DRUG THERAPY OF KIDNEY DISEASES

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DRUG THERAPY OF KIDNEY DISEASES
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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

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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.

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Clinical suspicion

• It should be suspected when a patient presents
  with generalized oedema, protein detected in
  urine, hypoalbuminemia.

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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.
  

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Diagnosisof nephrotic syndrome

• The diagnosis maybe established with proteinuria
  in the nephrotic range alone without the other
  criteria.
• 1.  Proteinuria gt 3.5 g/m2/dayOn 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
  lt1.5g/day this is refered to as isolated
  proteinuria. 2. gt3.5g/day this establishes
  nephrotic syndrome.
• 2.  Hypoalbuminaemia
• 3.  HyperlipidaemiaAs 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

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Diagnosisof nephrotic syndrome

• Nitrogen balance diorders, hypercoaguloability,
  disturbances of calcium and bone metabolism, and
  thyroid hormones are often found in NS.

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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.

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• 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.

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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 Glomerulonephritis1. Infections
• HIV, Hepatitis B and C virus
• Syphilis, Malaria
• TBC, Leprosy
• 2. Malignancy
• Adenosarcoma
• Lymphoma
• Multiple Myeloma
• Renal Carcinoma

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• 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

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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.

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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 obscuresthe
  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.

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Causes and Symptoms of CRF

• Diabetes General ill feeling and
  fatigueHigh Blood Pressure Generalized
  itching dry skinGlomerulonephritis
  HeadachesPolycycstic Kidney DiseaseWeight
  lossAnalgesic Nephropathy Appetite
  LossPolycycstic Kidney Disease

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Chronic Renal Failure

• A. Definitions
• Azotemia - elevated blood urea nitrogen (BUN
  gt28mg/dL) and creatinine (Crgt1.5mg/dL)
• Uremia - azotemia with symptoms or signs of renal
  failure
• End Stage Renal Disease (ESRD) - uremia requiring
  transplantation or dialysis
• Chronic Renal Failure (CRF) - irreversible kidney
  dysfunction with azotemia gt3 months
• Creatinine Clearance (CCr) - the rate of
  filtration of creatinine by the kidney (GFR
  marker)
• Glomerular Filtration Rate (GFR) - the total rate
  of filtration of blood by the kidney

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• B. Etiology
• Episodes of ARF (usually acute tubular necrosis)
  often lead, eventually, to CRF
• Over time, combinations of acute renal insults
  are additive and lead to CRF
• The definition of CRF requires that at least 3
  months of renal failure have occurred
• 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

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• 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
• Renal (glomerular) deposition diseases
• Renal Vascular Disease - renal artery stenosis,
  atherosclerotic vs. fibromuscular

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• Medications - especially causing
  tubulointerstitial diseases (common ARF, rare
  CRF)
• Analgesic Nephropathy over many years
• Pregnancy - high incidence of increased
  creatinine and HTN during pregnancy in CRF
• Black men have a 3.5-4 fold increased risk of CRF
  compared with white men
• Blood pressure and socioecomonic status
  correlated with CRF in whites and blacks
• Unclear if blacks have increased risks when blood
  pressure and income are similar

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• Analgesic Nephropathy
• Slow progression of disease due to chronic daily
  ingestion of analgesics
• Drugs associated with this entity usually contain
  two antipyretic agents and either caffeine or
  codeine
• More common in Europe and Australia than USA
• Polyuria is most common early symptom
• Macroscopic hematuria / papillary necrosis
• Chronic interstitial nephritis, renal papillary
  necrosis, renal calcifications
• Associated with long-term use of non-steroid
  anti-inflammatory drugs

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Analgesic Nephropathy contd

• Patients at risk
• DM, CHF, CRI, Hepatic disease, elderly, etc
• Pathophysiology-
• nonselective NSAIDS inhibit synthesis
  vasodilatory prostaglandin in the kidneyprerenal
  state ARF
• COX2 not so innocent afterall.

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• Electrolyte Abnormalities
• Excretion of Na is initially increased, probably
  due to natriuretic factors
• As glomerular filtration rate (GFR) falls, FeNa
  rises
• Maintain volume until GFR lt10-20mL/min, then
  edema
• Renal failure with nephrotic syndrome, early
  edema
• Cannot conserve Na when GFR lt25mL/min, and FeNa
  rises with falling GFR
• 3. Tubular K secretion is decreased
• Aldosterone mediated. Also increased fecal loss
  of K (up to 50 of K ingested)
• Cannot handle bolus K, avoid drugs high K
• Do not use K sparing diuretics

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• Control of acids
• Normally, produce 1mEq/kg/day H
• When GFR lt40mL/min then decrease NH4 excretion
  adds to metabolic acidosis
• When GFR lt30mL/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

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• Loss of urine diluting and concentrating
  abilities
• Osmotic diuresis due to high solute concentration
  for each functioning nephron
• Reduce urinary output only by reducing solute
  excretion
• Major solutes are salt and protein, so these
  should be decreased

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• 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 lt30mL/min
• Chronic hyperparathyroidism and bone buffering of
  acids leads to severe osteoporosis

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• 7. Other abnormalities
• Slight hypermagnesemia with inability to excrete
  high magnesium loads
• Uric acid retention occurs with GFR lt40mL/min
• Vitamin D conversion to dihydroxy-Vitamin D is
  severely decreased
• Erythropoietin (EPO) levels fall and anemia
  develops
• 8. Accumulation of normally excreted substances,
  "uremic toxins", MW 300-5000 daltons

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Uremic Syndrome

• Symptomatic azotemia
• Fever, Malaise
• Anorexia, Nausea
• Mild neural dysfunction
• Uremic pruritus

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• Associated Problems and Treatment
• Immunosuppression
• Patients with CRF, even pre-dialysis, are at
  increased risk for infection
• Cell mediated immunity is particularly impaired
• Hemodialysis seems to increase immunocompromise
• Complement system is activated during
  hemodialysis
• Patients with CRF should be vaccinated
  aggressively

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• Anemia
• Due to reduced erythropoietin production by
  kidney
• Occurs when creatinine rises to gt2.5-3mg/dL
• Anemia management Hct goal - 33
• Hyperphosphatemia
• Decreased excretion by kidney
• Increased phosphate load from bone metabolism (by
  high parathyroid hormone levels)
• Increased PTH levels leads to renal bone disease
• Eventually, parathyroid gland hyperplasia occurs
• Danger of calciphylaxis (Ca x Phosp product)

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• Hypertension
• Blood pressure control is very important to
  slowing progression of renal failure
• About 30 of end-stage renal disease (ESRD) is
  related to hypertension
• Overall risk of CRF with creatinine gt2.0mg/dL is
  2X in five years with HTN
• Patients with grade IV (severe) HTN have 22X
  increased risk vs. normal for CRF
• Targetted mean pressure 92-98mm Hg in patients
  with renal failure and proteinuria
• Patients with HTN and albuminuria gt1gm/day,
  blacks, diabetics have higher ESRD risk

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• 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 gt2.5-3mg/dL
• Goal B/P 130/80 mmHg for all renal patients.
• African American study of kidney disease (AASK),
  ACE gtgtBB or CCB
• Heart Outcome Prevention and evaluation study
  (HOPE), ramipril dec mobidity/mortality.
• Less hyperkalemia with ARB vs ACE.

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• Poor coagulation
• Platelet dysfunction - usually with prolonged
  bleeding times
• May be partially reversed with DDAVP
  administration
• 7. Proteinuria gt0.25gm per day is an independent
  risk factor for renal decline
• 8. Uremic pruritus may respond to dialysis or
  opiate antagonists (eg. naltrexone 50mg/d)

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• F. Evaluation
• Search for underlying causes
• Laboratory
• Full Electrolyte Panel
• Calcium, phosphate, uric acid, magnesium and
  albumin
• Urinalysis, microscopic exam, quantitation of
  protein in urine (proteincreatinine ratio)
• Calculation of creatinine clearance and protein
  losses
• Complete blood count
• Consider complement levels, protein
  electrophoresis, antinuclear antibodies, ANCA
• Renal biopsy - particularly in mixed or
  idiopathic disease

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• 3. Radiographic Evaluation
• Renal Ultrasound - evaluate for obstruction,
  stones, tumor, kidney size, chronic change
• Duplex ultrasound or angiography or spiral CT
  scan to evaluate renal artery stenosis
• MRA preferred over contrast agents
• 4. Bone Evaluation
• Severe secondary hyperparathyroidism can lead to
  osteoporosis
• Some patients will require parathyroidectomy to
  help prevent this
• Bone densitometry should be done on patients with
  CRF

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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.

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• Pre-Dialysis Treatment
• Maintain normal electrolytes
• Potassium, calcium, phosphate are major
  electrolytes affected in CRF
• ACE inhibitors may be acceptable in many patients
  with creatinine gt3.0mg/dL
• ACE inhibitors may slow the progression of
  diabetic and non-diabetic renal disease
• Reduce or discontinue other renal toxins
  (including NSAIDS)
• Diuretics (eg. furosemide) may help maintain
  potassium in normal range
• Renal diet including high calcium and low
  phosphate

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• Reduce protein intake to lt0.6gm/kg body weight
• Appears to slow progression of diabetic and
  non-diabetic kidney disease
• In type 1 diabetes mellitus, protein restriction
  reduced levels of albuminuria
• Low protein diet did not slow progression in
  children with CRF
• Underlying Disease
• Diabetic nephropathy should be treated with ACE
  inhibitors until creatinine gt2.5-3mg/dL
• Hypertension should be aggressively treated (ACE
  inhibitors are preferred)

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• 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
  gt3gm/day, ramipril reduced progression
• Drug was titrated to a diastolic BP under 90mmHg
• Ramipril reduced rate of GFR decline by gt20,
  more than anti-hypertensive drugs alone
• Data for patients with lt3gm/day proteinuria is
  still being evaluated

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• 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

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Procedure for Chronic Hemodialysis

• Blood is run through a semi-permeable filter
  membrane bathed in dialysate
• Composition of the dialysate is altered to adjust
  electrolyte parameters
• Electrolytes and some toxins pass through filter

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Hemodialysis machine
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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

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• 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

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• Chronic Hemodialysis Medications
• Anti-hypertensives - labetolol, CCB, ACE
  inhibitors
• Erythropoietin (Epogen) for anemia in 80
  dialysis pts
• Vitamin D Analogs - calcitriol given
  intravenously
• Calcium carbonate or acetate to ? phosphate and
  PTH
• RenaGel, a non-adsorbed phosphate binder, is
  being developed for hyperphosphatemia
• DDAVP may be effective for patients with
  symptomatic platelet problems