Renal Disease Overview

July 10, 2018 9:24 PM

01 Glomerular disease - Overview

RENAL DISEASE OVERVIEW

Glomerular Diseases Tubulointerstitial Diseases Vascular Diseases Renal Cancer
- Nephrotic Syndromes - Pyelonephritis - Renal artery stenosis - Benign
- Nephritic Syndromes - Acute tubular nephritis - HTN: nephrosclerosis - Renal cell carcinoma
- Acute interstitial nephritis - Microangiopathy - Wilm's Tumor
- Cortical necrosis nephroblastoma
- Renal infarct

FEATURES OF RENAL DISEASE

General exam - Color: yellow, red, smoky/cola-colored, black
- Clarity: clear, cloudy
- Specific gravity : >1.023 excludes intrinsic renal disease, fixed SG seen in CRF
Chemical Exam - pH: alkaline urine suggests urease producing pathogens
- Protein: nephrotic, nephritic syndromes
- Glucose, Ketones: Diabetic ketoacidosis
- Blood: RBCs, Hemoglobin or Myoglobin
- Bilirubin, Urobilinogen: Conjugated v/s unconjugated hyperbilirubinemia
- Nitrites, Leukocyte esterase: Infections
Sediments - Cells: Bacteria, RBCs, WBCs, Oval fat bodies
- Casts: Hyaline, Waxy, RBC, WBC, Fatty
- Crystals: Calcium oxalate, Triple phosphate, Uric acid, Cystine

Proteinuria
- Proteinuria: more than 30mg/dL
- Persistent proteinuria indicates renal disease
- The more foamy, more protein content
- Nephritic Syndrome: 30 to 3 g/day
- Nephrotic Syndrome: more than 3g/ day

Hematuria and Casts

Dysmorphic RBC Non-glomerular

- Irregular appearance - Regular appearance - Presence of casts indicate hematuria/pyuria is of glomerular or

- Indicate glomerular damage tubular origin
• Dysmorphic RBC get through - Cells collect inside tubules, then get expelled out
GBM

Hyaline Cast Muddy Granular Cast Fatty Cast RBC Cast WBC Cast Waxy Cast

Significance - Non specific - Acute tubular necrosis - Contains Maltese crosses and - Glomerulonephritis - Tubulointerstitial inflammation - End stage renal disease
- No significance without oval fat bodies - Malignant HTN - Acute pyelonephritis - Chronic renal failure
proteinuria - Nephrotic syndrome - Transplant rejection

Kidney Stones
Calcium Oxalate Triple Phosphate Uric Acid Cystine

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 - Enveloped shape - Coffin-shaped - Rhomboid, rosettes - Hexagonal
Significance - Hypercalciuria - UTI - Hyperuricemia, gout - Cystinuria
- Normocalcemia - Staghorn calculi - Post-chemotherapy

Azotemia
- Azotemia: high nitrogen compounds in blood
○ Urea: filtered and reabsorbed
○ Creatinine: filtered, entirely excreted
- Uremia: azotemia + clinical signs and symptoms

Pre-renal Renal Post Renal

Description - Less blood flow to kidney = ↓ RPF, GFR - Necrotic debris block tubule and increase - Blocked ureter or bladder increases tubular pressure
- RAAS activate to improve blood flow pressure, prevent filtration = ↓ GFR = ↓ GFR
- Na, water, urea reabsorbed to conserve - Nephron dysfunction, urea not reabsorbed - Increased tubular pressure forces urea reabsorption
volume = ↑ BUN • More urea in urine than blood = ↑ BUN
- Persistent obstruction damages tubular epithelium
over time
• Urea not reabsorbed
Urine Osm 500+ < 350 < 350
(500 - 800)
Urine Na (<20) < 20 > 40 > 40
FeNa (1%) < 1% > 2% < 1% mild
> 2% severe
BUN/Creatinine > 15 < 15 - Initially, increases
= 15 - Chronically, decreases
Examples - Acute hemorrhage - Acute tubular injury/necrosis: - Children: congenital
- Gastrointestinal fluid loss • Ischemia - Adults: BPH
- Trauma, Surgery, Burns • Nephrotoxic drugs
- Renal artery stenosis - Acute interstitial Nephritis
- Sepsis - Renal Papillary necrosis
- Heart failure - Hemolytic Uremic Syndrome:
- Allergic reaction • E Coli 157:H7 Shiga toxin damages
endothelial cells in glomerulus →
bloody diarrhea
• No neurological symptoms

NEPHROTIC AND NEPHRITIC SYNDROME

Nephritic Syndrome Nephrotic Syndrome
Proteinuria > 150 mg > 3.5 mg
Etiology - Inflammatory process that damages - Disrupted podocyte with impaired charge
glomerular basement membrane barrier
- = allows passage of large proteins
Presentation - Oliguria and azotemia - Hypoalbuminia: severe edema
- Salt retention with periorbital edema - Hypogammaglobulinemia
and HTN - Hypercoagulable state
- RBC cast + dysmorphic RBC in urine - Hyperlipidemia: frothy urine, fatty casts
- Hypercholesterolemia
Examples - Post-strep Glomerulonephritis - Minimal change disease
- IgA Nephropathy Berger Disease - Focal segmental glomerulosclerosis
- Rapidly Progressive Crescentic - Membranous nephropathy
Glomerulonephritis - Membranoproliferative glomerulonephritis
- Alport Syndrome - Diabetes mellitus
- Thin BM disease - Systemic amyloidosis

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RENAL FAILURE
Acute Renal Failure Chronic Renal Failure
Description - Rapid ↓ GFR (within hours, days) - ↓ GFR for at least 3 months
Presentation - Oliguria/anuria + recent onset of azotemia - Prolonged uremia
- Anemia, bleeding diathesis
- Uremic pericarditis (bread and butter)
- Renal osteodystrophy
- Fluid and electrolytes: hyperkalemia, metabolic acidosis
Etiology - Glomerular injury - All chronic renal disease
- Interstitial injury
- Vascular injury
- Acute tubular necrosis

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Glomerular Lesions Pathology
July 12, 2018 11:23 AM

02 Glomerular disease

GLOMERULAR LESIONS
1. Hypercellularity
○ Proliferation of mesangial or endothelial cells
○ Infiltration of leukocytes
○ Formation of crescents
2. Basement Membrane Thickening
○ Deposits: on sub-endothelial or sub-epithelial side of GBM
○ Diabetes: Increased synthesis of GBM proteins
○ MPGN: Form more layers of GBM matrix
3. Hyalinosis
4. Sclerosis

LIGHT MICROSCOPE
- Focal: involves <50% of glomeruli
- Diffuse: involves > 50% of glomeruli
- Segmental: involves part of a glomerular tuft
- Global: involving entire glomerular tuft
- Endo-capillary proliferation: leukocytes + swelling + proliferation of mesangial and/or endothelial
cells
- Membranoproliferative: combined capillary wall thickening and mesangial or endocapillary
hypercellularity
- Mesangial hypercellularity: more than four nuclei in the contiguous matrix of a peripheral
mesangial segment
- Crescent: extra-capillary hypercellularity caused by proliferation of the parietal epithelial cells

Nephrotic Syndromes
Normal /Minimal Change Focal Segmental Membranous Glomerulonephritis Membranoproliferative Diabetic Nodular
Glomerulosclerosis Glomerulonephritis Glomerulosclerosis

- Capillary loops thin and delicate - Sclerosis/scarring - Thick basement membrane - Thick basement membrane - Small vessel sclerosis = thick BM
- Endothelial and mesangial cells - Focal: some glomeruli - Proliferation - Kimmelstiel Wilson nodules
are normal - Segmental: part of glomeruli tuft

H&E Nephritic Syndrome

Normal Post-Strep Glomerulonephritis Crescentic Glomerulonephritis Diffuse Proliferative
Glomerulonephritis in SLE

- Hypercellular: Neutrophils - Epithelial cell proliferation - Diffuse: all glomeruli

- Enlarged: takes up Bowman's - Proliferative: endocapillary deposits =
space wire loop capillaries

IMMUNOFLUROESCENCE PATTERNS
- Immunofluorescence on antibody complexes
Linear Granular Mesangium

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Pattern - Basement Membrane - Basement membrane - Between loops, mesangium
- Linear - Granular, disconnected
Crescen - Goodpasture - Diffuse proliferative
t glomerulonephritis in SLE
No - PSGN (lumpy bumpy) - IgA Nephropathy Berger Disease
crescen - Membranous glomerulopathy
t - Membranoproliferative
glomerulonephritis

ELECTRON MICROSCOPE

- Podocytopathy
- Basement membrane changes

Podocytopathy and Basement Membrane Changes

Podocytopathy Alport Syndrome Thin Basement
Membrane Lesion

- Cytokines, toxins, antibodies damage foot - Inherited defect in type IV - Inherited defect in type
process of epithelial cell podocytes collagen IV collagen
- Foot process flattens (effacement) or • X-linked (males) • X-linked (males)
detaches • α5 chain • α3, α4 chain
- = no filtration; proteins leak through - Eyes, ears, renal

EM - Location of Deposits

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 Mesangial - IgA Nephropathy
Subepithelial - Humps: acute post-strep
glomerulonephritis
- Spike and Dome: membranous
nephropathy
Intramembranous - Type 2 MPFG
Subendothelial - Type I MPFG
- Diffuse proliferative glomerulonephritis in
SLE

PROGRESSION IN GLOMERULAR DISEASE

- Once damage causes ↓ GFR to 50%, steady rate progression to end-stage renal failure
- Glomerulosclerosis
○ Systemic HTN → mesangial cell hyperplasia, ECM deposition
○ Intraglomerular HTN → intraglomerular coagulation
○ Glomerular hypertrophy → epithelial and endothelial injury
- Proteinuria
○ Glomerular hypertrophy → epithelial and endothelial injury

Patterns of Progressive Renal Damage

- Focal Segmental Glomerulosclerosis:
○ Unaffected glomeruli undergo hypertrophy to keep up GFR
○ = mesangial hyperplasia + segmental fibrosis of glomeruli
○ = renal hypertension
○ RAAS inhibitors reduce intraglomerular HTN, delay progression
- Tubulointerstitial Fibrosis: caused by
○ Ischemic tubules: inflammation and damage of of post-capillary area
○ Proteinuria: direct damage to tubular cells

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Glomerular Nephrotic Syndrome
July 9, 2018 6:58 PM

03 Glomerular disease - Nephrotic Syndrome

06 Glomerular disease - Systemic Glomerular syndromes (Diabetes, Amyloid)

NEPHROTIC SYNDROME
- Proteinuria 3.5 g/day
○ Caused by lack of negative charge on glomerulus = allow passage of large molecules
- Hypoalbuminia: ↓ oncotic pressure = pitting edema
- Hypogammaglobulinemia: lose γ globulins in urine, risk infection
- Hypercoagulable state: due to loss of AT III
- Hyperlipidemia, hypercholesterolemia: fatty casts with Maltese cross
○ Blood becomes "thin" so liver releases fat to beef up blood
- Microcytic anemia: loss of transferrin in urine

Effaced Foot Process

Minimal Change Disease Focal Segmental Glomerulosclerosis
Lipid Nephrosis

Etiology - Most common nephrotic syndrome in kids, girls - Most common cause of nephrotic syndrome in
- Idiopathic Hispanics, African Americans
- Hodgkin lymphoma: T cell cytokines cause flat - Idiopathic
foot processes, disrupting negative charge - Associated with HIV, heroin, sickle cell disease
Histology - LM: normal glomeruli, may have lipids - LM: some glomeruli involved, and only part of
- IF: nothing glomeruli (segmental) sclerosis and hyalinosis
- EM: Effacement of foot process - IF: negative
- EM: effacement of foot process
Notes - Selective proteinuria: albumin only - Progress to chronic renal failure
- Kids respond well with corticosteroid treatment - Collapsing variant: rapidly progressive; need
transplant

Immune Complexes
- Subepithelial: membranous glomerulonephritis
- Subendothelial: MPGN Type 1
- Intramembranous: MPGN Type 2
Membranous Glomerulonephritis Membranoproliferative Glomerulonephritis MPGN Membranoproliferative Glomerulonephritis MPGN
Membranous Nephropathy Type 1 Type 2: Dense Deposit Disease

Histolog - LM: thick glomerular basement membrane - LM: thick glomerular basement - LM: thick glomerular basement
y - IF: granular appearance • Proliferative mesangial cells • Proliferative mesangial cells
- EM: Subepithelial immune complex - IF: granular appearance - IF: granular appearance
• Spike and dome: podocytes try to lay down basement - EM: Subendothelial immune complex - EM: Intramembranous immune complex
membrane over immune complex to sit on • Mesangial cell cytoplasm proliferates to cut between • Ribbon-like density in basement membrane
immune complex = tram-track appearance on PAS
stain
Etiology - Most common cause of nephrotic syndrome in Caucasian adults - Hep B - Associated with C3 nephritic factor (C3 convertase
- Idiopathic - Hep C stabilized)
- Chronic Hep B ○ C3 convertase: C3 → C3a + C3b
- Cancer, malignancy ○ Overactive complement system: Inflammation,
- SLE, autoimmune disease low C3 level
- Drugs - Renal transplant patients
Notes - Highest incidence of thrombosis - Seen in nephritic/nephrotic syndrome - Seen in nephritic/nephrotic syndrome
- More common than Type 2

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Systemic
Diabetic Glomerulopathy Systemic Amyloidosis

Descrip - Hyaline arteriosclerosis: Non-enzymatic glycosylation of - Kidney most commonly involved organ in systemic amyloidosis
tion glomerular efferent arteriole - AL Amyloidosis: multiple myeloma
- Narrow efferent arteriole = ↑ GFR • Cancer of plasma cell
- Hyperfiltration damage mesangium, microalbuminuria • Plasma cell Ig light chains misfold, deposit in glomerulus
- Progresses to nephrotic syndrome - AA Amyloidosis: chronic inflammatory disease
• Bronchiectasis, rheumatoid arthritis, osteomyelitis
• Circulating inflammatory protein (serum amyloid A)
Epidem - Type I DM > Type 2 DM - Primary Amyloidosis: associated with monoclonal plasma cell proliferation
iology - Most common cause of chronic renal failure - Secondary Amyloidosis: complication of chronic inflammation/tissue
destruction
- Hereditary or Familial Amyloidosis: separate, heterogeneous group
Histolo - Kimmelstiel Wilson nodules: nodular glomerulosclerosis - Amyloid deposits in mesangium
gy • Thick, nodular pink mesangial matrix proliferate due to - Congo red stain:
hyaline changes • Pink/red
• apple-green birefringence under polarized light
Notes - Nephrosclerosis
- Renal vascular lesions
- Pyelonephritis
- ACE inhibitors slow progression of damage

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Glomerular Nephritic Syndrome
July 9, 2018 6:58 PM

04 Glomerular disease - Nephritic Syndrome

06 Glomerular disease - Systemic Glomerular syndromes (SLE)

NEPHRITIC SYNDROME
- Glomerular disorders characterized by glomerular inflammation and bleeding
○ Bleeding → RBC cast + dysmorphic RBC in urine
○ Glomerular inflammation → enlarged and hypercellular with neutrophils
- Limited proteinuria
- Oliguria and azotemia
- Salt retention with periorbital edema and HTN

Post Streptococcal Glomerulonephritis PSGN IgA Nephropathy Berger Disease Alport Syndrome Thin Basement Membrane Disease
Henoch Schonlein Pupura

Granular, differentiate from

membranous nephropathy

Descrip - Nephrotic syndrome after Strep Pyogenes infection of - IgA immune complex deposit in - Split and laminated GBM - Very thin GBM
tion impetigo skin or pharynx mesangium of glomeruli
- Immune complex • Mucosal infection (episodic) = ↑
IgA
• Glycosylated IgA deposits in kidney
Epidem - Strep pyogenes M protein in kids - Most common nephropathy worldwide - Inherited defect in type IV collagen - Inherited defect in type IV collagen
iology - Non-streptococcal organisms - Associated with Henoch Schonlein • X-linked (males) - Autosomal dominant
- Kids > adults purpura • α5 chain • α3 or α4 chains
• Kid with bright red skin purpura,
abdominal pain, hematuria
- Associated with celiac disease (mucosal
IgA) in duodenum
Histolo - LM: glomeruli enlarged and hypercellular, inflamed - LM: mesangial proliferation, pink deposits - LM: irregular thickening and thinning, IF: very thin GBM
gy • Neutrophils - EM: mesangial IgA deposits splitting of basement membrane
- IF: starry sky, lumpy bumpy granular - IF: IgA-based immune complex deposits • Foamy renal tubular cells: fats,
• IgG, IgM, and C3 deposition along GBM and in mesangium mucopolysaccharides accumulate
mesangium. - EM: none
- EM: subepithelial immune complex humps - IF: abnormally thin and split GBM
• Immune complex in blood, begin deposits as
subendothelial
• Pile up, push into subepithelial region
• Eventually get pushed through filter and excreted
Present - Hematuria: coca cola urine - Presents in childhood - Presents age 5-20 with nephritic - Asymptomatic
ation - Oliguria - Recurrent hematuria: coca cola urine - Affects basement membranes
- HTN - Microscopic hematuria • Renal: Isolated hematuria
- Periorbital edema • RBC cast • Ear: Sensory hearing loss
- Adults risk RPGN • Eye: Ocular disturbances
Treatm - Supportive
ent

Rapidly Progressive Crescentic Glomerulonephritis

Type I: Linear Type II: Immune Complex Type III: Pauci Immune
Granular Follow up with ANCA test

Crescent - Goodpasture Syndrome - Diffuse proliferative - Wegner Granulomatosis: C-ANCA

glomerulonephritis in SLE • Nose, lungs, kidney
- Churg Strauss Allergic: P-ANCA
• Lungs, heart, kidney
• Eosinophilia
- Microscopic Angiitis: P-ACNCA
• Lungs, kidney

- Crescents: in Bowman's space filled with inflammatory debris (fibrin + macrophages)

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 - Crescents: in Bowman's space filled with inflammatory debris (fibrin + macrophages)
○ Activation of thrombin = crescent
- Diagnose with clinical picture and immunofluorescence

Goodpasture Syndrome Diffuse Proliferative Glomerulonephritis Wegner Granulomatosis

Systemic Lupus

Descrip - Antibody against collagen in glomerular - Autoimmune complexes deposit in organs, - Necrotizing granulomatous vasculitis
tion and alveolar basement membranes glomeruli causing damage • Nose: URTI, sinusitis
• Lung: Hemoptysis ○ Type III hypersensitivity • Lungs: hemoptysis, cough, dyspnea
• Kidney: Hematuria - Anti-dsDNA • Renal: hematuria, RBC cast
- Type II hypersensitivity - Anti Smith antigen
- Antiphospholipid antibodies
○ False positive for syphilis
○ Coagulation abnormalities: repeated
abortions
Epidem - Young, adult males - Most common subtype of glomerular disease in - Middle age man with associated organ symptoms
iology - Active smokers SLE
- 25 year old African woman
- HLA-DR2, HLA-DR3
- Procainamide, hydralazine
- Determines prognosis of SLE
• Most common cause of renal failure in SLE
Histolo - LM: crescent - LM: crescent in Bowman's
gy - IF: linear • Wire loop capillaries: subendothelial
immune complex cause capillary wall
thickening
- IF: granular
- EM: Subendothelial immune complex deposits
Notes - Treat with plasmapheresis

Classes of SLE Glomerular Lesion

1. Class I: Minimal mesangial
2. Class II: Mesangial proliferative
3. Class III: Focal segmental/global
4. Class IV: Diffuse
5. Class V: Membranous
6. Class VI: Advanced sclerosing

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Chronic Renal Failure
July 9, 2018 6:59 PM

05 Glomerular disease - Chronic Renal Failure and chronic glomerulonephritis

Chronic Renal Failure

Bilateral with red brown granular surface Scarred glomeruli in glomerulonephritis

Thin cortex Burst cell RBC

Description - End stage kidney failure due to irreversible nephron loss

- Diminished GFR for 3 months
- Bilateral, shrunken kidney
Etiology 1. Diabetes: mesangial expansion and proliferation, podocytopathy, GBM thickening, sclerosis
2. HTN: glomerulosclerosis → ischemic injury, nephron loss
3. Chronic glomerulonephritis: Crescentic > focal segmental glomerulosclerosis > RPGN, MN, IgA Nephropathy, MPGN
Histology - Bilateral shrunken kidney with red brown diffusely granular surface
• Thin cortex; only see medulla
• Peripelvic fat
- Scarred, sclerotic glomeruli: fibrosis
Pathology - Initially, blood goes to functioning nephron = hyperfiltration
• Increased pressure→ sclerosis → nephron loss
- All nephrons loss = ↓ GFR, urine output, uremia
Presentation - Uremia: azotemia + symptoms
• Azotemia: ↑ nitrogen waste products
• Nausea, anorexia
• Uremic pericarditis: bread and butter
• Platelet dysfunction: no adhesion nor aggregation = ↑ bleeding time
• Encephalopathy with asterixis
• Uremic frost: deposition of urea crystals in skin
- Na, water retention: HTN, edema
- Anemia: no renal peritubular interstitial cells to make EPO
- Renal Osteodystrophy: hypocalcaemia
Lab - Hyperkalemia: can't excrete K
- Metabolic acidosis
- Hyperphosphatemia: PO4 not excreted
• Binds to Ca → hypocalcaemia
- Hypocalcaemia
• Vitamin D not activated
○ Proximal renal tubular cells: no 1 α hydroxylation of 25 (OH) D3 → 1,25 (OH)2 D3
• No Ca, PO4 release from bone
• No kidney Ca reabsorbed
• No GIT Ca, PO4 reabsorbed
- Normocytic anemia
- Prolonged bleeding time
- Increased serum cystatin C
- Waxy, broad casts in urine
Treatment - Dialysis
• Cysts develop within shrunken end-stage kidneys = risk renal cell carcinoma
- Renal transplant

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Renal Osteodystrophy
- Hypocalcaemia and hyperphosphatemia

- Osteomalacia: no Ca to mineralize osteoid to bone

- Osteitis fibrosis cystica:
○ Parathyroid detect hypocalcaemia, release PTH = secondary hyperparathyroidism
○ ↑ PTH = release Ca from bone
▪ Destroy bone = subperiosteal thinning of bones
○ Brown tumor: fibrotic, cystic bone
- Osteoporosis: bone weakness

Renal - Path Page 12

Upper UTI and Tubulointerstitial Disease
July 10, 2018 9:30 PM

07 Urinary tract infections - upper UTI

08 Tubulointerstitial disease

UPPER UTI
Acute Pyelonephritis Chronic Pyelonephritis

Description - Infection of kidney - Interstitial fibrosis and atrophy of tubules due to recurrent acute pyelonephritis
Etiology - Ascending infection - Vesicoureteral reflux-associated
• E Coli - Obstruction
• Enterococcus faecalis • Bilateral: congenital posterior urethral valve; BPH
• Klebsiella • Unilateral: stones
- Vesicoureteral reflux
- Hematogenous spread: Staph aureus
Histology - Neutrophils infiltrate - Thyroidisation of kidney: atrophic tubules contain eosinophilic proteinaceous material, look
like colloid of thyroid
- Interstitial fibrosis
Gross - Yellow abscess - Asymmetrically contracted, scarred kidneys
appearance - Vesicoureteral reflux: Scar upper and lower poles
- Obstruction: Cortical scarring with blunted, dilated calyces
Clinical - Fever - Waxy casts
presentatio - Flank pain: Costovertebral angle tenderness
n - WBC casts
- Leukocytosis
- Symptoms of cystitis
- May lead to chronic pyelonephritis
- May lead to renal papillary necrosis
- May lead to septicemia, shock

TUBULOINTERSTITIAL DISEASE
- Diseases involving interstitium and tubules, sparing glomeruli
- Pyelonephritis: bacterial infection
- Interstitial nephritis: non-bacterial causes

Acute Drug-Induced Interstitial Nephritis Urate Nephropathy Pb Lead Nephropathy Multiple Myeloma Acute Phosphate Nephropathy

Normal and BJ Cast

Eosinophils in interstitium

Descripti - Drug-induced hypersensitivity involving - Urate crystal deposit in and block - Lead deposit in interstitium and - WBC cancer - Calcium phosphate precipitates,
on interstitium > tubules tubules tubules - Bence Jones proteins: Light chain deposit in tubules
deposits in interstitium (toxic)
Epidemiol - NSAIDs - Acute: Leukemia, lymphoma, - Chronic lead poisoning - Consume high dose of oral
ogy • Most common cause chemo (Tumor lysis syndrome) phosphate before colonoscopy
• Women > men - Chronic: gout
- Penicillin - Nephrolithiasis
- Diuretics
Appearan - Eosinophils in interstitium - Monosodium urate crystals - Nuclear acid-fast inclusions in PCT - Bence Jones protein casts: glassy, - Purple on H&E stains
ce - Yellow-brown necrotic papillae on gross deposits in tubules refractile, PAS negative
- Tophus: granulomatous reaction - Surrounded by inflammatory cells
- Cortical atrophy and scarring (histiocytes)
Presentat - Oliguria - Saturnine gout: decrease in uric - Chronic kidney failure - Presents weeks after exposure
ion - Fever and rash acid excretion - Acute kidney injury with oliguria
- Eosinophils in urine - Bence-Jones proteinuria:
- May lead to renal papillary necrosis • BJ proteins + urinary glycoprotein =
- Acute renal failure tubular casts
• Casts block lumen, trigger foreign
body giant cell formation

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Renal - Path Page 14
Acute Renal Failure
July 16, 2018 11:43 AM

09 Acute Renal Failure

ACUTE RENAL FAILURE

- Rapid decline in GFR (within hours to days)
- Azotemia: nitrogenous compounds not filtered, build up in blood
• Urea: filtered and reabsorbed
• Creatinine: filtered, entirely excreted
- Oliguria, anuria
- Causes can be pre-renal, renal, or post-renal

Pre-renal Renal Post Renal

Description - Less blood flow to kidney = ↓ RPF, GFR - Necrotic debris block tubule and increase - Blocked ureter or bladder increases tubular pressure
- RAAS activate to improve blood flow pressure, prevent filtration = ↓ GFR = ↓ GFR
- Na, water, urea reabsorbed to conserve - Nephron dysfunction, urea not reabsorbed - Increased tubular pressure forces urea reabsorption
volume = ↑ BUN • More urea in urine than blood = ↑ BUN
- Persistent obstruction damages tubular epithelium
over time
• Urea not reabsorbed
Urine Osm 500+ < 350 < 350
(500 - 800)
Urine Na (<20) < 20 > 40 > 40
FeNa (1%) < 1% > 2% < 1% mild
> 2% severe
BUN/Creatinine > 15 < 15 - Initially, increases
= 15 - Chronically, decreases
Examples - Acute hemorrhage - Acute tubular injury/necrosis: - Children: congenital
- Gastrointestinal fluid loss • Ischemia - Adults: BPH
- Trauma, Surgery, Burns • Nephrotoxic drugs
- Renal artery stenosis - Acute interstitial Nephritis
- Sepsis - Renal Papillary necrosis
- Heart failure - Hemolytic Uremic Syndrome:
- Allergic reaction • E Coli 157:H7 Shiga toxin damages
endothelial cells in glomerulus →
bloody diarrhea
• No neurological symptoms

Intrinsic Renal Failure

Acute Tubular Nephritis Acute Interstitial Nephritis Renal Papillary Necrosis
Ischemia, Drug Drug Induced

Descript - Ischemic: damaged, necrotic cells block PCT - Acute interstitial renal inflammation - Necrosis of tips of renal papillae
ion - Nephrotoxins: damage epithelial cells - Allergic reaction to drugs that act like haptens
Epid - Most common cause of acute kidney injury in - NSAIDs - Pyelonephritis
hospitalized patients - Penicillin - Sickle Cell Disease
- Ischemia: decreased blood flow - Diuretics - Analgesics: chronic interstitial nephritis

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 - Ischemia: decreased blood flow - Diuretics - Analgesics: chronic interstitial nephritis
• Hypotension, shock, sepsis, hemorrhage, heart - Proton pump inhibitors - Diabetes
failure - Sulfonamides
- Nephrotoxins: aminoglycosides, radiocontrast - Rifampin
agents, lead, cisplatin, myoglobin, hemoglobin
Present - Oliguria - Oliguria, fever, rash - Gross hematuria, proteinuria
ation - Brown granular casts: Tam-Horsfall protein + - Eosinophils in interstitium, urine • Necrotic material sloughs off
hemoglobin + plasma proteins - Yellow-brown necrotic papillae on gross
- Tam-Horsfall protein: glycoprotein normally - Costovertebral angle tenderness
secreted by thick ascending limb and distal tubule
- Metabolic acidosis
- Hyperkalemia
Notes - Ischemia is irreversible: damaged basement - Reversible
membrane
- Toxins is reversible

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Kidney Vascular Disease
July 10, 2018 9:31 PM

10 Vascular diseases of the kidney

VASCULAR DISEASES

Renal Artery Stenosis Benign Nephrosclerosis Malignant Nephrosclerosis Thrombotic Diffuse Cortical Necrosis Renal Infarct
Hypertensive Kidney Disease Hypertensive Kidney Disease Microangiopathies

Descript - Narrowed renal artery → - Sclerosis of renal arterioles, small - Sclerosis of renal arterioles, small - Thrombosis of small capillaries - Decreased perfusion→ renal - Abrupt blocked blood
ion renin arteries arteries and arterioles cortex necrosis supply to kidney
Epidemi - Atherosclerotic renal disease: - Benign HTN - Malignant HTN - Hemolytic uremic syndrome: - Obstetric emergency: - Emboli
ology elderly men, diabetic - Diabetes • Shiga-like toxin, E Coli abruption placenta
• Ischemic: bilateral O157:H7 - Septic shock
• Embolic : unilateral • Mutate Factor H: no C3 - Extensive surgery
- Fibromuscular dysplasia: 30 convertase breakdown
year old women - Thrombotic thrombocytopenic
• Beads on a string purpura: 40 year old woman with
angiogram neurological symptom
- Drugs, autoimmune disease,
pregnancy
Gross - Small, contracted kidney - Flea-bitten kidney - Flea-bitten kidney - Ischemic necrotic cortex (may - White, wedge-shape
- Granular, leathery appearance be bilateral)
Histo - Atherosclerosis: fat crystals - Hyaline arteriosclerosis: thick - Hyperplastic arteriosclerosis: - Platelet-fibrin in glomerulus - Coagulative necrosis:
- Fibromuscular dysplasia: glassy homogenous arteriole onion skin • No nuclei
fibrous thick renal artery • Tubular atrophy • Smooth muscle hyperplasia • Inflammatory
• Interstitial fibrosis • Fibrinoid deposits infiltrate
• Glomerular sclerosis • Vessel wall necrosis

Bilateral Renal Stenosis

- Stenosis of renal arteries → decreased perfusion to kidney, ↓ GFR
- Under perfused kidney macula densa activate RAAS
- Angiotensin II constricts efferent arterioles to increase GFR
- ACE inhibitors: prevents AT II production
○ No AT II = can't maintain GFR → renal failure
○ So, do not ACE inhibitors to bilateral renal stenosis patients

KIDNEY APPEARANCE
Small, contracted kidney Flea Bitten Kidney

Caused by - Chronic glomerulonephritis: - Malignant nephrosclerosis

granular - Acute PSGN
- Benign nephrosclerosis: V shape - Rapidly progressive glomerulonephritis
scar - Thrombotic microangiopathies
- Chronic pyelonephritis: U shaped • Hemolytic uremic syndrome
- Amyloidosis • Thrombotic thrombocytopenic purpura
• Henoch Schonlein purpura

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Renal and Urinary Tract Cancer
July 9, 2018 6:59 PM

11 Genitourinary tract tumors - Renal

12 Genitourinary tract tumors - Lower urinary tract

KIDNEY TUMORS

Benign
Renal Papillary Adenoma Angiomyolipoma Oncocytoma

Description - Small, pale yellow-grey - Harmatoma of blood, smooth - Benign tumor from intercalated cells of collecting ducts
discrete nodules in cortex muscle and adipose tissue - Large eosinophilic cells with small, round benign nuclei
- Seen in tuberous sclerosis - Well-encapsulated central scar
- Resected to exclude malignancy

RENAL CARCINOMA
- Renal cell carcinoma: most common
- Urothelial carcinoma of renal pelvis: caused by smoking, analgesic nephropathy
- Wilm's tumor nephroblastoma

Renal Cell Carcinoma

- Fever, weight loss > hematuria
- Paraneoplastic syndromes:
○ EPO → reactive polycythemia
○ Renin → HTN
○ PTHrP → hypercalcemia
○ ACTH → Cushing Syndrome
- Hematogenous spread
- Left-sided varicocele (rare)
• Left testicular vein drains into left renal vein → IVC
□ If left renal vein blocked, fluid build up in testicular vein = varicocele
• Right testicular vein drains into IVC
- Aldesleukin: recomb IL2 to treat renal cell carcinoma

Clear Cell Renal Carcinoma Papillary Renal Cell Carcinoma Chromophobe Carcinoma Wilm's Tumor Nephroblastoma

Descriptio - Malignant epithelial tumor from PCT - Malignant cell from DCT - Malignant tumor from intercalated cells of - Malignant tumor of blastema, primitive glomeruli
n collecting ducts and tubules, stromal cells
Morpholo - Polygonal clear cells with granular - Papillary formation with interstitial foam - Prominent cell membrane, pale cytoplasm - Blastema: sheets of blue cells
gy cytoplasm cells - Halo around nucleus - Epithelial: tubules, glomeruli
• Clear because filled with glycogen - Psammoma bodies - Stromal: fibrocytic, myxoid
and lipid that were washed out - Multifocal
during staining
- Lesions on poles
Gene - Deleted VHL 3p tumor suppressor gene - Mutated, activated MET - Mutate WT1
• HIF  VEGF, PDEF proliferation
Epidemiol - Sporadic: 60 year old male smoker - Sporadic: single tumor - Most common primary renal tumor of childhood
ogy • Single tumor in upper pole - Familial: multiple tumors - WAGR syndrome
- Von Hippel Lindau Syndrome - Deny's Drash Syndrome
• Autosomal dominant - Beckman Wiedmann Syndrome
• Hemangioblastoma of cerebellum,
retina
• Renal cell carcinoma; multiple
lesions
Presentat - Fever, weight loss > hematuria - Fever, weight loss > hematuria - Large abdominal mass in kids
ion - Hematuria

Wilm's Tumor Syndromes

- Wilm's Tumor: Malignant tumor of blastema, primitive glomeruli and tubules, stromal cells

Renal - Path Page 18

 - Wilm's Tumor: Malignant tumor of blastema, primitive glomeruli and tubules, stromal cells
• Blastema: immature kidney mesenchyme
- WT1: tumor suppressor gene, located at 11p13
WAGR Syndrome Deny's Drash Syndrome Beckwith Widemann Syndrome

Descrip - Wilm's tumor - Wilm's Tumor - Wilm's Tumor

tion - Aniridia - Progressive glomerular disease - Neonatal hypoglycemia
- Genital abnormalities - Male pseudo hermaphroditism - Muscular hemihypertrophy
- Mental, motor retardation - Organomegaly (tongue)
Etiology - Deleted WT1 - Mutated WT1 - Mutated WT2 cluster gene
• Imprinted gene at 11p15.5, IGF2
Notes - Risk gonadoblastoma - Risk hepatoblastoma, pancreatoblastoma,
adrenocortical tumors, rhabdomyosarcoma

LOWER URINARY TRACT

- Normal epithelium: transitional
- Risk factors: Males > females; smoking
- Painless hematuria
- Non-invasive: gain of function FGFR3, HRAS mutation
- Invasive: P53, RB mutation
- Tend to recur after resection

Urothelial Transitional Cell Tumors Squamous Cell Carcinoma Adenocarcinoma

Descrip - Malignant tumor from urothelial lining of renal - Malignant tumor of squamous cells; bladder - Malignant proliferation of glands; bladder
tion pelvis, bladder, urethra
Etiology - Most common type of lower urinary cancer; bladder - Chronic cystitis: older woman - Urachal remnant
- Smoke: naphthylamine - Schistosoma haematobium: embeds in bladder - Cystitis glandularis
- Azo dyes: textiles wall; Egypt/Middle East - exstrophy
- Long term cyclophosphamide or phenacetin use - Chronic nephrolithiasis
- Older adults
Present - Painless hematuria - Painless hematuria
ation
Patholo - Papillary: low grade → high grade → invades - Normal bladder surface is transitional - Urachal remnant: urachus fails to involute
gy - Flat: high grade flat tumor → invades - Chronic inflammation, mutation → squamous • Urachus: tube that connects dome of bladder to umbilical
• P53 mutations metaplasia → squamous dysplasia → cancer cord to yolk sac
• Lined by glandular cells
- Entire urothelium chronically affected and mutated = - Uteritis cystitis glandularis: chronic bladder inflammation causes
multiple tumors cells to become columnar, glandular
• Smooth cysts project into lumen
- Exstrophy: congenital
• Caudal portion of anterior abdominal wall and bladder walls
don't form
• Bladder surface exposed

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Congenital, Cysts, Kidney Stones
July 9, 2018 6:50 PM

13 Congenital anomalies and Cystic lesions

14 Urolithiasis

CONGENITAL DISORDERS
- Ectopic kidney: found in pelvis (kidney develops in pelvis, ascends upwards)
Horseshoe Kidney Unilateral Renal Agenesis Bilateral Renal Agenesis
Potter Sequence

Description - Conjoined kidneys connected at lower pole - One kidney doesn't form - No kidney = no amniotic fluid →
oligohydramnios
Pathology - Kidney develops in pelvis - Existing kidney - Lung hypoplasia
- Ascends upwards • Hypertrophy - Flat face with low set ears
- Get stuck at root of IMA • Hyperfiltration - Deformed extremities
- Kidneys function normally -
Associations - Hydronephrosis
- Renal stones
- Infections
- Chromosomal aneuploidy syndromes
- Renal cancer

CYSTIC KIDNEY
- Simple Cysts: differentiate from kidney tumors
• Common post-mortem, no clinical significance
- Acquired Dialysis Cystic Disease: contain calcium oxalate crystals
• Risk renal cell carcinoma

Multicystic Dysplastic Kidney Adult Child Medullary Cystic Kidney Disease

Polycystic Kidney Disease Polycystic Kidney Disease Nephronophthisis

Descript - Non-functioning kidney with cysts and - Bilateral enlarged kidney with cyst in renal - Bilateral enlarged kidney with cyst in renal - Cyst in medullary collecting duct
ion abnormal tissue cortex and medulla cortex and medulla
• Mesenchyme, smooth muscle,
cartilage
- Usually unilateral
Etiology - Non-inherited - Autosomal Dominant: mutate APKD1 or - Autosomal Recessive: infant - Autosomal dominant
- Uretic bud fails to induce differentiation APKD2 gene • Kids: NPHP1
of metanephric mesenchyme - Most common inherited renal disorder • Adults: MCKD1
Present - Bilateral presents as Potter's sequence - Worsening renal failure and HTN (due to - Worsening renal failure and HTN (due to ↑ - Tubulointerstitial nephritis
ation ↑ renin) renin) - Shrunken kidney: swiss cheese
- Young adult; cyst develops over time - May present as Potter sequence - Worsening renal failure
- Berry aneurysm → subarachnoid - Associated with congenital hepatic fibrosis - Can't concentrate urine
hemorrhage (portal HTN) and hepatic cysts - Leads to end-stage renal disease
- Polycystic liver disease
- Mitral valve prolapse

Renal - Path Page 20

 - Mitral valve prolapse

HYDRONEPHROSIS
- Hydronephrosis: dilated collecting duct due to urinary obstruction
○ Staghorn calculi
○ BPH
○ Metastatic carcinomas

Staghorn Calculi

KIDNEY STONES
- Precipitation of urinary solute as a stone
- Risk factors: high [solute], low urine volume
- Presents as colicky pain with hematuria, unilateral flank tenderness
- Stone passes within hours

Composition
Calcium Oxalate > Ammonium Magnesium Uric Acid Cystine
Calcium Phosphate Phosphate

Epidem - Most common - Second most common - Third most common - Rare AR disease in children
iology - Adults - Most common in gout patient - Positive CN nitroprusside test
Causes - Idiopathic hypercalciuria: Blood Ca level - Infection with urease positive - Hot arid climates - Cystinuria: Genetic defect of cystine-
normal organisms - Low urine volume reabsorbing transporter in PCT
- Hypercalcemia, hyperparathyroidism • Proteus - Acidic pH • Cystine
- Ethylene glycol (antifreeze) • Klebsiella • Ornithine
- Vitamin C abuse • Staph saprophyticus - Hyperuricemia • Lysine
- Hypocitraturia - Alkaline urine • Gout • Arginine
- Crohn's disease: bowel damage increases • High cell turnover conditions:
oxalate absorption Leukemia, myeloproliferative
• Fat malabsorption; fat stays in gut disorders
• Ca binds to fat instead of oxalate
• Oxalate gets absorbed in gut, deposit
in kidney
X-Ray - Radiopaque - Radiopaque - Radiolucent - Radiolucent
Treatm - Hydrochlorothiazide: Ca sparing diuretic - Staghorn calculi surgically - Hydration - Staghorn caliculi surgically remove
ent removed - Alkalinize urine (KHCO3) - Hydration
- Antibiotic - Allopurinol in gout - Alkaline urine

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Lower Urinary Tract and Transplant Pathology
July 14, 2018 2:49 PM

15 Lower urinary tract and transplant pathology

LOWER URINARY TRACT

- Ureteritis cystica: smooth cysts project from mucosa into lumen
- Sclerosing Retroperitoneal Fibrosis:
- Interstitial Cystitis: chronic pelvic pain syndrome
○ Hunner ulcers: chronic mucosal ulcers
○ Biopsy to rule out carcinoma

Cystitis Malakoplakia

Description - Cystitis: infection of bladder - Acquired defect phagocyte function

- Urethritis: infection of urethra - Large, foamy macrophages can't digest bacteria
• Michaelis Gutmann bodies: partially digested bacteria
with Ca deposits in macrophages
Etiology - E coli - Chronic bacterial infection
- Staph saprophyticus: young, sexually active woman - Immunosuppressed, transplant patient
- Klebsiella
- Proteus: alkaline urine with ammonia scent
- Enterococcus faecalis
- Urethritis: Chlamydia trachomatis > Neisseria gonorrhea
Presentation - Dysuria, urinary frequency and urgency - Soft yellow raised mucosal plaques
- Suprapubic pain
- NO FEVER/systemic signs
Lab - Urinalyses: cloudy urine with >10 WBC
- No casts
- Dipstick:
• Positive leukocyte esterase due to pyuria
• Nitrates: bacteria convert nitrites to nitrates
- Urine culture: gold standard

Incontinence Disorders
- SANS: relax bladder, contracts sphincter = keep urine
- PANS: contract bladder, relax sphincter = pee

Stress incontinence Urgency incontinence Overflow incontinence

Description - Leak with increased intra-abdominal - Overactive bladder (detrusor instability) - Incomplete emptying (detrusor underactivity or outlet
pressure (sneeze, lift) - Leak with urge to void immediately obstruction)
- Dribbling, low urine outflow
Etiology - Women - Bladder irritation to BPH, atrophic urethritis, infection - Outflow obstruction: BPH
- Risk with obesity, vaginal delivery, - Autonomic neuropathy: DM
prostate surgery
Treatment - Kegel exercises - Kegel exercises - catheterization,
- Weight loss - Bladder training (timed voiding, distraction or - Relieve obstruction (eg, α-blockers for BPH)
- pessaries. relaxation techniques) -
- Antimuscarinics

RENAL TRANSPLANT
- HLA matching for best results of kidney transplants
○ No HLA matching needed for heart, lung, liver, ilset
- Give immunosuppressant drugs to prevent rejection

Hyperacute Rejection Acute Cellular Rejection Acute Humoral Rejection Chronic Rejection

Renal - Path Page 22

 Small clots inside capillaries T-cells target endothelial cells C4d deposits: complement breakdown products
Respons Minutes to hours 15 days to a few weeks 15 days to a few weeks Years later
e Time
Mediate - Pre-formed anti-donor antibodies - CD8 T-cells - Anti-donor antibodies - CD4 T-cells
d by - CD4 T-cells - CD8 T-cells and alloantibodies
Patholog - Recipient antibodies bind to antigen - Direct Allorecognition: Recipient T-cells - Antibodies damage graft vasculature - Indirect Allorecognition: Recipient CD4
y (foreign tissue) against foreign MHC on donor's APC cell T-cells against foreign MHC presented
- Compliment activation - Interstitial inflammation, cell damage by self APC
- Neutrophil damage endothelium - Alloantibodies: CD4 activates B cells,
- Clotting cascade → thrombosis, ischemic make alloantibodies to bind to
necrosis endothelial cells = inflammation
- Loss of functioning
Histo - Cyanotic, mottled, flaccid kidney - Focal tubular necrosis - Necrotizing vasculitis - Vascular smooth muscle proliferation
- Acute fibrinoid necrosis - Interstitial inflammation - C4d deposits in peritubular capillaries, - Parenchymal fibrosis
• T cell infiltrate glomerulus
- Does not respond to immunosuppressants

Renal - Path Page 23