Pathoma Kidney and Urinary Tract Pathology Flashcards
What is the inheritance pattern of multicystic dysplastic kidney and what will be seen on histology?
It is sporadic and non-hereditary, usually unilateral
May be bilateral for the purposes of confusing you on examinations
Multiple cysts with CARTILAGE is typical
Where do the cysts arise from in ADPKD vs ARPKD? What genes are awry in both conditions?
ADPKD - can arise from any duct (cuboidal epithelium)
-> polycystin 1 / 2 (PKD1/2) can be mutated
ARPKD - arise from collecting duct**
-> polyDUCTin is wrong -> cilia syndrome
What are the clinical manifestations of ARPKD and what is the function of the missing protein? When does it present?
Missing protein = polyDUCTin - another nonmotile cilia syndrome
Presents in infancy, often prenatally
-> associated congenital hepatic fibrosis leading to portal hypertension
-> renal failure and hypertension.
Think “Cysts in the liver, cysts in the kidney”
What are the clinical manifestions of ADPKD? One of these is a cardiac condition.
Cysts in the liver, brain, and kidney:
Liver - benign hepatic cysts
Brain - berry aneurysms of Circle of Willis
Kidney - Cysts destroying renal parenchyma, hypertension due to renin secretion -> progressive renal fialure
Heart - mitral valve prolapse
What is medullary cystic kidney disease and how can you distinguish it from the polycystic kidney diseases? How is it inherited?
Autosomal dominant disease which predominantly features tubulointerstitial parenchymal fibrosis resulting in SHRUNKEN kidneys and progressively worsening renal function.
Cysts would be present in the medulla (collecting ducts), but are generally small and insignificant. Medullary cystic is a bit of a misnomer.
What happens to the serum BUN/Cr ratio in intrarenal vs extrarenal causes of ATN and why?
serum BUN/Cr ratios -> increases above 15 in extrarenal causes, as tubules try to preserve volume and are functioning properly, and BUN can be reabsorbed while Cr cannot. Think BUN is resorbed to preserve medullary gradient.
Ratio falls below 15 in intrarenal AKI (i.e. ATN) because tubules are not functioning properly in reabsorption of BUN.
What happens to the FENa in intrarenal vs extrarenal causes of ATN and why?
FENa = fractional excretion of sodium
Extrarenal - will be below 1% -> proper reabsorption of Na (until damage causes tubular failure)
Intrarenal - tubules failing - will be above 1%
What happens to urinary sodium in pre-renal vs intrinsic renal? Urinary osmolality?
Urinary sodium: <20 mEq/L in pre-renal, >40 in intrinsic renal
Urinary osmolality: >500 mOsm/kg in pre-renal, <350 in intrarenal
-> loss of urine concentrating ability
What physiologically causes post-renal azotemia and how do the values of post-renal change overtime from early to late?
Post-renal azotemia causes a backpressure which decreases GFR:
Early on:
Looks like pre-renal azotemia with decreased GFR:
Urine osmolality is normal (>500), FENa normal (<1%), and BUN/CR >15.
Late - excessive tubular damage causes intrarenal picture
Urine osmolality drops (<350), FENa abnormal (>2%), and BUN/CR <15
What accounts for 90% of intrarenal azotemia and what will appear in the urine? What are the two subtypes?
Acute tubular necrosis - Muddy brown granular casts
- Ischemic - usually preceded by pre-renal azotemia
- Nephrotoxic
What are the endogenous, toxic causes of ATN?
Hemoglobinuria (intravascular hemolysis)
Myoglobinuria - very common, due to severe muscle trauma / rhabdomyolysis
Endotoxemia - cytokine overproduction
Urate crystals - tumor lysis syndrome
What are the exogenous toxic causes of ATN?
Aminoglycosides, radiocontrast dye, lead, cisplatin (gyno malignancies), ethylene glycol (oxalate crystals), amphotericin B
How does the damage appear in ATN and where is it worst?
Appears patchy in ischemic causes and more continuous in nephrotoxic causes
Worst in proximal tubule and outer medullary segment of TALH
What are the three distinct phases of ATN?
- Initiation phase - potentially reversible period if insult is corrected
- Maintenance period - irreversible loss of renal function lasting 1-3 weeks, as tubular cells take time to re-enter cell cycle / regenerate
- Recovery phase - renal function returning to normal, marked by polyuria
What are the metabolic risks in the maintenance phase of acute renal failure?
Oliguria -> hyperkalemia, anion gap metabolic acidosis (unable to excrete daily produced acids), increased BUN (uremia) and creatinine
What happens to urine production, electrolytes, and nitrogenous substances during the recovery period of ARF?
Polyuria -> BUN and serum creatinine fall as GFR recovers
Risk of hypokalemia from overexcretion
What is the drug-induced hypersensitivity cause of intrarenal azotemia called? What are the symptoms?
Acute interstitial nephritis (AIN / ATIN)
-> involvement of interstitium with WBCs and eosinophils causes an acute renal failure
Symptoms are oliguria, fever, and rash starting days after administering a drug.
What is the general progression of AIN?
Generally resolves with cessation of the drug, but may progress to renal papillary necrosis
What drugs commonly cause acute interstitial nephritis?
Remember the P's Pee - diuretics -> since many are sulfa drugs Pain-free - NSAIDs Penicillins and cephalosporins Proton pump inhibitors RifamPin
Sulfa antibiotics can also cause it (i.e. TMP/SMX)
What are causes of renal papillary necrosis other than progression from AIN?
SAAD papa with papillary necrosis
Sickle cell disease / trait - damages vasa recta
Analgesic nephropathy - think of the kletes in sketchy
Acute Pyelonephritis - damages tubules
Diabetes mellitus - damages vasa recta
-> conditions reduce renal blood flow and induce coagulative necrosis
How does renal papillary necrosis present?
Gross hematuria and flank pain
-> will hurt alot because there is necrosis and sloughing off of papillae
What is the #1 defining characteristic of nephrotic syndrome which causes the majority of the other symptoms?
Heavy proteinuria (>3.5 g/day), leading to hypoalbuminemia.
Most of the other symptoms will be as a result of this protein loss.
What are the other general symptoms of nephrotic syndrome other than proteinuria (some will be related). What will be seen in the tubules?
- Generalized edema - dependent areas and periorbital, secondary to hypoalbuminemia
- Hyperlipidemia - liver increases lipoprotein synthesis to compensate for how thin blood has become due to protein loss
- Lipiduria - leakage of plasma lipoproteins into urine
- > creates fatty casts / “oval fat bodies” in the tubules - Increased risk of bacterial INFECTIONS and thromboembolic complications - due to loss of immunoglobulins and antithrombin III, respectively.
What is the pathogenesis of Minimal Change Disease (MCD)?
Usually a primary disease, but may begin secondary to another immune disease, commonly Hodgkin’s lymphoma (cytokine-mediated cellular recruitment).
Insult is due to cytokine production -> damage podocytes -> massive proteinuria, mostly albumin.
What proteins are lost in MCD and what is the treatment? Why does this make sense?
Selective albuminuria due to loss of negative charge in GBM
Responds well to corticosteroids
- > corticosteroids should be the empiric treatment in children with nephrotic syndrome, without renal biopsy
- > makes sense b/c the damage is cytokine mediated, which would be able to be tuned down by steroids
What disorders and comorbidities are associated with causing secondary FSGS?
Most common cause of nephrotic syndrome in Blacks and Hispanics
- Sickle cell disease - blacks
- Heroin abuse - think of Mexican druglords
- HIV infection - think of dz association with African American men
- Glomerular hyperfiltration - obesity. Think of low income minorities.
What is primary FSGS caused by, and what will happen to the glomeruli / ECM?
Idiopathic
- > it is like really bad MCD -> nonselective proteinuria
- > damage to podocytes -> leakage of plasma proteins = hyalinosis
- > hyalinosis -> increased ECM production = sclerosis
Patchy hyalinosis and sclerosis can be seen.
What does focal vs segmental mean?
Focal - affects only certain foci of the kidney -> not all glomeruli affected (opposite of diffuse)
SeGMental - Sections of the glomerulus are affected, not the whole glomerulus. Just remember than SGM is in the word segmental. GM = glomerulus, S = sectioning. Sectioning of glomerulus
Why do we say FSGS is like a really bad minimal change disease?
On EM, we see effacement of the foot processes
Like minimal change disease, no immune complexes will be seen on IF
However, it responds poorly to steroids and progresses to chronic renal failure
Who is membranous nephropathy (also called membranous glomerulonephritis since it is the sister of membranoPROLIFERATIVE glomerulonephritis) common in and what causes the primary form? Is it immune-mediated?
Most common cause of nephrotic syndrome in Caucasian adults
Primary form is due to antibodies to the phospholipase A2 receptor
Caused by antibodies in all cases, so YES it is immune-mediated. However, we don’t get a lot of complement deposition so it is nephrotic rather than nephritic.
What are the causes of secondary membranous nephropathy?
- Medications - NSAIDs, penicillamine (also causes of AIHA, antibody production)
- Infections - HBV, HCV, syphilis -> all things causing massive antibody production
- Malignancies - solid tumors put new Ags in circulation
- SLE - this is the nephrotic presentation of SLE (ANA-mediated antibody disease)
What is the pathogenesis of membranous nephropathy, other than the initial generation of antibodies?
Immune complexes form / deposit in subepithelial area
- > activation of complement, especially MAC (although C5a doesn’t seem to recruit more cells)
- > podocyte and mesangial cell activation and production of injurious substances
- > capillary wall damage + proteinuria WITHOUT hypercellularity
What does LM and DIF show in membranous nephropathy?
LM - diffuse capillary wall THICKENING (membranous) with NORMOcellular glomeruli
DIF - Lumpy bump, granular appearance with immune complex deposition (IgG and complement)
EM - “spike and dome” appearance as spikes of GBM encircle the immune complexes (membrane is proliferating, forming a DOME), with spikes separating the immune complex domes.
-> subEPIthelial immune complex deposition (vs MPGN1/2)
What disease is associated with a mixed nephrotic / nephritic presentation? What disease is it related to?
Membranoproliferative Glomerulonephritis (MPGN)
Membrano - nephrotic
Proliferative - nephritic (inflammatory cells), as well as proliferation of mesangial cell processes
Related to membranous glomerulonephropathy -> immune deposits are just actually subendothelial or intra-membranous instead of subepithelial
What is MPGN, Type I caused by if it is primary or seconday? Where do things deposit?
Primary - idiopathic (all nephrotic syndromes can be idiopathic)
Secondary - related to SLE, or associated with HBV or HCV, other autoimmune conditions -> pretty much the same causes as membranous nephropathy
Subendothelial immune complex deposits
What is MPGN type II also called, and what causes it? What will happen to serum complement levels?
Type 2 = 2 letters = DD
Dense-Deposit disease -> development of an auto-antibody called C3 nephritic factor
-> IgG antibody stabilizes C3 convertase of alternative pathway (C3bBb) for persistent complement activation and decreased C3 levels
What does LM show for MPGN, both Types I and II?
Both show a “tram-track” or “split” appearance with PAS stain (stains only the glycoproteins in the basement membrane) -> GBM is split through the middle by mesangial cell processes
Glomerulus is hypercellular and proliferative, also appears somewhat lobulated (semidiscretely divided)
What do DIF show for MPGN Type I vs Type II?
Type I - granular deposition of IgG, C3, C1q, and C4 in the glomerulus diffusely (all complement components, not just alternative)
Type II - C3 deposition would be prominent in GBM adjacent to dense deposits, and in mesangium. C3 nephritic factor is IgG but will not stain because the C3 is formed peripherally. Also C1q and C4 would not be present (classical pathway components)
What would TEM show for MPGN Type I vs Type II?
Type I - Predominantly subendothelial electron-dense deposits, with duplication of GBM associated with mesangial cell processes coming (proliferating) through (tram-tracking is actually more prominent in this condition)
Type II - Extremely electron dense material in the lamina densa (dense-deposit disease) which splits GBM into two layers. No idea whats even accumulating cuz its not even C3.
What light microscopic changes of the glomeruli accompanies diabetic nephropathy?
Diffuse and nodular glomerulosclerosis
-> GBM thickening
-> Exaggerated mesangial expansion
-> Frank, hypocellular nodules with eosinophilic material
called Kimmelstiel-Wilson nodules (pathognomonic)
What is the pathogenesis of diabetic nephropathy? What will happen to GFR?
Nonenzymatic glycosylation of the glomerular basement membrane as well as arterioles, predominantly the efferent arteriole. Leads to hyaline arteriolosclerosis of vessels and sclerosis of mesangium
-> increases GFR initially, followed by decrease in GFR later in the disease
Where does amyloid tend to deposit in the kidney? How does this cause dysfunction?
In the mesangium, but can deposit anywhere
Causes dysfunction by compressing and decreasing luminal area of surrounding capillaries
-> causes a nephrotic syndrome
How do you tell amyloid nephropathy from diabetic nephropathy?
- Congo red stain
- General clinical picture should make it obvious
- > they can look very similar via LM.
Why do azotemia, oliguria, HTN, proteinuria, and edema happen in nephritic syndrome?
Reduction in GFR due to hypercellular inflammation blocking filtration
-> azotemia, oliguria, hypertension (sodium retention)
Glomerular membrane damage but not high enough GFR for massive proteinuria
-> RBCs lost, proteins not as much. Proteinuria -> edema from loss of oncotic pressure.
What urinary finding is a hallmark of glomerulonephritis?
RBC casts -> due to glomerular bleeding
What is the general shared characteristic of glomeruli in nephritic syndrome? What is the pathogenesis behind that?
Hypercellular, inflamed glomeruli
Immune-complex deposition activates complement; C5a attracts neutrophils, which mediate damage
What is the pathogenesis of acute post-strept glomerulonephritis (PSGN)? What type of hypersensitivity is it? This is all obvious, but what type of Strept must cause the infection to cause this syndrome?
Infection with nephritogenic strain of GAS -> production of antibodies to microbial antigens, especially strept exotoxins -> formation and deposition of immune complexes within glomeruli -> activation of complement with leukocyte infiltration and proliferation of mesangial cells
- Type III hypersensitivity reaction
Nephritogenic strain = Strain which possesses M protein to cause antibody production. Occurs following impetigo or strept pharyngitis.
