prevention of CKD

1. Mostafa Abdel Salam
Lecturer of nephrology
Mansoura University Hospitals

2. • Chronic kidney disease (CKD) is currently
defined by abnormal measurements of the
actual or estimated glomerular filtration rate
(GFR) for a minimum of 3 months

3. CKD with normal GFR

4. Scope of Disease:
NHANES data
Figure 1.1 (Volume 1)
NHANES participants age 20 & older.
USRDS Annual Data Report 2011 Fig 1.1, Vol 1

5. • It is clear that the great majority of these
patients do not reach end-stage renal disease
(ESRD) in their lifetimes. Many of these
patients have relatively stable kidney function
and are more likely to die with rather than of
CKD.

6. CKD Co-Morbidities
0
10
20
30
40
50
60
70
80
90
100
DM
HTN
CVD
PVD
COPD
% of Patients48%
90%
75%
32%
25%
USRDS 2010 ADR
Late Stage CKD (CKD Stage 4 & 5) Patients have multiple co-morbidities
that require complex care

7. However, for patients who initiate dialysis to
treat chronic kidney failure, there is, on
average, 75% mortality by 5 years.

8. Coronary Cerebral
peripheral
vascular
disease
arrhythmias heart failure
sudden
death
Cardiovascular disease

9. • The most common causes of CKD and ESRD
are diabetic nephropathy and hypertensive
nephrosclerosis. Primary glomerular diseases
(i.e., IgA nephropathy, membranous
glomerulonephritis), secondary glomerular
diseases (i.e., lupus nephritis, amyloidosis),
tubulointerstitial, vascular, cystic, and
hereditary kidney diseases are all much less
common.

10. Frequency of Primary Disease Causing End-Stage
Renal Disease
Diabetes mellitus
type 1 3.9
Diabetes mellitus
type 2 41.0
Hypertension 27.2
Primary
glomerulonephritis
8.2

11. Tubulointerstitial 3.6
Hereditary or cystic 3.1
Secondary glomerulonephritis
or vasculitis 2.1
Neoplasm or plasma cell
dyscrasias 2.1
Miscellaneous 4.6
Unknown 5.2

12. • Over the last 20 years, specific treatments
have been developed and proven to delay
progression to ESRD, and other therapies
continue to be studied.

13. Early
detection
Delay
progression
mortality

14. CONCLUSIONS
•The pathophysiology of CKD is largely dependent on the primary
insult, but common pathways exist across almost all subsets of
kidney disorders. This includes hemodynamic-mediated
hyperfiltration and eventual nephron loss, as well as inflammatory
and cellular mediated fibrosis. Much of the pathophysiology arises
from maladaptation to autoregulation with hyperactivation of the
RAAS. Theoretically, blocking these pathways will interrupt this
progression; in fact, the most robust clinical evidence for slowing or
reversing the progression is with disruption of the RAAS system.
Controlling blood pressure, lowering proteinuria, avoiding AKI, and
attempting cardiovascular risk reduction are important goals for the
physicians treating patients with CKD. Exciting novel therapies are
eagerly anticipated, but these must be tested through rigorous
clinical study for safety, tolerability, and efficacy.

15. The CKD Continuum
NephrologistPCP
ESRDCKD
Diabetes
Hypertension
Obesity
CVD
Advanced CKD Care
• 30-20-10 & Timely Referral
• Promote Co-management and
Coordinated Care
• Multidisciplinary Team Care in
Nephrology
• Vascular Access management
• Case Management
– Diabetes
– Nutrition & Obesity
– Hypertension & CVD
• Treatment Options Education
RightStart
• At Renal Replacement
Therapy Start Reduce:
• Mortality
• Hospitalization
• CHF
• Transplant & Home
Therapies when
possible
• Support for:
• Permanent Access
• Nutrition
• Adequate Dialysis
• Anemia, Bone
Mgmt
PCP & Nephrology
Practice
• Public Awareness
• Screening of “At Risk”
patients
• Recommended evaluation
and monitoring of CKD
• Timely Referral to
Nephrology
• Education for Patients
RightReturn
• Reduce Repeat Hospitalization
• Medication Reconcilliation
• Integrated return to chronic
dialysis care
Early CKD Care impacts Late CKD Outcomes

16. PATHOPHYSIOLOGIC MECHANISMS OF
CHRONIC KIDNEY DISEASE

17. • The pathophysiology of CKD is complex and in
large part dependent on the primary cause.
many common pathways are activated to
perpetuate glomerular and tubulointerstitial
injury These harmful adaptations, occurring as
a result of an initial injury

18. hemodynamic nonhemodynamic

19. HEMODYNAMIC INJURY

20. progressive decline in GFR
proteinuria
hypertension
Model: 5/6
nephrectomy

21. • Pathologic examination of the remaining
tissue exhibits hyperfiltration injury, as
evidenced by glomerular hypertrophy and
focal segmental glomerular sclerosis (FSGS).
The process occurs at a linear rate in
proportion to the greater reduction in kidney
mass.

22. Micropuncture techniques reveal an increase in
renal plasma flow and hyperfiltration of the
remaining nephrons

23. Systemic
hypertension
glomerular
hypertension,
(RAAS)
progressive
glomerular
damage
proteinuria.

24. • As a result of these changes, afferent
arteriolar tone decreases less than efferent
tone. This net efferent vasoconstriction
increases intraglomerular and filtration
pressure further, perpetuating hyperfiltration
injury.

25. • Animal models of other kidney diseases, such
as that of diabetic nephropathy in the rat,
reveal similar pathophysiologic changes of
glomerular hypertension, hypertrophy, and
hyperfiltration

27. RAAS
Glomerular
hemodynamic
maladaptation.

28. • The net effect of all of these mechanisms is an
integral component of autoregulation, helping
to maintain GFR when perfusion is decreased.

29. A primary
kidney insult
or CKD
systemic and
glomerular
hypertension.
increases the
filtration
fraction
increase in
hydrostatic
pressure
increases the
radius of the
pores in the
GBM
results in
clinical
proteinuria
and
glomerular
destruction.

30. • The best example of a human model of
decreased nephron mass or number would be
in the setting of a solitary kidney, or unilateral
renal agenesis.

31. • In the 1980s, autopsy series and case series
confirmed the association of unilateral renal
agenesis with hypertension, proteinuria,
progressive kidney disease, glomerulomegaly,
and FSGS

32. NONHEMODYNAMIC INJURY

33. activation of
the RAAS
inflammation
and fibrosis.

35. Activation of the RAAS
connective tissue growth factor (CTGF)
epidermal growth factor (EGF)
insulin-like growth factor-1 (IGF-1)
platelet-derived growth factor (PDGF)
vascular endothelial growth factor (VEGF),
transforming growth factor-β (TGF-β)
monocyte chemotactic protein-1 (MCP-1)

36. • proliferation and hypertrophy of glomerular
endothelial and epithelial cells, mesangial
cells, tubulointerstitial cells, and fibroblasts.

37. • overproduction of extracellular matrix, such as
type 1 procollagen, plasminogen activator
inhibitor 1, and fibronectin.

38. • In addition, excess adhesion molecules, such
as integrins or vascular cellular adhesion
molecule 1, allow the increased extracellular
matrix and hypercellularity to accumulate and
persist.

39. • Stimulating endothelin-1 (ET-1) and increases
production of nuclear factor κ-light-chain-
enhancer of activated B cells (Nf-κB).
Increased expression of TGF-β also creates
cellular recruitment.
• free radical oxygen species lead to additional
injury, which enables further inflammation
and fibrosis

40. proteinuria
macrophages and inflammatory
mediators, such as ET-1 and MCP-1
as well as other chemokines
inflammation and subsequent
tubulointerstitial and glomerular
fibrosis

41. Risk Factors for the Development
or Progression of Kidney Disease
Proteinuria
Hypertension
Episodes of acute kidney injury
Underlying cause of kidney disease (e.g., diabetic nephropathy)

42. Obesity
Hyperlipidemia
Smoking
High-protein diet
Metabolic acidosis
Hyperphosphatemia
Hyperuricemia

43. African-American
or Native
American race
Male gender
Older age
Family history of
DM, CKD, or
ESRD
Low birth weight

44. TREATMENT AND PREVENTION OF
CHRONIC KIDNEY DISEASE PROGRESSION
safely slow or reverse the vicious cycle
RAAS activation
glomerular hypertension
systemic hypertension
Proteinuria
inflammation
progressive fibrosis.

45. Therapies for Slowing Progression
of Chronic Kidney Disease
Angiotensin converting enzyme inhibitors
Angiotensin receptor antagonists
Blood pressure control
Proteinuria reduction

46. Dietary measures, exercise
Weight loss in obesity
Smoking cessation
Glycemic control in diabetes mellitus

47. Reduction of hyperuricemia,
hyperlipidemia,
hyperphosphatemia
Acid-base balance

48. Novel therapies
Endothelin-1 antagonists
Pirfenidone
Vitamin D
Inhibitors of advanced glycation end products

49. ANTAGONISM OF THE RENIN-
ANGIOTENSINALDOSTERONE SYSTEM
reduction in glomerular hypertrophy and injury.
glomerular relaxation
Vasodilatation of the efferent arteriole
angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)
interruption of the RAAS cascade could lead to renoprotection.

50. Reduction of
glomerular
hypertension
improvement
s in systemic
hypertension
RAAS
blockade

51. Blockade of the RAAS in animals
impair the inflammatory and fibrosing effects
of the various cytokines, including TGF-β.

52. RAAS
antagonism
Hemodynamic
Antifibrotic
antiproteinuric

53. • randomized controlled clinical trial, 409 patients
with overt type 1 diabetic nephropathy
• dramatic 43% reduction in the doubling of the
serum creatinine, as well as a significant reduction
in the time to death, dialysis, or transplantation
with captopril compared with placebo.

54. • Thus for the first time in human patients, ACE
inhibitors established renoprotection and
remission in advanced diabetic nephropathy

55. In the Irbesartan for Microalbuminuria in Type 2
Diabetes (IRMA-2) trial
The Reduction in Endpoints in NIDDM with the
Angiotensin-II Antagonist Losartan (RENAAL)
trial.
Reduction of proteinuria
Slowing the progression of CKD

56. • Similar results are seen in nondiabetic kidney
disease, where a metaanalysis by Jafar and
colleagues demonstrated that RAAS inhibition
slows progression, particularly in individuals
with proteinuria exceeding 1000 mg/day.

57. • REIN trial: Ramipril in non-diabetic renal
failure
• randomized 352 proteinuric patients with
hypertension but without diabetic
nephropathy
• 50% lower risk for progression to ESRD during
the 3 years of follow-up..

58. • Dual blockade of the RAAS cannot be
recommended, and it may incur harm
• development of hyperkalemia when using any
agent to block the RAAS.
• check the serum potassium 7 to 14 days after
initiating therapy with these agents.

59. BLOOD PRESSURE CONTROL
• Observational studies and randomized
controlled trials have shown that lowering
blood pressure in patients with hypertension
and CKD slows the rate of disease progression

60. (<140/90 mm Hg)
The ideal
goal blood
pressure in
patients with
CKD

63. • limit protein intake to approximately 0.8-1.0
g/kg of body weight per day
• limit dietary sodium to <2.4 g a day.
• dietary protein restriction demonstrated
reduced kidney injury by decreasing afferent
arteriolar vasodilation, glomerular
hypertension, and oncotic pressure.

64. Obesity and obesity-related glomerulopathy are
increasing in prevalence.

65. • Preexisting albuminuria is exacerbated by
weight gain and decreases with weight loss.

66. • Hyperlipidemia, similar to obesity, may be a
modifiable risk factor to slow progressive
CKD. Hyperlipidemia may contribute to CKD
progression through proinflammatory and
profibrotic mechanisms, considering the fact
that lowdensity lipoproteins (LDL) have these
properties.

67. • Animal models reveal that rats fed high-
cholesterol diets exhibit a greater degree of
glomerulosclerosis and interstitial disease
compared with those fed a low-cholesterol
diet.

68. • In the same animal models, 3-hydroxy-3-
methyl-glutaryl-CoA reductase inhibitors
(statins) have been shown to limit
inflammatory cytokines and adhesion
molecules and slow the progression of kidney
disease.

69. PROTEINURIA REDUCTION
• In patients with or without a reduced GFR,
proteinuria is an independent risk factor for
progressive kidney injury.

70. • Therefore reducing proteinuria to the lowest
possible amount would seem beneficial.

71. • Ramipril in non-diabetic renal failure (REIN
study).
• The African American Study of Kidney Disease
and Hypertension (AASK )
• The Modification of Diet in Renal Disease (MDRD)
• Nondiabetic patients in the MDRD trial, the AASK
trial, and the REIN trial with higher levels of
proteinuria had a greater benefit from a lower
blood pressure goal.

72. NOVEL METHODS
• Novel therapies attempting to reduce the
progression of chronic kidney disease exist;
these target the inflammatory and/or fibrotic
effects that occur in the pathophysiology of
CKD progression.

73. • Pirfenidone is a novel agent that targets the
fibrosing pathway of CKD and has beneficial
effects in animal models of CKD and diabetic
nephropathy. However, positive, large, long-
term human clinical trials showing a reduction
in the progression of CKD have not yet been
completed.

74. • Endothelin antagonists are another promising
area for the future as ET-1 contributes to
kidney damage via both vasoconstrictive
properties as well promotion of interstitial
fibrosis.

75. • Another novel medication, pyridoxamine,
exerts its effect through antioxidant properties
and impairment in advanced glycation end
products (AGEs).

76. • Sulodexide, a glycosaminoglycan, was
rigorously tested in clinical trials of patients
with diabetic nephropathy and failed to show
a benefit

77. • Treatment of hyperuricemia,
hyperphosphatemia, and vitamin D deficiency
and maintaining appropriate acidbase balance
with sodium bicarbonate therapy have been
shown in observational studies and/or small
clinical trials to be associated with a reduction
in albuminuria and/or the progression of CKD.

79. Nephrology Care and CKD Outcomes
• Late Nephrology evaluation in CKD is associated with
increased risk for unplanned first dialysis, higher dialysis
complications, and higher hospital costs
–(Ann Intern Med 2002, Kinchen)
• Late Referral to Nephrology is associated with a 44% higher
risk of death in the first year of dialysis
–(NDT 2004, Kazmi)
• Late Referral is associated with poorer diabetic control based
on HbA1c, poorer management of proteinuria, less frequent
use of ACEI/ARB therapy, increased rate of emergency initial
dialysis and increased 1-year mortality on dialysis
–(Int J Clin Pract 2010, Herget-Rosenthal)

80. 80
Timely Referral:
Long-lasting benefits
• Late Referral patients have a 44% higher
risk of mortality in the first year of dialysis
compared to Early Referral patients
• Timely Referral from Primary Care to the
Nephrology Practice reduces patient
mortality

81. CKD Co-management
• Primary Care Provider is responsible for:
– Screening the “at risk” patient population
– Diagnosing CKD based on KDOQI guidelines
– Appropriate referral to Nephrology
• Unclear diagnosis
• eGFR <60
• Rapid progression
• Uncontrolled HTN
• Referral with patient CKD evaluation
information

82. CKD Co-management
• Nephrology Practice
– Sees referral in a timely manner
– Continues evaluation and diagnosis
– Identifies CKD co-morbidities and complications
– Implements a treatment plan
• Informs Primary Care Provider about
evaluation, results and treatment plan

83. CKD is common

86. To “Pee” or not to “Pee”
“It is no exaggeration to say that the
composition of the blood is determined not by
what the mouth takes in but by what the
kidneys keep.” Homer W. Smith (1895-1962)
Left to right:
Herbert Chasis, MD, William Goldring, MD, and Homer Smith, MD