Transcript Chronic Renal Failure

DRUG THERAPY OF
KIDNEY DISEASES
NEPHROLOGY
Kidney disease and kidney failure are increasingly
common in this 21st century. Often caused by other
conditions such as diabetes and hypertension, the
severity of kidney disease can be greatly reduced if
appropriate and early treatment.
Diabetic nephropathy
Hypertension
Kidney stones
Vasculitis
Nephritis, glomerular and interstitial
Chronic renal insufficiency, anemia and other
complications
Dialysis care
Transplantation
Edema and disorders of electrolytes
Nephrotic Syndrome
Nephrotic syndrome Is a
clinical syndrome
associated with
proteinuria in the
nephrotic range
(3.5mg/m2/24hrs), edema
and hyperlipidemia.
Nephrotic syndrome is
not due to inflammatory
processes but due to
direct action of the
membrane attack unit of
complement on the
glomerulus.
Clinical suspicion
It should be suspected when a patient
presents with generalized oedema, protein
detected in urine, hypoalbuminemia.
Some of the symptoms of nephrotic
syndrome
swelling, especially around the eyes, ankles,
and feet.
Other symptoms include weight gain, because of
the fluid and swelling, loss of appetite, and
vomiting.
serious side effects such as pleural effusion,
high blood pressure, and problems with the liver.
Diagnosis
of nephrotic syndrome
The diagnosis maybe established with proteinuria in the nephrotic
range alone without the other criteria.
1. Proteinuria > 3.5 g/m2/day:
On detection of protein in urine a 24 hour urinary protein test is in
order. There are two cut off values for this test: 1. increased urinary
protein <1.5g/day; this is refered to as isolated proteinuria. 2.
>3.5g/day; this establishes nephrotic syndrome.
2. Hypoalbuminaemia
3. Hyperlipidaemia:
As albumen in serum is lost through the kidneys, the liver increases
its production of albumen and concomitantly increases the
production of cholesterol.
4. Oedema: resulting from loss of intravascular fluid to the
extravascular space due decreased intravascular oncotic pressure
(decreased albumen).
However, the presence of proteinuria in the nephrotic range
(3.5g/day) establishes the diagnosis.
Differential diagnosis: proteinuria
Diagnosis
of nephrotic syndrome
Nitrogen balance diorders,
hypercoaguloability, disturbances of
calcium and bone metabolism, and thyroid
hormones are often found in NS.
Several different causes have been identified for nephrotic
syndrome. Damage to the small vessels, or glomeruli, can
usually be traced to one of the following conditions:
Minimal change disease. This is the most common
cause of this disorder in children. In children it results in
abnormal kidney function, but is often deceiving because
tissue samples look normal or nearly normal under a
microscope. When this disorder is the cause of nephrotic
syndrome, doctors are often unable to discern its cause.
Focal segmental glomerulosclerosis. When this
disorder occurs, the glomeruli are scarred, which
prevents them from working efficiently. The scarring
might be caused by genetic factors, the presence of
another disease, or for no discernible reason.
Membranous nephropathy. In this disorder, the
membranes inside the glomeruli thicken, making it
difficult for them to filter properly. This thickening is
thought to be caused by several different problems,
including hepatitis B, malaria, lupus, and cancer.
Systemic lupus erythematosus. This is a chronic
inflammatory disease, and can lead to serious damage
of the kidneys.
Diabetic kidney disease. Diabetic nephropathy, or
kidney damage, is particularly common in poorly
controlled diabetes or in people who have high blood
pressure.
Amyloidosis. This is a disorder that occurs when
amyloid proteins accumulate in the organs. This build-up
damages the kidneys’ filtering system.
Nephrotic syndrome can be caused by
primary and secondary Glomerulonephritis
A. Primary Glomerulonephritis
GN with minimal lessions
Glomerulosclerotic focal
Membranous Glomerulonephritis
GN membranoproliferatif
Other proliferative
B. Secondary Glomerulonephritis
1. Infections:
HIV, Hepatitis B and C virus
Syphilis, Malaria
TBC, Leprosy
2. Malignancy:
Adenosarcoma
Lymphoma
Multiple Myeloma
Renal Carcinoma
3. Connective Tissue Disease:
SLE
Rhematoid Arthritis
Mixed Cinnective Tissue Disease
4. Drugs and Toxins:
NSIDs
Gold Preparations
Penicillamine
Probenecid
Mercury
Captopril
Heroin
5. Other:
Diabetes Mellitus
Amyloidosis
Pre-Eclampsia
Vesikoureter reflux
Treatment
Treatment of nephrotic syndrome depends primarily on
the cause, however, it frequently involves the use the
glucorticoids given over long periods of time. Especially
in cases of minimal change disease. Here the role of
steroids is to suppress the autoimmune basis for this
disease. The use of cytotoxic agents maybe required in
some cases (e.g. cyclophosphamide).
Dietary salt control, treatment of hypertension and
hypercholestrolemia is also recommended. ACE
inhibitors, in addition to controlling blood pressure have
also been found to decrease the protein loss. Diuretics
may help control the edema and the hypertension.
Chronic Renal Failure
Chronic renal failure (CRF) is a slowly progressive loss
of renal function over a period of months or years.
The kidneys attempt to compensate for renal damage by
hyper filtration with the remaining functional nephrons.
Chronic loss of function causes generalized wasting or
shrinking and progressive scarring within all parts of the
kidneys. In time, overall scarring obscures
the site of the initial damage. But, it is not until over 70%
of the normal combined function of both kidneys is lost
that most patients begin to experience symptoms of
kidney failure.
Causes and Symptoms of CRF:
•Diabetes
• General ill feeling and fatigue
•High Blood Pressure
• Generalized itching & dry skin
•Glomerulonephritis
• Headaches
•Polycycstic Kidney Disease
•Weight loss
•Analgesic Nephropathy
• Appetite Loss
•Polycycstic Kidney Disease
Chronic Renal Failure
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
B. Etiology
1. Episodes of ARF (usually acute tubular
necrosis) often lead, eventually, to CRF
2. Over time, combinations of acute renal insults
are additive and lead to CRF
3. The definition of CRF requires that at least 3
months of renal failure have occurred
4. Causes of Acute Renal Failure (ARF)
a.
Prerenal azotemia - renal hypoperfusion,
usually with acute tubular necrosis
b. Intrinsic Renal Disease, usually glomerular
disease
c. Postrenal azotemia - obstruction of some type
1.
Common Underlying Causes of CRF
There are about 50,000 cases of ESRD per year
Diabetes: most common cause ESRD (risk 13x )
Over 30% cases ESRD are primarily to diabetes
CRF associated HTN causes ~ 23% ESRD cases
Glomerulonephritis accounts for ~10% cases
Polycystic Kidney Disease - about 5% of cases
Rapidly progressive glomerulonephritis (vasculitis)
- about 2% of cases
h. Renal (glomerular) deposition diseases
i. Renal Vascular Disease - renal artery stenosis,
atherosclerotic vs. fibromuscular
a.
b.
c.
d.
e.
f.
g.
Medications - especially causing
tubulointerstitial diseases (common ARF,
rare CRF)
b. Analgesic Nephropathy over many years
c. Pregnancy - high incidence of increased
creatinine and HTN during pregnancy in
CRF
a.
Black men have a 3.5-4 fold increased risk of
CRF compared with white men
a. Blood pressure and socioecomonic status
correlated with CRF in whites and blacks
b. Unclear if blacks have increased risks when
blood pressure and income are similar
Analgesic Nephropathy
a. Slow progression of disease due to chronic
daily ingestion of analgesics
b. Drugs associated with this entity usually
contain two antipyretic agents and either
caffeine or codeine
c. More common in Europe and Australia than
USA
d. Polyuria is most common early symptom
e. Macroscopic hematuria / papillary necrosis
f. Chronic interstitial nephritis, renal papillary
necrosis, renal calcifications
g. Associated with long-term use of non-steroid
anti-inflammatory drugs
Analgesic Nephropathy cont’d
Patients at risk:
DM, CHF, CRI, Hepatic disease, elderly, etc
Pathophysiologynonselective NSAIDS inhibit synthesis
vasodilatory prostaglandin in the
kidney=prerenal state ARF
COX2 not so innocent afterall.
Electrolyte Abnormalities
1. Excretion of Na+ is initially increased, probably due to
natriuretic factors
2. As glomerular filtration rate (GFR) falls, FeNa rises
a. Maintain volume until GFR <10-20mL/min, then
edema
b. Renal failure with nephrotic syndrome, early edema
c. Cannot conserve Na+ when GFR <25mL/min, and
FeNa rises with falling GFR
3. Tubular K+ secretion is decreased
a. Aldosterone mediated. Also increased fecal loss of K+
(up to 50% of K ingested)
b. Cannot handle bolus K+, avoid drugs high K+
c. Do not use K+ sparing diuretics
Control of acids
Normally, produce ~1mEq/kg/day H+
When GFR <40mL/min then decrease NH4+
excretion adds to metabolic acidosis
When GFR <30mL/min then urinary
phosphate buffers decline and acidosis
worsens
Bone CaCO3 begins to act as the buffer and
bone lesions result (renal osteodystrophy)
Usually will not have wide anion gap even
with acidosis if can make urine
Acidosis caused by combination
hyperchloremia and hypersulfatemia
Defect in renal generation of HCO3-, as well
as retention of nonvolatile acids
Loss of urine diluting and concentrating
abilities
a. Osmotic diuresis due to high solute
concentration for each functioning nephron
b. Reduce urinary output only by reducing solute
excretion
c. Major solutes are salt and protein, so these
should be decreased
Bone Metabolism
↓GFR leads to ↑ phosphate ↓ calcium + acidosis
In addition,↑ tubular resorption Ca+ ↑ hypocalcemia
Other defects include acidosis and decreased
dihydroxy-vitamin D production
Bone acts as a buffer for acidosis, leading to chronic
bone loss in renal failure
Low vitamin D causes poor calcium absorbtion and
hyperparathyroidism (high PTH)
Increased PTH maintains normal serum Ca2+ and
PO42- until GFR <30mL/min
Chronic hyperparathyroidism and bone buffering of
acids leads to severe osteoporosis
7. Other abnormalities
a. Slight hypermagnesemia with inability to
excrete high magnesium loads
b. Uric acid retention occurs with GFR
<40mL/min
c. Vitamin D conversion to dihydroxy-Vitamin
D is severely decreased
d. Erythropoietin (EPO) levels fall and anemia
develops
8. Accumulation of normally excreted
substances, "uremic toxins", MW 300-5000
daltons
Uremic Syndrome
1. Symptomatic azotemia
2. Fever, Malaise
3. Anorexia, Nausea
4. Mild neural dysfunction
5. Uremic pruritus
Associated Problems and Treatment
Immunosuppression
a. Patients with CRF, even pre-dialysis, are at
increased risk for infection
b. Cell mediated immunity is particularly
impaired
c. Hemodialysis seems to increase
immunocompromise
d. Complement system is activated during
hemodialysis
e. Patients with CRF should be vaccinated
aggressively
Anemia
Due to reduced erythropoietin production by
kidney
b. Occurs when creatinine rises to >2.5-3mg/dL
c. Anemia management: Hct goal - 33%
a.
Hyperphosphatemia
Decreased excretion by kidney
Increased phosphate load from bone metabolism
(by high parathyroid hormone levels)
c. Increased PTH levels leads to renal bone
disease
d. Eventually, parathyroid gland hyperplasia occurs
e. Danger of calciphylaxis (Ca x Phosp product)
a.
b.
Hypertension
a. Blood pressure control is very important to
slowing progression of renal failure
b. About 30% of end-stage renal disease (ESRD)
is related to hypertension
c. Overall risk of CRF with creatinine >2.0mg/dL
is ~2X in five years with HTN
d. Patients with grade IV (severe) HTN have 22X
increased risk vs. normal for CRF
e. Targetted mean pressure 92-98mm Hg in
patients with renal failure and proteinuria
f. Patients with HTN and albuminuria >1gm/day,
blacks, diabetics have higher ESRD risk
g. ACE inhibitors shown be most effective at
preserving renal function by preferential dilation
efferent arterioles which IGCP.
h. ACE inhibitors are avoided in patients with serum
creatinine >2.5-3mg/dL
Goal B/P 130/80 mmHg for all renal patients.
African American study of kidney disease (AASK),
ACE >>BB or CCB
Heart Outcome Prevention and evaluation study
(HOPE), ramipril dec mobidity/mortality.
Less hyperkalemia with ARB vs ACE.
Poor coagulation
Platelet dysfunction - usually with prolonged
bleeding times
b. May be partially reversed with DDAVP
administration
7. Proteinuria >0.25gm per day is an
independent risk factor for renal decline]
8. Uremic pruritus may respond to dialysis or
opiate antagonists (eg. naltrexone 50mg/d)
a.
F. Evaluation
1. Search for underlying causes
2. Laboratory
a. Full Electrolyte Panel
b. Calcium, phosphate, uric acid, magnesium and
albumin
c. Urinalysis, microscopic exam, quantitation of protein in
urine (protein:creatinine ratio)
d. Calculation of creatinine clearance and protein losses
e. Complete blood count
f. Consider complement levels, protein electrophoresis,
antinuclear antibodies, ANCA
g. Renal biopsy - particularly in mixed or idiopathic
disease
3. Radiographic Evaluation
Renal Ultrasound - evaluate for obstruction,
stones, tumor, kidney size, chronic change
b. Duplex ultrasound or angiography or spiral
CT scan to evaluate renal artery stenosis
c. MRA preferred over contrast agents
a.
4. Bone Evaluation
a. Severe secondary hyperparathyroidism can
lead to osteoporosis
b. Some patients will require
parathyroidectomy to help prevent this
c. Bone densitometry should be done on
patients with CRF
Treatment
The most important differential diagnosis is to decide
whether the renal failure is acute or chronic. History
could provide indications as to the onset of problems
from the history of urinary changes in terms of quantity
and quality; and history of a loss in body weight, chronic
fatigue etc. The presence of anaemia suggests CRF;
bilateral small kidneys suggest CRF; neuropathy,
lipiduria, and osteodystrophy. The presence of loin pain
is always a good sign indicating that the kidney is still
responsive.
CRF cannot be treated apart from by renal transplant. In
the period usually required to find a transplant, dialysis
(renal function replacement therapy) is the only way to
clear waste products from the blood that are usually
excreted through the urine (urea, potassium).
Replacement of erythropoietin and vitamin D3, two
hormones processed by the kidney, is usually
necessary, as is calcium.
Pre-Dialysis Treatment
1. Maintain normal electrolytes
a. Potassium, calcium, phosphate are major
electrolytes affected in CRF
b. ACE inhibitors may be acceptable in many
patients with creatinine >3.0mg/dL
c. ACE inhibitors may slow the progression of
diabetic and non-diabetic renal disease
d. Reduce or discontinue other renal toxins
(including NSAIDS)
e. Diuretics (eg. furosemide) may help maintain
potassium in normal range
f. Renal diet including high calcium and low
phosphate
Reduce protein intake to <0.6gm/kg body weight
a. Appears to slow progression of diabetic and nondiabetic kidney disease
b. In type 1 diabetes mellitus, protein restriction
reduced levels of albuminuria
c. Low protein diet did not slow progression in
children with CRF
Underlying Disease
Diabetic nephropathy should be treated with ACE
inhibitors until creatinine >2.5-3mg/dL
b. Hypertension should be aggressively treated (ACE
inhibitors are preferred)
a.
a.
1.
a.
b.
c.
d.
e.
Caution with use of ACE inhibitors in renal
artery stenosis
Ramipril in Non-Diabetic Proteinuric
Nephropathy
Ramipril is a second generation ACE
inhibitor with efficacy in HTN and heart
Failure
In patients with non-diabetic proteinuria
>3gm/day, ramipril reduced progression
Drug was titrated to a diastolic BP under
90mmHg
Ramipril reduced rate of GFR decline by
>20%, more than anti-hypertensive drugs
alone
Data for patients with <3gm/day proteinuria
is still being evaluated
a.
b.
a.
b.
c.
d.
e.
f.
Ramipril may be preferred agent for treatment of
non-diabetic proteinuric nerphropathy
A meta-analysis of ACE inhibitors in non-diabetic
renal disease showed benefit
H. Hemodialysis
Indications
Uremia - azotemia with symptoms and/or signs
Severe Hyperkalemia
Volume Overload - usually with congestive heart
failure (pulmonary edema)
Toxin Removal - ethylene glycol poisoning,
theophylline overdose, etc.
An arterio-venous fistula in the arm is created
surgically
Catheters are inserted into the fistula for blood flow
to dialysis machine
Procedure for Chronic
Hemodialysis
Blood is run through
a semi-permeable
filter membrane
bathed in dialysate
b. Composition of the
dialysate is altered
to adjust electrolyte
parameters
c. Electrolytes and
some toxins pass
through filter
a.
Hemodialysis machine
Hemodialysis
By controlling flow rates (pressures),
patient's intravascular volume can be
reduced
Most chronic hemodialysis patients
receive 3 hours dialysis 3 days per week
a.
b.
c.
d.
e.
f.
Efficacy
Some acids, BUN and creatinine are reduced
Phosphate is dialyzed, but quickly released from
bone
Very effective at reducing intravascular
volume/potassium
Once dialysis is initiated, kidney function is often
reduced
Not all uremic toxins are removed and patients
generally do not feel "normal"
Response of anemia to erythropoietin is often
suboptimal with hemodialysis
Chronic Hemodialysis Medications
a. Anti-hypertensives - labetolol, CCB, ACE
inhibitors
b. Erythropoietin (Epogen®) for anemia in
~80% dialysis pts
c. Vitamin D Analogs - calcitriol given
intravenously
d. Calcium carbonate or acetate to 
phosphate and PTH
e. RenaGel, a non-adsorbed phosphate
binder, is being developed for
hyperphosphatemia
f. DDAVP may be effective for patients with
symptomatic platelet problems