Approach to CKD

1. Approach to CKD Pateint
By
Mostafa Abd_Elsalam,MD
MUH,MNDU

2. Definitions
Azotemia - elevated
blood urea nitrogen
(BUN >28mg/dL)
and creatinine
(Cr>1.5mg/dL)
Uremia - azotemia
with symptoms or
signs of renal failure

3. End Stage Renal
Disease (ESRD) -
uremia requiring
transplantation or
dialysis
Chronic Renal
Failure (CRF) -
irreversible kidney
dysfunction with
azotemia >3 months

4. Creatinine Clearance
(CCr) - the rate of
filtration of creatinine
by the kidney (GFR
marker)
Glomerular Filtration
Rate (GFR) - the
total rate of filtration
of blood by the
kidney

5. Unfortunately,
chronic kidney
disease is ‘‘under-
diagnosed’’ and
‘‘under-treated’’ in
the United States
K/DOQI, 2002

6. Chronic kidney disease
progressive loss of
nephrons and function
due to multiple etiologies
and frequently leading to
end stage renal disease
(ESRD).

7. presence
of
following
for three
months
or more
GFR less than 60
ml/min/1.73 m2
with or without
kidney damage.

8. Structural
and
functional
abnormalities
of the kidney
Pathological abnormalities.
Clinical markers of renal damage in the form of
proteinuria
Abnormal imaging studies
Tubular syndromes.
Kidney transplant recipient.

10. Epidemiology of chronic
kidney disease
CKD affects almost 14–15% of
the adult United States (U.S)
population.
The prevalence of CKD is highest
in the elderly population
especially those above the age of
65 years.

11. Not all patients with
CKD progress to
ESRD.
Significant
proportion of
patients with CKD
die before reaching
dialysis.
Currently almost
600000 people in
U.S are undergoing
hemodialysis for
ESRD
. U.S. Renal Data System (2013) USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage
Renal Disease

12. CKD as a Public Health Issue
26 million American affected
Prevalence is 11-13% of adult
population in the US
28% of Medicare budget in
2013, up from 6.9% in 1993
$42 billion in 2013
1. NKF Fact Sheets.
http://www.kidney.org/news/newsroom/factsheets/FastFac
ts. Accessed Nov 5, 2014.
2. USRDS. www.usrds.org. Accessed Nov 5, 2014.
3. Coresh et al. JAMA. 2007. 298:2038-2047.
ESRD, end stage renal disease

13. Increases risk for all-cause
mortality, CV mortality, kidney
failure (ESRD), and other
adverse outcomes.
6 fold increase in mortality rate
with DM + CKD
Disproportionately affects
African Americans and
Hispanics

14. 100 patients with eGFR < 60
(Tomorrow morning in Outpatients)

15. 1 year later: 1 patient needs RRT, 10 patients have
died (> 50% CV death)

16. 10 years later: 8 patients need RRT, 65 patients
have died, 27 have ongoing CKD

17. Why?
ageing of the general population
rising incidence of obesity

18. type 2 diabetes mellitus
improved survival from
cancer as well as major
cardiovascular accidents

19. Major causes of CKD
hypertension
diabetes mellitus
Glomerulonephritis
cystic kidney disease
urinary tract obstruction
interstitial nephritis
vesico-ureteric reflux
nephrolithiasis and recurrent kidney infection.

22. natural physiological reduction in glomerular filtration
rate (GFR) with aging which behaves differently from
the various etiologies mentioned above in terms of
progression of the disease

23. The renal prognosis is favorable in most patients
who demonstrate age related drop in GFR, BUT
associated with increased risk of cardiovascular
morbidity and mortality
Nitta K, Okada K, Yanai M, Takahashi S (2013) Aging and chronic kidney disease. Kidney Blood Press
Res 38: 109- 120.

26. Pathophysiology of Chronic
Kidney Disease
The pathophysiology of
CKD involves initiating
mechanisms specific to
the underlying etiology

27. As well as a set of progressive
mechanisms, glomerulosclerosis
and tubulo interstitial fibrosis that
are common consequences
following long term reduction in
renal mass, irrespective of the
etiology.

28. Structural and functional
changes in surviving nephrons
lead to hypertrophy and hyper
filtration of the surviving
nephrons.

29. This compensatory hypertrophy
mediated by vasoactive molecules,
cytokines, growth factors and renin
angiotensin axis mediators
eventually lead to intra-glomerular
hypertension and accelerated
sclerosis of surviving nephrons.

30. Raised intra-glomerular hypertension will lead to
reduction of glomerular permeability and filtration surface
area resulting in decreased GFR

32. Tubulointerstitial injury manifested by
tubular dilatation and interstitial
fibrosis.
The degree of tubulointerstitial disease
is a better predictor of glomerular
filtration rate decline and long term
prognosis than the severity of injury.

33. Other factors that play a role in the
initiation and pathogenesis of
fibrosis in CKD include :
1) Upregulation of profibrotic factors
such as transforming growth factor
beta 1 (TGF-β1), platelet derived
growth factor, fibroblast growth
factor, osteopontin and endothelin.

34. 2) Down regulation of anti-fibrotic factors like
hepatocyte growth factor and bone
morphogenic protein.
3) Dysregulation of vasoactive factors with
an increase in vasoconstrictors such as
angiotensin II, and a decrease in
vasodilators such as nitric oxide (NO).

35. 4) Microvascular injury and obliteration (due to
hypoxia)
5) Disruption of normal homeostatic interactions
between adjacent cell populations, especially
the one between tubular epithelial cells and
interstitial fibroblasts.

36. Role of renin angiotensin-
aldosterone system in CKD
The renin-angiotensin-
aldosterone system (RAAS)
plays a major role in maintaining
the blood volume and salt-water
balance. It has effect on the
blood pressure and tissue
perfusion through a number of
multiple complex actions
including vasoconstriction and
sodium retention.
.

37. Despite its role in maintaining
homeostasis, long-lasting
stimulation of RAAS can lead to
development of kidney lesions
and progression of CKD.

38. An excess of angiotensin II
increases intraglomerular
pressure by preferentially
constricting the efferent
arterioles, thus promoting
glomerular hypertension

39. Additionally angiotensin II can
stimulate aldosterone production
which triggers the activation
of a cascade of profibrotic
cytokines resulting in glomerular
sclerosis and tubulointerstitial
fibrosis.

40. Prorenin and renin can stimulate TGF-
β1 production via the activation of
p42/p44 mitogen-activated protein
kinase (p42/p44MAPK), which
sub¬sequently result in the
upregulation of profibrotic and
prothrombotic molecules, such as
fibronectin, collagen-1, and
plasminogen activator inhibitor-1 (PAI-
1) inducing renal fibrosis.

41. A high prorenin
level =
micro¬albuminuria,
and development
of nephropathy
especially in
diabetic patients

42. Role of proteinuria in CKD
Proteinuria is an
important risk factor for
the progression of CKD.
Increased protein
filtration results in
excess reabsorption of
filtered proteins by
proximal tubular cells.

43. The reabsorbed proteins eventually leak into the
renal tubular interstitium through focal breaks in
tubular basement membrane attracting
macrophages.

44. These macrophages can promote
tubulointerstitial fibrosis by release
of proinflammatory mediators

45. Role of sympathetic system in progression
of chronic kidney disease
Hyperactivity of the
sympathetic nervous
system has been found to
have considerable adverse
consequences on
progression of CKD and
cardiovascular disease.

46. hypertension
Proteinuria
accelerated atherosclerosis
vasoconstriction
and proliferation
of smooth
muscle cells as
well as
adventitial
fibroblasts in the
vessel wall

47. Ischemic nephropathy and
chronic kidney disease
Ischemic nephropathy
is a common cause of
renal disease
especially in the
elderly population.

48. It is defined by the gradual
reduction of the GFR or a
loss of renal parenchyma
resulting from vascular
occlusion and not explained
by other etiologies.

49. The pathogenesis of this
disease involves not only
the narrowing of the major
renal artery due to
atherosclerosis but also
renal microvascular
disease.

50. The role of microvascular disease
is supported by the fact that the
severity of renal vascular disease
on imaging has not been found to
correlate with the onset or
progression or time to reach ESRD
in patients with atherosclerotic
renal vascular disease

51. . Microvascular involvement
can result from vascular
rarefaction within
interstitium increased
vascular wall to lumen ratio
and atheroembolic renal
vascular disease.

52. Induction of hypoxia secondary
to these, results in activation of
renin-angiotensin system, growth
factors, different cytokines and
chemokines playing a major role
in the pathogenesis of ischemic
nephropathy.

53. Hypoxia additionally
promotes fibrosis by up
regulating extracellular matrix
production, suppressing
turnover of collagen and
promoting epithelial-to
mesenchymal transition.

54. The other mechanisms responsible for
renal injury in ischemic nephropathy aldosterone–mediated damage
sympathetic over activity
increased release of reactive oxygen species
reduction in NO activity.
leading to endothelial dysfunction.

55. Role of genetics in chronic
kidney disease
Monogenic inheritance like polycystic kidney
disease, focal segmental glomerulosclerosis
(FSGS), congenital nephrotic syndrome, Fabry’s
disease, Alport disease, nephronophthisis as
well as medullary cystic kidney disease
Polygenic inheritance like diabetic nephropathy
and hypertensive nephropathy.

56. Polycystic kidney disease
(PKD) is the best-known
and most easily
recognizable inherited
kidney disease. There are
mainly two genetic variants
of PKD-PKD1 and PKD2.

57.  Point mutations in the Alpha-actinin-4
(ACTN4), Transient Receptor Potential
Cation Channel Type 6 (TRPC6), and
Inverted Formin 2 (INF2) genes can
lead to phenotypes characterized by
injury to glomerular podocyte
associated filtration barrier and cause
progressive deterioration in renal
filtration function resulting in FSGS

58. Recent genomewide association
studies have identified several
genetic loci that may affect renal
function. UMOD gene is the
most important among them
which is strongly linked to
effects on CKD and GFR.

59. The other major genetic
locus associated with
progression of kidney
disease especially in the
African American
population is the APOL-1

60. Who should be screened for
CKD?
(KDOQI)
guidelines
Diabetes
cardiovascular disease
hypertension,
hyperlipidemia
Obesity
metabolic syndrome
Smoking
HIV
hepatitis C virus infection

61. KDIGO malignancy,
family history of kidney disease
treatment with potentially
nephrotoxic drugs
should be screened.

62. KDIGO)
Controversies
Conference
suggested
screening all
patients over
age 60 years.
By
urine
albumin/creatinine ratio
estimated GFR
creatinine clearance)

63. CKD Risk Factors*
Modifiable
 Diabetes
 Hypertension
 History of AKI
 Frequent NSAID
use
Non-Modifiable
• Family history of kidney
disease, diabetes, or
hypertension
• Age 60 or older (GFR
declines normally with
age)
• Race/U.S. ethnic
minority status
*Partial list
AKI, acute kidney injury

64. Effective
management
should
include the
following
steps:
1) History, physical examination and laboratory
studies to establish the diagnosis of CKD.
2) Modification of risk factors.
3) Treatment of complications.
4) Preparation for renal replacement
therapy.
5) Patient education

65. History and physical examination
History
RISK
FACTORS
Diabetes
Hypertension
systemic inflammatory disorders
nephron/urolithiasi
metabolic diseases

66. History exposure to drugs as well as toxins
exposure to intravenous
contrast
herbal medications
exposure to phosphatecontaining enema
family history of renal diseases (polycystic
kidney disease)and urologic disorders.
Smoking

67. uremia
related
symptoms
appetite, diet, nausea, vomiting
shortness of breath, edema
weight change
pruritus, skin rash
mental acuity and activities of daily
living.

68. Physical
examination blood pressure
Fundoscopy (hypertensive retinopathy
and diabetic retinopathy)
precordial examination (fourth heart
sound, murmurs, pericardial rub)
abdomen (renal bruit, aortic bruit,
palpable masses)
Edema

69. Physical
examination peripheral pulses
central nervous system (asterixis,
muscle weakness, neuropathy),
rectum (prostate size) and vagina
(pelvic masses)

70. Clinical features of CKD

73. Methods of estimating GFR
The most reliable
markers of GFR
estimation include
inulin clearance and
use of radionuclides
like iothalamate and
iodohexol

74. The most commonly used
methods for estimating GFR
is based on creatinine.
Creatinine is a protein
derived from metabolism of
creatine in skeletal muscle
and dietary meat intake

75. Levels can be altered by medications interfering with
measurement (cephalosporin, ketone) or reduced
secretion by medications (cimetidine, Bactrim).
It can also be altered by factors like variability in
muscle mass
presence of liver disease, age, sex, race and weight,
chronic illness, and consumption of cooked meat

76. Creatinine
based
formula
for
estimating
GFR
include
Modification of Diet in Renal Disease (MDRD) formula
(takes into account age, gender and race).
Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formula (takes into account age, gender and
race).
Cockcroft-Gault (CG) equation (takes into account the
age, weight and gender).
24 hour urine estimation of creatinine clearance.

77. The MDRD equation was found to be less accurate than
CKD-EPI in predicting risk for those with GFR more than 45-
60 ml/min/1.73 m2
But at the same time CKD –EPI was not superior in
estimating GFR in the elderly or those with extreme body
mass.
MDRD and CKD-EPI are more accurate in young compared
to CG equation.
In terms of gender, CKD-EPI was most accurate in women
whereas MDRD was most accurate in men

78. Creatinine does not fulfill the
criteria of an ideal marker for
estimating GFR

79. Cystatin
C
freely filtered
reabsorbed
metabolized by proximal
tubules
no urinary excretion.

80. The use of cystatin C also has its own
limitations
• Among patients with a GFR <60 ml/min/ 1.73 m2, cystatin
C offers only a moderate gain over creatinine for
approximating renal function.
A combined serum cystatin C and creatinine
based formula is sometimes used in practice

83. Role of proteinuria in the
classification of CKD

84. Biomarkers in CKD
• Accurate
• non-invasive
indicators
• reflect the
pathophysiologic
mechanisms
underlying CKD.
Effective
CKD
screening
and
management
should
ideally
involve

85. Neutrophil gelatinase
associated lipocalin (NGAL)
Asymmetric dimethylarginine
(ADMA)
liver-type fatty acidbinding
protein (L-FABP)

86. Other
investigations Urea
electrolytes (sodium, potassium, chloride,
bicarbonate)
calcium, phosphorus, alkaline
phosphatase, PTH, 25-hydroxy vitamin D
Hemoglobin

87. Urine
analysis
urine dipstick (pH, specific gravity, blood,
leucocyte esterase, nitrates, glucose and
protein),
urine protein to urine creatinine ratio,
urine albumin to creatinine ratio
urine microscopy (dysmorphic red blood
cells, white blood cells, white blood cell
casts, red blood cell casts, broad casts,
cellular casts and granular casts).

88. workup related to
the aetiology and
risk factors

89. Ultrasound of renal system.
Estimate size of the kidneys
Assess echogenicity
Corticomedullary differentiation
Extent of intact cortex
Rule out renal masses
Obstructive nephropathy.

90. Others renal duplex sonography of renal
vessels
radionuclide scintigraphy
magnetic resonance angiography
spiral computed tomography
scan

91. Renal
biopsy

92. Special Circumstances
Human
immunodeficiency
virus and CKD
CKD can range
between 2.4% and
10%
HIV associated
nephropathy (almost
50%).

93. CKD in
elderly Between 1988 and 1994
National Health and Nutrition
Examination Survey (NHANES)
study and the 2003–2006
NHANES study, the prevalence
of CKD in peopleages 60 and
older increased from 18.8 to
24.5 percent.

94. Evaluation and Management of Patients
with CKD Care of CKD patients
 Patients with CKD should receive
multidisciplinary comprehensive
clinical management by kidney
disease professionals for at least 6
months before requiring renal
replacement therapy (RRT).

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

96. When to refer patients
Referral to
nephrology
1) Acute kidney injury or abrupt sustained
fall in glomerular filtration rate (GFR).
2) GFR <30 ml/min/1.73 m2.
3) A consistent finding of significant
albuminuria

97. Referral to
nephrology
4) Rapid progression of CKD.
5) Presence of microscopic hematuria.
6) CKD and hypertension refractory to treatment with 4 or more
antihypertensive agents.
7) Persistent abnormalities of serum potassium.
8) Recurrent or extensive nephrolithiasis.
9) Hereditary kidney disease.
10) Abnormal structural findings in kidney on imaging.

98. NB
 Ambulatory blood pressure (particularly
nighttime blood pressure) has been found to
be a significant and an independent predictor
of renal function in both cross-sectional and
longitudinal studies.
 The other factors found to have association
with impaired renal function include elevated
nighttime blood pressure, non-dipping and
decreased circadian variation.

99.  Additionally, the risk for micro-
albuminuria was 70% lower in dippers
(night/day blood pressure ratio ≤ 0.90)
compared with non-dippers which
means that lowering nighttime blood
pressure in patients with CKD is
associated with decreased urinary
protein excretion and improvement in
renal function.

100. Nighttime blood
pressure also seems to
be a good predictor of
adverse cardiovascular
events in patients with
hypertension and CKD

101. NB
KDIGO guidelines suggest
measurement of serum total
calcium, phosphorus, 25-
hydroxyvitamin D, PTH, and
bone alkaline phosphatase as
baseline values if patients are
diagnosed with stage 3 CKD
(GFR 30-59 mL/min).

102. Measurement of
alkaline
phosphatase
should be done on
a regular basis

103.  Metabolic bone disease and laboratory
monitoring
a) For GFR categories G3a & G3b, serum
calcium, phosphorus every 6-12 mos and PTH
based on baseline level and CKD progression.
b) For GFR categories G4, serum calcium,
phosphorus every 3-6 mos and PTH every 6-12
months.
c) For GFR categories G5 (including dialysis),
serum calcium, phosphorus every 1-3 mos
and PTH every 3-6 months.

105.  Albuminuria
a) Assess Albuminuria at least annually
irrespective of the stage of kidney disease.
b) Assess albuminuria more often for individuals
at higher risk of progression, and/or
where measurement will impact therapeutic
decisions.
 Hemoglobin
a) CKD and GFR categories G1 &2 when
clinically indicated.
b) For GFR categories G3a & G3b: annually.
c) For GFR categories G4 &G5 twice per year.

106.  Key Question 1. In asymptomatic
adults with or without recognized risk
factors for CKD incidence,
progression, or complications, what
direct evidence is there that
systematic CKD screening improves
clinical outcomes?

107.  Key Question 2. What harms result
from systematic CKD screening in
asymptomatic adults with or without
recognized risk factors for CKD
incidence, progression, or
complications?

108.  Key Question 3. Among adults with
CKD stages 1–3, whether detected by
systematic screening or as part of
routine care, what direct evidence is
there that monitoring for worsening
kidney function and/or kidney damage
improves clinical outcomes?

109.  Key Question 4. Among adults with
CKD stages 1–3, whether detected by
systematic screening or as part of
routine care, what harms result from
monitoring for worsening kidney
function and/or kidney damage?

110.  Key Question 5. Among adults with
CKD stages 1–3, whether detected by
systematic screening or as part of
routine care, what direct evidence is
there that treatment improves clinical
outcomes?

111.  Key Question 6. Among adults with
CKD stages 1–3, whether detected by
systematic screening or as part of
routine care, what harms result from
treatment?

113. Consider discussion with nephrologist by
phone or letter if you feel clinic referral may
not be necessary
Single clinic visit with agreed management
plan and specified criteria for re-referral may
be all that is necessary