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CHRONIC RENAL FAILURE

MRS. S.SARUMATHY M.PHARM., (PH.D)


ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACY PRACTICE
VELS UNIVERSITY

Function of Kidneys
Remove

toxic waste products


Remove excess water and salts
Play a part in controlling blood pressure
Produce erythropoetin (epo) which
stimulates red cell production
Helps to keep calcium and phosphate
in balance for healthy bones
Maintains proper pH for the blood

(a) Nephron
(b) Renal Pyramid with Nephrons
(c) Section of Kidney

Shier,D., Butler, J., Lewis, R (1999). Holes human anatomy


and physiology.(8th ed.). The McGraw-Hill Co, Inc.
Used with permission: The McGraw-Hill

Renal Hormone
Regulation
Synthesis and activation of hormones
by the kidney include:
Active form of Vitamin D
Erythropoietin
Renal blood flow regulated by:
Renin-angiotensin aldosterone sy
stem (RAAS)

How the RAAS Pathway


Works

Valerie Kolmer
2006

A. Definitions
1.Azotemia - elevated blood urea nitrogen (BUN
>28mg/dL) and creatinine (Cr>1.5mg/dL)
2.Uremia - azotemia with symptoms or signs of
renal failure
3.End Stage Renal Disease (ESRD) - uremia
requiring transplantation or dialysis
4.Chronic Renal Failure (CRF) - irreversible kidney
dysfunction with azotemia >3 months
5.Creatinine Clearance (CCr) - the rate of filtration
of creatinine by the kidney (GFR marker)
6.Glomerular Filtration Rate (GFR) - the total rate of
filtration of blood by the kidney

Chronic Renal Failure


Definition:
final stage of numerous renal diseases
resulting from progressive loss of glomerular,
tubular and endocrine function in both kidneys.
This leads to
disturbed excretion of end products of
metabolism
disturbed elimination of electrolytes and water
disturbed secretion of hormones(eg.
Erythropoietin, renin, prostaglandins, active
form of vitamin D)

Chronic Renal Failure


The

mild chronic renal insufficiency


denotes a creatinine clearance of 5080 ml/min, moderate cri 30-50 ml/min
and severe cri 15-30 ml/min. Patients
requiring chronic dialysis of renal
transplantation for relief of uremic
symptoms are said to have end stage
renal disease (ESRD)

Stages of Chronic Renal Failure


Stage 1

Kidney damage with GFR 90


normal or GFR
ml/min/1.73 m2

Stage 2

Kidney damage with GFR 60-89


mild GFR

Stage 3

Moderate GFR

GFR 30-59

Stage 4

Severe GFR

GFR 15-29

Stage 5

Kidney failure

GFR <15 (or


dialysis)

Etiology

Diabetic Nephropathy
50K cases of DN ESRD annually
Diabetes most common contributor to ESRD
>30% of ESRD cases attributed to Diabetes
Hypertension
CFR with Hypertension causes 23% of ESRD
annually
Glomerulonephritis: 10%
Polycystic Kidney Disease: 5%
Rapidly progressive glomerulonephritis (vasculitis):
2%
Renal Vascular Disease (i.e., renal artery stenosis)
Medications
Analgesic Nephropathy (progression after many
years)
Pregnancy: high incidence of increased creatitine
and HTN during pregnancy associated with CRF

Causes of End Stage Renal


Disease

USRDS Annual Data Report

Chronic Renal Failure


Measurement

of GFR

Gold standard is Inulin Iothalamate.


Creatinine Clearance calculated by timed (24h)
urine collection along with serum collection for
Creatinine.
Overestimate GFR when CKD is severe due to an
increase in tubular secretion of creatinine.
This factor can be corrected by cimetidine.
Estimation

of GFR

More than 10 formulae for estimation of GFR.


MDRD most widely accepted now.

CRF Risk Factors


Diabetes

Mellitus
Hypertension
Cardiovascular Disease
Obesity
Metabolic Syndrome
Age and Race
Acute Kidney Injury
Malignancy
Proteinuria

Family

history of CKD
Kidney Stones
Infections like Hep C
and HIV
Autoimmune diseases
Nephrotoxics like
NSAIDS
Environmental exposure
(heavy metals and
organic compounds)

Pathophysiology
Susceptibility factors increase the risk for kidney disease but do not directly cause kidney
damage. Susceptibility factors include advanced age, reduced kidney mass and low birth
weight, racial or ethnic minority, family history, low income or education, systemic
inflammation, and dyslipidemia.
Initiation factors initiate kidney damage and can be modified by drug therapy. Initiation
factors include diabetes mellitus, hypertension, autoimmune disease, polycystic kidney
disease, and drug toxicity.
Progression factors hasten decline in kidney function after initiation of kidney damage.
Progression factors include glycemia in diabetics, hypertension, proteinuria, and smoking.
Most progressive nephropathies share a final common pathway to irreversible renal
parenchymal damage and ESRD. Key pathway elements are loss of nephron mass,
glomerular capillary hypertension, and proteinuria.

Pathogenesis
Hyperfiltration Injury
* Final common pathway of glomerular
destruction
* Hypertrophy of remaining nephrons
* Increase glomerular blood flow
* glomerular filtration in surviving
nephrons
* Progressive damage to surviving nephrons
(due to elevated hydrostatic pressure /
toxic effect)
* excretory burden on surviving nephrons
* Sclerosis of nephrons

CRF- Clinical Manifestations

Normal.
Mild- Generally asymptomatic
Moderate Insufficiency- Generally asymptomatic,
nocturia, HTN,
Mild Anemia
Severe/ Advanced Renal Insufficiency- nocturia, fatigue,
cold intolerance, abnormal taste, anorexia,
hyperphosphatemia, hypoclacemia, hyperkalemia,
metabolic acidosis, worsening anemia
ESRD- Malaise, Lethargy, pruritis, intactable nausea and
vomiting, leg cramps, seizures, worsening parameters,
myoclonus, asterixis Etc

CRF - Manifestations

Abnormal Sodium-Water metabolism


Edema, Hypertension
Abnormal Acid-base abnormalities
Metabolic Acidosis due to uremia or RTA
Abnormal hematopoesis
Anemia of CKD
Cardiovascular Abnormalities
LVH, CAD, Diastolic Dysfunction
Abnormal Calcium-Phosphorus metabolism
Hyperphosphatemia, pruritus, arthralgia
Hyperparathyroidism
Renal Osteodystrophy

CRF - Management
Diagnostic

work up to decide underlying

etiology
Treatment of Hypertension and Dyslipidemia
Treatment of Anemia
Treatment of Hyperphosphatemia
Avoidance of Dehydration & Nephrotoxic
agents
Proper Dosing of Drugs
Preparation for Renal Replacement Therapy

CRF - Evaluation

CRF- Evaluation
Serum

electrolytes
Urine spot protein analysis (24 hour no
longer recommended).
ANA, C3, C4
SPEP, UPEP
Kidney Ultrasound
Urine sediment analysis
Biopsy
Evidence of glomerular disease without diabetes
Sudden onset of nephrotic syndrome or
glomerular hematuria

CRF - Management
Diagnostic

work up to decide underlying

etiology
Treatment of Hypertension and Dyslipidemia
Treatment of Anemia
Treatment of Hyperphosphatemia
Avoidance of Dehydration & Nephrotoxic
agents
Proper Dosing of Drugs
Preparation for Renal Replacement Therapy

CKD - Hypertension

Anti-Hypertensive Agents
Single most important measure could be adequate BP control
Target BP <130/80 with minimal proteinuria and BP<125/75
with significant proteinuria (>1g).
ACEIs and ARBs have been demonstrated to slow both
diabetic and non-diabetic renal disease in both experimental
and human studies.
Nondihydropyridine calcium channel blockers are generally used
as second-line antiproteinuric drugs when ACEIs or angiotensin II
receptor blockers are not tolerated.
Decrease the sodium intake to 2.5 g /day
Usually requires more than 2 medications.
Diuretics enhance the antihypertensive and antiproteinuric
effects of other agents.
Hyperkalemia to be monitored with ACEI drugs.

CKD - Dyslipidemia

Dyslipidemia and Cardiovascular morbidity


Several studies like the 4D study showed no benefit
of statins in dialysis patients.
However, post hoc analysis of this data does
suggest that the management of dyslipidemia in
CKD 2 4 improves cardiac mortality and morbidity.
Dyslipidemia is frequently seen in glomerular
disease with proteinuria (nephrotic syndrome) and
its control reduces atherosclerosis related morbidity
and mortality.
Dietary protein restriction, lipid-lowering medications,
smoking cessation, and anemia management may
help slow the rate of CKD progression.

CKD - Management
Diagnostic

work up to decide underlying

etiology
Treatment of Hypertension and Dyslipidemia
Treatment of Anemia
Treatment of Hyperphosphatemia
Avoidance of Dehydration & Nephrotoxic
agents
Proper Dosing of Drugs
Preparation for Renal Replacement Therapy

CKD - Anemia
Decreased

quality of
life with anemia.
Diagnosis of
exclusion.
Mostly apparent in
the stage 4 and 5 of
CKD.
Due to decrease in
EPO production in
the kidney.

CKD - Anemia

Erythropoietin are well tolerated (ADR- Hypertension)


Epoetin alfa :Procrit , Epogen
Darbepoietin Alpha: ARANESP
Darbepoetin alfa has a longer half-life than epoetin alfa
and prolonged biologic activity. Doses are administered less
frequently, starting at once a week when administered IV or SC.
Target Hg levels between 11g and 12g but not exceeding 13g.
Greater than 13g showed increased mortality as per the CHOIR study.
Adverse effects of IV iron include allergic reactions, hypotension,
dizziness, dyspnea, headaches, lower back pain, arthralgia, syncope,
and arthritis. Sodium ferric gluconate and iron sucrose have better
safety records than iron dextran. Iron dextran requires a test dose to
reduce the risk of anaphylactic reactions.
Subcutaneous (SC) administration of epoetin alfa is preferred
because IV access is not required, and the SC dose that maintains
target indices is 15% to 50% lower than the IV dose.

CKD - Management
Diagnostic

work up to decide underlying

etiology
Treatment of Hypertension and Dyslipidemia
Treatment of Anemia
Treatment of Hyperphosphatemia
Avoidance of Dehydration & Nephrotoxic
agents
Proper Dosing of Drugs
Preparation for Renal Replacement Therapy

SECONDARY HYPERPARATHYROIDISM
AND RENAL OSTEODYSTROPHY

Calciumphosphorus balance is mediated through a complex interplay of hormones


and their effects on bone, GI tract, kidney, and parathyroid gland.
As kidney disease progresses, renal activation of vitamin D is impaired,
which reduces gut absorption of calcium. Low blood calcium concentration stimulates
secretion of parathyroid hormone (PTH). As renal function declines, serum calcium
balance can be maintained only at the expense of increased bone resorption,
ultimately resulting in renal osteodystrophy
Secondary hyperparathyroidism can cause altered lipid metabolism, altered insulin
secretion, resistance to erythropoietic therapy, impaired neurologic and immune
functions, and increased mortality.
ROD progresses insidiously for several years before the onset of symptoms such as
bone pain and fractures. Skeletal complications include osteitis fibrosa cystica (high
bone turnover), osteomalacia (low bone turnover) and a dynamic bone disease. When
ROD symptoms appear, the disease is not easily amenable to treatment.
Monitor Intact PTH levels and keep between 100 and 500.
Maintain Phosphorus and Calcium within normal ranges.
Vitamin D analog paricalcitol.
Calcimimetic agents like cinacalcet

CKD - Hyperphosphatemia

Control of Hyperphosphatemia
Due to decreased excretion in urine.
Control of hyperphosphatemia by dietary measures slow progression in
experimental models of CKD.
Hyperphosphatemia leads to pruritus, calcification in synovial membranes,
blood vessels and even cardiac valves.
Therapy includes Phosphorus restriction to 800mg/day and use of
phosphrous binders with food.
Calcium Carbonate (TUMS), Ca-acetate (PHOSLO)
Lanthanum carbonate
sevelamer HCL
Phosphate-binding agents decrease phosphorus absorption from the gut andare
first-line agents for controlling both serum phosphorus and calcium
Concentrations .

METABOLIC ACIDOSIS

A clinically significant metabolic acidosis is commonly seen when the GFR


drops below 20 to 30 mL/min (stage 4 CKD). The goals of therapy in CKD are
to normalize the blood pH (7.35 to 7.45) and serum bicarbonate (22 to 26
mEq/L).
Consequences of metabolic acidosis include renal bone disease, reduced
cardiac contractility, predisposition to arrhythmias, and protein catabolism.
Oral alkalinizing salts (e.g., sodium bicarbonate, Shohl solution, And
Bicitra) can be used in patients with stage 4 or 5 CKD. Polycitra should not
be used (hyperkalemia).
The replacement alkali dose can be approximated by multiplying
bicarbonates volume of distribution (0.5 L/kg) by the patients weight (in kg)
and by their deficit (24 mEq/L minus patients serum bicarbonate value).
The dose should be administered over several days. The daily maintenance
dose is usually 12 to 20 mEq/mL and should be titrated as needed.
Metabolic acidosis in patients undergoing dialysis can often be managed by
using higher concentrations of bicarbonate or acetate in the dialysate.

CKD - Management
Diagnostic

work up to decide underlying

etiology
Treatment of Hypertension and Dyslipidemia
Treatment of Anemia
Treatment of Hyperphosphatemia
Avoidance of Dehydration & Nephrotoxic
agents
Proper Dosing of Drugs
Preparation for Renal Replacement Therapy

CKD - Nephrotoxics
Avoidance

Agents

of Dehydration/Nephrotoxic

Drugs such as Aminoglycosides, NSAIDs


Avoiding exposure to Radio contrast agents.
In presence of dehydration, even in absence of
renovascular disease, ACEIs or ARBs can
aggravate renal dysfunction
Dehydration is frequent in tubulo-interstitial
disorders where urinary concentration is
impaired.
Proper Dosing of Drugs eg. Allopurinol

CKD - Management
Diagnostic

work up to decide underlying

etiology
Treatment of Hypertension and Dyslipidemia
Treatment of Anemia
Treatment of Hyperphosphatemia
Avoidance of Dehydration & Nephrotoxic
agents
Proper Dosing of Drugs
Preparation for Renal Replacement Therapy

CKD Medication Dosing


Proper

Dosing of Drugs

Uremia affects GI absorption; eg Iron.


Impaired plasma protein binding of drugs; eg
Dilantin.
Increased volume of distribution;
Excretion of many drugs depends upon the
kidney;
Some

drugs used in normal dose will lead to nephrotoxic


effects eg. Allopurinol
Other drugs when used in normal dose will lead to other
toxic effects eg. Vancomycin.

Dose

Reduction or Interval Extension

CKD - Management
Diagnostic

work up to decide underlying

etiology
Treatment of Hypertension and Dyslipidemia
Treatment of Anemia
Treatment of Hyperphosphatemia
Avoidance of Dehydration & Nephrotoxic
agents
Proper Dosing of Drugs
Preparation for Renal Replacement Therapy

CKD - RRT
Preparation

Therapy

for Renal Replacement

Education for Options of Dialysis & Renal


Transplantation for Renal Replacement
Hemodialysis Vs Peritoneal Dialysis
Avoidance of Veni-puncture & insertion of
catheters in peripheral veins once GFR <
60mls.
Timely placement of vascular access or
PD catheter.

CKD - RRT
Indications

Uncontrolled hyperkalemia and acidosis


Uncontrollable hypervolemia (pulmonary edema)
Pericarditis
AMS and somnolence (advanced encephalopathy)
Bleeding diathesis

Indications

(Absolute):

(Relative):

Nausea, vomiting and poor nutrition


Metabolic acidosis
Lethargy and Malaise
Worsening kidney function <10 ml or <15 ml in
diabetics

CKD - RRT
Transplantation:

Preemptive transplant
carries both patient
and graft survival
advantage.
Graft survival better
with living donor
kidneys.
Immunosuppresion is
almost always a
must.

CKD - RRT
Transplantation:

Diseases like FSGS may reccur early in the


transplanted kidney.
Increased risk for infection, bone loss,
cardiovascular disease.
Contraindications:
Malignancy

(recent or metastatic)
Current infection
Severe extra renal disease
Active use of illicit drugs

CKD - Summary
In

creasing prevalence of CKD in the


population.
Early detection and prevention of
progression.
Early involvement of nephrologists in
the care (when GFR<30).
Treatment of Manifestations and
complications.
Renal Replacement Therapy
Timely referral for Access
Timely Transplant Work up.