Renal patho Flashcards by Emily Cheston

A five year old male is referred for evaluation after his fourth episode of urinary tract infection. Mother received limited antenatal care during pregnancy. Creatinine is normal. Renal ultrasound shows a small echogenic right
kidney with a dilated ureter. Radionucleotide scan shows left kidney contributes 80% of function, right kidney 20%. Based on the kidney biopsy below, what is his diagnosis, prognosis and treatment?

Renal dysplasia

Congenital anomalies of the kidney and urinary tract (CAKUT) due to:

Malformation of renal parenchyma resulting in failure of normal nephron development–> renal dysplasia, renal agenesis, renal tubular dysgenesis, and polycystic renal diseases.
Abnormalities of embryonic migration of the kidneys as seen in renal ectopy (eg, pelvic kidney) and fusion anomalies, such as horseshoe kidney.
Abnormalities of the developing urinary collecting system as seen in duplicate collecting systems, posterior urethral valves, and UPJ obstruction

Kidneys are variable in size but most are smaller

Discovered during routine antenatal screening.(increased echogenicity as a result of abnormal renal parenchymal tissue, poor corticomedullary differentiation, and parenchymal cysts.)
By 20 weeks gestation, fetal urine accounts for 90 percent of the amniotic volume. Oligohydramnios is a clue .
Associated urological findings- abnormalities of the renal pelvis and calyces (congenital hydronephrosis) and ureters (duplicating collecting system), megaureter, ureteral stenosis, and vesicoureteral reflux (VUR).
Symptomatic presentation due to urinary tract infection, hematuria, fever, and abdominal pain

Clinical:
Important Contributor to ESRD in children (Especially in bilateral disease)
- In past, thought was that progressive loss of renal function was due to associated collecting system abnormality leading repeated bouts of pyleonephritis
- Modern belief is that parenchymal abnormalities are the cause of progressive decline in renal function

Management:
- Medical prophylaxis of UTI versus surgical correction of collecting system abnormalities
- No convincing evidence that surgery is superior
- Severe reflux with very frequent and/or severe UTI’s is
nevertheless often managed surgically.
- The rate of spontaneous resolution is dependent upon age, grade of reflux, and whether the reflux is unilateral or bilateral.

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A 56-year old woman with no significant medical history who presents with 2 months of LE swelling, nocturia and foamy urine. On exam, BP 138/76, periorbital edema, 3+ pitting edema of lower extremities.
Laboratory studies: Cr 1.3, TC 556, Albumin 1.8, Ur Protein: Cr ratio 13, C3 135, C4 38
HIV, HBV, HCV, ANA all negative

Focal segmental glomerulosclerosis:
AKA: Focal Sclerosis

*First AID:**
Nephrotic syndrome= proteinuria (> 3.5 g/day, frothy urine), hyperlipidemia, fatty casts, edema. Can cause thromboembolism (hypercoagulable due to ATIII loss in urine) and increased infection risk (loss of Ig)
LM: segmental slerosis, hyalinosis
EM: effacement of foot processes (like minimal change disease)
MOST common cause of nephrOtic syndrome in adults
Associated with HIV, heroin, obesity, IFN treatment, chronic kidney disease due to congenital absence/surgical removal

Clinical presentation:
35-40% cases of nephrotic syndrome in adults
- 50% of cases of NS in blacks
- only 20% of nephrotic syndrome cases in children

Clinical course/prognosis:

Immunosuppressive therapy only for primary FSGS
50% will have partial or complete remission with treatment
Poor prognostic factors- proteinuria >10 grams/day; histology (collapsing), renal failure at presentation, poor response to therapy, black race
*Treatment:**
Immunosuppression if nephrotic at preserved GFR
Prolonged/high dose steroids - 1 mg/kg for at least 6 months
If unable to tolerate steroids – cyclosporine
If GFR
Transplant is option once ESRD–> may recur immediately post-kidney transplant

Two Major Clinical Forms:

Primary or Idiopathic (includes familial/genetic forms)
Secondary
- Virus (HIV, Parvovirus B19)
- Drugs (Heroin, Interferon, Lithium)
- Adaptive functional response (obesity, loss of one kidney)

Multiple Histologic Subtypes:

Classic
Perihilar
Cellular
Tip Variant
Collapsing (Associated with HIV)

*Histology**:
*Light microscopy:**
Mesangial cell proliferation
Focal process: not all glomeruli involved
Segmental process: only tufts involved
Trichrome stain: expansion of mesangium

Immunofluorescence:
- Trapping of IgM within mesangium

Electron microscopy:
Epithelial Cell Injury
- Foot process fusion
- Detachment from underlying basement membrane
Mesangial Changes
- Fibrosis
- Mesangial Matrix Increase
- Insudative deposition of IgM and C3
- Lipid vacuoles

*Pathogenesis**:
1. Primary event is Epithelial Cell injury induced by circulating factor (SuPAR)
Can see return of proteinuria within 24 hr’s after transplant
Candidate circulating factor has been tentatively identified
2. Subsequent loss of GBM integrity
3. Glomerular structure becomes hyper permeable
4. See secondary extracellular matrix depositions and insudative trapping of IgM in the mesangium

Genetic predisposition:
- Polymorphisms/mutations in: Nephrin gene, Podocin gene

Injury:
Angio-poietin-like-e–> alters slit diaphragm between podocyte processes–> loss of GBM integrity–> proteinuria

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PT is a 56-year old woman with no significant medical history who presents with 2 months of LE swelling, nocturia and foamy urine
On exam, BP 138/76, periorbital edema, 3+ pitting edema of LE
Laboratory studies: Cr 1.3, TC 556, Albumin 1.8, Ur Protein: Cr ratio 13, C3 135, C4 38
HIV, HBV, HCV, ANA all negative

IgM deposition noted in histologic sample below. What is her diagnosis and treatment?

Focal segmental glomerulosclerosis:
AKA: Focal Sclerosis

*First AID:**
Nephrotic syndrome= proteinuria (> 3.5 g/day, frothy urine), hyperlipidemia, fatty casts, edema. Can cause thromboembolism (hypercoagulable due to ATIII loss in urine) and increased infection risk (loss of Ig)
LM: segmental slerosis, hyalinosis
EM: effacement of foot processes (like minimal change disease)
MOST common cause of nephrOtic syndrome in adults
Associated with HIV, heroin, obesity, IFN treatment, chronic kidney disease due to congenital absence/surgical removal

Clinical presentation:
35-40% cases of nephrotic syndrome in adults
- 50% of cases of NS in blacks
- only 20% of nephrotic syndrome cases in children

Clinical course/prognosis:

Immunosuppressive therapy only for primary FSGS
50% will have partial or complete remission with treatment
Poor prognostic factors- proteinuria >10 grams/day; histology (collapsing), renal failure at presentation, poor response to therapy, black race
*Treatment:**
Immunosuppression if nephrotic at preserved GFR
Prolonged/high dose steroids - 1 mg/kg for at least 6 months
If unable to tolerate steroids – cyclosporine
If GFR <35-40 ml/min usually no role for immunosuppression
Transplant is option once ESRD–> may recur immediately post-kidney transplant

Two Major Clinical Forms:

Primary or Idiopathic (includes familial/genetic forms)
Secondary
- Virus (HIV, Parvovirus B19)
- Drugs (Heroin, Interferon, Lithium)
- Adaptive functional response (obesity, loss of one kidney)

Histology:
Light microscopy:
- Mesangial cell proliferation
- Focal process: not all glomeruli involved
- Segmental process: only tufts involved
- Trichrome stain: expansion of mesangium

*Immunofluorescence:
Trapping of IgM within mesangium**

Electron microscopy:
Epithelial Cell Injury
- Foot process fusion
- Detachment from underlying basement membrane
Mesangial Changes
- Fibrosis
- Mesangial Matrix Increase
- Insudative deposition of IgM and C3
- Lipid vacuoles

Pathogenesis:

Primary event is Epithelial Cell injury induced by circulating factor (SuPAR)
- Can see return of proteinuria within 24 hr’s after transplant
- Candidate circulating factor has been tentatively identified
Subsequent loss of GBM integrity
Glomerular structure becomes hyper permeable
See secondary extracellular matrix depositions and insudative trapping of IgM in the mesangium

Genetic predisposition:
- Polymorphisms/mutations in: Nephrin gene, Podocin gene

Injury:
Angio-poietin-like-e–> alters slit diaphragm between podocyte processes–> loss of GBM integrity–> proteinuria

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MM is a 36 yr old male was noted with new 3+ proteinuria on an insurance physical. History of hypertension.
On exam, he presents with facial edema and elevated blood pressure
3.5gm protein/day on 24 hr urine, SCr 0.8, normal serum complements

Below is a silver stain of a kidney biopsy. What is his diagnosis and treatment?

Membranous glomerulonephropathy:

*First AID**:
Nephrotic syndrome= proteinuria (> 3.5 g/day, frothy urine), hyperlipidemia, fatty casts, edema. Can cause thromboembolism (hypercoagulable due to ATIII loss in urine) and increased infection risk (loss of Ig)
LM- diffuse capillary and GBM thickening
EM: “Spike and dome” appearance with subepithelial deposits
IF: granular. Nephrotic presentation of SLE
Second most common cause of primary nephrotic syndrome in adults
Idiopathic (serum Ab against phospholipase A2-R= PLA2R; transmembrane protein on podocytes)
Drugs, infections, SLE, solid tumors

Clinical course:

1/3 with spontaneous complete remission
1/3 with persistent proteinuria
1/3 with progression to ESRD
*Primary:**
Autoimmune Disease – IgG4 linked to certain MHC loci
Production of autoantibody to M-type phospholipase A2 receptor
Immune complexes are formed in situ: C5b-C9 attack complex that injures epithelial cells
*Secondary:**
Chronic circulating immune complexes of a specific size are trapped (IgG mediated)
Antigen-antibody complex activate complement attack complex, causing epithelial and BM injury

Causes:

Systemic lupus erythematosus (WHO Class V)
Drugs:
- Penicillamine
- Bucillamine
- Gold salts
- Anti-TNF therapy
- Tiopronin
- NSAIDs
Hepatitis B virus/ Hepatitis C virus
Malignancy
Hematopoietic cell transplant / GVHD Status post renal transplantation
Sarcoidosis
Treponema,
Thyroglobulin

*Treatment**:
ACE/ARB for tight BP control
Immune-suppression for those at high risk of ESRD:
1. elevated creatinine at presentation
2. proteinuria > 8g/dL for 6 months after conservative treatment (ACE/ARB)
3. worsening kidney function
4. Refractory manifestations of nephrosis

Immune suppression:

Cyclophosphamide or calcineurin inhibitor + Corticosteroids
Alternate Agents- Rituximab (NIH clinical trials)

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M.S. is a 3yr old boy who presents to the office with generalized edema and abdominal distention
UA – 3+protein, no RBCs
CXR – bilateral pleural effusions
Labs – Albumin 1.2 g/dL, total cholesterol 472 mg/dL, BUN 21 mg/dL, creatinine 1.2 mg/dL

Electron microscopy: below

What is the diagnosis and treatment?

Minimal Change disease:
“Nil” disease= Proteinuria with epithelial cell foot processes fusion

*FIRST AID:**
Nephrotic syndrome= proteinuria (> 3.5 g/day, frothy urine), hyperlipidemia, fatty casts, edema. Can cause thromboembolism (hypercoagulable due to ATIII loss in urine) and increased infection risk (loss of Ig)
LM= normal glomeruli
EM= foot process effacement/fusion
Labs: GBM polyanion loss (heparin sulfate defect)–> selective loss of albumin, not globulins
Cause: Recent infection/immune stimulus (children): abnormal T-cell production of glomerular permeability factor–> capillary wall–> foot process fusion–> proteinuria
Responds to STEROIDS

Most common cause of nephrotic syndrome in children

Prognosis:

Progression to renal failure v. rare
Responsive to steroids
50-65% of adults relapse (have steroid dependence)
Good prognosis in children

Pathogenesis:

Probably immunologic basis
More prevalent in certain HLA haplotypes
Proposed Immune dysfunction: Circulating cytokine (IL-13) that damages epithelial cells; innate T cell dysregulation (cmyb pathway)

Treatment: directed at T cells

Prednisone (first-line)
Cyclophosphamide or cyclosporine (relapsing or steroid resistant)
Mycophenolate mofetil (relapsing or steroid-resistant), rituximab, tacrolimus

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RW is a 60 yr old male who has been on renal dialysis for the past 15 years. His urinary protein electrophoresis is notable for light chains. Based on his history and the histology below, what is his diagnosis?

Amyloidosis–> Glomerulonephritis:

*FIRST AID**
Nephrotic syndrome= proteinuria (> 3.5 g/day, frothy urine), hyperlipidemia, fatty casts, edema. Can cause thromboembolism (hypercoagulable due to ATIII loss in urine) and increased infection risk (loss of Ig)

A collection of diseases sharing a common feature:
- common feature = Extracellular deposition of pathologic insoluble fibrillar proteins
- Protein deposition impairs normal function
Multiple organs and tissues can be involved
Virchow coined the term amyloid, meaning starch like

** Chronic Renal dialysis–> alpha-2-beta globulin deposition

Histo:
Light microscope:
- Amorphous deposition of pink material around glomeruli, afferent, efferent arterioles
- Congo red positive, Not PAS positive

Immunofluorescence:
- Non-specific staining with Ig reagents

Characteristics of protein:

Many precursor proteins
Abnormal folding
Beta pleated sheet configuration
Appear as fibrils by EM, 8-10nm in diameter, indefinite length
Appears “apple green” with Congo red stain under polarized light

Primary amyloidosis:
Plasma cell dyscrasia with fragment of light chains forming amyloid fibrils

Treatment: chemo +/- bone marrow transplant

Secondary amyloidosis:
chronic inflammatory states (e.g. RA, IBD, CF, psoriasis) with acute phase reactant serum amyloid A forming fibrils

Causes:

Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Chronic infections (e.g. bronchiectasis, TB, osteomyelitis)
Inflammatory bowel disease
Cystic Fibrosis
Malignancy (e.g. RCC, NHL)
Familial Mediterranean Fever

Treatment: treat underlying inflammatory disorder

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*Amyloidosis–> Glomerulonephritis:**
*FIRST AID**
Nephrotic syndrome= proteinuria (> 3.5 g/day, frothy urine), hyperlipidemia, fatty casts, edema. Can cause thromboembolism (hypercoagulable due to ATIII loss in urine) and increased infection risk (loss of Ig)

** Chronic Renal dialysis–> alpha-2-beta globulin deposition

Histo:
Light microscope:
- Amorphous deposition of pink material around glomeruli, afferent, efferent arterioles
- Congo red positive, Not PAS positive

*Immunofluorescence:
Non-specific staining with Ig reagents**

Characteristics of protein:

Many precursor proteins
Abnormal folding
Beta pleated sheet configuration
Appear as fibrils by EM, 8-10nm in diameter, indefinite length
Appears “apple green” with Congo red stain under polarized light

Primary amyloidosis:
Plasma cell dyscrasia with fragment of light chains forming amyloid fibrils

Treatment: chemo +/- bone marrow transplant

Secondary amyloidosis:
chronic inflammatory states (e.g. RA, IBD, CF, psoriasis) with acute phase reactant serum amyloid A forming fibrils

Causes:

Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Chronic infections (e.g. bronchiectasis, TB, osteomyelitis)
Inflammatory bowel disease
Cystic Fibrosis
Malignancy (e.g. RCC, NHL)
Familial Mediterranean Fever

Treatment: treat underlying inflammatory disorder

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45-yr old male presents with microscopic hematuria and proteinuria (2 gm/d)

Further evaluation reveals low C3, normal C4 and Hepatitis C viral Ab positivity

Based on the light microscope slide below, what is his diagnosis and treatment?

Membranoproliferative glomerulonephritis: Type 1

*FIRST AID**:
Subendothelial Immune complex deposits with granular immunofluorescence
“tram-track” appearance due to mesangial ingrowth–> GBM splitting
Associated with HBV, HBC

Primary and Secondary forms

Both involve activation of classic and alternative complement pathways
1. Stimulating Antigen in Primary form is not known (truly idiopathic)
2. Secondary Type I MPGN associated with antigens from:
SLE, Hep B, Hep C, HIV, Endocarditis, CLL,
Alpha 1-antitrypsin deficiency
*Histo**:
*Light microscopy:**
Small urinary space, enlarged glomerulus
Lobular proliferation of tuft (vs diffuse in post-strep)
NO neutrophils (not actively inflammatory)
PAS stain (glycoproteins): see basement membrane duplication/splitting “railroad tracking”

Immunofluorescence:
- IgG, C3 (low in serum–> ends up in glomerulus), C1q located in subendothelium (vs epithelial)

Electron microscopy:

Focal foot process fusion
Capillary Basement membrane duplication
Subendothelial electron dense deposits
Mesangial electron dense deposits

Treatment:
Treat underlying condition (e.g. HCV)
Idiopathic, nephrotic - Corticosteroids
Antiplatelets? Cyclosporine?
*Relapse is common

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A 6-year old child presents to his physician for an annual physical. An opthalmic exam shows small accumulations in his retina. Additionally his urine shows microscopic hematuria and proteinuria. A blood sample taken shows elevated cholesterol. A kidney biopsy is taken (below). Based on his clinical picture and the electron microscope, what is his diagnosis?

Membranoproliferative glomerulonephritis type 2:

*FIRST AID:
**Intramembranous Immune complex deposits= “dense deposits”
Associated with C3 nephritic factor

dense deposit disease, seen in children. Clinical features:
- Partial lipodystrophy
- Retinal drusen
* Recurs in > 90% of kidney transplants

*Pathogenesis**:
Uncontrolled activation of alternative complement pathway
Loss of control secondary to an inherited deficiency of factor H (Factor H normally inactivates the C3bBb complex)
Without inactivation, continuous cleavage of C3 leading to the formation of abundant C3bC3bBb (the C5 convertase)
*–> C3b dimer deposition along the GBM= “Dense deposits**

Histology:
Light microscopy (same as Type 1):
- Small urinary space, enlarged glomerulus
- Lobular proliferation of tuft (vs diffuse in post-strep)
- NO neutrophils (not actively inflammatory)
- PAS stain (glycoproteins): see basement membrane duplication/splitting

Immunofluorescence (same as type 1):
- IgG, C3 (low in serum–> ends up in glomerulus), C1q located in Basement membrane (vs subendothelium)

Electron microscopy:
- band-like dense deposits in basement membrane

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A 56 yo woman with a 25 year history of type II diabetes presents to the clinic. She has required insulin for 20 yrs. Eye exam last year was notable for diabetic retinopathy
On exam, 168/102
UA with 3+ protein, Creatinine 2.6

Based on the histologic specimen below, what is her diagnosis and treatment?

Severe Diabetic Nephropathy:

*FIRST AID**:
Nonenzymatic glycosylation (NEG) of GBM–> increased permeability, thickening
Glycosylation of efferent arterioles–> thickened–> increased GFR–> mesangial expansion
LM: mesangial expansion, GBM thickening, eosinophilic nodular glomerulosclerosis (Kimmelstiel-Wilson lesion)

Most common cause of end stage renal disease in the U.S.
Occurs in both Type I and Type II DM

Clinical course:
Early:
- Increased GFR
- Glomerular hypertrophy
- Increased kidney size
- Microalbuminuria

Late:

GFR decreases
Macroalbuminuria–> proteinuria
*Treatment**:
Blood sugar control (HbA1c~7%)
Screen for microalbuminuria - if present treat with ACEI or ARBs
Tight control of blood pressure (500-1000 mg/g creatinine)

Pathophys:
Hyperglycemia results in:
- Activated protein kinase C pathway
- Polyol pathway
- Oxygen radical production
- Increase in system wide glycation of proteins
Events due to hyperglycemia cause:
- General accumulation of hyperglycosylated proteins
- Glomerular hypertrophy
- Mesangial expansion
- Basement membrane thickening
- Hyperfiltration injury (related to obesity)

*Histo**:
*Light microscopy:
Nodular diffuse nephropathy:
Acellular, PAS, glycosylated proteins deposited in glomerular tuft
Start in mesangium and spread to rest of glomerulus, compress capillaries**

Immunofluorescence:

Pseudo-linear peripheral IgG and Albumin
Nodular mesangial deposition of IgM and C3
Insudative Vascular deposition of IgM and C3, especially in hilar vessels

Electron microscopy:

Thickened GBM and TBM, >600nm
Fused epithelial foot processes
Mesangial expansion, nodular, by the deposition of amorphous ground substance
Insudative electron dense deposits in mesangium and blood vessels

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A 56 yo woman with a 25 year history of type II diabetes presents for an annual physical. She has required insulin for 20 yrs. Eye exam last year was notable for diabetic retinopathy
On exam, BP= 168/102
UA with 3+ protein, Creatinine 2.6

What is her diagnosis and treatment?

Severe Diabetic Nephropathy:

*FIRST AID:**
Nonenzymatic glycosylation (NEG) of GBM–> increased permeability, thickening
Glycosylation of efferent arterioles–> thickened–> increased GFR–> mesangial expansion
LM: mesangial expansion, GBM thickening, eosinophilic nodular glomerulosclerosis (Kimmelstiel-Wilson lesion)

Most common cause of end stage renal disease in the U.S.
Occurs in both Type I and Type II DM

Clinical course:
Early:
- Increased GFR
- Glomerular hypertrophy
- Increased kidney size
- Microalbuminuria

Late:

GFR decreases
Macroalbuminuria–> proteinuria
*Treatment**:
Blood sugar control (HbA1c~7%)
Screen for microalbuminuria - if present treat with ACEI or ARBs
Tight control of blood pressure (500-1000 mg/g creatinine)

Pathophys:
Hyperglycemia results in:
- Activated protein kinase C pathway
- Polyol pathway
- Oxygen radical production
- Increase in system wide glycation of proteins
Events due to hyperglycemia cause:
- General accumulation of hyperglycosylated proteins
- Glomerular hypertrophy
- Mesangial expansion
- Basement membrane thickening
- Hyperfiltration injury (related to obesity)

Histo:
Light microscopy:
- Nodular diffuse nephropathy:
- Acellular, PAS, glycosylated proteins deposited in glomerular tuft
- Start in mesangium and spread to rest of glomerulus, compress capillaries

*Immunofluorescence:
Pseudo-linear peripheral IgG and Albumin
Nodular mesangial deposition of IgM and C3
Insudative Vascular deposition of IgM and C3, especially in hilar vessels**
*Electron microscopy:
Thickened GBM and TBM, >600nm
Fused epithelial foot processes
Mesangial expansion, nodular, by the deposition of amorphous ground substance
Insudative electron dense deposits in mesangium and blood vessels**

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6 year old boy presents with periorbital edema. Parents report URI two weeks ago.

BP : 131/93 mm Hg

Urinalysis with +1 protein, 2+ blood

Based on clinical picture on sample below, what is his diagnosis, prognosis, and treatment?

Post-streptococcal glomerulonephritis

*FIRST AID**:
Nephritic syndrome= inflammatory; hematuria, RBC casts in urine; azotemia, oliguria, HTN (salt retention), proteinuria (< 3.5 g/day)
LM: glomeruli enlarged, hypercellular; neutrophils, “lumpy bumpy” appearance
EM: subepithelial immune complex deposition
IF: granular appearance: IgG, IgM, C3 ALL deposit on GBM and mesangium (Type III immune complex deposition)
Presentation: Children, weeks after URI/infection. Peripheral, periorbital edema, dark urine, hypertension; Low C3 levels, resolves spontaneously
Better outcome in children (95% recovery) vs adults with 40% chronic glomerulonephritis or RPGN

Diagnosis:

Often a clinical diagnosis
Latent period of 10-21 days from infection to nephritis
Low Complement (C3) levels
Elevated titers of antistreptolysin O, antihyaluronidase and Anti-DNAase B antibodies

Clinical course:

Due to: Nephritogenic group A streptococcipharyngitis or impetigo
More common in children
Usually self-limited, renal function normalizes in 3-4 weeks

Treatment:
Treatment is supportive only
Dietary sodium restriction
Loop diuretics for edema

Path:
Immune complex mediated disease
**Follow group A beta-Hemolytic Strep infection**
- See elevated antibody titers to strep Ag’s
- Antigenic component not well characterized
- ? endostreptosin or cationic protein related to streptokinase
- Complexes lodge in glomerulus

*Histo**:
*Light microscopy:**
Glomerular tuft enlarged, small urinary space
Capillary lumens congested
Segmented neutrophils
Peripheral inflammatory glomerulonephritis

Immunofluorescence:
- Coarse Granular Pattern
- Capillary wall mainly but some mesangial
IgG and C3

Electron microscopy:

Coarse Electron Dense Deposits (cross-react with streptococcal antigens)
Subepithelial and Mesangial Location
Epithelial and Mesangial Cell Proliferation
Some Foot Process Fusion

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6 year old boy presents with periorbital edema. Parents report recent URI.

BP : 131/93 mm Hg

Urinalysis with +1 protein, 2+ blood

Electron microscope below- what is his diagnosis?

Post-streptococcal glomerulonephritis

*FIRST AID:**
Nephritic syndrome= inflammatory; hematuria, RBC casts in urine; azotemia, oliguria, HTN (salt retention), proteinuria (< 3.5 g/day)
LM: glomeruli enlarged, hypercellular; neutrophils, “lumpy bumpy” appearance
EM: subepithelial immune complex deposition
IF: granular appearance: IgG, IgM, C3 ALL deposit on GBM and mesangium (type III immue complex deposition)
Presentation: Children, weeks after URI/infection. Peripheral, periorbital edema, dark urine, hypertension; Low C3 levels, resolves spontaneously

Electron microscopy:

Coarse Electron Dense Deposits (cross-react with streptococcal antigens)
Subepithelial and Mesangial Location
Epithelial and Mesangial Cell Proliferation
Some Foot Process Fusion

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MS is an 89 YO woman who presented to the hospital with SOB due to pulmonary edema.
On exam, pitting edema of lower extremities and palpable purpuric rash
Labs with creatinine 3.2 (up from 0.8) and positive serologies for P-ANCA

What is her diagnosis and treatment?

Pauci-immune rapidly progressive glomerulonephritis: Microscopic polyarteritis

FIRST AID:
- Nephritic syndrome= inflammatory; hematuria, RBC casts in urine; azotemia, oliguria, HTN (salt retention), proteinuria (< 3.5 g/day)
- LM/IF: Crescent-moon shaped fibrin, plasma proteins (C3b) with glomerular parietal cells, monocytes, macrophages
- Caused by:
1. Granulomatosis with polyangiitis (Wegener’s)
- c-ANCA
2. Microscopic polyangiitis
- p-ANCA
Poor prognosis: rapid deterioration in renal function (days to weeks)

Sparing of the upper respiratory tract (vs Wegener’s granulomatosis)
Pulmonary infiltrates/hemorrhage
RPGN
Crescentic GN with no immune deposits/negative immunostaining (Pauci immune)
Positive P-ANCA (vs C-ANCA in Wegener’s)

Treatment: immunosuppression (Cytoxins and steroids) + plasmapheresis in severe renal dysfunction.

Histo:
_Light microscopy:
- Proliferation of crescent-shaped cells compressing glomerular capillaries–> decreased GFR
- Lose nuclei with fibrinous material (necrosis)_

Immunofluorescence:

Negative for all reagents (Pauci-immune)
NOT mixed connective tissue disease
Must be vasculitis (Wegener’s, microscopic polyarteritis, etc.)

Electron microscopy:

No electron dense deposits, fibril deposits
No specific cellular injury

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A 15 year old boy is brought to the emergency department after he begins coughing up blood. Labs reveal traces of blood in his urine as well. A renal biopsy is tagged and reveals the following. What is his diagnosis?

*RPGN: Goodpasture’s syndrome**:
*FIRST AID:**
1. Goodpasture’s syndrome: type II hypersensitivity reacion: Ab against glomerular basement membrane (a1, a3 Type IV collagen), alveolar BM–> linear interstitial fibrosis

Symptoms: hematuria/hemoptysis

*LM/IF:** Crescent- moon shape; crescents= fibrin and plasma proteins with glomerular parietal cells, monocytes, macrophages
Poor prognosis–> rapid deterioration in renal function

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TG is a 25 YO woman with history of SLE complicated by pleural effusions and pericarditis
Referred to nephrology for microscopic hematuria, proteinuria and creatinine 1.7

Below is a histologic specimen from her kidneys. What is her diagnosis and treatment?

Lupus nephritis: Diffuse proliferative glomerulonephritis

FIRST AID:
- Nephritic syndrome= inflammatory; hematuria, RBC casts in urine; azotemia, oliguria, HTN (salt retention), proteinuria (< 3.5 g/day)
- Due to SLE or Membranoproliferative glomerulonephritis
- LM: “wire looping” of capillaries
- EM: subendothelial intramembranous IgG immune complexes, C3 deposition
- IF: granular
** MPGN can present as nephrotic and nephritic syndrome

Immune Complex Mediated Glomerulonephritis
Secondary to a Variety of Autoantigens
Associated with Systemic Lupus Erythematosus
*Classification:**
1. Class I and II: Mesangial electron-dense deposits

Class III and IV –Mesangial and subendothelial deposits with endocapillary proliferation
Class V – Subepithelial deposits- resembles idiopathic membranous glomerular nephritis

Activity index:

Leukocyte infiltration
Hyaline deposition
Necrosis
Cellular crescents
Interstitial inflammation

Chronicity index: predictive of rapid renal decline

Glomerular sclerosis
Fibrous crescents (epithelial cell proliferation compressing tuft)
Tubular atrophy
Interstitial fibrosis

Treatment:
Many factors play a role when deciding treatment:
- Pathology (activity and chronicity indexes)
- Symptoms (asymptomatic or full blown nephrotic syndrome)
- Risk factors for worse prognosis (AA race, males, low socioeconomic status, higher creatinine at presentation, high grade proteinuria)
- Compliance

Meds:

ACEI/ARB Rx
Immunosuppressive Rx for Classes III-V
- III and IV: Steroids + Cyclophosphamide or MMF
- IV and V: FK+MMF+steroids
- V alone (similar to membranous): Steroids+CYA or CsA
No immunosuppression for Stage VI
Rarely recurs after kidney transplant

Histo:
Lupus nephritis ressembles many diseases–> plastic disease (nothing specific!)

*_Light microscopy:
Mesangial cell proliferation_**

_**Immunofluorescence:

See deposition of all immunoglobulins, complement proteins**_
Peripheral and mesangial deposition, granular
IgM, IgG, IgA, C3, C1q

Electron microscopy:
- Presence of Ig detected

35 yr old Asian woman who presents with nocturia and foamy urine. 3 days ago she had a bad cold.
BP: 130/94 mm Hg
Creatinine 0.9, Urinalysis with many RBCs, and few WBCs.
24-hour urine with 1.3 g of protein

Based on the labs and histology below, what is her diagnosis, prognosis, and treatment?

*IgA nephropathy**= Berger’s disease
*Begins with infection–> excess IgA–> kidney can’t clear IgA from blood–> deposition**
*FIRST AID**:
Related to Henoch-scholein purpura
LM: mesangial proliferation
EM: mesangial IC deposits
IF: IgA-based immune complex deposits in mesangium
Presentation: presents/flares with URI/acute gastroenteritis a few days after infection
*Path**: Immune complex glomerulonephritis involving intense deposition of dimeric and polymeric forms of IgA1 within the mesangium of the glomerulus
There is a defect in IgA metabolism
The O-glycosylation pattern of serum IgA1 is abnormal
The precise mechanism responsible for this aberrant glycosylation is not established.
Genetic deficiency in the enzymatic machinery mediating O-glycosylation of IgA1 (galactosyltransferase)

Clinical:
Most common cause of GN worldwide**
- Young age (15-30 years of age)
- Asian**

Variable clinical presentation:

40%-”Synpharyngitic” gross hematuria (pharyngitis with hematuria)
40%-Microscopic hematuria with mild proteinuria (asymptomatic
10%-Nephrotic proteinuria
10%-RPGN (rapid progressive glomerulonephritis)

Prognosis:

Good prognosis if minimal proteinuria (
Worse outcome if elevated Cr, HTN or moderate/nephrotic proteinuria
*Treatment**:
Observation if mild disease
If proteinuria >500mg/day – ACEI/ARBs + fish oil
Nephrotic or RPGN – Steroids +/- cyclophosphamide
Severe disease may require maintenance rx with azathioprine or mycophenolate

Histo:
Light microscopy:
Capillary lumens open
Proteinuria generally swells epithelium (not a lot of swelling here)
Too many cells in section of mesangium= mesangial hypercellularity and increase in matrix
= mesangial proliferation
RBCs in mesangial space

Immunofluorescence:
IgA deposition

Electron microscopy:

Mesangial Expansion and increased mesangial cellularity
Finely granular electron dense deposits are present along mesangial reflections

A 65 year old woman who has been hopitalized for an infection presents with generalized edema 4 days after starting penicillin to treat her infection. Eosinophilia is noted in her CBC. Based on the biopsy specimen below, what is her diagnosis?

Acute interstitial nephritis: Caused by medications

Patchy interstitial inflammation

Can become Chronic, especially with long-term analgesic (acetaminophen, NSAID use)
- Patchy interstitial inflammation–> fibrosis, necrosis, scarring of papillae, distorted calices, tubular atrophy

A 6 year old boy presents to the family physician with worsening hearing and vision problems. On physical exam the physician notes swelling in the boy’s feet and ankles. A urine sample reveals hematuria. What is his diagnosis?

Alport syndrome

Mutation in type IV collagen–> split basement membrane (X-linked)

Conventional (clear cell) Renal cell carcinoma

FIRST AID:
- Origin= PCT cells–> polygonal clear cells filled with accumulated lipids, carbs
Presentation:
- Male, 50-70 years
- Smoker, obese
- Hematuria, palpable mass
- Secondary polycythemia, flank pain, fever, weight loss
- Invades renal vein–> IVC–> hematogenous spread–> mets to bone, lung
* MOST common renal malignancy
• Hereditary cases, like Von Hippel- Lindau (VHL) chromosome 3 (3p) VHL tumor suppressor gene
- Cause paraneoplasic syndrome: ectopic EPO–> polycythemia, ACTH–> cortisol, PTHrP–> hypercalcemia, bone loss
- Silent in retroperitoneum (presents at metastatic stage)
Treatment: resection (if localized), resistant to chemo, radiation

Presentation: – Hematuria
– Few with the classic triad of hematuria, flank pain, and a palpable mass
– Metastasis
– Paraneoplastic syndrome: Hypercalcemia, hypertension, polycythemia (produces EPO)
– Incidental finding (CT or MRI) Risk factor is tobacco smoking

6th to 7th decade • 2:1 male predominance • Majority of cases are sporadic
Hereditary cases, like Von Hippel- Lindau (VHL) chromosome 3 (3p) VHL tumor suppressor gene

Grossly: Clear cell RCC: well circumscribed, golden yellow, cystic solid, hemorrhagic, necrosis.

Wilm’s tumor= Nephroblastoma

*FIRST AID:
** Most common renal malignancy of early childhood
Contains Embryonic glomerular structures
Presentation: huge palpable flank mass, hematuria
*Deletion of tumor-suppressor WT1 on chrom 11**:
Widemann syndrome: WAGR complex= Wilm’s tumor, Aniridia, GU malformation, mental Retardation

Embryonal tumor from nephrogenic nests
Abdominal mass does not cross midline
Chromosome 11 (11p); WT1 and WT2 genes overexpressed
- 85% of pediatric renal tumors

Associated with dysmorphic tumor syndromes in 10% of the cases:
– Wilms-Aniridia-genital anomaly-retardation syndrome
– Beckwith-Wiedemann syndrome (abdominal wall defect, macroglossia,macrosomia)
– Hemihypertrophy
– Denys-Drash syndrome (pseudohermaphroditism glomerulopathy)
– Familial nephroblastoma

Gross: Large round demarcated tumor with tan-grey, fleshy, hemorrhagic surface

Histo: Mixture of immature renal elements
Hematoxylin-Eosin (H&E stain): Blastema, Stroma and Epithelia.
- Blastema= small blue cells in solid nests.
- Hypocellular stroma with myxoid spindle cells.
- Epithelia arranged in tubules

Transitional cell carincoma:
High Grade Papillary Urothelial Carcinoma (HGPUC)

*FIRST AID:**
Most common tumor of urinary tract system: can occur in calyces, pelvis, ureters, bladder
Painless hematuria with no casts
Associated with: Phenacetin, smoking, aniline dyes, cyclophosphamide
Prognosis based on invasiveness (through muscular layer?)

The most dysplastic
• Frequent mitosis
• Disorganized architecture Nuclear atypia similar to Urothelial Carcinoma In Situ

Most common high grade tumor of urothelium

Clinical features:

Hematuria
15% of the cases have regional or distant metastases at presentation
4th most common cancer
3:1 M:F
Rare <40
Median age 65 - medical comorbidities
Often multifocal
Can involve the urothelium from the renal pelvis to the urethra

Cytogenic abnormalities:
- Deletion of chromosome 9 (9p- or 9q-), 11p, 13p, 14q, or 17p

Risk factors:

Cigarettes
Arsenic exposure

Treatment:
TURBT: transurethral resection of bladder tumor;
- Low risk: observe
- Intermediate: chemo, BCG/maintenance
- High risk: BCG/maintenance
* Recurrence–> radical cystectomy

Chemo: Cisplatin

Surgery:

urinary diversion: ileum connected to ureters
Neobladder/continent diversion: patients may have to self-catheterize

A 32 year old female presents to emergency room with fevers, shaking chills, and flank pain and tenderness. Based on the histology below, what is her diagnosis and treatment? What scenarios would require hospitalization?

Acute pyelonephritis

*FIRST AID:**
Affects cortex with sparing of glomeruli/vessels
Presentation: fever, CVA (costo-vertebral angle) tenderness, N/V
Histo: white cell casts in urine
*FIRST AID: renal papillary necrosis**
Presentation: gross hematuria, proteinuria; recent infection/immune stimulus
Associated with: DM, acute pyelonephritis, chronic phenacetin use (acetaminophen), sickle cell anemia/trait

Path:

Acute inflammation of tubules
Secondary tubular damage
Spill-over into interstitium
Neutrophilic casts in tubular lumens
Casts may be seen in urine

Symptoms:

Cystitis- dysuria,frequency,urgency, suprapubic pain, and/or hematuria.
Pyelonephritis consist of the above symptoms (symptoms of cystitis may or may not be present) plus fever (>38oC), chills, flank pain, costovertebral angle tenderness, and nausea/vomiting

Management:
* Untreated cases can lead to chronic pyelonephritis
1. Complicated Cystitis:
- oral fluoroquinolone such as ciprofloxacin (500 mg orally twice daily or 1000 mg extended release once daily)
- levofloxacin (750 mg orally once daily) for 7 to 14 days.
- Avoid moxifloxacin..
2. Complicated Pyelonephritis — should be managed initially as inpatients. Use broad spectrum antibiotics while awaiting susceptible testing
3. Underlying urinary tract anatomic or functional abnormalities (such as obstruction or neurogenic bladder) should be addressed in consultation with an urologist.

Complications requiring hospitalization:
Diabetes
- Pregnancy
- History of acute pyelonephritis in the past year
- Symptoms for seven or more days before seeking care
- Broad-spectrum antimicrobial resistant uropathogen
- Renal failure
- Urinary tract obstruction
- Presence of an indwelling urethral catheter, stent, nephrostomy tube or urinary diversion
- Recent urinary tract instrumentation, Renal transplantation, Immunosuppression

A 47 year old woman with a history of recurrent UTIs expires in her home. An autopsy is performed that reveals the following in her kidney. What has occurred and what is her diagnosis?

Chronic pyelonephritis

Interstitial fibrosis and atrophy of tubules due to multiple bouts of acute pyelonephritis

Due to vesicoureteral reflux (children) or obstruction (e.g., BPH or cervical carcinoma)

Leads to cortical scarring with blunted calyces; scarring at upper and lower poles is characteristic of vesicoureteral reflux.

Atrophic tubules containing eosinophilic proteinaceous material resemble thyroid follicles (‘thyroidization’ of the kidney); waxy casts may be seen in urine.

Histology: thyroidization, eosinophilic infiltration

A 76 year old female with peripheral vascular disease and poorly healing of lower extremity ulcers develops osteomyelitis. She is admitted to the hospital and started on ampicillin/sulbactam. After 10 days, creatine is noted to rise to 1.0 from baseline of 0.8. It rises to 1.6 over then next two days. Urinalysis shows 3+ Leukocyte esterase. Urine culture is negative. Based on her clinical presentation and this histology below, what is her diagnosis?

Interstitial nephritis

*FIRST AID**:
Acute interstitial renal inflammation
Pyuria (eosinophils) and azotemia) after administration of drugs–> haptens–> hypersensitivity
Nephritis usually 1-2 weeks after certain drugs: diuretics, penicillin derivatives, sulfonamides, rifampin
Can occur months after starting NSAIDs
Presentation: fever, rash, hematuria, costovertebral angle tenderness (can be asymptomatic)

Causes:
- DRUGS: NSAIDS, PCN, cephalosporins, rafampin, cimetidine, ciprofloxacin, allopurinol
- Infections: legionella, mycobacteria, streptococcus, CMV, BK polyoma etc
- Idiopathic- 8%  Autoimmune disorders-SLE, sarcoidosis, Sjögren’s
syndrome.
- TINU (tubulo-interstital nephritis and uveitis) syndrome- flank pain, sterile pyuria, hematuria, proteinuria (usually subnephrotic range) and uveitis.

Histo:

Key is eosinophilic infiltrate in interstitium - Variable amount of interstitial edema
Can see “spill-over” effects on glomerulus
Interstitial fibrosis is dependent on duration of disease.

66 year old previously healthy male presents with 7 day history of fevers, shaking chills, and productive cough. He requires intubation for hypoxia and intravenous pressors for hypotension. His sputum and blood cultures are positive for Staphlococcus Aureus. On day two of admission creatinine noted to be 2.0mg/dl (up from 0.8mg/dl on day of admission). Based on his presentation and the histology below, what is his diagnosis?

Acute tubular injury

First AID:
- Most common cause of instrinsic renal failure
- Associated with ischemia (shock, sepsis), crush injury (myoglobinuria), drugs, toxins
Causes:
- drugs= aminoglycosides, amphotericin B
- Radio contrast dye, heavy metals
- Myoglobinuria, hyperuricemia, Bence-Jones proteins in MM
- Presentation: “Muddy brown” granular casts
1. Inciting event
2. Maintenance phase: oliguric (1-3 weeks), risk of hyperkalemia
3. Recovery phase: polyuric; BUN and creatinine fall, risk of hypokalemia
** Self-reversible but can be fatal (especially during oliguric phase)

*FIRST AID: diffuse cortical necrosis**:
Acute cortical infarction of BOTH kidneys (generalized)
Due to vasospasm, DIC
Seen in obstetric catastrophes (abruptio placentae, septic shock)

Etiology:

Ischemic
Toxic
Inflammatory
Immunologic
Atrophy
Viral

Management:

Keep Mean arterial pressure>65
No nephrotoxins
Adjust Antibiotics dosage
Once euvolemic, cautiously give IVF based on insensible losses and urine output
Assess need for renal replacement therapy based on daily labs and clinical picture.

32 year old female who wishes to donate a kidney to a family member is referred for evaluation. A renal ultrasound shows four cysts on the right kidney and two on the left (below). What is her diagnosis based on the gross sample and ultrasound?

Autosomal dominant polycystic kidney disease

FIRST AID:

multiple bilateral cysts–> destroy kidney parenchyma
Presentation: flank pain, hematuria, HTN, urinary infection, progressive renal failure
Death from complications of chronic kidney disease, HTN (due to increased renin production)
Associated with berry aneurysms, MVP, benign hepatic cysts

AKA—Adult Polycystic Kidney Disease - Common congenital disease—1/1000 births

Accounts for 5% of all adult renal failure
Initial symptoms occur between 30 & 50 yrs
Back pain is most common complaint
Half of all ADPKD pts will require transplantation or dialysis

Symptoms:

**Typically asymptomatic until the fourth decade of life
loin “fullness”
Palpable flank masses in adults
Hematuria (gross clots)
Azotemia
Uremia**

Pathogenesis:
- 85% of cases show mutation in PKD 1 gene on chromosome 16 (40s-50s, worse outcome)
» Protein = polycystin-1
– 15% of cases show mutation in PKD 2 gene on chromosome 4 (70s-80s, better prognosis)
» Protein = polycystin-2 – Both proteins reside in tubular cell cilia
» Defects affect calcium signaling
» Mutations result in abnormal renal tubular growth

Gross pathology:

Bilateral Enlargement
Up to 4500 g
Distorted shape
Multiple cysts of varying sizes filled with clear, straw-colored fluid

Histo:

Simple cysts lined by flattened cuboidal and columnar epithelium
Arise from proximal and distal tubules as well as from the collecting ducts
Normal renal parenchyma can be present between the cysts

Associated path:

Hepatic Cysts—33% of cases
Splenic Cysts—10% of cases
Pancreatic Cysts—5% of cases
Cerebral Aneurysms—No Family history- 6 % prevalence, family history -21% prevalence.
Diverticular Disease of the colon often seen

Treatment:

Supportive Care
– Monitor Creatinine
– Aggressive blood pressure control
» ACEI, especially if there is evidence of proteinuria.
» Avoid caffeine, DASH diet

Future therapies:
– Vaptans (ADH antagonists) have been effective
in animal studies in preventing progression – Human Studies are ongoing

Antibiotics:
- Some drugs do not penetrate cysts well. - Fluoroquinolones, TMP- sulfa,
chloramphenicol best for cyst penetration.
- Do not adjust dose for UTI in renal insufficiency.

A woman delivers a 38-week infant who has deformed limbs and is unable to produce urine within the first 24 hours of life. The infant soon passes away due to acute renal failure. Based on the histologic sample below, what is the diagnosis?

Autosomal recessive polycystic kidney disease:

*FIRST AID:**
Infant
Congenital hepatic fibrosis
Presentation: renal failure in utero–> Potter’s syndrome; HTN, portal HTN, progressive renal insufficiency

AKA—Infantile Polycystic Kidney Disease

Rare—1/10,000 to 1/50,000 births
75% of affected infants die perinatally
Rare cases can manifest in older children

Clinical correlates:

Results in Oligohydramnios (decreased amniotic fluid as fetal kidneys can’t properly filter blood, produce urine)
Causes Pulmonary Hypoplasia due to mass effects
See Associated Hepatic and Pancreatic Cysts
Infants often have biliary dysgenesis and hepatic fibrosis

Pathogenesis:
Mutations in the PKHD1 gene
- Protein = fibrocystin
- Fibrocystin is involved in cell proliferation and adhesion
- Fibrocystin is found in the kidneys, liver, and pancreas

Pathology:

Disease is Bilateral
Enlarged Kidneys (often impede delivery)
Fusiform Cysts of Collecting Ducts – Affects cortical and medullary ducts
Cysts Arranged Radially, Perpendicular to renal capusule
Accompanying interstitial fibrosis and tubular atrophy (due to compression)

Treatment:
Supportive Care
– Monitor Creatinine
– Aggressive blood pressure control
» ACEI, especially if there is evidence of proteinuria.
» Avoid caffeine, DASH diet

Future therapies:
– Vaptans (ADH antagonists) have been effective
in animal studies in preventing progression – Human Studies are ongoing

Antibiotics:
- Some drugs do not penetrate cysts well. - Fluoroquinolones, TMP- sulfa,
chloramphenicol best for cyst penetration.
- Do not adjust dose for UTI in renal insufficiency.

A 36 year old woman presents to the Emergency Department with acute right- sided flank pain. A CT scan shows a right ureteral stone and calcium deposits (nephrocalcinosis) and cystic dilatations in the calyces are noted in both kidneys. Based on her clinical presentation and the gross pathology below, what is her diagnosis and prognosis?

Medullary sponge kidney (Medullary cystic disease)

*FIRST AID**:
Inherited disease–> tubulointerstitial fibrosis, progressive renal insufficiency; inability to concentrate urine
Can’t visualize medullary cysts
Shrunken kidneys on ultrasound
Poor prognosis

Unknown pathogenesis:
Epidemiology:
- Sex predilection-slight male predominance
- Symptomatic cases usually emerge at 30-60 yrs
- Nonhereditary

Symptoms:

flank pain, dysuria, hematuria, gravel sized stones.
Hypercalciuria in 50% of symptomatic pts

Clinical course:

Increased risk of kidney stones and urinary tract infection
Excellent long-term prognosis – progressive disease very rare

Pathology:

May be associated with hemihypertrophy
bilateral in 75% of patients
Cysts involve the branches of collecting ducts and papillae
Glomeruli are normal if secondarily affected by distal obstruction
Kidneys are not enlarged and are symetrical
Discovered in work-ups of nephrolithiasis

Microscopic
– Flattened cuboidal or transitional epithelium
– Intracystic calcifications
– Associated intersitial inflammation