Download Tubulointerstitial Disease

Renal Pathophysiology: Tubulointerstitial Diseases (Zeng)
ACUTE RENAL FAILURE:

Definition of Acute Renal Failure:
Acute and rapid decline in renal function characterized by:
o Azotemia
o Oliguria (<400ml urine/day; often earliest sign of impaired renal function)
o Increased ECF volume
o Hyperkalemia
o Metabolic acidosis
May be due to processes affecting ANY compartment of the kidney

Development of Acute Renal Failure:
Outside the Hospital: minority of cases*
o Evaluation of the following immediately:

Hyperkalemia

Metabolic acidosis

Pulmonary edema

Edema/ascites
o Usually a SINGLE cause
o Good prognosis
Inside the Hospital: most cases*
o Common causes:

Hypovolemia

Effects of anesthesia or surgery

Diuretics

Nephrotoxic drugs

Contrast media
o Multiple renal insults, often leading to SEVERE failure
o Prognosis not as good

Principal Causes of Acute Renal Failure:
Pre-Renal Causes: due to HYPOPERFUSION of the kidney
o Absolute decrease in effective blood volume:

Hemorrhage (trauma, surgery)

GI fluid loss (diarrhea, vomiting, NG suction)

Renal losses (diuretics, glycosuria)
o Relative decrease in peripheral vascular resistance:

Sepsis

Anaphylaxis

Shock
o Reduced cardiac output

MI

Pulmonary embolism

CHF
o Local renal vasoconstriction
Post-Renal Causes: due to OBSTRUCTION of urine flow (obstructive uropathy)
o Upper Urinary Tract Obstruction: ureteral obstruction of one or both kidneys

Tumor

Fibrosis
o Lower Urinary Tract Obstruction: bladder outlet obstruction (more common)

Prostatic hypertrophy
Renal (Intrinsic) Causes: processes affecting any of the renal compartments
o Glomerular causes:

Crescentic Glomerulonephritis
o Vasculature causes
o Interstitial/Tubular Causes:

Acute Tubulo-Interstitial Nephritis (related to drugs, infections, or cancer)

Acute Tubular Necrosis (due to ischemia or toxicities)
ACUTE TUBULAR NECROSIS:

Basics: results from the injury and/or destruction of the RENAL TUBULAR EPITHELIUM
May be responsible for ¾ of cases of acute renal failure

Causes (2 Categories):
Ischemic Injury: due to inadequate blood flow to the kidneys (usually secondary to a pre-renal cause)
o Shock/hypotension from sepsis
o Massive burns
o Major surgery or hemorrhage
Tubulo-Toxic Injury: introduction of a substance that is toxic to tubular cells
o Nephrotoxic drugs (ie. aminoglycoside Abx such as gentamycin)
o Solvents
o Heavy metals (ie. mercury)
o Pigments (ie. diagnostic radiocontrast dyes)

Result- Injury to Tubular Epithelial Cells:
Features:
o Impaired synthetic functions (cells cannot make ATP or proteins)
o Decreased high energy phosphate stores (not making ATP)
o Activation of destructive lysosomal processes
Important Point: although the name suggests death of the tubular cells, this is RARELY the case*
o Cells may become injured and lose most functions without actually becoming necrotic
o However, actual necrosis MAY occur if insult is severe

Regeneration of necrotic cells is possible if basement membrane is intact

Insult must be removed and patient must be supported for regeneration to occur

Pathology of Acute Tubular Necrosis:
Basics: pathological changes vary based on severity of insult and when biopsy is done
Mild Cases:
o Loss of tubule cell brush border (cell injury)
o Vacuolization of cytoplasm
o Swelling of cells
Severe Cases:
o Necrosis of cells slough off into tubular lumen
o Bare basement membranes
Changes of Recovery: seen when biopsy is done after patient recovery has begun*
o Flattened epithelial cells (as they attempt to re-cover basement membranes)
o Mitotic figures
o Reactive nuclei with large nucleoli

Reduction in GFR:
Mechanisms for GFR Reduction in ATN:
o Vasoconstriction: ischemic injury/nephrotoxin may also lead to vasoconstriction (in addition to direct
tubular damage)
o Obstruction of Tubules by Necrotic Cells (Casts): causes increased tubular pressure and decreased
filtration
o Backleak of Filtered Urine: leaks through damaged tubules back into kidney vasculature and
interstitium
ACUTE TUBULO-INTERSTITIAL NEPHRITIS:

Basics: inflammation of the interstitium of the kidney, which also affects the tubules

Immunologic Phenomenon:
Patients have a history or evidence of hypersensitivity
Immune complexes may be present in tubular basement membranes
Anti-tubular basement membrane Abs may be found in some patients
T cell mediated damage (type IV hypersensitivity) has been shown to occur*
o Likely the explanation in MOST cases

Causes:
Drug Reaction: most common cause*
o Mechanism: drug acts as a hapten to elicit the immune response
o Common Drugs:

Beta-lactam antibiotics (ie. penicillin, methicillin, ampicillin)



Sulfonamides (ie. Bactrim)

NSAIDs (ie. Motrin)

Diuretics (only some)
Systemic Infections:
o Mechanism: antigens are deposited in the tubulo-interstitium, eliciting the response

Note: condition is NOT due to the direct infectious nature of the organisms themselves*
o Common Infectious Agents:

Group A strep

Diphtheria

Toxoplasmosis

Legionnaire’s disease (Legionella)
Systemic Illnesses: SLE
Pathology:
Tubules separated by pronounced edema
Inflammatory infiltrate (lymphocytes, monocytes, eosinophils, neutrophils)
o Lymphocytes may be noted “percolating” through the tubular epithelium
Clinical Features: features of HYPERSENSITIVITY*
Fever
Hematuria
Eosinophilia
Pyuria
Skin rash
Mild proteinuria
Eosinophiluria
INFECTION OF THE KIDNEY- ACUTE PYELONEPHRITIS:

Basic Definitions:
Urinary Tract Infection: general term that implies a patient has a bacterial/viral/fungal infection at any point in
the urinary tract (from urethra to kidney)
o Generally used to describe LOWER UTIs
o Most common cause of acute pyelonephritis
Acute Pyelonephritis: actual infection of the renal parenchyma
o Usually associate with a UTI
Causative Organisms: the organisms that cause UTI/AP are the same as the one’s found in the patient’s own gut
o E.coli
o Klebsiella
o Proteus
o Enterococcus
o Enterobacter
o Other infections in special scenarios:

Candida albicans (immunosuppressed patients and diabetics)

CMV (transplant and other immunosuppressed patients)

Route of Infections in Acute Pyelonephritis:
Hematogenous Infection (5%):
o Bacteremia in septic patients
o Infected emboli (endocarditis)
Ascending Infection (95%):
o Pre-existing UTI that ascends (urethra bladder ureter renal pelvis kidney)

Risk Factors for Ascending Infections:
Obstruction of urine flow: may occur at ANY level
o Urethral/ureteral stricture
o Functional bladder obstruction with incomplete emptying (neurogenic bladder of DM)
o Prostatic hypertrophy (urethral obstruction)
Vesicoureteral reflex: covered later
Instrumentation of the GU tract: catheters, diagnostic procedures
Pregnancy: uterus obstructs one or both ureters
Age and sex: covered later
Immune dysfunction: AIDS, diabetes, steroids
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

Risk Factors for UTIs (May Lead to Acute Pyelonephritis):
Age and Sex VERY IMPORTANT:
o <1 year old: male infants more likely (congenital anomalies more common- urethral/ureteral valves)
o 1-50 years old: females much more likely (8:1)

Shorter urethra (less distance for migration)

Lack of antibacterial prostatic secretions (men)

Hormonal influences

Trauma during sexual intercourse (“honeymoon cystitis”)
o >50 years old: men more likely

Secondary to prostatic hypertrophy
Vesico-Ureteral Reflux:
o Process: reflux of urine from the bladder to the ureters

If urine infected, the infected column of urine makes its way to the renal pelvis and
parenchyma
o Cause: interference with the functional sphincter that normally closes off the ureters with contraction
of the bladder (ureters normally enters the wall at an angle)

Absence of the intravesicular ureter (ureter enters perpendicular to the bladder wall)

Congenital para-ureteral diverticulum (interferes with normal function)

Inflammation of bladder wall
Pathology of Acute Pyelonephritis:
Gross:
o Outer kidney has pinpoint pustules that may become confluent in severe cases
o Inner kidney shows streaks of yellow pus extending from renal pyramids into the cortex (streaks of
infected tubules)
Microscopic:
o Intense neutrophilic interstitial AND tubular infiltrate
o Marked tubular destruction
o Glomeruli relatively unaffected (early in disease)
Complications of Acute Pyelonephritis:
Pyonephrosis: infection so severe that the kidney is transformed into a “bag of pus”
Perinephric Abscess: infection breaks through the renal capsule and infection spreads to perinephric soft tissue
Necrotizing Papillitis (Papillary Necrosis): necrosis of the renal papillae; slough off into the renal pelvis and
cause further destruction
o Requirements: papillary necrosis requires 3 elements to be present in order to occur*

Acute pyelonephritis (infection)

Obstruction to urinary flow

Compromised blood flow
 Severe arteriolosclerosis (ie. diabetics)
 Clogging of vasa recta (ie. sickle cell anemia)
o Gross Appearance: coagulation necrosis with sharply demarcated edges undergoing inflammation
INFECTION OF THE KIDNEY- CHRONIC PYELONEPHRITIS:

Basics: represents recurrent, repeated bouts on acute pyelonephritis
Causes SEVERE SCARRING of the renal parenchyma, calyces and pelvis

Common Associations:
Patients with chronic urine reflux and numerous episodes of UTIs (most common)*
Patients with vesico-ureteral reflex
Patients with intrarenal reflux
Patients with acute pyelonephritis

Pathology:
Gross:
o Scarred and asymmetric kidneys
o Pelvis and calyces are markedly thickened and scarred
o Cortex thinned by numerous broad cortical scars
Microscopic: NON-SPECIFIC (requires GROSS diagnosis); all components of the kidney are affected
o Glomerulosclerosis
o Interstitial fibrosis
o Tubular atrophy