1.
Chronic Renal Failure

2.
Chronic Renal Failure
DEFINITION
• CKD is defined as either of the following conditions
for a minimum of 3 months: glomerular filtration rate
(GFR) less than 60 mL/min/1.73 m2, or old damage
to the kidney(s) with or without a decrease in GFR
• This damage may be evidenced by abnormalities in
the composition of blood or urine, or by changes
seen in imaging studies

3.
Chronic Renal Failure
• The K/DOQI2 Working Group further categorizes
the extent of kidney disease according to the
presence of kidney damage and the GFR
• Stage 1 CKD is defined as the presence of kidney
damage even though GFR may be normal or
even increased (≥90 mL/min/1.73 m2)
• Stage 2 CKD is evidenced by a GFR between 60
and 89 mL/min/1.73 m2
• Patients with stage 3 CKD may or may not have
kidney damage, while their GFR is reduced to
between 30 and 59 mL/min/1.73 m2

4.
Chronic Renal Failure
• CKD patients with stage 4 disease also may not
have intrinsic kidney damage, but their GFR is
severely reduced to between 15 and 29
mL/min/1.73 m2
• The last stage, stage 5, is also known as end-stage
kidney disease (ESKD)
• End-stage renal disease (ESRD) is defined as a
GFR less than 15 mL/min/1.73 m2 or the need for
renal replacement therapy (RRT) for survival

5.
Chronic Renal Failure
Pathophysiology
GLOMERULAR HYPERFILTRATION AND
INTRAGLOMERULAR HYPERTENSION
• The nephron, the functional unit of the kidney,
comprises the glomerulus and the tubules
• Approximately 1 million nephrons are located in each
kidney
• When the number of functioning nephrons is
reduced because of insult or disease, the remaining
nephrons compensate by enlarging (hypertrophy)
and by increasing their individual GFRs

6.
Chronic Renal Failure
Pathophysiology
• Sustained elevations of blood flow and pressure
within the glomeruli cause damage to remaining
nephrons, ultimately leading to their demise
• Glomerular injury is also believed to result from
increased capillary permeability (reduced
permselectivity), which allows proteins and other
macromolecules to leak through capillaries into the
renal tubules

7.
Chronic Renal Failure
Pathophysiology
• Microalbuminuria is one of the earliest clinical
manifestations of glomerular damage
• This process in turn may promote the secretion of
proinflammatory mediators and induce renal mesangial
cells to deposit an extracellular glycoprotein matrix,
leading to a type of renal fibrosis and scarring called
sclerosis
• Sclerosis may involve the entire nephron
(nephrosclerosis), extending from the glomerulus
(glomerulosclerosis) to the tubules and interstitium

8.
Chronic Renal Failure
Pathophysiology
PROTEINURIA
• Because protein (mostly albumin) is a relatively large
molecule, it generally is not filtered in the glomerulus but
is returned to systemic circulation via the efferent
arteriole
• The presence of small amounts of protein in the urine
(microalbuminuria) or larger amounts (proteinuria) is due
to damage within the glomerulus
• Although this may be the result of a self-limiting
situation (e.g., acute muscle breakdown), it occurs more
often as a result of injury caused by a disease process
such as diabetes or hypertension

9.
Chronic Renal Failure
Pathophysiology
• Both of these disease states may lead to
intraglomerular hypertension and altered glomerular
permeability
• Filtering of protein in the glomerulus causes direct
damage, and protein deposition evokes an
inflammatory response that may cause more damage
in the glomerulus or the tubules
• The association of proteinuria with direct kidney
damage is so strong that clinicians often use the
degree of albuminuria as a measure of nephropathy

10.
Chronic Renal Failure
Pathophysiology
DIABETIC NEPHROPATHY
• DM is the single most important disease leading to ESKD
• The incidence of diabetic nephropathy peaks after 10 to 15
years of diabetes; however, functional renal abnormalities are
often present within 2 years of the onset of type 1 DM
• Tthe diagnosis of type 2 DM is often delayed by actual onset,
renal changes are usually present at diagnosis in this
population
• Aside from hyperglycemia, comorbidities such as
hypertension and hyperlipidemia are common in patients
with diabetes and are believed to contribute to progression of
nephropathy in most cases

11.
Chronic Renal Failure
Pathophysiology
HYPERTENSION
• Moderate to severe hypertension is strongly
correlated with the risk of developing ESKD,
consistent with observations that systemic
hypertension may both cause and result from renal
disease
• Assuming that an elevated systemic blood pressure is
transmitted to the glomerulus, systemic hypertension
may be anticipated to exacerbate CKD progression by
contributing to intraglomerular hypertension and
hyperfiltration

12.
Chronic Renal Failure
Pathophysiology
• Antihypertensive therapies have been postulated to
protect against glomerulopathy by several
mechanisms, including reduction in blood pressure
or blood flow reaching the glomerulus, attenuation
of intraglomerular hypertension via reductions in
afferent or efferent arteriolar tone, alteration of
nonhemodynamic factors such as membrane
permselectivity, inflammation, and oxidative stress,
or possibly some combination of these mechanisms

13.
Chronic Renal Failure
Pathophysiology
HYPERLIPIDEMIA
• Dyslipidemia is more prevalent in patients with CKD than
in the general population (30% vs. 20%).4 In patients
with nephrotic range proteinuria (>3 g/24 hours), the
incidence may be as high as 70% to 100% because of
increased hepatic lipoprotein synthesis
• In these patients, the degree of proteinuria is directly
proportionate to the increase in total cholesterol
• Dyslipidemia may lead to the progression of CKD caused
by oxidation and deposition of lipoproteins in the
glomerulus and the mesangial cells

14.
Chronic Renal Failure
Pathophysiology
• Oxidized low-density lipoprotein (LDL) may cause
synthesis of inflammatory cytokines, vasoactive
substances, and macrophage chemotactic factors
• These changes eventually lead to glomerular scarring
• Common abnormalities seen in patients with CKD
include increased LDL, decreased HDL, and elevated
triglycerides

15.
Chronic Renal Failure
Pathophysiology
METABOLIC AND SYSTEMIC CONSEQUENCES OF CHRONIC
KIDNEY DISEASE
• The extent to which renal dysfunction reduces urinary
solute excretion has been found to vary for different
substances
• For example, rises in urea and creatinine are observed
early in CKD and inversely correlate with GFR, whereas
the renal excretion of potassium, urate (uric acid),
phosphorus, and hydrogen ion is generally preserved
until GFR falls to below 25% of normal.

16.
Chronic Renal Failure
Pathophysiology
• Excretion of these solutes may be enhanced by
increased tubular secretion or reduced reabsorption
until GFR is 25 to 30 mL per minute or less, at which
point accumulation becomes unavoidable and
plasma levels of these solutes begin to rise
• Finally, the renal handling of other solutes (e.g NaCl)
may be well preserved late into CKD but differs
substantially among the various types of renal
disease

17.
Chronic Renal Failure
Pathophysiology
VOLUME, SODIUM, AND WATER BALANCE
• Because daily sodium intake usually exceeds
requirements, the kidneys are able to maintain sodium
balance by simply reducing urinary Na reabsorption .
• Conversely, if sodium intake is below output, the
kidney is usually able to increase its conservation of
sodium, except in certain salt-wasting nephropathies.

18.
Chronic Renal Failure
Pathophysiology
• At creatinine clearances below 25 mL per minute,
however, renal adaptation to wide fluctuations in
sodium or water intake is sluggish and incomplete
• The kidney becomes unable to concentrate or
dilute urine efficiently, and urinary excretion of
water and salt tends to become fixed at nearly iso-
osmotic concentrations, in volumes of about 2 L
per day

19.
Chronic Renal Failure
Pathophysiology
ELECTROLYTE BALANCE: POTASSIUM AND MAGNESIUM
• Potassium is carefully regulated in the body. Only a
small amount—approximately 2%—is extracellular.
Potassium is moved into and out of cells via sodium,
potassium adenosine triphosphatase pumps
• Various factors may upregulate or downregulate the
number of pumps on the cell membrane, causing a shift
in potassium to other mechanisms.
• Insulin and β2-agonists increase the movement of
potassium intracellularly, and hyperparathyroidism and
hypertonicity may cause potassium to shift to the
extracellular compartment

20.
Chronic Renal Failure
Pathophysiology
• As the degree of kidney failure progresses, an adaptive
increase in colonic elimination of potassium occurs; in
patients with ESKD
• This increase may be up to two fold to threefold greater than
that in subjects with normal kidney function
• This increased gastrointestinal secretion and an increase in
distal tubular secretion prevent hyperkalemia until kidney
function declines to 10 to 15 mL per minute
• Factors that increase the risk of hyperkalemia include an
increase in potassium intake and use of drugs that impair
potassium excretion (ACE-Is, potassium-sparing diuretics), or
drugs or conditions that shift potassium to the extracellular
fluid from the intracellular fluid

21.
Chronic Renal Failure
Pathophysiology
ACID-BASE REGULATION
• A normal adult who consumes a mixed diet generates
approximately 1 mEq per kg of metabolic acid daily
• This hydrogen ion is rapidly buffered by circulating
bicarbonate and is excreted by the lungs as respiratory
acid (CO2)
• Bicarbonate lost during this process is regenerated by the
kidney through the excretion of acid which must be
buffered by ammonia or other urinary buffers

22.
Chronic Renal Failure
Pathophysiology
• In kidney disease, renal ammonia formation
(ammoniagenesis) is generally impaired as a
consequence of reduced nephron mass
• Because urinary acid secretion and renal
regeneration of bicarbonate are coupled with the
availability of ammonia, these associated processes
become impaired in CKD
• Bicarbonate is also filtered into the urine and must
be reclaimed by reabsorption; however, this tends to
remain intact until CKD is far advanced

23.
Chronic Renal Failure
Pathophysiology
ANEMIA OF CHRONIC KIDNEY DISEASE
• Erythropoietin (EPO) is a hormone that is produced
and secreted by the granular cells of the kidney in
response to hypoxia or ischemia.
• When secreted, EPO travels to the bone marrow
and causes the proliferation and differentiation of
committed erythroid progenitor cells
• Additionally, EPO prevents apoptosis of these cells,
allowing them to mature

24.
Chronic Renal Failure
Pathophysiology
• The primary cause of anemia in CKD is the
diminished production of EPO by the failing
kidneys
• Other causes include frequent phlebotomy,
malnutrition, iron or vitamin deficiencies, and, for
those patients on hemodialysis, blood loss in the
dialytic circuit
• Another contributing factor to anemia is the
shortened life cycle of red blood cells in uremia

25.
Chronic Renal Failure
Pathophysiology
CALCIUM, PHOSPHORUS, AND BONE HOMEOSTASIS
• As GFR decreases, excretion of solutes is impaired.
Phosphorus may begin to accumulate in the early
stages of CKD—stages 3 and 4
• Hyperphosphatemia causes a decrease in serum
calcium brought about through a physiochemical
interaction and complexation
• Reduction in serum calcium triggers the parathyroid
gland to synthesize and secrete more parathyroid
hormone (PTH)

26.
Chronic Renal Failure
Pathophysiology
• PTH in turn causes an increase in osteoclast activity
in the bone, breaking down bone to release calcium
and restore serum levels. These abnormalities are
compounded by a relative deficiency of vitamin D
• The failing kidneys are not able to convert vitamin D
to the active form—1,25-dihydroxycholecalciferol
(vitamin D3)

27.
Chronic Renal Failure
Pathophysiology
ENDOCRINE AND HORMONAL ABNORMALITIES
• Abnormalities in female and male gonadal hormones
are common in ESKD and result in high incidences of
infertility and sexual dysfunction
• Hyperprolactinemia is common, and gonadotropin,
follicle-stimulating hormone (FSH), and luteinizing
hormone (LH) levels may be low in both men and
women. Women may cease to ovulate or
menstruate, or they may do so irregularly

28.
Chronic Renal Failure
Pathophysiology
• Although pregnancy is still possible, these are
considered high-risk cases and only 40% result in
successful deliveries
• Decreased libido and erectile dysfunction are
common among men with ESKD, which may be
related not only to reduced testosterone levels but
also to concurrent malaise, anemia, and vascular and
neurologic abnormalities

29.
Summary
• Chronic kidney disease (CKD), also known as chronic renal disease,
is progressive loss in kidney functionover a period of months or
years.
• The symptoms of worsening kidney function are not specific, and
might include feeling generally unwell and experiencing a reduced
appetite.
• This disease may also be identified when it leads to one of its
recognized complications, such as cardiovascular
disease, anemia, pericarditis orrenal osteodystrophy (the latter
included in the novel term CKD-MBD).
• CKD is a long-term form of kidney disease; thus, it is differentiated
from acute kidney disease (acute kidney injury) in that the
reduction in kidney function must be present for over 3 months.

30.
Chronic Renal Failure
SIGNS AND SYMPTOMS
• Most patients experience few symptoms of CKD until
less than 25% of normal renal function remains
• CKD can therefore progress insidiously over months
to years, evident only through abnormal biochemical
parameters, such as gradually rising levels of BUN
and serum creatinine values
• Nonspecific complaints such as malaise, fatigue, and
nocturia may be noted

31.
Chronic Renal Failure
• Urine output may or may not be diminished.
Hypertension may develop and, if discovered,
presents a critical opportunity for investigation of
renal implications
• Unless patients are recognized to be at risk of and
are monitored for kidney disease, they usually do not
seek medical attention until the onset of uremic
symptoms
• At this point, interventions to forestall progression to
ESKD are largely unfruitful

32.
Chronic Renal Failure
Pharmacotherapy
TREATMENT OF DIABETIC NEPHROPATHY
• Diabetic nephropathy is caused mainly by the
presence of hyperglycemia, as has been previously
discussed
• In this situation, the best way to prevent or slow
renal damage is to prevent hyperglycemia
• Several trials have shown that minimizing
hyperglycemia can delay the onset and slow the
progression of the microvascular and macrovascular
complications of diabetes

33.
Chronic Renal Failure
• The Diabetes Control and Complications Trial
Research Group (DCCT trial) demonstrated that
patients with type 1 diabetes who maintain
hemoglobin A1C levels at approximately 7% (vs. 9%)
delayed the onset and progression of retinopathy,
nephropathy, and neuropathy

34.
Chronic Renal Failure
Pharmacotherapy
TREATMENT OF DYSLIPIDEMIA
• The benefits of treating dyslipidemia in patients with
CKD have been demonstrated through many studies.
• Specifically, studies suggest that hydroxymethylglutaryl
coenzyme A reductase inhibitors (HMG-CoA, statins)
are particularly beneficial
• Statins may decrease proliferation of mesangial and
proximal tubular cells, reducing glomerulosclerosis
• They may also decrease the inflammatory response
stimulated by endothelin-1

35.
Chronic Renal Failure
• They have been shown to have an antiproteinuric
effect, as well as the ability to slow progression of
renal dysfunction. Studies have shown decreases in
carotid intimal thickening (a marker of total body
atherosclerosis)
• Statins have also been shown to decrease plasma
homocysteine levels; fibrates may have the opposite
effect

36.
Chronic Renal Failure
Pharmacotherapy
TREATMENT OF METABOLIC AND SYSTEMIC
CONSEQUENCES OF CHRONIC KIDNEY DISEASE- DIURETICS
AND VOLUME MANAGEMENT
• Until patients become dialysis dependent, diuretic
therapy is a mainstay of fluid and volume
management.
• When used as single agents, thiazides lose much of
their diuretic efficacy after GFR falls to below 20 to
30 mL per minute.
• At this point, loop diuretics such as furosemide,
bumetanide, and torsemide become drugs of choice
in maintaining volume balance.

37.
Chronic Renal Failure
• These agents enter the urine through tubular
secretion, producing dose-dependent diuretic
responses that require a “threshold” urinary
concentration to be present
• In patients with CKD, drug entry into urine and at the
site of action is impaired
• Administration of doses two to ten times higher
than those given to patients with normal renal
function may be required to produce a comparable
diuretic response

38.
Chronic Renal Failure
Pharmacotherapy
ANEMIA
• Before the introduction of recombinant human
erythropoietin (epoetin alfa [EPO]) in the late 1980s,
anabolic steroids and red cell transfusions were the
primary modalities by which anemia was treated in
the CRD population
• The synthesis of epoetin revolutionized anemia
management in the ESRD population, but despite
more than a decade of clinical use, opinions are still
evolving regarding the most appropriate manner of
EPO use, optimal therapeutic hemoglobin (or
hematocrit) goals, and their associated risk-benefit
ratios

39.
Chronic Renal Failure
• Epoetin alfa, a recombinant molecule with the
same structure as endogenous erythropoietin, is
manufactured under two name brands (Procrit,
Epogen)
• This modification gives darbepoetin [also known as a
novel erythropoiesis-stimulating protein (NESP)], an
increased half-life compared with epoetin alfa.
• This characteristic allows it to be dosed less
frequently than epoetin was traditionally dosed

40.
Chronic Renal Failure
• All three products have the same mechanism of
action—stimulation of the production and
differentiation of erythrocytes.
• Procrit and Epogen are the same molecule but with
different FDA-approved indications.
• Only Epogen and Aranesp are approved for the
treatment of patients with anemia of chronic kidney
disease

41.
Chronic Renal Failure
Pharmacotherapy
BLEEDING AND HEMOSTATIC DEFECTS
• In the absence of clinical bleeding or in situations of increased risk
for bleeding (e.g., invasive or surgical procedures), no specific
therapy is required
• Bleeding diathesis may be reduced by adequate treatment of
patients in the uremic state through hemodialysis or peritoneal
dialysis, and by avoidance of unnecessary agents with antiplatelet
effects
• Through EPO therapy (or transfusion), correction of hematocrit to
levels to above 30% may help enhance platelet–endothelium
interactions.
• Although the benefit has largely been attributed to improved
intravascular dispersion of platelets by red blood cell (RBC) mass,
EPO has been proposed to increase the expression of platelet
membrane GPIIb-IIIa receptors.

42.
Chronic Renal Failure
Pharmacotherapy
• Acute treatment for severe bleeding necessitates RBC
transfusion and, in life-threatening circumstances,
administration of cryoprecipitate
• The role of platelet transfusion is more controversial, given
that repeated platelet transfusions are likely to promote
the development of antiplatelet antibodies
• Moreover, platelets transfused into uremic environment
are thought to become deficient in function, in the manner
described in earlier sections for native platelets
• Relatively rapid improvements in bleeding time can be
produced in most uremic patients through the
administration of desmopressin (DDAVP) 0.3 µg per kg by IV
infusion

43.
Chronic Renal Failure
Pharmacotherapy
GASTROINTESTINAL COMPLICATIONS
• Antacids were once used heavily in patients with CKD for
relief of dyspepsia or gastrointestinal irritation. In the
setting of renal insufficiency, many of these agents
present potential problems. Bicarbonate-based products
may cause the inadvertent administration of large
sodium loads, but they may be useful in controlling
metabolic acidosis
• When magnesium-containing antacids or cathartics are
given on a long-term basis to patients with renal failure,
accumulation of magnesium becomes a concern, as
creatinine clearance falls to below 30 mL per minute

44.
Chronic Renal Failure
Pharmacotherapy
• Serum magnesium levels may rise to above 6 mEq
per L (3 mmol/L), leading to central nervous system
depression, lethargy, somnolence, and loss of deep
tendon reflexes
• Dialysis removes magnesium effectively and may be
indicated in cases of severe toxicity.
• long-term use of aluminum-based antacids or
phosphate binders may lead to aluminum
intoxication syndromes

45.
Chronic Renal Failure
Pharmacotherapy
UREMIC PRURITUS
• The uremic milieu and the use of dialyzer
membranes that are less biocompatible have been
implicated in the pathogenesis of uremic pruritus
(UP)
• This appears to be true, and with the improvements
in hemodialysis adequacy and more compatible
dialyzer membranes, a decrease in the incidence of
pruritus has been reported

46.
Chronic Renal Failure
Pharmacotherapy
• Still, UP is a significant issue, especially in the dialysis
population.
• A variety of topical and systemic therapies have been
reported as beneficial in reducing or relieving uremic
pruritus
• Unfortunately, none of these has proved uniformly
effective, often necessitating a trial-and-error
approach

47.
Chronic Renal Failure
Pharmacotherapy
MUSCULOSKELETAL COMPLAINTS
• Control of acute gouty attacks is often achieved through
cautious use of traditional agents such as NSAIDs (e.g.,
indomethacin) and colchicine.
• Upon initiation of an NSAID, patients should be
monitored closely for bleeding, worsened renal function,
and loss of diuretic efficacy
• Allopurinol, which decreases uric acid production, is the
preferred prophylactic agent because it possesses an
active metabolite (oxypurinol) that is renally eliminated;
doses are usually reduced to 100 to 200 mg daily in
advanced CKD

48.
Chronic Renal Failure
PATIENT EDUCATION
• Patients with advanced renal disease are expected to
understand and follow complex dietary, medication, and
physical care regimens
• Data indicate that intense educational effort in ESKD is
associated with increased patient autonomy, improved
quality of life, increased compliance with therapies, and
clinician ability to delay initiation of dialysis
• The need for renal replacement therapy (RRT) can often
be predicted more than 1 year in advance, providing
ample opportunity for early education of patients who
face ESKD (and their caregivers)

49.
Chronic Renal Failure
PATIENT EDUCATION
• Educational programs generally emphasize patient
comprehension of:
– The most common complications of kidney disease (anemia,
bone disease, hypertension),
– Measures to slow progression of renal disease (if still
feasible),
– Dietary management (protein, phosphorus, potassium,
sodium, and fluid restrictions),
– Medication management (reason for use, manner of use,
and precautions),
– Choice of rrt modality and physical preparation for this (e.G.,
Catheter or fistula placement, transplantation referral),
– Options for medical care and prescription coverage, and
– Possibilities for vocational support

50.
Chronic Renal Failure
PATIENT EDUCATION
• Patient referral to a renal care specialty team may
help ensure that the patient gains an adequate
understanding of kidney disease and participates in
decisions regarding options for renal replacement
modality

51.
Summary
• The presence of CKD confers a markedly increased risk of
cardiovascular disease, and people with CKD often have other
risk factors for heart disease, such as high blood lipids.
• The most common cause of death in people with CKD is
cardiovascular disease rather than kidney failure.
• Aggressive treatment of hyperlipidemia is warranted.
• Apart from controlling other risk factors, the goal of therapy is
to slow down or halt the progression of CKD to stage 5.
• Control of blood pressure and treatment of the original
disease, whenever feasible, are the broad principles of
management. Generally, angiotensin converting enzyme
inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs)
are used, as they have been found to slow the progression of
CKD to kidney failure