Integrated Therapeutics-II

Chapter-1
Renal Disorders Pharmacotherapy
By Salahadin A.
 Outline
1. Acute Kidney Injury
2. Chronic Kidney Disease
3. Drug induced Renal Disease
4. Glomerulonephritis
5. Acid-base disorders
6. Disorders of fluid and electrolyte homeostasis

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1. ACUTE KIDNEY INJURY
(AKI)

Kirubel Minsamo, BPharm, MSc.

[Clinical Pharmacist]
 Learning Objectives
§ Upon completion of the Unit, the students will be able to:
§Assess a patient with acute kidney injury (AKI)
using clinical and laboratory data.
§Classify the extent of AKI in a patient.
§Distinguish between AKI resulting from prerenal
and intrinsic injury
§Justify appropriate therapeutic interventions for a
patient with AKI.

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 Introductory Case
§ A 73-year-old man with a history of DM, CKD, gout,
osteoarthritis, and HTN is hospitalized with possible urosepsis.
He recently completed a 10-day course of antibiotics and was
ready for discharge when his morning labs showed an increase
in BUN and serum creatinine concentration. Upon
examination, he was found to have 2+ pitting edema, weight
gain, nausea, elevated blood pressure, and rales on chest
auscultation. Then;
§ What sign & symptoms does the patient have that may
indicate AKI?
§ What risk factors does he have for the development of AKI?

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 Definition of AKI
 AKI is a clinical syndrome characterized by:
 Rapid decline in GFR (hours to days)
 Retention of nitrogenous waste products(e.g., creatinine
and urea nitrogen)
 with or without a decrease in urine output.
 AKI is defined as any of the following
 ↑ in SCr by≥0.3 mg/dl (≥26.5 lmol/l) within 48 hours; or
 ↑ in SCr to ≥1.5 times baseline, which is known or
presumed to have occurred within the prior 7 days; or
 Urine volume <0.5 ml/kg/h for 6 hours.

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 Classification and Staging of AKI
Three classification systems exist for staging severity
§ Acute Dialysis Quality Initiative (ADQI)
§ RIFLE criteria include five categories (Risk, Injury, Failure,
Loss, ESRD)
§ Define abrupt (1 to 7 days) but sustained (>24 hours)
decrease in renal function from baseline
§ Acute Kidney Injury Network (AKIN)
§ Three stages(Stage 1, Stage 2, and Stage 3)
§ Define abrupt (1 to 7 days) but sustained 48-hour period for
the decrease in renal function from baseline
§ Kidney Disease: Improving Global Outcomes (KDIGO):
§ Three stages(Stage 1, Stage 2, and Stage 3)
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 Classification and Staging
§ All system uses oliguric period of >6 hrs (<0.5 ml/kg/hr) as
minimum criteria
§ Anureic: <50ml/kg/24 hr (worse outcome)
§ Oliguric: 50-500 mL/kg/24 hrs
§ Non-oliguric: >500 mL/kg/24 hrs….better outcome

RIFLE UOP criteria AKIN AKIN criteria

category criteria
Risk <0.5 mL/kg/h for ≥ 6 h Stage 1 <0.5 mL/kg/h for ≥ 6 h
Injury <0.5 mL/kg/h for ≥ 12 h Stage 2 <0.5 mL/kg/h for ≥ 12 h
Failure Anuria for ≥ 12 h Stage 3 <0.3 mL/kg/h for ≥ 24 h or
anuria for ≥ 12 h

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9
 Epidemiology
 AKI occurs almost exclusively in hospitalized patients
 The incidence of community-acquired ARI is just 1%
 ICU patients have the highest risk of developing AKI
 Increased mortality and morbidity are two well-
recognized complications of AKI.
 The odds of death increase further with the severity of
the RIFLE category.
 Even though the majority of patients will recover
normal kidney function, 25% will have CKD, and
12.5% will remain dialysis-dependent
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Table: Incidence & Outcomes of Acute Kidney Injury
Community-Acquired Hospital-Acquired AKI ICU-Acquired AKI
AKI
Incidence Low (<1%) Moderate (7–20%) High (35–70%)
Cause Single Single or multiple Multifactorial
Mortality rate 15% 15–40% 30–90%
(%)
Common risk •Poor fluid intake •Volume depletion •Sepsis/septic shock
factors •Dehydration •Hypotension •major surgery
•drugs (ACEIs, ARBs, •low cardiac output •multiorgan failure
diuretics, NSAIDs, •nephrotoxic drugs •Hypotension
chemotherapy) •radiocontrast dyes •low cardiac output
•Infection, trauma •nephrotoxic drugs

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 Etiology and Pathophysiology
§ The causes of AKI have been categorized as
a. Prerenal (Prerenal Azotemia)
§ which results from decreased renal perfusion in the setting
of undamaged parenchymal tissue
b. Intrinsic (intrinsic renal ARI)
§ the result of structural damage to the kidney, most
commonly the tubule from a ischemic or toxic insult
c. Postrenal (postrenal ARI): caused by obstruction of
urine flow downstream from the kidney

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13
HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura 14
 Clinical Presentation and Diagnosis

· Signs and Symptoms of Uremia

None specific:
• Peripheral edema, Weight gain,
Nausea/vomiting/diarrhea/anorexia, Mental status changes,
Fatigue, Shortness of breath, Pruritus
Specific
• Volume depletion, Weight loss (prerenal AKI)
• Anuria alternating with polyuria and Colicky abdominal pain
radiating from flank to groin(postrenal AKI)

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 Clinical Presentation and Diagnosis…..

· Physical Examination Findings

None specific:
• Hypertension, Jugular venous distention, Pulmonary edema
Specific:
• Hypotension/orthostatic hypotension (prerenal AKI)
• Rash (acute interstitial nephritis)
• Bladder distention (postrenal bladder outlet obstruction)
• Prostatic enlargement (postrenal AKI)

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 Complications of AKI

 Hyperkalemia(reduced excretion + increased intercellular

K release…. Tissue damage, acidosis)
 Metabolic acidosis
 Hyperphosphatemia and hypocalcemia(rare)
 Anemia……..decreased EPO production and bleeding
 Uremic bleeding……urea interferes platelet function
leading to increased bleeding
 Infection is a common and serious complication of AKI

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 Prevention and Treatment of AKI
§ Desired Outcomes
§Short-term goals
§ minimizing the degree of insult to the kidney
§reducing extrarenal complications, and
§ expediting the patient’s recovery of renal function.
§The ultimate goal
§ to have the patient's renal function restored to his
or her pre-AKI baseline.

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 Prevention of AKI
§ Risk factors Identification:
§ advanced age, acute infection, preexisting chronic
respiratory or cardiovascular disease, dehydration, CKD,
Surgery, acute blood loss in trauma
§ Nephrotoxin administration (e.g., radiocontrast dye)
should be avoided whenever possible.
§ If can not be avoided renal perfusion should be
maximized through strategies such as
§ assuring adequate hydration, administration of oral N-
acetylcysteine and Ascorbic acid

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 Prevention of AKI…
§ Strict glycemic control with insulin in diabetics has
also reduced the development of ARF.
§ Amphotericin B nephrotoxicity can be reduced by
slowing the infusion rate to 24 hours or, in at-risk
patients, substituting liposomal amphotericin B
§ Many other strategies are popular but lack supportive
evidence, including mannitol, loop diuretics,
dopamine, and fenoldopam

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Table; Prevention of Acute Kidney Injury
Therapies of definite/possible benefit
Normal saline infusion
Sodium bicarbonate infusion
Ascorbic acid
N-acetylcysteine
Not recommended therapies
Dopamine (low-dose)
Loop diuretics
Renal replacement therapy
Epoietin alfa

Microsof t Off ice

Pow erPoint Pre se ntation

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 Dosage Regimen
§ Sodium bicarbonate:154 mEq/L (154 mmol/L) infused at 3
mL/kg/h for 1 hour before the procedure and at 1 mL/kg/h for 6
hours after the procedure.
§ Normal saline:1 mL/kg/h for 12 hours before and 12 hours after
the procedure
§ Ascorbic acid is 3 g orally before the procedure, then 2 g orally
twice daily for two doses after the procedure.
§ N-acetylcysteine 600 to 1,200 mg orally every 12 hours for four
doses, with the first two doses administered prior to contrast
exposure
§ Low doses of intravenous (IV) dopamine (2 mcg/kg/min) increase
renal blood flow
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 Management of Established AKI
§ No drugs have been found to accelerate ARI recovery
§ Supportive care is the mainstay of AKI management
regardless of etiology.
§ Prerenal sources of ARF should be managed with
hemodynamic support and volume replacement.
§ interstitial nephritis or glomerulonephritis, appropriate
immunosuppressive therapy must be promptly initiated.
§ Postrenal therapy focuses on removing the cause of the
obstruction.
§ Once acute renal failure is established, the cause is known,
and any specific therapy implemented.
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 Nonpharmacologic
§ Initial modalities to reverse or minimize prerenal AKI
include
§eliminating medications associated with diminished
renal blood flow, improving cardiac output, and
removing a prerenal obstruction
§ If dehydration is evident, then appropriate fluid replacement
therapy
§Moderately volume-depleted patients can be given oral
rehydration fluids;

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 Nonpharmacologic……
§ If IV fluid is required, isotonic normal saline is the
replacement fluid of choice.
§ Typically, IV fluid challenges are initiated with 250 to 500 mL
of normal saline over 15 to 30 minutes with an assessment
after each challenge of the patient's volume status.
§ Unless profound dehydration is present, as may be seen
in diabetic ketoacidosis(DKA) and hyperosmolar
hyperglycemic states(HHS), 1 to 2 L is usually
adequate.
§ Up to 10 L may be required in the septic patient during
the first 24 hours
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 Nonpharmacologic……

§ If the prerenal AKI is a result of blood loss or is

complicated by symptomatic anemia
§ red blood cell transfusion to a hematocrit no higher than 30%
is the treatment of choice.
§ Albumin use should be limited to individuals with severe
hypoalbuminemia (e.g., liver disease and nephritic syndrome)
who are resistant to crystalloid therapy.
§ Treating patients with intrinsic or postobstructive AKI
involve fluid and electrolyte management.

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 Nonpharmacologic…..
§ In the presence of severe AKI, RRTs are commonly
prescribed to manage
§ uremia, metabolic acidosis, hyperkalemia, and complications
of excess fluid retention, such as pulmonary edema and
accumulation of renally cleared medications.
§ Although precise indications for starting RRT are
unclear, some general guidelines for therapy have been
proposed (Table –)

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Table: The AEIOUs that Describe the Indications for RRT

Indication for RRT Clinical Setting

A- Acid–base Metabolic acidosis resulting from the
abnormalities accumulation of organic and inorganic
acids
E-Electrolyte imbalance Hyperkalemia, hypermagnesemia
I-Intoxications Salicylates, lithium, methanol, ethylene
glycol, theophylline, phenobarbital
O-fluid overload Postoperative fluid gain
U-Uremia High catabolism of acute renal failure

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 Pharmacologic
§ Diuretics can facilitate management of fluid overload
§ The most effective are mannitol and loop diuretics
§ IV furosemide
Typical furosemide dose 40 mg IV (treatment naiive
patients); should see response in 30min-1h (UOP >1mL/kg/h)
(may need  doses in nephrotic patients & patients with ATN)
If there is no response: double dose
Equipotent doses of loop diuretics have similar efficacy
If there is resistance to furosemide: shorten dosing
interval or start infusion at 10-40 mg/h after bolus of 40-80
mg; can also initiate a thiazide
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 Pharmacologic……
§ Mannitol 20% typical started at dose of 12.5 to 25 g
IV over 3 to 5 minutes
§ Disadvantages of Mannitol:
§ IV administration, hyperosmolality risk, and need for
monitoring because may cause AKI itself
§Because of these limitations, reserved for the management of
cerebral edema

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 Electrolyte Management and Nutrition
Therapy
§ Hyperkalemia is the most common and serious electrolyte
abnormality in AKI.
§ K must be restricted to <3 g/day and monitored daily
§ Hypernatremia and fluid retention commonly occur, necessitating
restricting daily sodium intake to no more than 3 g. All sources of
sodium, including antibiotics, need to be considered when
calculating daily sodium intake.
§ Phosphorus and magnesium should be monitored; neither is
efficiently removed by dialysis.
§ Enteral but not parenteral, nutrition has been shown to improve
patient outcomes.

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 Drug-Dosing Considerations
§ Drug therapy optimization in ARF is a challenge
§ Volume of distribution for water-soluble drugs is
significantly increased due to edema.
§ Drug concentrations should be monitored frequently
because of changing volume status, changing renal
function, and RRTs in patients with ARF.

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 Evaluation of Therapeutic Outcomes
Vigilant monitoring of patient status is essential

Key Monitoring Parameters for Patients with Established AKI

Parameter Frequency
Fluid ins/outs Every shift
Patient weight Daily
Hemodynamics (blood pressure, heart rate, Every shift
mean arterial pressure, etc.)
Blood chemistries Daily
Drugs and their dosing regimens Daily
Nutritional regimen Daily

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2. CHRONIC KIDNEY DISEASE
(CKD)
 Learning Objectives
§ Upon completion of the chapter, the students will be able to:
§ List the risk factors for progression of CKD
§ Explain the mechanisms associated with progression of CKD.
§ Identify the desired outcomes for treatment of CKD.
§ Develop a therapeutic approach to slow progression of CKD,
including lifestyle modifications and pharmacologic therapies.
§ Identify specific consequences associated with CKD.
§ Design an appropriate therapeutic approach to specific
consequences associated with CKD.
§ Recommend an appropriate monitoring plan to assess the
effectiveness of pharmacotherapy for CKD and specific
consequences
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Introductory case

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 CKD: Definitions
§ CKD is defined as abnormalities of kidney structure or
function for 3months
§ Criteria for CKD (either of the ff present for 3months )
1. Markers of kidney damage (one or more)
§Protieneuria/Albuminuria (AER ≥30 mg/24 hours;
Albumin-to-creatinine ratio ≥30 mg/g)
§Hematuria, Biopsy results showing kidney damage, or
anatomic abnormalities(eg. Cysts), History of kidney
transplantation
2. Decreased GFR
§ GFR <60ml/min/1.73m2
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(stages 1 to 5)

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Estimating GFR
Equations 
· MDRD Study and Cockcroft-Gault equations provide
useful estimates of GFR in adults:
Modification of Diet in Renal Disease (MDRD)
Prediction based on age, gender, race and serum creatinine.
GFR (mL/min/1.73m2) = 186 x SCr-1.154 x age-0.203 x (0.742 if
female) x (1.21 if AA/black)

Cockcroft-Gault:
GFR = [(140-age) x IBW] / [SCr x72] x (0.85 if female)

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 CKD: Epidemiology
§Worldwide public health problem: “silent epidemic “
§The prevalence of CKD is correlated with specific
demographic factors: increased age, African-American
race, and hypertension.
§CKD affects mainly young adults aged 20–50 years and
is primarily due hypertension and glomerular diseases
(DM in western countries)…… sub-Saharan Africa
§Hypertension is a cause of chronic kidney failure in
Africa, especially in Black patients.

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 CKD: Risk Factors
§ Classified into three categories
§ Susceptibility factors:
§ Associated with an increased risk but not proven to cause
CKD
§ Generally Not modifiable by pharmacologic therapy or
lifestyle modifications and Useful for identifying high risk
gps
§ Initiation factors
§ Directly cause CKD and modifiable
§ Progression factors
§ Most important predictors/independent risk factor
§ Result in a faster decline/worsening in kidney function and44
45
 Common Causes of CRF Microsoft
Pow e rPoint Presenta tion

Disease Proportion of Endstage

renal failure
Congenital and 5% Polycystic kidney
inherited disease
Renal artery stenosis 5%
Hypertension 5-25%
Glomerular diseases 10-20% IgA nephropathy is most
common
Interstitial diseases 5-15%
Systemic inflammatory 5% SLE, vasculitis
diseases
Diabetes mellitus 20-40%
Unknown 5-20%

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 CKD: Pathophysiology
· Regardless of the cause, however, the damage results in loss
of nephron mass w/c leads to compensatory hypertrophy of
kidney which in turn leads to glomerular capillary hypertension
§ Increased glomerular capillary pressure expands the pores in
the glomerular basement membrane, altering the size-
selective barrier and allowing proteins to be filtered through
the glomerulus Protienuria
§ Proteinuria alone may promote progressive loss of nephrons
as a result of direct cellular damage.
§ the remaining nephrons are no longer able to maintain
clinical stability and renal function declines
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 CKD: Clinical Presentation
§ Symptoms
§Symptoms are generally absent in CKD stages 1& 2
§Stages 3 and 4 CKD may be associated with minimal
symptoms.
§Typical symptoms associated with stage 5 CKD
include pruritus, dysgeusia, nausea, vomiting,
constipation, muscle pain, fatigue, and bleeding
abnormalities.

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System Signs of CKD
Cardiovascular– edema, worsening HTN, ECG evidence of left
pulmonary ventricular hypertrophy, arrhythmias, dyslipidemia
Gastrointestinal GERD, weight loss
Endocrine 2˚ hyperparathyroidism, decreased vitamin D
activation, β2-microglobulin deposition, gout
Hematologic anemia of CKD, iron deficiency, bleeding
Fluid/ hyper- or hyponatremia, hyperkalemia, metabolic
electrolytes acidosis
Neuropsychiatric: Depression, anxiety, impaired mental cognition
Genitourinary: Changes in urine volume and consistency, “foaming” of urine
(indicative of proteinuria), and sexual dysfunction.
Laboratory Increased BUN and SCr and decreased GFR
Tests
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 Complications
§ 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.
§ fluid and electrolyte abnormalities
§ anemia
§ hyperphosphatemia
§ hyperparathyroidism
§ metabolic acidosis
§ cardiovascular complications, and
§ poor nutritional status.

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 CKD: Treatment

§ Principles of management of CKD:

1. Treatment of reversible causes of renal dysfunction
2. Preventing or slowing the progression of renal disease
3. Treatment of the complications of renal dysfunction
4. Identification and adequate preparation for renal
replacement therapy

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Metabolic Acidosis
§ Cause
Kidneys regulate hydrogen and bicarbonate filtration & excretion
Advanced CKD -> decreased acid excretion and positive H+
balance -> metabolic acidosis
§ Goal
Serum HCO3 > 20 mEq/L….. and ….pH > 7.35
§ Agents
Sodium bicarbonate tablets - (650 mg = ~ 8 mEq HCO3-)
Sodium citrate (Shohl’s solution)
§ Dose of HCO3……….1.0–1.5 mEq/kg/day
Dependent upon initial serum HCO3- and degree of renal
insufficiency

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Hyperkalemia

· Kidneys excrete 90-95% of potassium

· Hyperkalemia(Serum K > 5.5)
· occurs when GFR <20 mL/min (stage 4-5)
· Primary reason for emergent Hemodialysis

·Emergent: IV calcium gluconate, insulin/glucose,

and/or β2-adrenergic agonists (albuterol)

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Pharmacologic interventions can help to limit the progression
of CKD in nondiabetic patients

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Pharmacologic interventions can help to limit the progression
of CKD in diabetic patients

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Pharmacologic interventions can help to limit the progression of
CKD in diabetic patients

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Optimal Blood Pressure Control
§ Reductions in blood pressure are associated with a
decrease in proteinuria, leading to a decrease in the
rate of progression of kidney disease.
§ The NKF recommends a goal blood pressure of
§ <130/80 mm Hg in pts with stages 1 to 4 CKD
§ < 140/90 before and <130/80 mm Hg after hemodialysis for
Stage 5 CKD pts who are receiving hemodialysis
§ Notice: three or more agents are generally required to
achieve the BP goal of <130/80 mm Hg in CKD pts

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Treatment of HTN in patients with CKD

58
CONTINUED FROM PREVIOUS SLIDE

59
 Reduction in Proteinuria
§ The ability of antihypertensive agents to preserve
kidney function differs.
§ All patients with documented proteinuria should receive an
ACE-I or ARB, regardless of BP
§ Pts who do not achieve adequate reductions in BP or protein
excretion may benefit from combination therapy with an
ACE-I and an ARB.
§ CCBs: Effective for HTN in pts with nondiabetic CKD
§ Only nondihydropyridine CCBs shown to reduce rate of renal
function decline
§Generally 2nd line when ACEIs or ARBs not tolerated

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 Hyperlipidemia Treatment
§ The NKF suggests that CKD should be classified as a
coronary heart disease (CHD) risk equivalent and the
goal LDL-C level should be <100 mg/dL in all pts with
CKD
§ statins and the fibric acid derivatives are the most frequently
used agents
§ Another important consideration in treating lipid
disorders in pts with CKD is management of
proteinuria.
§ Protein excretion in the nephrotic range (3 g/day) is
associated with an increase in both total & LDL-C levels
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Anemia Treatment

· Primary cause
 erythropoietin by proximal tubular cells (responsible for
90% of production)
· Other factors
Decreased RBC life span, vitamin B and folate
deficiencies, and HD
· Strong correlation between stage
Stage 4 – prevalence 50%
Stage 5 – prevalence 75%
· Many patients will also be iron deficient
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 Anemia Treatment
§ 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
§ Erythropoietin stimulating agents
§ higher target Hgb (13.o to 15.0 mg/dL) increases CV risk
63
without improving quality of life
Anemia Treatment
§ target Hgb 10.5 to 11.5 mg/dL associated with fewer CV
events than target Hgb level in the normal range
§ Epoetin alfa
§Stimulates the proliferation and differentiation of erythroid
progenitor cells,
§increases hemoglobin synthesis, and accelerates the release
of reticulocytes from the bone marrow.
§Starting doses for SC administration are 80 to 120 U/kg/wk

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 Anemia Treatment
§ the total weekly dose is usually divided into smaller
doses, administered one to three times per week with
SC administration and three times per week for IV
administration
§ Extended dosing intervals ,
§ Doses of 10,000 U once weekly to 40,000 U once every 4
weeks have been shown to maintain target hemoglobin values
for those patients with CKD not on dialysis.
§ Iron Status
§ Because iron deficiency is the primary cause of ESA-
hyporesponsiveness, assessment of iron status is essential
before initiating erythropoietic therapy. 65
Mineral and Bone Disorders
· Ca and Phosphate mediated by
Bone, kidney, parathyroid ,GI
· CKD progresess
a decreased glomerular filtration rate of phosphorus and an
increased tubular reabsorption of phosphorus results
hyperphosphatemia
It leads to stimulation of parathyroid hormone and
suppression of vitamin D3 activation which in turn decreases
calcium absorption
 PTH mobilizes Ca from the bone, causes kidneys to
eliminate Phos and reabsorb Ca
This stabilizes Ca/Phos until CKD progresses

66
Mineral and Bone Disorders

· Complications
Bone abnormalities
Vascular calcifications, CVD
Increased mortality

67
 Hyperphosphatemia
Complication Diagnosis Treatment
Goal
  CKD Stages 3-4: CKD Stages 3-4:
Hyper- P > 4.6 2.7 -4.6 mg/dL
phosphatemia  
CKD Stage 5: CKD Stage 5:
P > 5.5 3.5 – 5.5 mg/d
 

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Hyperphosphatemia
· Treatment approach:
dietary restriction of phosphate (meat, dairy
products, peas, beans, lentils, bran, and cola
soft drinks).
· Phosphate binders approved by FDA for Stage 4
chronic kidney disease
· Before 1985…Aluminum-based
Toxicity: osteomalacia, bone and muscle pain, neurologic
abnormalities, and iron-resistant anemia led to a dramatic
reduction in its use

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 Hyperphosphatemia

· Current - calcium-based phosphate binders are very

effective
Calcium acetate and Calcium carbonate
S/E: Gastrointestinal symptoms such as
……….. change in bowel habits, abdominal
discomfort and dyspepsia, and hypercalcemia.
· Lanthanum carbonate …………….Fosrenol

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Vitamin D Treatment

Diagnosis: CKD Stages 3-4; 25-hydroxyvitamin D <

30 ng/ml
Goal: CKD Stages 3-4; 25-hydroxyvitamin D > 30
ng/mL
Tx: Ergocalciferol
50,000 IU/week po for 12 weeks
Followed by 50,000 per month for 6 months (varies by
vitamin D deficiency severity)

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 Outcome Evaluation

§ Monitor serum creatinine and potassium levels and BP

within 1 week after initiating ACEIs or ARBs therapy
§ Typically acute but sustained 25 to 30% GFR reduction
§ 3 to 7 days after ACEI initiation due to reduced
intraglomerular pressure
§ Discontinue the medication and switch to another agent
if
§sudden increase in SCr. 30% occurs
§hyperkalemia develops, or
§pt becomes hypotensive
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Outcome Evaluation

§ Titrate the dose of the ACE-I or ARB every 1 to 3

months to the maximum tolerable dose.
§ If BP is not reduced to <130/80 mm Hg, add another
agent to the regimen.
§ Refer the pt to a nephrologist to manage
complications associated with CKD
§ As CKD progresses to stage 4, to prepare the pt for RRT

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3. DRUG-INDUCED KIDNEY
DISEASES

74
 Learning Objectives
Upon completion of the Unit, the students will be
able to:
Define DIKD and Cite the most common manifestation
Classify various nephrotoxicities according to their
corresponding renal structural–functional alterations.
Compare the pathogenesis of hemodynamically mediated
kidney injury induced by ACEIs with that induced by
NSAIDs.
Create a list of drugs implicated in the development of
allergic interstitial nephritis.

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Drug-Induced Kidney Disease(DIKD)
· Numerous diagnostic and therapeutic agents
have been associated with the development of
DIKD
· Manifestations: acid–base abnormalities,
electrolyte imbalances, urine
sediment ,proteinuria, pyuria, and/or hematuria.
· Community-acquired DIKD led ….to 20% of
hospital admissions due to AKI.
· Drug induced cases implicated in up to 60% of
all cases of in-hospital AKI
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 DIKD: Clinical Presentation
· General
Most common manifestation is a decline
in GFR leading to a rise in Scr and BUN
· Symptoms
Malaise, anorexia, vomiting, shortness of
breath, or edema
· Signs
Decreased urine output with progression
to volume overload & HTN
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Sign….
· Proximal tubular injury Indicators:
Metabolic acidosis with bicarbonaturia
Glycosuria in the absence of hyperglycemia
Reductions in serum phosphate, uric acid, K, and
Mg as a result of increased urinary losses
· Distal tubular injury Indicators:
Polyuria from failure to maximally concentrate
urine
Metabolic acidosis from impaired urinary
acidification
Hyperkalemia from impaired K excretion 78
Laboratory tests:
· An abrupt (within 48 hours) reduction in
kidney function defined as
absolute in Scr of 0.3 mg/dL (27 mol/L) or %age
in Scr of 50% (1.5-fold from baseline), or
in urine output (documented oliguria of less than
0.5 ml/kg/hr for 6 hours)]
when correlated temporally with the initiation of
drug therapy may indicate DI-AKI.

79
 Principles for Prevention DIKD

· Avoid the use of nephrotoxic agents for

patients at increased risk for toxicity
If exposure to these drugs/Agents cannot
be avoided, proposed interventions:
• Adjustment of medication dosage regimens
based on accurate estimates of renal function
• Careful and adequate hydration to establish
high urine flow rates.

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81
Tubular Epithelial Cell Damage
· Also termed Acute tubular necrosis (ATN)
· ATN is the most common presentation of DIKD in
the inpatient setting.
· Drugs that lead to this damage typically do so via
direct cellular toxicity or ischemia.
· Classical manifestations: cellular debris-filled, muddy-
brown, granular casts in the urinary sediment
· Primary Causes of ATN
Aminoglycoside Nephrotoxicity, Radiographic Contrast
Media Nephrotoxicity and Amphotericin B Nephrotoxicity
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 Aminoglycoside Nephrotoxicity
· 10% and 25% of patients receiving a therapeutic
course and 58% in Critically ill pts
· Within 5-10 days after initiation of therapy
· Present with non-oliguria (>500 mL/day)
microscopic hematuria and proteinuria
· Full recovery of kidney function is common if
therapy is discontinued
· Higher rates of toxicity with neomycin versus
gentamicin, followed by tobramycin, then amikacin

83
 Prevention and management

· Avoid volume depletion, limit the total

aminoglycoside dose administered, and avoid
concomitant therapy with other nephrotoxic
drugs
· Once daily dosing is preferable than with
standard dosing
· The pt should be maintained adequately
hydrated and hemodynamically stable.

84
Radiographic Contrast Media
Nephrotoxicity
· Risk Factors: CHF, CKD, DM, HTN, volume
depletion, concurrent use of Nephrotoxic
meds
· Usually seen within 3 days of administration
· Seen with SCr within 24 hours, peak in 5
days
· Recovery after 7 to 10 days
· Etiology
Vasoconstriction
85
Direct cellular injury and death
Prevention and Management of CIN

86
 Amphotericin B Nephrotoxicity

· Risk factors: large individual and cumulative doses,

short infusion times, volume depletion,
hypokalemia, age, and concomitant administration
of diuretics and other nephrotoxins (cyclosporine in
particular)
· Nephrotoxicity depends on cumulative doses
· Usually manifests 1-2 weeks after treatment is begun
· Mechanism:
direct tubular epithelial cell toxicity resulting from
interaction of amphotericin B with ergosterol in the cell
membrane(increased cell membrane permeability and 87
lipid peroxidation …necrosis )
 Prevention and management

· Use lipid formulations of amphotericin B…

enhancing drug delivery to sites of infection and
reducing interaction with tubular epithelial cell
membranes.
· Limiting the cumulative dose, increasing the
infusion time, hydration(daily and prior to
administration of each dose give..1L 0.9% saline),
and avoiding concomitant administration of other
nephrotoxins
· Itraconazole & voriconazole are viable alternatives
88
Hemodynamically Mediated Kidney Injury

· Refers to any cause of AKI resulting from an

acute decrease in intraglomerular pressure,
including
"prerenal" states leading to reduced effective renal blood
flow (e.g., hypovolemia, CHF) and medications that
affect the renin–angiotensin system
· Afferent and efferent arteriolar vasoconstrictions
are primarily mediated by Ag-II, whereas
afferent vasodilation is primarily mediated by
PGs
89
Glomerular autoregulation during "prerenal"
states (i.e., reduced blood flow).

90
Hemodynamically Mediated Kidney
Injury
· Drug-induced causes of hemodynamic
kidney injury typically stem from
constriction of glomerular afferent arterioles
and/or dilation of glomerular efferent arterioles.
ACEIs, ARBs, and NSAIDs are the agents that
have been most commonly implicated.

91
ACEIs and ARBs

· Between 20% to 25% of hospitalized patients with

CHF develop AKI after treatment with ACEIs is
initiated.
· An increase in Scr of up to 30% is commonly
observed within 3 to 5 days of initiating therapy
and is an indication that the drug has begun to exert
its desired pharmacologic effect.
· But …increase in Scr of more than 30% above
baseline in the course of 1 to 2 wks may necessitate
discontinuation of the offending drug
92
Pathogenesis of angiotensin-converting
enzyme inhibitor (ACEI) nephropathy

93
Prevention and management

· Avoid factors that could leads to decreased

renal perfusion
· Initiate therapy with very low doses of a
short-acting ACEI (e.g., captopril 6.25 mg to
12.5 mg)
· Acute decreases in kidney function and the
development of hyperkalemia usually
resolve over several days after ACEI or
ARB therapy is discontinued
94
NSAIDs and Selective Cyclooxygenase-2
Inhibitors
• 500,000 to 2.5 million people develop some degree of
NSAID nephrotoxicity in the United States annually
· Can occur within days of initiating therapy
· Patients typically present with complaints of
diminished urine output, weight gain, and/or edema
· Risk Factors: Age >60 years, CHF, CKD, DM, volume
depletion, Combined use of NSAIDs or COX-2
inhibitors and concurrent use of Nephrotoxic meds

95
Prevention and management
· Discontinuation of therapy and supportive
care…..Kidney injury is rarely severe, and
recovery is usually rapid
· avoiding potent compounds such as indomethacin
and using analgesics with less prostaglandin
inhibition, such as acetaminophen, aspirin,
tramadol
· If it is important to use ….minimal effective dose
should be used for the shortest duration possible

96
 Crystal Nephropathy
· Caused by precipitation of drug crystals in distal tubular
lumens, which commonly leads to intratubular
obstruction, interstitial nephritis, and occasionally
superimposed ATN.
· Nephrolithiasis is a type of crystal nephropathy that
results from abnormal crystal precipitation in the renal
collecting system, potentially causing urinary tract
obstruction with kidney injury

97
 Intratubular Obstruction
Mechanism: direct…precipitation of the drug itself
Acyclovir, Foscarnet, indinavir, Sulfadiazine,,
methotrexate,Triamterene, quinolone
· Can be largely prevented and possibly treated by
administering the drug after vigorously
prehydrating the patient, maintaining a high urine
volume, and urinary alkalinization.
· indirect means (i.e., promoting release of chemicals
that form casts)…antineoplastic drugs leads to
tumor lysis syndrome(high uric acid production
which in turn form crystals with in the tubules
98
· Uric acid precipitation can be prevented by
vigorous pretreatment hydration with normal saline,
beginning at least 48 hours prior to chemotherapy, to maintain
urine output 100 mL/h in adults,
administration of allopurinol 100 mg/m2 thrice daily
(maximum of 800 mg/day) started 2 to 3 days prior to
chemotherapy, and
urinary alkalinization to pH 7.0

99
 Nephrolithiasis

· Nephrolithiasis (formation of renal calculi or kidney

stones) does not present as classic nephrotoxicity
since GFR is usually not decreased.
· Drug-induced nephrolithiasis can be the result of
abnormal crystal precipitation in the renal collecting
system, potentially causing pain, hematuria, infection,
or, occasionally, urinary tract obstruction with kidney
injury.
· The overall prevalence of drug-induced
nephrolithiasis is estimated to be 1%
100
Tubulo-interstitial Nephritis(AIN)

Acute Allergic Interstitial Nephritis

· It usually manifests 2 weeks after exposure to a drug but may
occur sooner if the patient was previously sensitize
· Acyclovir, Indinavir, Aminoglycosides, Amphotencin B,
Sulfonamides, beta Lactams, Tetracyclines, Erythromycin,
Ethambutol, Vancomycin, Thiazide diuretics,…
· Carbamazepine, Phenytoin, Lithium, Valporic acid, Phenobarbital,
..
· NSAIDs, Acetaminophen, Lansoprazole, Allopurinol,
Methyldopa, Omeprazole, Azathiopnne, Captopril
Propyithiouracil, Cimetidne, Ranitidine, Cyclosponne,
Sulfinpyrazone, Glyburide, Warfarin
101
AIN…

· AIN is considered to be an allergic hypersensitivity

response.
Clinical presentation
· Fever, maculopapular rash, eosinophilia, arthralgia
· NSAID-induced AIN ….onset delayed (mean of 6
months).. No fever, rash,
Prevention and management
· Patients must be monitored carefully to recognize the
signs and symptoms
· high-dose oral prednisone 1 mg/kg/day for 8 to 14 weeks
102
4. Glomerulonephritis
Learning Objectives
· Upon completion of the chapter, the students will be able
to:
Describe the pathophysiology and etiology of GN
Describe the general clinical presentation of and
diagnostic approach for GN
Describe the key differences between nephritic and
nephrotic syndrome
Describe the general approach for GN treatment
Describe the supportive therapy for associated
complications
Describe the key parameters for outcome evaluation
104
 Glomerulonephritis(GN)
· Refers to a specific set of renal diseases in which an
immunologic mechanism triggers inflammation and
proliferation of glomerular tissue that result in damage
to the basement membrane, mesangium or capillary
endothelium
· Characterized by:
Sudden onset of haematuria, proteinuria and RBC casts
Often accompanied by hypertension, oedema and impaired
renal function
· Represents 10-15% of glomerular disease
· GN most common cause of chronic renal failure (25%)
105
106
 Etiology

• Humoral and cellular immunologic mechanisms

participate in the pathogenesis of most GN
• Abnormalities in coagulation and metabolism, as well
as hereditary and vascular diseases, also contribute to
glomerular damage.
· The extent and severity of glomerular injury and
clinical presentation depends on the:
nature of the insult, site of injury within the glomerulus and
speed of onset, the extent, and intensity of disease.

107
UNIT 6
Pathophysiology [1]
• The glomerular lesion may be
 diffuse (involving all glomeruli)
 focal (involving some but not all glomeruli)
 Segmental/local(involving part of the individual glomerulus)
• Pathologic manifestations may also be described as
 proliferative (overgrowth of epithelium, endothelium,or
mesangium)
 membranous (thickening of GBM), and/or sclerotic
• The glomerular capillary wall is particularly susceptible
to immune-mediated injury because antigen and
antibody tend to localize in the glomerulus.
109
 Pathophysiology [2]
· Glomerular damage generally occurs in two phases:
acute and chronic.
During the acute phase, immune reactions occur within
glomeruli that stimulate the complement cascade, ultimately
resulting in glomerular damage.
Nonimmune mechanisms that occur in response to loss of
nephron function and hyperfiltration of remaining nephrons
are characteristic of the chronic phase.
Chronic GN may lead to scarring of the tubulo-interstitial
areas of the kidney, with progressive renal impairment

110
 Clinical presentation [1]
· Although patients with glomerular disease may present with an
array of signs and symptoms, they are often categorized into one
of two broad classifications: nephritic syndrome or nephrotic
syndrome
· Nephritic syndrome:
 reflects glomerular inflammation and frequently results in
hematuria.
 White cells and cellular and granular casts are commonly
found in the urine
· Nephrotic syndrome
 reflects noninflammatory injury to the glomerular structures
and results in few cells or cellular casts in the urine. Initially,
there may be limited or no reduction in renal excretory 111

function
Tendencies of Glomerular Diseases to Manifest ….[2]

112
113
114
115
Treatment [1]

General Approach
• The management can be
 specific pharmacologic therapy for the disease and
 Supportive measures to prevent and/or treat the
pathophysiologic sequelae (eg. HNT, edema, and
progression of renal disease.)

116
117
118
Treatment [4]
• Immunosuppressive agents, alone or in combination,
are commonly used to alter the immune processes
that are responsible for the glomerulonephritides
• Corticosteroids
 Immunosuppressive effect
 inhibition of the release of IL-1 and tumor necrosis factor by
activated macrophages, and interleukin-2 (IL-2) by activated T cells
 antiinflammatory activities
 They reduce the production and/or release of substances that mediate the
inflammatory process, prostaglandins, leukotrienes, platelet-activating
factors, tumor necrosis factors

119
 Treatment [5]….. Proteinuria
• Dietary protein restriction reduces proteinuria and may
retard renal function deterioration
• ACEIs and ARBs
• reduce proteinuria and glomerular scarring
• reduce the effect of angiotensin II on renal cell proliferation,
thereby reducing sclerosis
• Combination has maximum effect than either agents alone
• NSAIDs
• reduce proteinuria through prostaglandin E2 inhibition, resulting
in a reduction of intraglomerular pressure, a decrease in GFR,&
restoration of the barrier size-selectivity of the GBM
• Nephrotoxicity issue vs NSAIDsavoid long term use 120
 Treatment [6]…. Hyperlipidemia
• Dyslipidemia increases the risk of atherosclerosis and
coronary heart disease in patients with nephrotic syndrome
• Beside low-fat diet, Statins are used to reduce total plasma
cholesterol, LDL-C and TG concentrations
• Additional benefits of statins:
 confer renoprotection through reduction of cell proliferation &
inflammation
 reduce proteinuria & delay renal function loss(recent clinical
studies)
• The combined use of an ACEI with a statin may offer
additional benefits in controlling Nephrotic hyperlipidemia
121
 Treatment [7]….. Anticoagulation
• Renal vein thrombosis, or other thromboembolic events,
are serious and common complications of nephrotic
syndrome(NS)
• Pts with documented thromboembolic episodes need
anticoagulation by Warfarin until remission of NS
• Prophylactic anticoagulation is controversial
• High risk patients for thrombosis; e.g., those who
• require prolonged bedrest
• receiving high-dose intravenous steroids
• post surgical patients
• Dehydrated….. ……………Consider anticoagulation 122
Therapeutic Outcome Evaluation
· Renal function Test
· Urinalysis and CBC
· BP, Serum Protein and Lipid profile
· Renal biopsy
· drug-related toxicities
For cytotoxic drug evaluate pts Every week during the
initial treatment period.
Long-term steroid treatment monthly visits

123
5. ACID-BASE DISORDERS (ABD)
Learning Objectives…After
completion…
· State the mechanisms by which the kidney
participates in the maintenance of acid–base
homeostasis.
· Determine the likely cause of an ABD given the
patient history, arterial blood gases, and medication
history.
· Differentiate the likely type of metabolic acidosis
that is present on the basis of the serum anion gap.
· Propose an initial treatment plan for the management
of patients with ABDs
125
 Acid-Base Physiology
· Most acid comes from carbohydrate and fat metabolism,
which generates 15,000 to 20,000 mmol of CO2 daily
· CO2 is not an acid itself but combines with water (H2O)
in the blood to create carbonic acid (H2CO3), which in
the presence of the enzyme carbonic anhydrase
dissociates into H+ and HCO3-.
· The H+ binds with Hb in RBCs and is released with
oxygenation in the alveoli, at which time the reaction is
reversed, creating H2O and CO2, which is exhaled in
each breath.
126
 Acid-Base Physiology
· Lesser amounts of organic acid derive from the
following:
Incomplete metabolism of glucose and fatty acids into lactic
acid and ketoacids
Metabolism of sulfur-containing amino acids (cysteine,
methionine) into sulfuric acid etc
· Most base comes from metabolism of anionic amino
acids (glutamate and aspartate) and from oxidation and
consumption of organic anions such as lactate and
citrate, which produce HCO3-.

127
Acid-Base Balance

· Acid-base balance is maintained by

Chemical buffering and
Pulmonary and Renal elimination
· Chemical buffering:
The body's buffering system can be divided into three
components:
• bicarbonate/carbonic acid, proteins, and phosphates.
Chemical buffers are solutions that resist changes in pH.
Intracellular and extracellular buffers provide an
immediate response to acid-base disturbances.

128
 Chemical buffering….
· The most important extracellular buffer is the
HCO3-/CO2 system, described by the equation:
H+ + HCO3- ⇔ H2CO3 ⇔ CO2 + H2O
· An increase in H+ drives the equation to the right and
generates CO2. This important buffer system is highly
regulated;
· CO2 concentrations can be finely controlled by alveolar
ventilation, and H+ and HCO3- concentrations can be
finely regulated by renal excretion.

129
 Chemical buffering….
· The relationship between HCO3- and CO2 in the system
can be described by the Kassirer-Bleich equation,
derived from the Henderson-Hasselbalch equation:
H+ = 24 × PCO2/HCO3-
· This equation illustrates that acid-base balance depends
on the ratio of PCO2 and HCO3-, not on the absolute
value of either one alone.
· With this formula, any 2 values (usually H+ and PCO2)
can be used to calculate the other (usually HCO3-).

130
 Pulmonary regulation:
· CO2 concentration is finely regulated by changes in
tidal volume and respiratory rate (minute ventilation).
· A decrease in pH is sensed by arterial chemoreceptors
and leads to increases in tidal volume or respiratory
rate; CO2 is exhaled and blood pH increases.
· In contrast to chemical buffering, which is immediate,
pulmonary regulation occurs over minutes to hours.
· The usual steady-state PaCO2 is maintained at 40 mmHg.
Under-excretion of CO2 produces hypercapnia and
Over-excretion of CO2 causes hypocapnia
131
Renal Regulation
· The kidneys control pH by adjusting the amount of
HCO3- that is reabsorbed and the amount of H+ that is
excreted; increase in HCO3- is equivalent to removing
free H+.
· Changes in renal acid-base handling occur hours to
days after changes in acid-base status.
· HCO3- reabsorption occurs mostly in the proximal
tubule and, to a lesser degree, in the collecting tubule.

132
Proximal tubular bicarbonate 133
reabsorption.
Collecting duct acid excretion. 134
Renal Regulation
· Acid is actively excreted into the proximal and distal
tubules where it combines with urinary buffers—
primarily freely filtered HPO4-2, creatinine, uric acid,
and ammonia—to be transported outside the body
· Ammonium is generated from the deamination of
glutamine in the proximal tubule
· For each ammonium ion excreted in the urine, one
bicarbonate ion is regenerated and returned to the
circulation

135
 Production and secretion of ammonium ion (NH4+) by PT cell

REABSORPTI
ON

136
 Formation of titratable acid

REABSORPTI
ON

137
 Table: Normal Blood Gas Values

HCO3 –, bicarbonate; PCO 2, partial pressure of carbon dioxide; PO 2, partial

pressure of oxygen; SaO 2, saturation of arterial oxygen.
138
Acid–Base Disturbances
· Are changes in arterial PCO2, serum HCO3-, and serum
pH
· Alterations in blood pH are designated by the suffix “-
emia”;
Acidemia is serum pH < 7.35
Alkalemia is serum pH > 7.45
· Acidosis refers to physiologic processes that cause acid
accumulation or alkali loss.
· Alkalosis refers to physiologic processes that cause
alkali accumulation or acid loss.
139
 Classification
· Primary ABDs are defined as metabolic or respiratory
Metabolic ABDs, the primary disturbance is in the
plasma bicarbonate concentration.
• Metabolic acidosis: is serum HCO3- < 24 mEq/L
• Metabolic alkalosis: is serum HCO3- > 24 mEq/L.
Respiratory ABDs, the primary disturbance is in the
PaCO2
• Respiratory acidosis: is PCO2 > 40 mm Hg (hypercapnia).
• Respiratory alkalosis is PCO2 < 40 mm Hg (hypocapnia).
· Whenever an ABD is present, compensatory
mechanisms begin to correct the pH 140
 Table: Interpretation of Simple Acid–Base
Disorders

HCO3 –, bicarbonate; PaCO 2, partial pressure of carbon dioxide from arterial blood.
141
142
Diagnosis of ABDs

143
Analysis of Arterial Blood Gas Data

Analysis of arterial blood gases. 144

 Anion Gap
· AG is defined as Na+ - (Cl- + HCO3-).
· because certain cations (+) and anions (-) are not
measured on routine laboratory chemistry panels. Thus
Na+ + unmeasured cations (UC) = Cl- + HCO3- + unmeasured
anions (UA)
And the anion gap, Na+ - (Cl- + HCO3-) = UA - UC
· UA: PO43-, sulfate (SO4-)…. 20 to 24 mEq/L
· UC: K+, Ca++, Mg++ …..11 mEq/L
· Thus the typical anion gap is 23 - 11 = 12 mEq/L.
· The anion gap can be affected by increases or decreases
in the UC or UA. 145
146
 Metabolic Acidosis
· Primary reduction in HCO3-, typically with compensatory
reduction in PCO2; pH may be markedly low or slightly
subnormal.
· Categorized as high or normal AG based on the presence
or absence of UA in serum
· Causes: accumulation of ketones and lactic acid, renal
failure, and drug or toxin ingestion (high AG) and GI or
renal HCO3- loss (normal AG).
· Symptoms and signs in severe cases (pH <7.15 to 7.20)
include nausea and vomiting, lethargy, and hyperpnea
· Diagnosis is clinical and with ABG and serum electrolyte
147
measurement.
 Metabolic Acidosis: Treatment

· Asymptomatic pts with mild to moderate degrees of

acidemia [Plasma HCO3- : 12 to 20 mEq/L , pH of 7.2
to 7.4]
• Treatment is directed at the underlying cause
• do not require emergent therapy.
• Gradual correction of the acidemia, over a period of days
to weeks, using oral sodium bicarbonate or other alkali
preparations.

148
 Metabolic Acidosis: Treatment

· Patients with life-threatening acute metabolic acidosis

(Plasma HCO3- of 8 mEq/L] and pH <7.20) is
Treatment dependent on the underlying cause and the
patient’s cardiovascular status.
In some cases patients will require emergent hemodialysis
and Intravenous alkali therapy

149
 Sodium Bicarbonate[NaHCO3 ]

· NaHCO3 is clearly indicated:

When metabolic acidosis results from loss of HCO3- or
accumulation of inorganic acids (ie, normal AG acidosis)
· NaHCO3 therapy is controversial and with possible risks:
when acidosis results from organic acid accumulation (ie, high
AG acidosis)
· Despite these and other controversies, most experts still
recommend HCO3- IV for severe metabolic acidosis (pH
< 7.00), with a target pH of 7.20.

150
 Sodium Bicarbonate[NaHCO3 ]
· Treatment requires 2 calculations.
· The first is the level to which HCO3- must be raised, calculated by
the Kassirer-Bleich equation, using a value for [H+] of 63 nmol/L
at a pH of 7.2:
63 = 24 × PCO2/HCO3- or desired HCO3- = 0.38 × PCO2
· The amount of HCO3- needed to achieve that level is
NaHCO3 required (mEq) = (desired [HCO3-] - observed [HCO3-]) × 0.4 ×
body weight (kg)
This amount of NaHCO3 is given over several hours.
Serum pH and HCO3- levels can be checked 30 min to 1 h after
administration, which allows for equilibration with extravascular HCO3-.

151
 Metabolic Alkalosis

· Primary increase in HCO3- with or without

compensatory increase in PCO2; pH may be high or
nearly normal.
· Common causes: prolonged vomiting, hypovolemia,
diuretic use, and hypokalemia
· Symptoms and signs in severe cases: headache,
lethargy, and tetany
· Diagnosis: clinical and with ABG and serum electrolyte
measurement.

152
 Metabolic Alkalosis

· The underlying cause is treated;

· Oral or IV acetazolamide or HCl is sometimes indicated
· Sodium chloride–responsive disorders usually result
from volume depletion and chloride loss, which can
accompany severe vomiting, prolonged nasogastric
suction, and diuretic therapy.
· Initially therapy is directed at expanding intravascular
volume and replenishing chloride stores.
· Sodium and potassium chloride–containing solutions
should be administered to patients who can tolerate the
volume load. 153
Metabolic Alkalosis
· Acidifying agents including hydrochloric acid, ammonium
chloride, and arginine monohydrochloride can be used to treat
severe (pH >7.6) symptomatic metabolic alkalosis.
· Management of these disorders usually consists of treatment of
the underlying cause of the mineralocorticoid excess.
· Patients who are taking corticosteroids can require a dosage
reduction or can need to be switched to a corticosteroid with
less mineralocorticoid activity (e.g., methylprednisolone).
· Patients with an endogenous source of excess
mineralocorticoid activity can require surgery or the
administration of spironolactone, amiloride, or triamterene.
154
156
 Respiratory Acidosis
· Primary increase in PCO2 with or without compensatory
increase in HCO3-; pH is usually low but may be near
normal.
· Cause is a decrease in respiratory rate, volume
(hypoventilation), or both due to CNS, pulmonary, or
iatrogenic conditions.
· Can be acute or chronic; the chronic form is asymptomatic,
but the acute, or worsening, form causes headache,
confusion, and drowsiness.
· Signs include tremor, myoclonic jerks, and asterixis.
· Diagnosis is clinical and with ABG and serum electrolyte
measurements. 157
 Respiratory Acidosis: Treatment
· Patients with few or no symptoms and pH alterations are
usually mild (pH not exceeding 7.50), treatment is often
not required.
· The first consideration in the treatment of acute
respiratory alkalosis with pH >7.50 is the identification
and correction of the underlying cause.
Relief of pain,
correction of hypovolemia with intravenous fluids,
treatment of fever or infection,
treatment of salicylate overdose, and other direct measures can
prove effective.
158
 Respiratory Acidosis: Treatment

· A rebreathing device, such as a paper bag, can be useful

in controlling hyperventilation in patients with the
anxiety/hyperventilation syndrome.
· Oxygen therapy should be initiated in patients with
severe hypoxemia.
· Patients with life-threatening alkalosis (pH >7.60),
particularly if it is a mixed respiratory and metabolic
condition and they have complications such as
arrhythmia or seizures can require mechanical
ventilation with sedation and/or paralysis to control
hyperventilation. 159
 Respiratory Alkalosis
· Primary decrease in Pco2 with or without compensatory
decrease in HCO3-; pH may be high or near normal.
· Cause is an increase in respiratory rate or volume
(hyperventilation) or both.
· Respiratory alkalosis can be acute or chronic.
· The chronic form is asymptomatic, but the acute form
causes light-headedness, confusion, paresthesias,
cramps, and syncope.
· Signs include hyperpnea or tachypnea.
· Diagnosis is clinical and with ABG and serum
electrolyte measurements. 160
 Respiratory Alkalosis: Treatment
· Respiratory decompensation in patients with chronic
elevations in PaCO2 are frequently seen in those with acute
infections and those recently started on narcotic analgesics.
· Aggressive treatment of these conditions can offer
considerable benefit and should be initiated.
· Furthermore, tranquilizers and sedatives should be avoided.
· When carbon dioxide excretion is severely impaired
(PaCO2 >80 mm Hg) and/or life-threatening, hypoxia is
present (PaO2 <40 mm Hg); the immediate therapeutic goal
is to provide adequate oxygenation.

161
 Respiratory Alkalosis: Treatment
· Excessive secretions must be cleared from the airway
and oxygen administered to restore adequate
oxygenation.
Mechanical ventilation is usually required
· The underlying cause of the acidosis should be treated
aggressively
· Bicarbonate administration is rarely necessary in the
treatment of respiratory acidosis.
Furthermore, rapid correction of acidosis with bicarbonate
can eliminate the patient’s respiratory drive or precipitate
metabolic alkalosis.
162
 Evaluation of treatment outcomes
· Because acid–base disorders are such a common and
widespread problem,
pharmacists can play a key role in identifying, preventing,
and properly treating acid–base abnormalities.
· Pharmacists in all practice settings should use their
knowledge:
to identify patients at high risk for developing drug-related
problems which affect acid–base balance and
to undertake appropriate prevention and treatment measures
to improve the quality of life of the patients they care for.

163
 Quiz

· A 19-year-old male is brought to the Emergency

Department after being found unresponsive in a
shopping mall washroom. After being intubated, he
remains unconscious with a RR of 8 and has an arterial
blood gas measurement of pH 7.28(Normal: 7.35-7.45);
PaO2 78 mm Hg (Normal: 80-100); PaCO2 54 mm Hg
(Normal 35-45); HCO3- 23 mEq/L(Normal:22-26).
a) What is his acid-base disturbance ?
b) What is his expected compensation for his acid-base
disturbance?
c) What would be the most appropriate course of
therapy
6. Disorders of Fluid and
Electrolyte Homeostasis

Seminar Presentation