Integrated Therapeutics

- II for Year IV
Pharmacy1 Students:

Pharmacotherapy of Renal Disorders

Tigestu Alemu, B.Pharm, MSc in

Clinical Pharmacy

Email: tgfrekidan16@gmail.com

Addis Ababa University,

School of Pharmacy
Tigestu A. 11/24/2017
 Seminar Presentation
2

 Acid-base disorders
 Disorders of fluid and electrolyte homeostasis
 Hemodialysis and peritoneal dialysis
 Cardiovascular testing
 Cardiopulmonary Resuscitation
 Hyperlipidemia

Tigestu A. 11/24/2017
 Pharmacotherapy of Renal Disorders
3

 Acute Kidney Injury (AKI)

 Drug Induced Kidney Disease(DIKD)

 Chronic Kidney Disease (CKD)

Tigestu A. 11/24/2017
Pharmacotherapy of4 Acute Kidney Injury
(AKI)

Tigestu A. 11/24/2017
 Group Work
5

 Please sit in Groups of 6, elect leader and rapporteur,

 Discuss on the following points and report to the class.

1. Please discuss on the physiologic functions of kidney and its

anatomical structures
2. Please define and classify acute kidney injury
3. Discuss the causes of AKI
4. What manifestations will a patient with AKI have? How do you
diagnose AKI?

5. Please discuss management practices of AKI

6. Can we prevent AKI and how?

11/24/2017
 Learning Objectives
6

 At the end of this session you will be able to:

 Identify patients at high risk of developing acute kidney injury
(AKI).
 Describe the pathophysiology and etiology of prerenal,
intrinsic, and postrenal AKI

 Monitor and assess the safety and efficacy of the therapeutic

plan for a patient with AKI.

 Devise strategies for adjusting medication therapy in the

setting of AKI

 Develop prevention and treatment strategies for the different

types of AKI
Tigestu A. 11/24/2017
 Introduction
7

Major physiologic functions of the kidney

 Fluid and electrolyte balance

 Acid-base balance

 Clearance of wastes and toxins

 Clearance of drugs

 Production of vitamin D ( activation of 1,25 dihydroxy

chole calciferol)
 Hormone production (erythropoietin)

Tigestu A. 11/24/2017
 Anatomy of the Renal System
8

Tigestu A. 11/24/2017
 Glomerular Architecture
9

Tigestu A. 11/24/2017
 Acute Kidney Injury: Definition
10

 AKI is an abrupt decrease in renal function (GFR) over a

period of hours to days,
 accumulation of nitrogenous waste products (azotemia)
 Increase in Scr & decrease in urine output.
 inability of kidney to maintain and regulate
 fluid, electrolyte, and acid–base balance

 Regardless of the definitions used, the clinician should

suspect AKI when the kidney is unable to regulate
 fluid, electrolyte, acid–base, or nitrogen balance, even in the
presence of a normal SCr concentration.

Tigestu A. 11/24/2017
 Acute Kidney Injury: Definition
11

 Kidney Disease: Improving Global Outcomes(KDIGO)

defines AKI as being present if any of the following three
criteria are met:
1. Increase in Scr by at least 0.3 mg/dL within 48 hours,
2. Increase in Scr by at least 1.5 times baseline within the prior 7
days, or
3. Decrease in urine volume to less than 0.5 mL/kg/h for 6
hours.

Tigestu A. 11/24/2017
 Rifle Classification Schemes for Acute Kidney Injury
12

RIFLE Scr or GFR criteria Urine output

category criteria

Risk Scr to 1.5-fold or GFR >25% from baseline <0.5 mL/kg/h for 6 h

Injury Scr to 2-fold or GFR >50% from baseline <0.5 mL/kg/h for 12 h

Failure Scr to 3-fold or GFR >75% from baseline, or Anuria for 12 h
Scr 4 mg/dL with an acute increase of at least
0.5 mg/dL

Loss Persistent acute renal failure = complete loss of

function (RRT) for >4 weeks

ESKD RRT >3 months

Tigestu A. 11/24/2017
 AKIN Classification Schemes for Acute
Kidney Injury
13

AKIN criteria Scr criteria Urine output criteria

Stage 1 Scr increase 0.3 mg/dL or <0.5 mL/kg/h for 6 h
1.5- to 2-fold from baseline

Stage 2 Scr increase >2- to 3-fold <0.5 mL/kg/h for 12 h

from baseline

Stage 3 Scr increase >3-fold from <0.3 mL/kg/h for 24 h or

baseline or Scr 4 mg/dL anuria for 12 h
(354 mol/L), with an acute
increase of at least 0.5
mg/dL (44 mol/L) or need
for RRT

Tigestu A. 11/24/2017
 Epidemiology
14

Incidence and Outcomes of Acute Kidney Injury

Community-Acquired Hospital-Acquired ICU-Acquired AKI
AKI AKI
Incidence Low (<1%) Moderate (7–20%) High (35–70%)
Cause Single Single or multiple Multifactorial
Overall mortality 15% 15–40% 30–90%
rate (%)
Common risk Poor fluid intake, Volume depletion, Sepsis/septic shock,
factors dehydration, hypotension, low major surgery,
drugs (ACEIs, ARBs, cardiac output, multiorgan failure,
diuretics, NSAIDs, nephrotoxic drugs, hypotension, low
chemotherapy), radiocontrast dyes cardiac output,
infection, trauma, nephrotoxic drugs
rhabdomyolysis

Tigestu A. 11/24/2017
 Etiology and Pathophysiology
15
 The production and elimination of urine requires three
basic physiologic events.

 Blood flow to the glomeruli

 The formation and processing of ultrafiltrate by the
glomeruli and tubular cells
 Urine excretion through the ureters, bladder, and urethra

 Any condition that alter the above physiologic events

leads to AKI.

Tigestu A. 11/24/2017
 Etiology and Pathophysiology
16
AKI may be due to:
 Prerenal AKI (prerenal azotemia) (~55%)
 Diseases that cause renal hypoperfusion without
compromising the integrity of renal parenchyma;

 Intrinsic renal AKI (renal azotemia) (~40%):

 Diseases that directly involve renal parenchyma; and

 Post renal AKI (post renal azotemia) (~5%):

 Diseases associated with urinary tract obstruction.

Tigestu A. 11/24/2017
 Etiology and Pathophysiology
17

Tigestu A. 11/24/2017
Tigestu A. 18 11/24/2017
 Prerenal AKI
19

 Risk factors for prerenal AKI are

 CHF with poor cardiac output
 Decreased effective circulating volume

 Impaired renal perfusion

 NSAIDs, ACEIs, ARBS

 Liver disease, the elderly, or dehydrated patients

 Dehydration, over diuresis, poor fluid intake, low-sodium

diet, acute blood loss (hemorrhage), Hypoalbuminemia

Tigestu A. 11/24/2017
 Prerenal AKI
20

 Indomethacin is associated with the highest risk of NSAIDs-

induced renal ischemia,
 Aspirin has the lowest risk.

 Naproxen, ibuprofen, piroxicam, and diclofenac have

intermediate risk of renal ischemia.

 COX-2 inhibitors also inhibit prostaglandin synthesis,

Similar renal effect with that of NSAIDs

Tigestu A. 11/24/2017
 ACEIs and ARBs-Induced AKI
21

 Inhibition of the RAAS in patients with compromised renal

blood flow is a common cause of functional AKI
 AT-II induces two physiologic events to improve renal
perfusion

 Directly causes systemic vasoconstriction which shunts blood

to the major organs, and
 Indirectly increases intravascular volume through aldosterone-
and vasopressin-mediated activity

 vasoconstriction of the efferent renal arteriole to maintain

adequate intraglomerular hydrostatic pressure.
Tigestu A. 11/24/2017
 ACEIs and ARBs-Induced AKI
22

 The administration of ACE inhibitors directly inhibits the

formation of AT II, which is necessary for efferent arteriole
vasoconstriction.

 The compensatory physiologic event that maintains renal

blood flow is inhibited, thereby reducing intraglomerular
hydrostatic pressure and GFR.

11/24/2017
Tigestu A.
 ACEIs - and ARBs-Induced AKI
23

 ACE inhibitors are contraindicated in patients with

 bilateral renal artery stenosis or
 unilateral stenosis in patients with a single functioning kidney.

 AKI can be averted by

 withholding the ACE inhibitor or diuretic, or both for a day and
 repleting the intravascular fluid volume with a saline-
containing fluid (e.g., normal saline or 0.45% saline).

 The ACE inhibitor can be restarted at the same dose after

adequate hydration

Tigestu A. 11/24/2017
 ACEIs - and ARBs-Induced ARF
24

 ACE inhibitors can decrease the mean arterial pressure to

such a degree that renal perfusion cannot be sustained.
 This is more likely to occur with long-acting agents or
 in situations in which the pharmacologic half-life of the ACE
inhibitor is prolonged

 ACEIs may precipitate AKI in patients:

 taking concomitant drugs with renal afferent arteriole
vasoconstricting effects,
 most notably cyclosporine and NSAIDs

Tigestu A. 11/24/2017
 ACEIs and ARBs Induced ARF
25
 Once an ACEI is initiated, an increase in Scr of 20% to 30%
can be expected.
 typically normalizes within 2 to 3 months.
 Scr rises greater than this along with reduced urine output
signal AKI

 AKI related to ACEIs is usually reversible,

 the AKI is caused by inadequate glomerular capillary pressure,
which is restored as soon as sufficient AT II is produced

 Few differences are seen in the incidence of AKI between

ACEIs and ARBs, and one should not be interchanged with
the other in an attempt to decrease ARF risk.
Tigestu A. 11/24/2017
 Intrinsic AKI
26

 Intrinsic AKI is a general term that connotes damage at the

parenchymal level of the kidney.

 The term acute tubular necrosis (ATN) is often used to

describe this type of AKI,
 this is a histologic diagnosis that describes only one of several
intrinsic disorders.

Tigestu A. 11/24/2017
 Intrinsic AKI : Acute Tubular Necrosis
27

 ATN arises most often from ischemia or drug-induced

causes.
 Prolonged prerenal conditions, such as hypotension, surgery,
overwhelming sepsis, or major burns, can lead to ischemic
ATN.

 Unlike prerenal azotemia, tubular cell death occurs in ATN,

and immediate volume resuscitation will not reverse the
damage.

 The pathophysiology of ATN is complex and remains unclear

Tigestu A. 11/24/2017
 Intrinsic AKI : Acute Tubular Necrosis
28

 It is currently thought that when tubular cells die, they

slough off into the tubule lumen and contribute to cast
formation.

 The casts completely obstruct the tubule lumen and

increase intratubular pressure, which causes a back leak
of ultrafiltrate across the tubular basement membrane

Tigestu A. 11/24/2017
 Prevention of KI
29

 The preventive strategy will depend on the type of renal

insult.
 Complete avoidance of all potential causes of injury is the
most effective preventive method;
 however, it may not always be possible to implement.
 In outpatients,
 Educate on optimal daily fluid intake (˜2 L/day) to avoid
dehydration, especially if they are to receive a potentially
nephrotoxic medication.
 In inpatients,
 adequate hydration, standardized hemodynamic support in the
critically ill, and
 avoidance of nephrotoxic medications

Tigestu A. 11/24/2017
 Prevention of AKI : Desired Outcome
30

 The goals of AKI prevention are to

(a) screen and identify patients at risk,

(b) monitor high-risk patients until the risk has subsided, and
(c) implement prevention strategies when appropriate

Tigestu A. 11/24/2017
 Prevention :Nonpharmacologic Therapy
31

 Hydration
 KDIGO guidelines recommend isotonic crystalloids over
colloids for intravascular volume expansion in patients at risk
for AKI

 Sodium bicarbonate or NS infusion for the prevention of

CIN.

Tigestu A. 11/24/2017
 Prevention: Pharmacologic Therapy
32

 Loop diuretics
 Limiting the use of loop diuretics to the management of
fluid overload and avoiding their use for the sole purpose
of prevention or treatment of AKI

 They neither reduce the incidence of AKI nor improve

patient outcomes, such as mortality, need for RRT, and
renal recovery.
 Some evidence of potential harm associated with their use,
 Ototoxicity & possibly mortality in certain clinical settings.

Tigestu A. 11/24/2017
 Prevention: Pharmacologic Therapy
33

 Proposed explanations for lack of benefit are twofold.

 may not be reaching the PCT due to tubular obstruction
from debris,
 increased extrarenal clearance secondary to
hypoalbuminemia,
 increased urinary protein binding due to albuminuria.

 may also decrease renal blood flow by reducing effective

circulating arterial volume, which, in turn, may stimulate
the adrenergic and the renin–angiotensin systems.

 No role of antioxidants (N-Acetylcysteine & Ascorbic Acid)

Tigestu A. 11/24/2017
 Prevention: Pharmacologic Therapy
34

 Insulin therapy
 Current KDIGO guidelines suggest using insulin therapy to
target plasma glucose of 110 to 149 mg/do

 The recovery process for ATN typically occurs within 10 to

14 days after insult resolution.
 may be prolonged if the kidney is exposed to repeated
insults

Tigestu A. 11/24/2017
 The role of diuretics and dopamine in
treating established ATN
35

 It is well documented that patients with nonoliguric renal

failure have significantly better outcomes compared with
those with oliguria.

 probably because patients who are nonoliguric have less

extensive renal damage and are better able to maintain fluid
and electrolyte balance.

 Numerous clinical trials have failed to demonstrate

improved mortality or duration of azotemia in oliguric
patients who receive loop diuretics.

Tigestu A. 11/24/2017
 The role of diuretics and dopamine in
treating established ATN
36
 Two large systematic reviews of the primary literature
convincingly showed that
 diuretic therapy plays little role in:
 altering the course of ARF,
 decreasing length of hospitalization, or
 helping recover renal function

 although patients who are nonoliguric generally have better

outcomes, converting a patient from oliguria to nonoliguria
through pharmacologic intervention does not improve
patient outcomes.

Tigestu A. 11/24/2017
 The role of diuretics and dopamine in
treating established ATN
37

 Currently, the only role that diuretic administration has in

patients with established ATN is to increase urine output,
which facilitates fluid, electrolyte, and nutritional support.

 Dopamine is a catecholamine that stimulates dopaminergic

receptors at low dosages (1–3 mcg/kg/minute), and α- and
β-receptors at higher dosages (5–20 mcg/kg/minute).

 Low-dose dopamine improves renal blood flow by inducing

afferent arteriolar vasodilation.

Tigestu A. 11/24/2017
 The role of diuretics and dopamine in
treating established ATN
38

 A recent meta-analysis of 61 clinical trials including nearly

3,500 patients failed to detect any significant improvement
in variables such as
 occurrence of ARF, need for renal replacement therapy, or
mortality.

 Unequivocally, dopamine has no role in preventing or

treating ARF.

Tigestu A. 11/24/2017
 Post renal Acute Renal Failure
39

 Any condition that results in the obstruction of urine flow at

any level of the urinary tract is termed post renal ARF.

 Common causes of post renal ARF:

 stone formation,
 underlying malignancies of the prostate or cervix,
 prostatic hypertrophy, or
 bilateral ureter strictures

Tigestu A. 11/24/2017
 Post renal Acute Renal Failure
40

Tigestu A. 11/24/2017
 Post renal Acute Renal Failure
41

 Conditions that result in bladder outlet obstruction

(e.g.,prostatic hypertrophy) are the most common causes of
post renal ARF.

 The onset of signs and symptoms is generally gradual;

 often presents as decreased force of urine stream, dribbling, or
polyuria.

 Drugs can also result in insoluble crystal formation in the

urine and should be included in the differential diagnosis.

Tigestu A. 11/24/2017
 Diagnostic Parameters for Differentiating
Causes of Acute Kidney Injury
42
Laboratory Test Prerenal Acute Intrinsic Postrenal
Azotemia Kidney Injuryb Obstruction

Urine sediment Hyaline casts, may Graunular casts, Cellular debris

be normal cellular debris
Urinary RBC None 2–4+ Variable
Urinary WBC None 2–4+ 1+
Urine Na (mEq/L or <20 >40 >40
mmol/L)
FENa (% [fraction]) <1 [<0.01] >2 [>0.02] Variable

Urine/serum osmolality >1.5 <1.3 <1.5

Urinecr/Scr >40:1 <20:1 <20:1

BUN/Scr (SI units) >20 (<1:12.4) 15 (1:16) 15 (1:16)

Urine-specific
Tigestu A. gravity >1.018 <1.012 Variable 11/24/2017
 Drug-Induced Nephrolithiasis
43

 Many commonly prescribed drugs are insoluble in urine and

crystallize in the distal tubule.

 Risk factors that predispose patients to crystaluria

 severe volume contraction,
 underlying renal dysfunction, or
 acidotic or alkalotic urinary pH

 In conditions of renal hypoperfusion, high concentrations of

drug become stagnant in the tubule lumen.

Tigestu A. 11/24/2017
 Drug-Induced Nephrolithiasis
44

 Drugs that are weak acids (e.g., methotrexate, sulfonamides)

precipitate in acidic urine;
 drugs that are weak bases (e.g., indinavir, other protease
inhibitors) precipitate in alkaline urine.

 Prevention of crystal-induced ARF is targeted at

 dosage adjustment for patients with underlying renal
dysfunction,
 volume expansion to increase urinary output, and
 urine alkalization.

Tigestu A. 11/24/2017
 Drug-Induced Nephrolithiasis
45

 Similarly, for established crystal-induced ARF,

 the above general supportive measures of urinary alkalization
and volume expansion should be performed.

 Dialysis may be necessary in a small percentage of patients.

 With appropriate pharmacotherapy, crystal-induced ARF is

usually reversible without long-term complications.

Tigestu A. 11/24/2017
 Supportive Management of ARF
46

 Despite years of study, no pharmacologic “cure” for AKI

exists.

 Supportive therapy is directed at preventing its morbidity

and mortality.
 close patient monitoring;
 strict fluid, electrolyte, and nutritional management;
 treatment of life-threatening conditions, such as
 pulmonary edema, hyperkalemia, and metabolic acidosis;
 avoidance of nephrotoxic drugs; and
 the initiation of dialysis or continuous renal replacement
therapies (CRRT).

Tigestu A. 11/24/2017
 Diuretics for Edema in ARF
47
 Diuretics
 currently have no role in preventing ARF progression or reducing
mortality,
 but they can prevent complications, such as pulmonary and
peripheral edema, and they may prevent tubular obstruction from
ATN.

 If edema occurs, intravenous (IV) furosemide is preferred

because of its potency and pulmonary vasodilation properties.

Tigestu A. 11/24/2017
 Diuretics for Edema in ARF
48

 Oral furosemide therapy should be avoided because gut

edema may limit its bioavailability.

 Torsemide, another loop diuretic, has excellent oral

bioavailability and is unaffected by gut edema.

 Furosemide is highly protein bound, and thus binds to

filtered protein, which negates its pharmacologic effect on the
kidneys.

 Combinations of loop and thiazide diuretics may be needed in

patients with ARF if they become diuretic resistant.
Tigestu A. 11/24/2017
 Evaluation of Therapeutic Outcomes:
Monitoring Parameters
49
Parameter Frequency

Fluid ins/outs Every shift

Patient weight Daily
Hemodynamics (BP, HR, MAP, etc.) Every shift
Blood chemistries
Na+, K+, Cl-, bicarbonate, Ca2+, phosphate, Mg Daily
BUN/creatinine Daily
Drugs and their dosing regimens Daily
Nutritional regimen Daily
Blood glucose Daily (minimum)
Times of administered doses Daily
Urinalysis Every time measured urine
Calculate measured creatinine clearance collection performed
Calculate fractional excretion of sodium
Plans for renal replacement Daily
Tigestu A. 11/24/2017
 Case studies
50
 A 53-year-old woman presented to the emergency department
with a cough, fever, and yellow sputum production for 1 week. On
PE, she had crackles in the left lower and middle lung zones, and
the patient experienced pain on inspiration. Serum: Na, K and
BUN and creatinine were normal. The patient was admitted and
treated with I.V. antibiotics. On the day after admission, her BP
dropped to 90/75 mm Hg, and she became confused. After I.V.
administration of normal saline, her BP increased to 105/70 mm
Hg and there was improvement in the patient's mental status.
The patient's temperature was 39.5 0C). Gentamicin was added.
Six hours later, the patient's creatinine level was 2.1 mg/dl, and
her BUN was 32 mg/dl.
 What is the most likely cause of the increase in this patient's
creatinine level?
Tigestu A. 11/24/2017
 Case studies
51

 A.M. is a 54-year-old man who weighs 95 kg. He was admitted

to surgical ward two days ago for an emergency appendectomy.
He has type 2 diabetes and receives metformin and insulin. He
has chronic kidney disease Stage 3 with proteinuria for which he
is taking Enalapril 10 mg daily. His latest serum creatinine
taken preoperatively was 1.7 mg/dL. He also takes omeprazole
20 mg when required for indigestion. Prior to his emergency
appendectomy he was given gentamicin 300 mg and
metronidazole 500 mg. During the operation he was found to
have a perforated appendix and was prescribed a five-day
course of co-amoxiclav postoperatively. You visit your ward to
review AM’S antibiotics and are told by the nursing staff that he
is now in a side room as he has developed Clostridium difficile.
You recommend Scr test and find it is now 2.4 mg/dL.
Tigestu A. 11/24/2017
 Case studies
52

 What risk factors does A.M. have for developing

acute kidney injury?
 Has A.M. developed hospital-acquired acute kidney
injury? (Justify)

Tigestu A. 11/24/2017
 Case studies
53

 After all the necessary interventions A.M. was discharged

from hospital five days ago following admission for an
emergency appendectomy, after which he developed
acute kidney injury.
 He would like some advice about which medicines he
should be taking and is requesting a repeat prescription.
 His discharge Medications were: Insulin 18IU sc bid,
Gentamicin 300mg IV stat, Metformin 500g BID,
omeprazole 20 mg bid, Co-amoxiclav 1.2g po bid,
metronidazole 500mg IV stat, Enalapril 5mg po bid,
UFH 5000IU Sc bid.

Tigestu A. 11/24/2017
 Case studies
54

 What changes to his medicines would you

recommend at this time?
 What actions would you take regarding continuing or
discontinuing A.M’s medicines?


Tigestu A. 11/24/2017
 Chronic Kidney55 Disease (CKD)

Tigestu A. 11/24/2017
 Learning Objectives
56

 At the end of this session, you will be able to:

 Define and differentiate between CKD & CRF
 Differentiate the different classes of CKD

 Differentiate the different risk factors and etiologies of

CKD
 Analyze the pathophysiology of CKD

 Identify the complications of CKD

 Identify the clinical manifestations and analyze the

diagnostic modalities of CKD
 Develop preventive and treatment strategies for CKD

Tigestu A. 11/24/2017
 Introduction: Assessment of functional
status of the kidneys
57
 Done by estimation of GFR
 Cockcrouft-Gault Equation
GFR= (Age-140) * BW in KG
72 *Se Cr in mg/dl
 Multiply by 0.85 for women

 Normal GFR ranges from 90 to 125 ml/min/1.73 m2.

 Peak is 120 ml/min/1.73 m2, at 3rd decade of life.
 There is a gradual decline by ~1 mL/min/year /1.73 m2 after
that.
 Mean value of GFR at age 70 years is 70 mL/min per 1.73 m2
 The mean GFR is lower in women than in men at any age.

Tigestu A. 11/24/2017
 Definitions
58

 Chronic kidney disease (CKD) is a progressive deterioration

in kidney function ultimately leading to irreversible
structural damage to existing nephrons.
 Classically develops over a period of years

 Clinically it refers to kidney damage for ≥3 months, as

defined by structural or functional abnormalities of the
kidney, with or with out decreased GFR.

 Based on the progressive nature of this condition, a staging

system has been established to classify kidney disease
according to the GFR
Tigestu A. 11/24/2017
 Classification of CKD
59

Stage GFR, mL/min per 1.73 m2

0 >90 (With risk factors for CKD)

1 ≥90 (With demonstrated kidney damage. e.g., persistent

proteinuria, abnormal urine sediment, abnormal
blood & urine chemistry, abnormal imaging studies).

2 60–89

3 30–59

4 15–29

5 <15 (death is inevitable without RRT)

Tigestu A. 11/24/2017
 Classification of CKD
60

 Chronic renal failure (CRF)

 applies to the process of continuing significant irreversible
reduction in nephron number
 typically corresponds to CKD stages 3–5

 End-stage renal disease

 a stage of CKD where the accumulation of toxins, fluid, and
electrolytes normally excreted by the kidneys results in the
uremic syndrome.
 This syndrome leads to death unless the toxins are removed by
renal replacement therapy, using dialysis or kidney
transplantation.

Tigestu A. 11/24/2017
 Epidemiology
61

 The CKD prevalence is similar to that of other chronic

conditions such as hypertension, diabetes mellitus, and
cardiovascular disease.

•CKD is at least 3–4 times more frequent in Africa than in developed

countries.

•Hypertension is a cause of CRF in 21% of cases in Africa.

Tigestu A. 11/24/2017
 Risk Factors & Etiology of CKD
62
 Susceptibility
 Advanced age
 Reduced kidney mass and low birth weight
 Racial/ethnic minority
 Family history
 Low income or education
 Systemic inflammation & dyslipidemia

 Initiation
 Diabetes mellitus, Hypertension, Glomerulonephritis

 Progression
 Hyperglycemia (among diabetic patients)
 Hypertension, Proteinuria, Obesity, Smoking
Tigestu A. 11/24/2017
 Proteinuria
63

 Proteinuria is predictive of disease progression.

 With glomerular damage, proteinuria is commonly observed
 Proteinuria may precede elevations in SeCr and should be
considered as an early marker of kidney damage.
 The presence of albuminuria indicates irreversible kidney damage.

 Micro-albuminuria
 an albumin excretion rate of 20 to 200 mcg/minute or 30 to 300
mg/24 hr.
 Proteinuria
 a total protein excretion rate >200 mcg/minute or >300 mg/24 hour
(referred to as albuminuria if albumin is the only protein measured).

Tigestu A. 11/24/2017
 Common causes of CKD
64

Tigestu A. 11/24/2017
 Pathophysiology of CKD
65

 The pathophysiology of CKD involves two broad sets of

mechanisms of damage:

(1) Initiation mechanisms

 conditions that directly result in kidney damage and are
modifiable by pharmacologic therapy.
 Diabetes mellitus, hypertension, autoimmune diseases,
 polycystic kidney disease, systemic infections,
 urinary tract infections,
 urinary stones, lower urinary tract obstruction, and
nephrotoxicity
 genetically determined abnormalities in kidney development or
integrity,
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 Pathophysiology of CKD
66

 Approximately 20% to 40% of those with diabetes mellitus

will develop diabetic CKD
 Diabetics have a 12-fold greater relative risk of developing
stage 5 CKD than those without diabetes

 A systolic blood pressure of 180 mm Hg was associated

with a 14 mL/min per year decline in GFR

 Only a 2 mL/min per year decline in GFR among those with

a systolic blood pressure of 135 mm Hg.

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 Pathophysiology of CKD
67

(2) Progression mechanisms,

 associated with further declines in renal function.
 Persistence of the underlying initiation factors
 hyperfiltration and hypertrophy of the remaining viable
nephrons as adaptive mechanisms,
 mediated by vasoactive hormones, cytokines, and growth factors.

 Eventually, these short-term adaptations of hypertrophy and

hyperfiltration become maladaptive
 the increased pressure and flow predisposes to distortion of
glomerular architecture,
 with sclerosis and dropout of the remaining nephrons.

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 Pathophysiology of CKD
68

 Increased intrarenal activity of the RAAS axis

 Contributes both to the initial adaptive hyperfiltration and to
the subsequent maladaptive hypertrophy and sclerosis,
 This process explains why a reduction in renal mass from an
isolated insult may lead to a progressive decline in renal function
over many years

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 Pathophysiology of CKD
69

Tigestu A. 11/24/2017
 70

Tigestu A. 11/24/2017
 Pathophysiology
71
 High intraglomerular apillary pressure impairs the size-
selective function of the glomerular permeability barrier,
 increased urinary excretion of albumin and frank proteinuria
 Proteinuria promotes progressive loss of nephrons as a result of
direct cellular damage

 Filtered proteins such as

 albumin,
 transferrin,
 complement factors,
 immunoglobulins,
 cytokines and angiotensin II are toxic to kidney tubular cells
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 Complications of CKD
72

 Complications begin to develop as kidney disease progresses,

 most often when patients reach to stage 3 CKD and the GFR is
<60 mL/minute/1.73 m2.
 Volume overload
 Hyponatremia or hypernatremia, hyperkalemia
 Metabolic acidosis
 Anemia –due to EPO deficiency, RBC survival, chronic
inflammation
 Stress/Peptic ulcer
 poor nutritional status
 Vitamin D–deficiency
 Hyperphosphatemia
 Secondary hyperparathyroidism
 hypocalcemia


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 Complications of CKD
73

Pathogenesis of renal osteodystrophy.

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 Complications of CKD
74

 Cardiovascular disease is the leading cause of morbidity

and mortality in patients at every stage of CKD.

 Common cardiac complications of CKD are:

 Hypertension
 Congestive heart failure
 Pulmonary edema
 Pericarditis

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 Clinical Manifestations
75

 Symptoms are uncommon even until over 70% of the

normal function of both kidneys is lost.
 Initial manifestations are only as a biochemical
abnormality.
 The symptoms of CKD often develop slowly and are
nonspecific.

 Individuals can remain asymptomatic until kidney disease

is far advanced (GFR < 10–15 mL/min).

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 Clinical manifestations
76

 Nocturia, due to the loss of concentrating ability and

increased osmotic load, is often an early symptom.

 Non-specific symptoms include:

 Fatigue, weakness, and malaise.
 GI complaints, such as
 anorexia, nausea, vomiting, a metallic taste in the mouth, and
hiccups are common.

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 Investigations
77

 The diagnosis of CKD is made by documenting elevations

of the BUN and serum creatinine concentrations.
 Serum concentrations of :
 Na+, K+, Ca2+, phosphate, and PTH
 Investigations should focus on a search for underlying or
aggravating conditions.
 Hepatitis virus tests
 HIV serology
 SLE
 Diabetes mellitus
 Urinalysis

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 Investigations
78

 Ultrasound of kidneys is essential

 Patients often have bilateral small kidneys at presentation

Common exceptions are:

• Diabetic nephropathy, amyloidosis, HIV nephropathy -normal
size kidney in the face of CKD.
• Polycystic kidney disease - enlarged kidneys with multiple
cysts
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 Investigations
79

 Other important investigations

 Complete blood count
 Iron, Vit B12, and folate level.
 A 24-h urine to assess proteinuria
 Serum albumin
 Lipids level
 Blood glucose ± HbA1c
 Chest X-ray
 ECG

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 Treatment
80
Goal of Therapy
 The goal of therapy is to delay
 the progression of CKD, thereby minimizing the development
or severity of associated complications
 cardiovascular disease and ultimately limiting the progression
to ESRD.

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 Treatment
81

 Principles of management of CKD:

 Treatment of reversible causes of renal dysfunction
 Preventing or slowing the progression of renal disease

 Treatment of the complications of renal dysfunction

 Identification and adequate preparation for renal
replacement therapy

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 Nonpharmacologic Therapy
82

 Proteinuria is the most significant predictor of ESRD in T 2

DM patients & early CKD.
 Dietary protein restriction on the progression of CKD has
only a relatively small benefit

 Protein restriction to 0.8 g/kg/day is recommended only in

patients with an eGFR <30 mL/min/1.73 m2 with
appropriate monitoring

 Decreasing salt intake to <2 g or 5 g NaCl per day (90mEq),

particularly in patients with hypertension or proteinuria
 Smoking Cessation & Weight management (reduction)
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 Pharmacologic Therapy
83

 ACEI and/or an ARB should be used as first-line therapy if

the urine albumin excretion or equivalent test is >30 mg/24
h
 The dose is usually increased until albuminuria is reduced
by 30% to 50% or side effects such as a significant drop in
eGFR or elevation in serum potassium occur

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 Pharmacologic Therapy
84

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 ACEIs & ARABS in CKD
85

 For patients with DM and microalbuminuria,

 Progression to proteinuria was reduced by 65%

 For both diabetics and nondiabetics with macroalbuminuria

 progression of CKD (doubling of Scr) was reduced by 40%

 In CKD, the red blood cell life span is decreased, so

HgbA1C values may be falsely low.
 The HgbA1C should be interpreted along with the
patient’s home

 blood glucose readings before making a determination of

diabetic control. It is also important to note that patients
with stage 3 and 4 CKD are at higher risk of developing
hypoglycemia because the kidney metabolizes insulin.
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 ACEIs & ARABS in CKD
86

 The clearance of all ACEIs (except fosinopril) is reduced in

CKD; therefore, it is necessary to initiate therapy at lower
initial doses and subsequently titrate the dose to achieve the
optimal therapeutic effects such as decreased proteinuria
and lowering of BP.

 The antiproteinuric effects of ACEIs/ARBs are not

necessarily attained at the same doses as the
antihypertensive effects.

 Thus, individualization of therapy is required for patients

who have reached their BP goals yet require further
reductions in urinary protein excretion.
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 Pharmacologic Therapy:
optimal Hypertension control
87

 Elevated BP is often more difficult to control for patients

with CKD than for those with normal kidney function.
 to achieve adequate BP goals (≤130/80) may require three or
more different blood pressure medications
 Aldosterone escape ---????

 Some CCBs decrease glomerular injury without negatively

changing renal hemodynamics.
 The postulated mechanisms;
 suppression of glomerular hypertrophy,
 inhibition of platelet aggregation, and
 decrease in salt accumulation.
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 Pharmacologic Therapy:
optimal Hypertension control
88

 Nondihydropyridine agents (diltiazem and verapamil) have

beneficial effects on proteinuria, although not as
profoundly as ACEIs.
 These agents have been used to reduce proteinuria when
used in combination with an ACEI or ARB despite the fact
that data are limited to support this strategy.

 nondihydropyridine CCBs are used as second-line

antiproteinuric drugs when an ACEI or ARB is
contraindicated or not tolerated

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 Evaluation of Therapeutic Outcomes
89

 The monitoring necessary for patients with hypertension

and diabetes is the same in the CKD population as it is in
the non-CKD population

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 Recommended Outcome Measure
Monitoring Intervals for Patients with CKD
90

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 Statins in CKD
91
 Lipid management in CKD treatment with a statin is
recommend in:
 adults ≥50 years old with stage 1 to 5 CKD (not on dialysis).

 KDIGO only recommends statins in adults aged 18 to 49

years with stage 1 to 5 CKD (not on dialysis) who have one
or more of the following:
 Known coronary disease,
 diabetes mellitus,
 prior ischemic stroke, and
 an estimated 10-year incidence of coronary death or
 nonfatal MI >10%.

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 Statins in CKD
92

 It is not recommended that statins or statin/ezetimibe be

initiated in patients with stage 5 CKD on dialysis;
 however, therapy with these agents may be continued if
patients were receiving these medications at the time of
dialysis initiation.
 Due to the risk of adverse events with statins and absence
of safety data in patients with stage 3 to 5 CKD, KDIGO
recommends using statins at doses shown to be
beneficial in randomized studies conducted in this
population (e.g., atorvastatin 20 mg, fluvastatin 80 mg,
rosuvastatin 10 mg, simvastatin 20 mg

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 Treatment of Dyslipidemia
93

 Lipoprotein metabolism is altered early in the course of

kidney disease and
 becomes pronounced with more advanced disease, making
hyperlipidemia common in patients with CKD.

 Elevated triglyceride, total cholesterol, LDL cholesterol, and

decreased HDL cholesterol levels are generally observed.

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 Treatment of Dyslipidemia
94
 Statin therapy,
 decreased proteinuria and preserved GFR in a small number of
patients with CKD.

 A meta-analysis of trials, predominantly in DM and CKD

patients, showed that lipid-lowering therapy slowed the rate
of decline in GFR.

 Despite uncertainty of therapy to delay progression,

treatment of dyslipidemia should be considered,
 abnormal lipid metabolism predisposes patients to CVD.

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 Intensive Glucose Control
95
 Strict glycemic control
 to reduce proteinuria and to slow the rate of decline in GFR.

 One large RCT on T1 DM patients showed that;

 intensive insulin regimen (≥3 times insulin per day ) with a
goal FPG 70-120 mg/dl and postprandial PG<180 mg/dl,

 reduced the overall risk of microalbuminuria (defined as urine

albumin ≥40 mg/24 hours) by 39%, and
 albuminuria (defined as urine albumin ≥300 mg/24 hours) by
54%.

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 Intensive Glucose Control
96

 The effect of intensive glycemic control has also been studied

in patients with type 2 diabetes.

 Over a 10-year treatment period, glucose control with either

insulin or an oral sulfonylurea
 reduced microvascular complications, including albuminuria,
when compared with conventional dietary therapy.

 The recommended goals of BG in adult DM population are:

 a preprandial plasma glucose of 80 to 130 mg/dL,
 peak postprandial plasma glucose of <180 mg/dL, and
 an A1C <7%.
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 Anemia of Chronic Kidney Disease
97

 Anemia of CKD is caused by a decrease production of

erythropoietin (EPO)

 Anemia appears as early as stage 3 CKD

 characterized by normochromic and normocytic RBCs unless a
concomitant iron, folate, or B12 deficiency exists.

 A direct correlation between GFR and hematocrit

 a 3.1% decrease in hematocrit for every 10 mL/minute/1.73 m2
decline in GFR.

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 Anemia of Chronic Kidney Disease
98

 Complete workup for anemia of CKD is recommended for

patients with GFR of <60 mL/minute/1.73 m2.

 Monitor for
 Hgb and Hct,
 assess iron indices with correction if iron deficiency is present, &
 evaluate for sources of blood loss, such as bleeding from the GIT.

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 Anemia of CKD Treatment
99

 Recombinant human EPO to directly stimulate erythrocyte

production
 However, iron deficiency is the leading cause of
erythropoiesis stimulating agent (ESA) hyporesponsiveness
and must be corrected before ESA therapy is initiated.

 Iron deficiency can develop as a result of increased

requirements for RBC production with ESA administration

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 Anemia of CKD Treatment
100

Target Hemoglobin and Hematocrit

 a target of ≥11 g/dL for hemoglobin (≥33% for hematocrit)

in patients with CKD receiving ESA therapy.

Iron Status
 Because iron deficiency is the primary cause of ESA-
hyporesponsiveness, assessment of iron status is essential
before initiating erythropoietin therapy.

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 Prevention of CKD
101
 Adequate water intake
 Good personal hygiene, especially female to prevent UTI
 Balanced diet
 Avoid excessive salt and meat intake
 Avoid high intake of calcium – to prevent renal stones
 Good control of hypertension and diabetes
 Early and adequate treatment of UTI and renal stones
 Cautious drug administration including analgesics and
antibiotics
 Early detection of renal diseases by routine examination
of blood and urine
 Early treatment of kidney diseases

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 Summary
102

 What is the difference between CKD and CRF?

 How do you classify CKD?
 What are the risk factors and etiologies of CKD?
 How does the pathogenesis of CKD occur?
 What are the complications of CKD?
 What are the clinical manifestations and diagnostic
modalities of CKD?
 How do you prevent and treat CKD?

Tigestu A. 11/24/2017