
special
comment
Elderly > 80 years
< 150/90
Elderly < 80 years
< 150/90
Fit elderly
< 140/90
Diabetes
< 140/85
CKD+Proteinuria
< 130/90
„lower“ targets for
• elderly
• LVH
• systolic or diastolic
LV dysfunction
• diabetes
• kidney disease Diabetes
< 140/90
CKD
< 140/90
< 80 years
< 150/90
CKD +
Proteinuria
< 130/80

30. Pharmacological Treatment
Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4

31. KDIGO Blood Pressure Work Group. Kidney Int Suppl 2012
• 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
ACEIs and ARBs
• 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.

32. IDNT and RENAAL Studies
Brenner BM et al. NEJM 2001Lewis EJ et al. NEJM 2001
Time to primary composite end point (doubling of
serum creatinine, end-stage renal disease, or death)

33. Non-diabetic CKD: GISEN
The Gisen Group. Lancet 1997

34. When should clinicians prescribe
ACE inhibitors versus ARBs?
 Prescribe either for reducing progression of diabetic
nephropathy
 Prescribe either in hypertension or in diabetes when urine
albumin excretion >30mg / 24h
 Prescribe either in non-diabetic proteinuria
 Do not combine an ACE inhibitor with an ARB in CKD stage
IV and CKD stage V
 Monitor patients closely for side effects and adjust dose as
needed
 Safe to continue medication if GFR declines < 30% over 4
months and serum potassium <5.5 mEq/L

35. ACEIs and ARBs: Side Effects
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

36. ACEIs and ARBs: Side Effects
Schoolwert AC et al. Circulation 2001
AKI, especially in:
• Bilateral renal stenosis
• Diabetes and sepsis
• Combination with
NSAIDs
• State of volume
depletion (diarrhoea/
vomiting)

37. Diuretics
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) diuretics.

38. Calcium Channel Blockers
• Antihypertensive action
• Oedema and fluid retention
• Dihydropyridines predominantly dilate the afferent arteriole
and thereby increase GFR but also the glomerular
pressure
• Non-DHPs seem not to have this effect.

39. Calcium Channel Blockers
KDIGO Blood Pressure Work Group. Kidney Int Suppl 2012

40. Beta-Blockers
• Beta-blockers reduce increased sympathetic activity in CKD
• Indication in heart failure (but not in acute LVF)
• Often combined with diuretics in RCTs but no reason why
not combine with others
• No robust evidence for superiority of certain beta-blockers

41. Alpha-Blockers
• Alpha-blockers have additional antiproliferative
properties
• Hepatic excretion
• Beneficial in prostate hypertrophy

42. Often Combination Therapy will be Required
2013 ESH/ESC Guidelines. J Hypertens 2013

43. What is the role of glycemic control in
patients with diabetes and CKD?
 Identify and treat factors associated with
progression of CKD
 HTN
 Proteinuria
 Glucose control

44. What is the role of glycemic control in
patients with diabetes and CKD?
 Good glycemic control reduces:
 Progression of CKD
 Incidence proteinuria
 Maybe end-stage renal disease
 However, CKD increases risk for hypoglycemia
 Current CKD guidelines recommend a goal A1c level ~7%
 Avoid using Metformin if GFR <30 mL/min per 1.73 m2

45. Lancet 1998; 352: 837-53
UKPDS
 3867 patients with type 2 DM (median age 54 yrs) over
ten years
 Intensive tx with sulfonylureas and insulin (HbA1c 7.0%)
vs conventional tx (7.9%)
 25% RR in microvascular complications (95% CI 7-40;
p=0.0099)

46. Therapeutics in CKD
 Non Pharmacologic
 Risk Factor Modification
 Pharmacologic
 Treatment of complications

47. Pathophysiology of CKD

48. Metabolic changes with CKD
 Hemoglobin/hematocrit 
 Bicarbonate 
 Calcium
 Phosphate 
 PTH 
 Triglycerides 
 Monitor and treat
biochemical abnormalities
 Anemia
 Metabolic acidosis
 Mineral metabolism
 Dyslipidemia
 Nutrition

49. Acid Base Imbalance
 Damaged kidneys are unable to excrete the 1 mEq/kg/day of
acid generated by metabolism of dietary proteins.
 NH3 production is limited because of loss of nephron mass
 Decreased filtration of titrable acids – sulfates, phosphates
 Decreased proximal tubular bicarb reabsorption, decreased
positive H ion secretion
 Arterial pH: 7.33 - 7.37; serum HCO3 rarely below 15 –
buffering offered by bone calcium carbonate and phosphate
 Should be maintained over 22
 Treatment: Sodium bicarbonate, calcium carbonate, sodium
citrate

50.  Metabolic acidosis
 Seldom significant until GFR <30 mL/min per 1.73 m2
 Contributes to CKD progression, insulin resistance,
decreased cardiorespiratory fitness, altered bone
metabolism
 Use alkali therapy with serum bicarbonate <22 mmol/L to
maintain serum bicarbonate levels within normal range
How should clinicians manage metabolic
complications?

51. Metabolic acidosis
 Muscle catabolism
 Metabolic bone disease
 Sodium bicarbonate
 Maintain serum bicarbonate > 22 meq/L
 0.5-1.0 meq/kg per day
 Watch for sodium loading
 Volume expansion
 HTN

52. Hematological Abnormalities
 Anemia
 Chronic blood loss, hemolysis, marrow suppression by uremic
factors, and reduced renal production of EPO
 Normocytic, normochromic
 Rx: Iron and Epo as needed
 Coagulopathy
 Mainly platelet dysfunction – decreased activity of platelet factor
III, abnormal platelet aggregation and adhesiveness and
impaired thrombin consumption
 Increased propensity to bleed – post surgical, GI Tract,
pericardial sac, intracranial
 Increased thrombotic tendency – nephrotic syndrome

53. Major Minor
Inflammation/infection Hyperparathyroidism
Iron deficiency Aluminium toxicity
Inadequate dialysis B12/folate deficiency
Haemolysis
Bone marrow disorders
Haemoglobinopathies
Anti-EPO antibodies = PRCA
(pure red cell aplasia)
Non-adherence
Causes of ESA Hyporesponsiveness
(Macdougall, 2003)

54. Mechanisms in anemia leading to myocardial damage in chronic kidney
disease: Combination of factors secondary to diminished glomerular
filtration rate (GFR) and low hemoglobin. Consequences of anemia include
the hemodynamic compensatory mechanisms th...
Madhumathi Rao, Brian J.G. Pereira, Kidney International, Volume 68, Issue 4, 2005, 1432–1438
Optimal anemia management reduces CV
morbidity, mortality, and costs in CKD

55. Conclusions:
Treatment of Anemia in CKD
 Target Hgb
 < 12 g/dL
 RCTs in both D-CKD and ND-CKD
 CHOIR Post-hoc analysis: Hgb level and Epo dose
 Getting to Target
 Problem of Hgb cycling
 Causes of Hgb cycling multifactorial
 Difficult to achieve Hgb in narrow range: broader range or no range
 Hyporesponsive patient
 30-40% of D-CKD
 DRIVE 1 and 2 support greater role for iron therapy
 Using iron is cost-effective

56. Causes of Anaemia in CKD
• EPO deficiency
• Chronic blood loss (via GI tract/haemodialyser)
• Iron deficiency
• Vitamin B12 or folate deficiency
• Hypothyroidism
• Chronic infection or inflammation
• Hyperparathyroidism
• Chronic blood loss
• Aluminium toxicity
• Malignancy
• Haemolysis
• Bone marrow infiltration
• Pure red cell aplasia

57. Clinical Effects of Anaemia
Symptoms
Fatigue
Decreased exercise capacity
Exertional dyspnoea
Anorexia
Cognitive impairment
Diminished quality of life
Poor memory
Reduced libido
Pallor
Poor sleep pattern
Reduced immune function
Reduced platelet function
Cardiovascular Effects
Increased cardiac output/stroke volume
Tachycardia
Decreased vascular resistance
Worsening of pre-existing anginal
symptoms/myocardial ischaemia
Left ventricular hypertrophy
Impairment in nitric oxide synthesis
Limited oxygen reserve
Abnormal angiogenesis

58. How should clinicians manage patients
with anemia?
 Measure hemoglobin and hematocrit, RBC indices,
reticulocyte count, serum iron, percent transferrin
saturation, vitamin B12 and folate levels, serum ferritin
 Identify potential sources of bleeding
 Treat with erythropoietin when hemoglobin drops below 9-
10 g/dL
 Prescribe oral / IV iron as needed to maintain iron stores
 Maintain hemoglobin levels <11.5 g/dL
 Use caution with active malignancy or history of stroke

59. Bone Disease

60. NEJM 2000; 342(20): 1478-83
Mineral metabolism
 Calcium and phosphate metabolism abnormalities
associated with:
 Renal osteodystrophy
 Calciphylaxis and vascular calcification
 14 of 16 ESRD/HD pts (20-30 yrs) had calcification on CT
scan
 3 of 60 in the control group

61. Mineral metabolism

62. Mineral metabolism

63. Mineral metabolism

64. Mineral metabolism

65. Mineral metabolism

66. Mineral metabolism

67. Mineral metabolism

68. Mineral metabolism

69. Mineral metabolism

70. Mineral metabolism

71. Anemia

72. Mineral metabolism

73. Mineral metabolism

74. Anemia

75. Mineral metabolism

76. Mineral metabolism

77. Mineral metabolism

78. Anemia

79. Mineral metabolism

80. Mineral metabolism

81. Mineral metabolism

82. Mineral metabolism

83. Therapeutic targets for phosphate
binders and calcitriol

84. Calcium or Aluminium Containing Non-Calcium, Non-Aluminium Containing
Aluminium Hydroxide Lanthanum Carbonate
Calcium Acetate Magnesium Carbonate
Calcium Carbonate Sevelamar Hydrochloride and Carbonate
Summary of Phosphate Binders

85. Parathyroid sestamibi scan (with
technetium Tc 99m-MIBI) demonstrating
uptake in all 4 glands consistent with 4-
gland hyperplasia
Secondary Parathyroid Adenoma

86. Top Tip: Utilise dietary phosphate restriction, a
phosphate binder and calcitriol in all ESRD patients.
• Secondary hyperparathyroidism occurs as a result of hyperphosphataemia, hypocalcaemia
and impaired synthesis of renal vitamin D with reduction in serum calcitriol levels
• Patients with secondary hyperparathyroidism have a range of symptoms
• The aim of treatment is is to reduce: (1) the occurrence and/or severity of uraemic bone
disease; and, (2) cardiovascular morbidity and mortality caused by elevated serum levels of
PTH and 'calcium x phosphate' product
• Treatment includes control of phosphate retention, maintaining serum calcium
concentration within the normal range and prevention of excess PTH secretion
• The UK Renal Association recommends measuring serum calcium, phosphate and PTH
levels when GFR is < 60ml/min/1.73m 2 (CKD stage 3 and above). Italso recommends, in
dialysis patients:
• Serum calcium, should be maintained within the normal range and be between 2.2 and 2.5
mmol/L, with avoidance of hypercalcaemic episodes
• Serum phosphate should be maintained between 1.1 and 1.7 mmol/L
• The target range for parathyroid hormone (measured using an intact PTH assay) should be
2-9 times the upper limit of normal for the assay used
Tailor dosing to guideline targets

87. JAMA 1993; 269(23): 3015-23
Dyslipidemia
 Abnormalities in the lipid profile
 Triglycerides
 Total cholesterol
 NCEP recommends reducing lipid levels in high-risk
populations
 Targets for lipid-lowering therapy considered the same as
those for the secondary prevention of CV disease

88. Nutrition
 Think about uremia
 Catabolic state
 Anorexia
 Decreased protein intake
 Consider assistance with a renal dietician

97. Key Clinical Trials
Normal Hematocrit Study (Besarab, 1998)
• Open-label trial of 1233 HD patients with heart failure/IHD
• Epoetin given either to maintain a normal (42 ±3 %) or low (30 ±3 %) haematocrit
• Primary endpoint – MI/death
• Study was stopped after 29 months due to the higher (albeit non-statistically significant) death rate in the
normal haematocrit group – 183 vs 150 deaths
Note: this study raised concerns regarding the risks of trying to attain a higher level of haemoglobin
CHOIR (Singh, 2006)
• Open-label trial of 1432 CKD patients randomised to either a low-Hb (11.3 g/dl) or high-Hb arm (13.5 g/dl)
• Primary endpoints included death and CV events (and CVA)
• 125 events occurred among the high-Hb group and 97 events among the low-Hb group (HR 1.34; P = 0.03)
• No quality-of-life difference between the two groups
CREATE (Drueke, 2006)
• Multicentre trial of 603 CKD patients randomised to high-Hb (13.0-15.0 g/dl) or low-Hb (10.5-11.5 g/dl)
• No difference between groups in terms of primary endpoints (CV/death)
• Study ended up being underpowered
TREAT (Pfeffer, 2009)
• Multicentre, double-blind, placebo-controlled RCT
• Darbepoetin (Aranesp) (aiming for Hb 13 g/dl) vs placebo* (Hb of 9 g/dl) in 4038 predialysis CKD patients with
type 2 diabetes and anaemia
• No difference in primary CV endpoint/death
• Improved symptoms in treatment arm
• Two-fold increased risk of CVA in treatment arm

98. Treatment
Increase the Adequacy of Dialysis
Increasing the dialysis prescription has been shown to augment the response to ESA therapy.
Iron Management
The causes and diagnosis of iron deficiency in CKD are listed above. If a patient is considered
deficient in iron, then there are a number of iron preparations (both oral and intravenous) that are
available.
Erythropoiesis-Stimulating Agents (ESAs)
EPO is a large glycoprotein (30.4 KDa) that is injected intravenously (HD patients), or
subcutaneously. Current UK guidance recommends starting therapy when the Hb falls below 11
g/dl, but of late there has been a tendency for lower Hb’s to be accepted before intervening with
ESA therapy following data from the TREAT trial (see Key Clinical Trials). ESA therapy is
effective in correcting anaemia in the vast majority of patients, with 5-10% of patients deemed
ESA hyporesponsive.
Correction of Haematinic Deficiency
Folate (and less commonly vitamin B12) is a low molecular weight substance that may be lost
during haemodialysis (especially high-flux. Serum folate is not as accurate as red cell folate level,
as a marker of folate deficiency, but is the most commonly used initial screening test.

99. Top Tips: Consider an ESA in any CKD patient
with Hb <11 g/dL. Keep Ferritin >200 ng/L
• There is no worldwide consensus concerning target ranges for haemoglobin
and iron/ferritin levels. The new KDIGO renal anaemia guidelines are expected
in mid-late 2012
• Functional iron deficiency occurs when stored iron is sufficient but circulating
iron is deficient. It may be detected when serum ferritin levels are decreased
and TSAT levels are <20%, but this is not a hard and fast rule
• TSAT (transferrin saturation) is calculated by the following formula: Serum Fe ÷
TIBC x 100%
• Blood transfusions distort patients’ red cell indices, and it can take 3-4 months
for the normal steady state to be resumed
• Treatment includes Erythropoiesis-Stimulating Agents (ESAs), correcting iron
deficiency, treating infection/inflammation and increasing dialysis dose
• Major causes of ESA hyporesponsiveness are iron deficiency,
inflammation/infection and inadequate dialysis

100. Specific targets and potential therapeutic strategies
to inhibit or slow the progression of CKD

101. Antifibrotic strategies for treating CKD
Agent Setting Primary outcome and/or results
Preclinical studies
Anti-TGF-β antibody Leprdb/db diabetic mice3, 4
Reduction in plasma TGF-β1 levels,
prevention of increases in plasma
creatinine levels and glomerular
mesangial matrix expansion,
associated with decreased renal
mRNAs encoding collagen IV and
fibronectin
Anti-TGF-β antibody
Rats with chronic allograft rejection
nephropathy5
Reduction of proteinuria, attenuation
of mononuclear cell infiltration and
interstitial fibrosis along with
downregulation of mRNA levels of
TGF-β1, TGF-β2, and
proinflammatory cytokines, or with
upregulation of mRNA levels of HGF,
BMP-5, and BMP-7
Anti-TGF-β antibody Mice with STZ-induced diabetes12
Prevention of glomerular
hypertrophy, attenuated gain in
kidney weight, and attenuation of
increased mRNA levels of TGF-β1,
type II TGF-β receptor, collagen IV,
and fibronectin
Reduction of TGF-β isoform mRNA

102. Non-antifibrotic strategies
for treating CKD
Agent Setting Primary outcome and/or results
Vascular calcification
Klotho overexpression Mice with CKD62
Enhanced phosphaturia, improved
renal function, and decreased
calcification
Exogenous Klotho
Mice with UUO67 and mice with
adriamycin-induced CKD67
Inhibition of renal β-catenin
activation, suppression of
myofibroblast activation, reduction in
extracellular matrix protein
expression, and amelioration of renal
fibrosis
Oxidative stress and NADPH oxidases
NOX-2 deficiency
Mice with STZ-induced diabetic
nephropathy74
No beneficial effect on renal
function, and marked increase in
NOX-4 at the protein level in the
kidney
GKT136901* Leprdb/db diabetic mice80,81 Reduction in albuminuria and
oxidative stress
GKT137831* Diabetic Apoe−/− mice83
Reduction in ROS production,
inflammation, vascular
complications, and profibrotic

103. C

104. Treating Anemia
 Epoetin alfa (rHuEPO; Epogen/Procrit)
 HD: 50-100 U/kg IV/SC 3x/wk
 Non-HD: 10,000 U qwk
 Darbepoetin alfa (Aranesp)
 HD: 0.45 g/kg IV/SC qwk
 Non-HD: 60 g SC q2wks

105. Other Abnormalities
 Neuromuscular
 Central, peripheral and autonomic neuropathy
 Peripheral Sensory/Motor Neuropathy
 Stage 4 for more than 6 months
 Restless leg syndrome
 Gastrointestinal
 Uremic fetor
 Gastritis, peptic disease, mucosal ulcerations, AVMs
 Endocrine
 Glucose metabolism
 Estrogen levels – amenorrhea, frequent abortions
 Male: oligospermia, germinal cell dysplasia, delayed sexual
maturation
 Dermatologic
 Pallor, ecchymoses, hematomas, calciphylaxis, pruritus, uremic frost

106. Additional Clinical Interventions
for Adults with GFR <60 ml/min

107. How should clinicians manage metabolic
complications?
 Vitamin D and phosphorous metabolism
 Derangements occur if GFR <30-40 mL/min per 1.73 m2
 Use dietary phosphorous restriction, phosphate binders, and vitamin
D supplementation
 Hyperkalemia
 Dangerous elevations occur mostly only in stages 4 / 5
 Use dietary potassium restriction, and if necessary, sodium
polystyrene sulfonate
 Hyperkalemia >6mEq/L or hyperkalemic EKG change requires
emergency treatment with IV calcium gluconate, glucose, insulin,
bicarbonate (if acidosis present), and sodium polystyrene sulfonate
 If these measure fail, hemodialysis may be needed

108. How should clinicians treat
cardiovascular risk factors?
CKD
=
CVD

109. Anemia

110. Anemia

111. C
Syndromes
Acute cardio-
renal (type 1)
Chronic cardio-
renal (type 2)
Acute reno-
cardiac (type 3)
Chronic reno-
cardiac (type 4)
Secondary CRS
(type 5)
Organ failure
sequence
Definition
Acute worsening
of heart function
(AHF–ACS)
leading to kidney
injury and/or
dysfunction
Chronic
abnormalities in
heart function
(CHF-CHD)
leading to kidney
injury or
dysfunction
Acute worsening
of kidney function
(AKI) leading to
heart injury
and/or
dysfunction
Chronic kidney
disease (CKD)
leading to heart
injury, disease
and/or
dysfunction
Systemic
conditions leading
to simultaneous
injury and/or
dysfunction of
heart and kidney
Primary events
Acute heart failure
(AHF) or acute
coronary
syndrome (ACS)
or cardiogenic
shock
Chronic heart
disease (LV
remodelling and
dysfunction,
diastolic
dysfunction,
chronic
abnormalities in
cardiac function,
cardiomyopathy)
AKI CKD
Systemic disease
(sepsis,
amyloidosis, etc.)

112. Cardio–renal syndrome pathophysiology

113. C

114. Cardiovascular Abnormalities

115. Trends in the interactions of diabetes,
CHF & CKD: 2002-2003
 LVH and dilated CM are
the most ominous risk
factors for excess
mortality and morbidity
 High cardiac output
 Extracellular fluid overload
 AV shunt
 Anemia
Medicare: general Medicare CKD patients continuously enrolled in
Medicare Parts A & B for two consecutive years (numbers estimated
from 5 percent sample)

116. Hillege et al, 2002 Arnlov et al, 2005
Microalbuminuria and Survival

117. CKD and CVD Risk
HOORN Study, Henry et al, 2002 Pooled Analysis, Weiner et al, 2004
eGFR<60
eGFR>60

118. Kidney Int 1995; 47(1): 186-92
CV disease I
 70% of HD patients have concomitant CV disease
 Heart disease leading cause of death in HD patients
 LVH can be a risk factor

119. Am J Kidney Dis 2001; 37(6): 1191-200
CV disease II
 Patients with CKD (non-HD) have poor prognosis after MI
 Prospective CCU registry of 1724 pts with STEMI
 Graded increase in RR of post-infarct complications:
arrhythmia, heart block/asystole, acute pulmonary
congestion, acute MR, and cardiogenic shock
 Decreased survival over 60 months (RR 8.76; p<0.0001)

120. How should clinicians treat cardiovascular
risk factors?
 Aggressively reduce risk factors for atherosclerosis
 Encourage a healthy lifestyle regarding smoking, exercise, alcohol
intake, and BMI
 Assess for other cardiovascular risk factors
 Check BP, and treat hypertension
 Screen for diabetes, and treat elevated blood glucose
 For people with CKD, ACC/AHA guidelines recommend treatment with
statin or statin/ezetimibe combination regardless of cholesterol level

121. Plan
How should clinicians monitor patients
with CKD?

122. How should clinicians monitor patients
with CKD?
 Once a year check BP; GFR; hemoglobin level; and serum
potassium, calcium, phosphorous, PTH, and albumin
 More frequent monitoring may be needed if
 CKD is moderate to severe
 History of rapid decline in kidney function
 There are risk factors for faster progression (smoking, poorly
controlled hypertension or diabetes, proteinuria)
 Exposure to a cause of acute kidney injury
 Active or changing therapeutic interventions to treat CKD,
hypertension, or proteinuria

123. Plan
What are the indications for renal
replacement therapy?

124. What are the indications for renal
replacement therapy?
 Volume overload unresponsive to diuretics
 Pericarditis
 Uremic encephalopathy
 Major bleeding secondary to uremic platelets
 Hypertension that does not respond to treatment
 Hyperkalemia and metabolic acidosis that cannot be
managed medically
 Progressive “uremic” symptoms, which include fatigue;
anorexia, nausea or vomiting; malnutrition; and insomnia

125. Plan
When should clinicians consider
consulting with a nephrologist for treat
patients with CKD?

126. When should clinicians consider
consulting a nephrologist for treating
patients with CKD?
 To manage complications of advanced CKD
 For assistance with a care plan for advanced or complex
renal disease
 For therapeutic decision-making about complex acute or
chronic glomerular and tubulointerstitial diseases
 When dialysis is anticipated
 When GFR first falls below 30 mL/min per 1.73 m2
 To discuss treatment for end-stage renal disease
 For counseling, psychoeducational interventions, and
referral for fistula placement

127. Should clinicians screen patients for CKD?
If so, how?
 Screen individuals at increased risk for CKD
 Those older than 55 years
 Those with hypertension, diabetes, or obesity
 Screening: estimate GFR and test for kidney damage markers
 Serum creatinine to estimate GFR
 Urinalysis for leukocytes and red blood cells
 Qualitative test for urine albumin (or protein) with dipstick; if
positive, measure amount to calculate an albumin-to-creatinine
(or a protein-to-creatinine) ratio

128. Are preventive measures useful for patients at
increased risk for CKD?
 Diabetes
 Hyperglycemia is associated with development and progression
of diabetic nephropathy
 Good glycemic control reduces CKD risk
 Maintain hemoglobin A1c ~7% with dietary interventions, oral
hypoglycemic medications, and insulin
 Hypertension
 Hastens renal function decline
 Treatment reduces CV risks but not CKD risk
 Maintain blood pressure <140/90 mm Hg with lifestyle
modification and antihypertensive drug therapy

129. People with CKD do progress to kidney
failure–especially those middle-aged
and younger
Levey, et al., 2015
0
10
20
30
40
50
60
70
80
Progressed to Kidney
Failure
Died Before Kidney
Failure
Died After Kidney
Failure
Proportionofpatients
Long term (7 year) follow up of 408 non-diabetic CKD patients
(mean initial GFR=39, mean initial age=52 year old)

130. Primary care providers –
First line of defense against CKD
• Primary care professionals can play a significant role in
early diagnosis, treatment, and patient education
• Therapeutic interventions for diabetic CKD are similar to
those required for optimal diabetes care
• Control of glucose, blood pressure, and lipids
• A greater emphasis on detecting CKD, and managing it
prior to referral, can improve patient outcomes
CKD is Part of Primary Care

131. ESRD 0.1%
Undetected CKD: 10-15%?!

132. Should clinicians screen patients for CKD?
If so, how?
 Screen individuals at increased risk for CKD
 Those older than 55 years
 Those with hypertension, diabetes, or obesity
 Screening: estimate GFR and test for kidney damage markers
 Serum creatinine to estimate GFR
 Urinalysis for leukocytes and red blood cells
 Qualitative test for urine albumin (or protein) with dipstick;
if positive, measure amount to calculate an albumin-to-
creatinine (or a protein-to-creatinine) ratio

133. Urine albumin & protein to creatinine ratio
 Albumin-to-creatinine ratio
 Normal to mildly increased <30 mg/g
 Moderately increased 30-300 mg/g
 Severely increased >300 mg/g
 Protein-to-creatinine ratio
 Normal to mildly increased <150 mg/g
 Moderately increased 150-500 mg/g
 Severely increased >500 mg/g
 Type 2 diabetes: screen for albuminuria annually
 Positive when >30 mg/g creatinine in a spot urine sample

134.  Diabetics
 Hypertensives
 CVD
 Relatives of CKD5
 Systemic vasculitis
 Recurrent UTIs, and urological problems
 Chronic NSAIDs
Screening At-risk Population

135. ESRD
&
death
Stages in Progression of Chronic Kidney
Disease and Therapeutic Strategies
Complications
Screening
for CKD
risk factors
CKD risk
reduction;
Screening for
CKD
Diagnosis
& treatment;
Treat
comorbid
conditions;
Slow
progression
Estimate
progression;
Treat
complications;
Prepare for
replacement
Replacement
by dialysis
& transplant
Normal
Increased
risk
CKDDamage  GFR

136. Are preventive measures useful for
patients at increased risk for CKD?
 Diabetes
 Hyperglycemia is associated with development and
progression of diabetic nephropathy
 Good glycemic control reduces CKD risk
 Maintain hemoglobin A1c ~7% with dietary interventions,
oral hypoglycemic medications, and insulin
 Hypertension
 Hastens renal function decline
 Treatment reduces CV risks but not CKD risk
 Maintain blood pressure <140/90 mm Hg with lifestyle
modification and antihypertensive drug therapy

137. Key points
 The serum creatinine level is not enough!
 Target BP for CKD
 <130/80 mm Hg
 <125/75 mm Hg in proteinuria
 HTN and proteinuria are the two most important
modifiable risk factors for progressive CKD

138. CLINICAL BOTTOM LINE: Screening and
Prevention...
 Who to screen
 Individuals > 55 years of age
 Individuals with hypertension or diabetes
 How to screen
 Estimate GFR from serum creatinine, and do a urinalysis
 In patients with diabetes
• Screen for proteinuria with urine albumin-to-creatinine or protein-to-
creatinine ratio
• Maintain strict glycemic control to prevent CKD

139. CLINICAL BOTTOM LINE: Diagnosis...
o CKD is defined as kidney damage or a GFR <60 mL/min
per 1.73 m2 for > 3 months
o Classify
• Diabetic nephropathy
• Hypertensive nephropathy
• Nondiabetic, nonhypertensive kidney disease
• Then, into groups based on levels of GFR and albuminuria
o History and physical exam often point to a cause
o Definitive diagnosis requires:
• Diagnostic tests
• Renal ultrasound
• Sometimes renal biopsy

140. CLINICAL BOTTOM LINE: Treatment...
 The goals are to slow progression of CKD and prevent
complications from cardiovascular disease
 Maintain normal blood pressure in patients with hypertension
 Include an ACE inhibitor or an ARB when treating hypertension
 Control glycemia in patients with diabetes
 Manage electrolyte disturbances, anemia, secondary
hyperparathyroidism, and malnutrition
 Refer to a nephrologist as CKD progresses

142. CKD Management and the PCP

143. Goals of Care in CKD
 Slow decline in kidney function
 Blood pressure control1
 ACR <30 mg/g: ≤140/90 mm Hg
 ACR 30-300 mg/g: ≤130/80 mm Hg*
 ACR >300 mg/g: ≤130/80 mm Hg
 Individualize targets and agents according to age,
coexistent CVD, and other comorbidities
 ACE or ARB
*Reasonable to select a goal of 140/90 mm Hg, especially for moderate albuminuria (ACR 30-300
mg/g.)2
1) Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. Kidney Int Suppl.
(2012);2:341-342.

144. Slowing CKD Progression: ACEi or ARB
 Risk/benefit should be carefully assessed in the elderly and
medically fragile
 Check labs after initiation
 If less than 25% SCr increase, continue and monitor
 If more than 25% SCr increase, stop ACEi and evaluate
for RAS
 Continue until contraindication arises, no absolute eGFR
cutoff
 Better proteinuria suppression with low Na diet and diuretics
 Avoid volume depletion
 Avoid ACEi and ARB in combination1,2
 Risk of adverse events (impaired kidney function,
hyperkalemia)
1) Kunz R, et al. Ann Intern Med. 2008;148:30-48.
2) Mann J, et al. ONTARGET study. Lancet. 2008;372:547-553.

145. Goals of Care in CKD: Glucose Control
 Target HbA1c ~7.0%
 Can be extended above 7.0% with comorbidities or
limited life expectancy, and risk of hypoglycemia
 Risk of hypoglycemia increases as kidney function
becomes impaired
 Declining kidney function may necessitate changes to
diabetes medications and renally-cleared drugs
NKF KDOQI. Diabetes and CKD: 2012 Update.
Am J Kidney Dis. 2012 60:850-856.

146. Modification of Other CVD Risk
Factors in CKD
 Smoking cessation
 Exercise
 Weight reduction to optimal targets
 Lipid lowering therapy
 In adults >50 yrs, statin when eGFR ≥ 60
ml/min/1.73m2; statin or statin/ezetimibe combination
when eGFR < 60 ml/min/1.73m2
 In adults < 50 yrs, statin if history of known CAD, MI,
DM, stroke
 Aspirin is indicated for secondary but not primary
prevention
Kidney Disease: Improving Global Outcomes
(KDIGO) CKD Work Group. Kidney Int Suppls.
2013;3:1-150.

147. Detect and Manage CKD Complications
 Anemia
 Initiate iron therapy if TSAT ≤ 30% and ferritin ≤ 500 ng/mL
(IV iron for dialysis, Oral for non-dialysis CKD)
 Individualize erythropoiesis stimulating agent (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
 CKD-Mineral and Bone Disorder (CKD-MBD)
 Treat with D3 as indicated to achieve normal serum levels
 2000 IU po qd is cheaper and better absorbed than 50,000
IU monthly dose.
 Limit phosphorus in diet (CKD stage 4/5), with emphasis on
decreasing packaged products - Refer to renal RD
 May need phosphate binders

148. Detect and Manage CKD Complications
• Metabolic acidosis
o Usually occurs later in CKD
o Serum bicarb >22mEq/L
o Correction of metabolic acidosis may slow CKD progression and
improve patients functional status1,2
• Hyperkalemia
o Reduce dietary potassium
o Stop NSAIDs, COX-2 inhibitors, potassium sparing diuretics
(aldactone)
o Stop or reduce beta blockers, ACEi/ARBs
o Avoid salt substitutes that contain potassium
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.

149. A Balanced Approach to Nutrition in CKD:
Macronutrient Composition and Mineral Content*
Adapted from DASH (dietary approaches to stop hypertension) diet.
*Adjust so total calories from protein, fat, and carbohydrate are 100%. Emphasize such whole-food sources as
fresh vegetables, whole grains, nuts, legumes, low-fat or nonfat dairy products, canola oil, olive oil, cold-water
fish, and poultry.
NKF KDOQI. Am J Kidney Dis. 2007;49(suppl 2):S1-
S179.
*(CKD Stages 1-4)

150. What can primary care providers do? Recognize and test at-risk patients
 Educate patients about CKD and treatment
 Manage blood pressure and diabetes
 Address other CVD risk factors
 Monitor eGFR and ACR (encourage labs to report
these tests)

151. What can primary care providers do? Evaluate and manage anemia, malnutrition, CKD-
MBD, and other complications in at-risk patients
 Refer to dietitian for nutritional guidance
 Consider patient safety issues in CKD
 Consult or team with a nephrologist (co-management)
 Refer patient to nephrology when appropriate

152. Co-Management, Patient Safety, and
Nephrology Specialist Referral

153. Co-Management Model Collaborative care
 Formal
arrangement
 Curbside consult
 Care coordination
 Clinical decision
support
 Population health
 Development of
treatment protocols

154. Collaborative Care Agreements
 Soft Contract between primary care and nephrologist
 Defines responsibilities of primary care
 Provide pertinent clinical information to inform the consultation
prior to the scheduled visit.
 Initiate a phone call if the condition is emergent
 Provide timely referrals with adequate number of visits to treat the
condition.
 Defines responsibilities of nephrologist
 Timely communication of consultation (7 days routine & 48 hours
emergent) – fax if no electronic information sharing
 No consultation to other specialist initiated without primary care
input

155. Kidney
damage and
normal or  GFR
Kidney
damage and
mild 
GFR
Severe
 GFR
Kidney
failure
Moderate
 GFR
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
NephrologistPrimary Care Practitioner
The Patient (always)
and other subspecialists (as needed)
GFR 90 60 30 15
Who Should be Involved in the
Patient Safety Approach to CKD?
Patient safety
Consult?

156. Impact of primary care CKD detection
with a patient safety approach
Fink et al. Am J Kidney Dis. 2009,53:681-668
Patient Safety
Following
CKD detection
Improved diagnosis creates opportunity for strategic
preservation of kidney function

157. CKD Patient Safety Issues
 Medication errors
 Toxicity (nephrologic or other)
 Improper dosing
 Inadequate monitoring
 Electrolytes
 Hyperkalemia
 Hypoglycemia
 Hypermagnesemia
 Hyperphosphatemia
 Miscellaneous
 Multidrug-resistant infections
 Vessel preservation/dialysis access
Fink JC, Brown J, Hsu, VD, et al. Am J Kidney Dis 2009;53:681-668.

158. CKD Patient Safety Issues
 Diagnostic tests
 Iodinated contrast media: AKI
 Gadolinium-based contrast: NSF
 Sodium Phosphate bowel preparations: AKI, CKD
 CVD
 Missed diagnosis
 Improper management
 Fluid management
 Hypotension
 AKI
 CHF exacerbation
AKI = acute kidney injury; CHF = congestive heart failure; NSF = nephrogenic systemic fibrosis.
Fink JC, Brown J, Hsu, VD, et al. Am J Kidney Dis 2009;53:681-668..

159. Common Medications Requiring Dose
Reduction in CKD Allopurinol
 Gabapentin
 CKD 4- Max dose 300mg
qd
 CKD 5- Max dose 300mg
qod
 Reglan
 Reduce 50% for eGFR< 40
 Can cause irreversible EPS
with chronic use
 Narcotics
 Methadone and fentanyl
best for ESRD patients
 Lowest risk of toxic
metabolites
• Renally cleared beta blockers
o Atenolol, bisoprolol, nadolol
• Digoxin
• Some Statins
o Lovastatin, pravastatin,
simvastatin. Fluvastatin,
rosuvastatin
• Antimicrobials
o Antifungals, aminoglycosides,
Bactrim, Macrobid
• Enoxaparin
• Methotrexate
• Colchicine

160. Key Points on Medications in CKD
 CKD patients at high risk for drug-related adverse events
 Several classes of drugs renally eliminated
 Consider kidney function and current eGFR (not just SCr)
when prescribing meds
 Minimize pill burden as much as possible
 Remind CKD patients to avoid NSAIDs
 No Dual RAAS blockade
 Any med with >30% renal clearance probably needs dose
adjustment for CKD
 No bisphosphonates for eGFR <30
 Avoid GAD for eGFR <30

161. *Significant albuminuria is defined as ACR ≥300 mg/g (≥30 mg/mmol) or AER ≥300 mg/24 hours, approximately
equivalent to PCR ≥500 mg/g (≥50 mg/mmol) or PER ≥500 mg/24 hours
**Progression of CKD is defined as one or more of the following: 1) A decline in GFR category accompanied by a 25%
or greater drop in eGFR from baseline; and/or 2) rapid progression of CKD defined as a sustained decline in eGFR of
more than 5ml/min/1.73m2/year. KDOQI US Commentary on the 2012 KDIGO Evaluation and Management of CKD
Indications for Referral to Specialist Kidney Care Services
for People with CKD
• Acute kidney injury or abrupt sustained fall in GFR
• GFR <30 ml/min/1.73m
2
(GFR categories G4-G5)
• Persistent albuminuria (ACR > 300 mg/g)*
• Atypical Progression of CKD
**
• Urinary red cell casts, RBC more than 20 per HPF sustained
and not readily explained
• Hypertension refractory to treatment with 4 or more
antihypertensive agents
• Persistent abnormalities of serum potassium
• Recurrent or extensive nephrolithiasis
• Hereditary kidney disease

162. Observational Studies of Early vs. Late
Nephrology Consultation
Chan M, et al. Am J Med. 2007;120:1063-1070.
http://download.journals.elsevierhealth.com/pdfs/journals/0
002-9343/PIIS000293430700664X.pdf
KDIGO CKD Work Group. Kidney Int Suppls. 2013;3:1-

163. Take Home Points PCPs play an important role
 Identify risk factors
 Know patient’s GFR using appropriate
screening tools
 Help your patient adjust medication
 Modify diet
 Partner and refer to specialist

164. Pathophysiology of CKD

166. Overview of the CV impact caused by the
interaction of aldosterone and PTH in patients
with chronic HF and aldosterone excess.
Andreas Tomaschitz et al. Cardiovasc Res 2012;94:10-19

167. Advanced glycation end products
and their trafficking
Josephine M. Forbes, and Mark E. Cooper Physiol Rev 2013;93:137-188

168. Schematic overview of the major areas
contributing to diabetic complications
Josephine M. Forbes, and Mark E. Cooper Physiol Rev 2013;93:137-188

169. Major clinical predictors to be used for the
perioperative management of a patient with CKD

170. Major clinical predictors to be used for the
perioperative management of a patient with CKD

171. Major clinical predictors to be used for the
perioperative management of a patient with CKD

172. Screening Tools: eGFR
 Considered the best overall index of kidney function.
 Normal GFR varies according to age, sex, and body size, and
declines with age.
 The NKF recommends using the CKD-EPI Creatinine
Equation (2009) to estimate GFR. Other useful calculators
related to kidney disease include MDRD and Cockroft Gault.
 GFR calculators are available online at www.kidney.org/GFR.
Summary of the MDRD Study and CKD-EPI Estimating Equations:
https://www.kidney.org/sites/default/files/docs/mdrd-study-and-ckd-epi-gfr-estimating-equations-summary-ta.pdf

173. Screening Tools: ACR
 Urinary albumin-to-creatinine ratio (ACR) is calculated by dividing
albumin concentration in milligrams by creatinine concentration in
grams.
 Creatinine assists in adjusting albumin levels for varying urine
concentrations, which allows for more accurate results versus
albumin alone.
 Spot urine albumin-to-creatinine ratio for quantification of
proteinuria
 New guidelines classify albuminuria as mild, moderately or
severely increased
 First morning void preferable
 24hr urine test rarely necessary

174. C

176. Simple schema for the pathogenesis of
diabetic nephropathy

177. Pathophysi-
ological
events
underlying
the origin
and
evolution of
diabetic
nephropathy

178. Inflammatory pathways in the pathogenesis
of diabetic nephropathy
Jun Wada, and Hirofumi Makino Clin. Sci. 2013;124:139-152

179. Pathogenesis of
Diabetic
Chronic Kidney
Disease

180. Specific targets and potential therapeutic strategies
to inhibit or slow the progression of CKD
Declèves, A.-E. & Sharma, K. (2014) Novel targets of antifibrotic and anti-inflammatory treatment in CKD, Nat. Rev. Nephrol. doi:10.1038/nrneph.2014.31

181. Specific targets and potential therapeutic strategies
to inhibit or slow the progression of CKD
Declèves, A.-E. & Sharma, K. (2014) Novel targets of antifibrotic and anti-inflammatory treatment in CKD, Nat. Rev. Nephrol. doi:10.1038/nrneph.2014.31

182. Cardio–renal syndrome pathophysiology

183. Clinical Types of Cardiorenal Syndrome
Syndromes
Acute CRS
(type 1)
Chronic cardio-
renal (type 2)
Acute reno-
cardiac (type 3)
Chronic reno-
cardiac (type 4)
Secondary CRS
(type 5)
Definition
Acute worsening
of heart function
(AHF–ACS)
leading to kidney
injury and/or
dysfunction
Chronic
abnormalities in
heart function
(CHF-CHD)
leading to kidney
injury or
dysfunction
Acute worsening
of kidney function
(AKI) leading to
heart injury
and/or
dysfunction
Chronic kidney
disease (CKD)
leading to heart
injury, disease
and/or
dysfunction
Systemic
conditions leading
to simultaneous
injury and/or
dysfunction of
heart and kidney
Primary events
Acute heart failure
(AHF) or acute
coronary
syndrome (ACS)
or cardiogenic
shock
Chronic heart
disease (LV
remodelling and
dysfunction,
diastolic
dysfunction,
chronic
abnormalities in
cardiac function,
cardiomyopathy)
AKI CKD
Systemic disease
(sepsis,
amyloidosis, etc.)

184. Clinical Types of Cardiorenal Syndrome
Syndromes
Acute CRS
(type 1)
Chronic cardio-
renal (type 2)
Acute reno-
cardiac (type 3)
Chronic reno-
cardiac (type 4)
Secondary CRS
(type 5)
Criteria for
primary events
ESC, AHA/ACC ESC, AHA/ACC RIFLE–AKIN KDOQI
Disease-specific
criteria
Secondary
events
AKI CKD
AHF, ACS,
arrythmias, shock
CHD (LV
remodelling and
dysfunction,
diastolic
dysfunction,
abnormalities in
cardiac function),
AHF, ACS
AHF, ACS, AKI,
CHD, CKD
Criteria for
secondary
events
RIFLE–AKIN KDOQI ESC, AHA/ACC ESC, AHA/ACC
ESC, AHA/ACC,
RIFLE/AKIN ESC,
AHA/ACC KDOQI
Cardiac
biomarkers
Troponin, CK-MB,
BNP, NT-proBNP,
MPO, IMA
BNP, NT-proBNP,
C-reactive protein
BNP, NT-proBNP
BNP, NT-proBNP,
C-reactive protein
C-reactive protein,
procalcitonin, BNP
Renal
biomarkers
Serum cystatine
C, creatinine,
NGAL. Urinary
KIM-1, IL-18,
NGAL, NAG
Serum creatinine,
cystatin C, urea,
uric acid, C-
reactive protein,
decreased GFR
Serum creatinine,
cystatin C, NGAL.
Urinary KIM-1, IL-
18, NGAL, NAG
Serum creatinine,
cystatin C, urea,
uric acid,
decreased GFR
Creatinine, NGAL,
IL-18, KIM-1, NAG

185. Clinical Types of Cardiorenal Syndrome
Syndromes
Acute CRS
(type 1)
Chronic CRS
(type 2)
Acute RCS
(type 3)
Chronic RCS
(type 4)
Secondary CRS
(type 5)
Prevention
strategies
Acutely
decompensated
heart failure, acute
coronary syndromes,
Poorly controlled BP,
and noncompliance
with medication and
dietary sodium
intake.
Randomized trials:
improving
compliance with
heart failure has
reduced rates of
hospitalization and
mortality, and a
reduction in the rates
of acute CRS (type 1)
A common
pathophysiology
(neurohumoral,
inflammatory,
oxidative injury)
could be at work to
create organ
dysfunction. Drugs
that block the renin–
angiotensin system
reduce the
progression of both
CGF and CKD. It is
unknown whether
other classes of
drugs can prevent
chronic CRS (type 2)
Acute sodium and
volume overload are
part of the
pathogenesis. It is
unknown whether
sodium and volume
overload is
prevented with
different forms of
renal replacement
therapy and if this
will result in lower
rates of cardiac
decompensation.
The chronic processes
of cardiac and renal
fibrosis, LVH, vascular
stiffness, chronic Na
and volume overload,
and other factors
(neurohumoral,
inflammatory,
oxidative injury) could
be at work to create
organ dysfunction. A
reduction in the
decline of renal
function and
albuminuria has been
associated with a
reduction in CV
events. The role of
chronic uraemia,
anaemia, and
changes in CKD-
mineral and bone
disorder on the CVS is
known in chronic RCS
Potential systemic
factors negatively
impact function of
both organs acutelyIt
is uncertain if
reduction/elimination
of the key factors
(immune,
inflammatory,
oxidative stress,
thrombosis) will
prevent both cardiac
and renal decline.

186. Clinical Types of Cardiorenal Syndrome
Syndromes
Acute CRS
(type 1)
Chronic cardio-
renal (type 2)
Acute reno-
cardiac (type 3)
Chronic reno-
cardiac (type 4)
Secondary CRS
(type 5)
Management
strategies
Specific—depends on
precipitating
factorsGeneral
supportive—
oxygenate, relieve
pain & pulmonary
congestion, treat
arrhythmias
appropriately,
differentiate left from
right heart failure,
treat low cardiac
output or congestion
according to ESC
guidelines(a); avoid
nephrotoxins, closely
monitor kidney
function.
Treat CHF according
to ESC guidelinesa,
exclude precipitating
pre-renal AKI factors
(hypovolaemia
and/or hypotension),
adjust therapy
accordingly and avoid
nephrotoxins, while
monitoring renal
function and
electrolytesExtracorp
oreal ultrafiltration
Follow ESC guidelines
for acute CHFa
specific management
may depend on
underlying aetiology,
may need to exclude
renovascular disease
and consider early
renal support, if
diuretic resistant
Follow KDOQI
guidelines for CKD
management,
exclude precipitating
causes (cardiac
tamponade). Treat
heart failure
according to ESC
guidelinesa, consider
early renal
replacement support
Specific—according
to etiology. General—
see CRS
management as
advised by ESC
guidelines* 2008

187. Follow-up of
CKD Patients

188. Goals of Care in CKD
 Slow decline in kidney function
 Blood pressure control1
 ACR <30 mg/g: ≤140/90 mm Hg
 ACR 30-300 mg/g: ≤130/80 mm Hg*
 ACR >300 mg/g: ≤130/80 mm Hg
 Individualize targets and agents according to age,
coexistent CVD, and other comorbidities
 ACE or ARB
*Reasonable to select a goal of 140/90 mm Hg, especially for moderate albuminuria (ACR 30-300 mg/g.)2
1) Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. Kidney Int Suppl. (2012);2:341-342.
2) KDOQI Commentary on KDIGO Blood Pressure Guidelines. Am J Kidney Dis. 2013;62:201-213.

189. pathophysiological
events underlying
the chronic
nephropathy

190. direct and indirect
components of the renin –
angiotensin aldosterone
system (RAAS) and their
effects on the progression
of CKD

191. Nephrotic vs. Nephritic Syndromes
 Nephrotic Syndromes - glomerular disorders that affect
the glomerular capillary membrane & increases
permeability to plasma proteins
 Nephritic Syndromes – glomerular disorders that initiate
the inflammatory response within the glomeruli & initially
decreases permeability of the membrane

192. Nephritic Syndromes
Glomerulonephritis
• An inflammatory response in the endothelial, epithelial &
mesangial cells of the glomeruli
• Inflammatory process damages the capillary wall-
allowing RBCs into the urine
Symptoms:
• 1st oliguria, followed by hematuria, azotemia, low GFR
(d/t hemodynamic changes), hypertension

193. Nephrotic Syndromes
Primary causes:
 Lipoid Nephrosis
 Focal Segmental
glomerulosclerosis
 Membranous
glomerulonephritis
Secondary causes:
 Diabetes Mellitus
 SLE
 Amyloidosis
Characterized by:
 Proteinuria > 3.5g/day
 Lipiduria
 Hypoalbuminemia
 Hyperlipidemia
Increased permeability of
glomerular membrane
allows proteins to escape
into the filtrate

194. Pathophysiology
of CKD in DM
Jun Wada, and Hirofumi Makino Clin. Sci. 2013;124:139-152

195. Pathophysiology of CKD

196. Pathophysiology of CKD
 Final Common Pathway is loss of nephron mass
Structural/
Functional
Hypertrophy
of remnant
nephrons
Loss of
Nephron Mass
Sclerosis
of remnant
nephrons
Mediated by
vasoactive
molecules, cytokines
and growth factors,
renin angiotensin
axis
Diabetes
Hypertension
Chronic GN
Cystic Disease
Tubulointerstitia
l disease

197. Pathophysiological Events
Underlying the Nephropathy Caused
by Ureteral Obstruction

198. Mesangial Cell Contribution
Valerie Kolmer 2006

199. Old Classification of CKD as Defined by Kidney
Disease Outcomes Quality Initiative (KDOQI)
Modified and Endorsed by KDIGO
Note: GFR is given in mL/min/1.732 m²
National Kidney Foundation. KDOQI Clinical Practice Guidelines for Chronic Kidney Disease:
Evaluation, Classification, and Stratification. Am J Kidney Dis 2002;39(suppl 1):S1-S266
Stage Description Classification
by Severity
Classification
by Treatment
1 Kidney damage with
normal or increased GFR
GFR ≥ 90
2 Kidney damage with
mild decrease in GFR
GFR of 60-89 T if kidney
transplant
3 Moderate decrease in GFR GFR of 30-59 recipient
4 Severe decrease in GFR GFR of 15-29 D if dialysis
5 Kidney failure GFR < 15 D if dialysis
KDIGO, Kidney
Disease: Increasing
Global Outcomes

200. Which patients are at increased risk for CKD?
 Risk factors
 Diabetes
 Hypertension
 Autoimmune diseases
 Systemic infections
 UTI, nephrolithiasis, lower
urinary-tract obstruction
 Hyperuricemia
 Acute kidney injury
 Family history of chronic
kidney disease
 Sociodemographic risk
factors
 Older age
 Black race
 Smoking
 Heavy alcohol use
 Obesity
 NSAIDs

201.  Diabetes mellitus
 Hypertension
 Cardiovascular disease
o Note on pediatric patients:
 CKD may start with childhood
obesity
 No recommendations for routine
testing
The people to test are those at
greatest risk
 Age > 60 years
 Race or ethnic background
 African-American
 Hispanic
 American Indian
 Asian
 History of exposure to
chemicals/toxins
 Cigarette smoke
 Heavy metals
 Family history of CKD
National Kidney Foundation, 20012

202. Functional Changes of CRF
The Kidneys are unable to:
 Regulate fluids and electrolytes
 Balance fluid volume and renin-angiotensin system
 Control blood pressure
 Eliminate nitrogen and other wastes
 Synthesize erythropoietin
 Regulate serum phosphate and calcium levels

203. Investigations in Patients with CKD and
in Persons with Increased Risk for CKD

204. Clues to the Diagnosis of CKD from
the Patient’s History

205. Signs & Symptoms of CKD at a Glance

206. Pharmacological Treatment
Rodicio JL & Alcazar JM. ESH Newsletter 2011, No. 4