WEEK 2 Vs3

NEPHROTIC SYNDROME

A. BASIC PRINCIPLES
Glomerular disorders characterized by proteinuria (>3.5 g/day> 3.5 \text{ g/day}) resulting in

  1. Hypoalbuminemia—pitting edema

  2. Hypogammaglobulinemia—increased risk of infection

  3. Hypercoagulable state—due to loss of antithrombin III

  4. Hyperlipidemia and hypercholesterolemia—may result in fatty casts in urine

MINIMAL CHANGE DISEASE (MCD)

A. Most common cause of nephrotic syndrome in children
B. Usually idiopathic; may be associated with Hodgkin lymphoma
C. Normal glomeruli on H&E stain (Fig. 12.7A); lipid may be seen in proximal tubule cells.
D. Effacement of foot processes on electron microscopy (EM, Fig. 12.7B)
E. No immune complex deposits; negative immunofluorescence (IF)
F. Selective proteinuria (loss of albumin, but not immunoglobulin)
G. Excellent response to steroids (damage is mediated by cytokines from T cells)

III. FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

A. Most common cause of nephrotic syndrome in Hispanics and African Americans
B. Usually idiopathic; may be associated with HIV, heroin use, and sickle cell disease
C. Focal (some glomeruli) and segmental (involving only part of the glomerulus) sclerosis on H&E stain (Fig. 12.8)
D. Effacement of foot processes on EM
E. No immune complex deposits; negative IF
F. Poor response to steroids; progresses to chronic renal failure

IV. MEMBRANOUS NEPHROPATHY

A. Most common cause of nephrotic syndrome in Caucasian adults
B. Usually idiopathic; may be associated with hepatitis B or C, solid tumors, SLE, or drugs (e.g., NSAIDs and penicillamine)
C. Thick glomerular basement membrane on H&E (Fig. 12.9A)
D. Due to immune complex deposition (granular IF, Fig. 12.9B); subepithelial deposits with 'spike and dome' appearance on EM (Fig. 12.9C)
E. Poor response to steroids; progresses to chronic renal failure

V. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

A. Thick glomerular basement membrane on H&E, often with 'tram-track' appearance
B. Due to immune complex deposition (granular IF)
C. Divided into two types based on location of deposits

  1. Type I—subendothelial (Fig. 12.10); associated with HBV and HCV

  2. Type II (dense deposit disease)—intramembranous; associated with C3 nephritic factor (autoantibody that stabilizes C3 convertase, leading to overactivation of complement, inflammation, and low levels of circulating C3)
    D. Poor response to steroids; progresses to chronic renal failure

VI. DIABETES MELLITUS

A. High serum glucose
B. Glomerular efferent arteriole is more affected than the afferent arteriole, leading to high glomerular filtration pressure.

  1. Hyperfiltration injury leads to microalbuminuria.
    C. Eventually progresses to nephrotic syndrome

  2. Characterized by sclerosis of the mesangium with formation of Kimmelstiel-Wilson nodules (Fig. 12.11)
    D. ACE inhibitors slow progression of hyperfiltration-induced damage.

VII. SYSTEMIC AMYLOIDOSIS

A. Kidney is the most commonly involved organ in systemic amyloidosis.
B. Amyloid deposits in the mesangium, resulting in nephrotic syndrome.
C. Characterized by apple-green birefringence under polarized light after staining with Congo red

NEPHRITIC SYNDROME

I. BASIC PRINCIPLES
A. Glomerular disorders characterized by glomerular inflammation and bleeding

  1. Limited proteinuria (<3.5 g/day< 3.5 \text{ g/day})

  2. Oliguria and azotemia

  3. Salt retention with periorbital edema and hypertension

  4. RBC casts and dysmorphic RBCs in urine
    B. Biopsy reveals hypercellular, inflamed glomeruli (Fig. 12.12).

II. POSTSTREPTOCOCCAL GLOMERULONEPHRITIS (PSGN)
A. Nephritic syndrome that arises after group A β\beta-hemolytic streptococcal infection of the skin (impetigo) or pharynx

  1. Occurs with nephritogenic strains

  2. May occur after infection with nonstreptococcal organisms as well
    B. Presents 2–3 weeks after infection as hematuria (cola-colored urine), oliguria, hypertension, and periorbital edema

  3. Usually seen in children, but may occur in adults
    C. Hypercellular, inflamed glomeruli on H&E
    D. Mediated by immune complex deposition (granular IF); subepithelial 'humps' on EM (Fig. 12.13)
    E. Treatment is supportive.

  4. Children rarely (1%) progress to renal failure.

  5. Some adults (25%) develop rapidly progressive glomerulonephritis (RPGN).

III. RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
A. Nephritic syndrome that progresses to renal failure in weeks to months

  1. Immunofluorescence Findings (Table 12.1):

    • Linear (anti-basement membrane antibody, Fig. 12.15)

      • Disease: Goodpasture syndrome

      • Comments: Antibody against collagen in glomerular and alveolar basement membranes; presents as hematuria and hemoptysis, classically in young, adult males

    • Granular (immune complex deposition)

      • Disease: PSGN (most common) or diffuse proliferative glomerulonephritis

      • Comments: Diffuse proliferative glomerulonephritis is due to diffuse antigen-antibody complex deposition, usually sub-endothelial; most common type of renal disease in SLE

    • Negative IF (pauci-immune)

      • Disease: Wegener granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome

      • Comments: Wegener granulomatosis is associated with c-ANCA; microscopic polyangiitis and Churg-Strauss are associated with p-ANCA. Granulomatous inflammation, eosinophilia, and asthma distinguish Churg-Strauss from microscopic polyangiitis.
        B. Characterized by crescents in Bowman space (of glomeruli) on H&E stain; crescents are comprised of fibrin and macrophages (Fig. 12.14).
        C. Clinical picture and IF help resolve etiology (Table 12.1).

IV. IgA NEPHROPATHY (BERGER DISEASE)
A. IgA immune complex deposition in mesangium of glomeruli; most common nephropathy worldwide
B. Presents during childhood as episodic gross or microscopic hematuria with RBC casts, usually following mucosal infections (e.g., gastroenteritis)

  1. IgA production is increased during infection.
    C. IgA immune complex deposition in the mesangium is seen on IF (Fig. 12.16).
    D. May slowly progress to renal failure

V. ALPORT SYNDROME
A. Inherited defect in type IV collagen; most commonly X-linked
B. Results in thinning and splitting of the glomerular basement membrane
C. Presents as isolated hematuria, sensory hearing loss, and ocular disturbances

URINARY TRACT INFECTION

I. BASIC PRINCIPLES
A. Infection of urethra, bladder, or kidney
B. Most commonly arises due to ascending infection; increased incidence in females
C. Risk factors include sexual intercourse, urinary stasis, and catheters.

II. CYSTITIS
A. Infection of the bladder
B. Presents as dysuria, urinary frequency, urgency, and suprapubic pain; systemic signs (e.g., fever) are usually absent.
C. Laboratory findings

  1. Urinalysis—cloudy urine with >10\text{>} 10 WBCs/high power field (hpf)

  2. Dipstick—Positive leukocyte esterase (due to pyuria) and nitrites (bacteria convert nitrates to nitrites)

  3. Culture—greater than 100,000 colony forming units (gold standard)
    D. Etiology

  4. E. coli (80%)

  5. Staphylococcus saprophyticus—increased incidence in young, sexually active women (but E. coli is still more common in this population)

  6. Klebsiella pneumoniae

  7. Proteus mirabilis—alkaline urine with ammonia scent

III. PYELONEPHRITIS
A. Infection of the kidney

  1. Usually due to ascending infection; increased risk with vesicoureteral reflux
    B. Presents with fever, flank pain, WBC casts, and leukocytosis in addition to symptoms of cystitis
    C. Most common pathogens are

  2. E. coli (90%)

  3. Enterococcus faecalis

  4. Klebsiella species

IV. CHRONIC PYELONEPHRITIS
A. Interstitial fibrosis and atrophy of tubules due to multiple bouts of acute pyelonephritis
B. Due to vesicoureteral reflux (children) or obstruction (e.g., BPH or cervical carcinoma)
C. Leads to cortical scarring with blunted calyces; scarring at upper and lower poles is characteristic of vesicoureteral reflux.
D. Atrophic tubules containing eosinophilic proteinaceous material resemble thyroid follicles ('thyroidization' of the kidney, Fig. 12.17); waxy casts may be seen in urine.

NEPHROLITHIASIS

I. BASIC PRINCIPLES
A. Precipitation of a urinary solute as a stone (Table 12.2)
B. Risk factors include high concentration of solute in the urinary filtrate and low urine volume.
C. Presents as colicky pain with hematuria and unilateral flank tenderness

  1. Stone is usually passed within hours; if not, surgical intervention may be required.

CHRONIC RENAL FAILURE

I. BASIC PRINCIPLES
A. End-stage kidney failure

  1. May result from glomerular, tubular, inflammatory, or vascular insults

  2. Most common causes are diabetes mellitus, hypertension, and glomerular disease.
    B. Clinical features

  3. Uremia—Increased nitrogenous waste products in blood (azotemia) result in nausea, anorexia, pericarditis, platelet dysfunction, encephalopathy with asterixis, and deposition of urea crystals in skin.

  4. Salt and water retention with resultant hypertension

  5. Hyperkalemia with metabolic acidosis

  6. Anemia due to decreased erythropoietin production by renal peritubular interstitial cells

  7. Hypocalcemia—decreased kidney 1-α\alpha-hydroxylase (converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the active form) and hyperphosphatemia (decreased phosphate excretion)

  8. Renal osteodystrophy—bone pain