Renal Flashcards

0
Q

Azotemia

A

↑ BUN and creatinine levels with ↓ GFR

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1
Q

How are glomerular diseases mediated and how are tubular/interstitial diseases mediated?

A

Glomerular = immunologically mediated

Tubular/interstitial = toxic or infectious agents

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2
Q

Prerenal and postrenal azotemia

A

Prerenal = hypoperfusion of kidneys impairing renal function without parenchymal damage.

Postrenal = obstructed urine flow beyond level of kidney

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3
Q

Uremia and secondary manifestations

A

failure of renal excretory function, metabolic and endocrine alterations from renal damage.

secondary manifestations in: GI system, peripheral nerves, heart

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4
Q

Nephritic Syndrome

A

from glomerular disease.

from inflammation in glomeruli.

features: acute onset, hematuria, mild to mod proteinuria, HTN, red cell casts in urine, azotemia, oliguria.
classically: acute poststreptococcal glomerulonephritis

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5
Q

Rapidly progressive glomerulonephritis

A

nephritic syndrome with rapid decline in GFR.

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6
Q

Nephrotic Syndrome

A
  • from glomerular disease.
  • deranged capillary wall ⇒ ↑ permeability to plasma proteins (↑ proteinuria) ⇒ hypoalbuminemia and reversed albumin:globulin ratio.
  • ↓ colloid osmotic pressure and Na/water retention ⇒ edema
    • most markedly in periorbital regions. also ascites and pleural effusions.
  • hypogammaglobulinemia ⇒ ↑ risk infection.
  • hypercoagulable state - from loss of antithrombin III.
  • ↑ synthesis lipoproteins in liver, abnormal transport of circulating lipid particles, and ↓ catabolism ⇒ hyperlipidemia and hypercholesterolemia may ⇒ fatty casts in urine, oval fat bodies or free fat in urine.
  • in kids: primary kidney lesion ⇒ minimal change disease, membranous GN (older adults), and FSGS (all ages).
  • in adults: from systemic diseases = SLE, diabetes, amyloidosis
  • features: heavy proteinuria (>3.5gm/day), hypoalbuminemia, severe generalized edema, hyperlipidemia, lipiduria, hypogammaglobulinemia
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7
Q

Asymptomatic Hematuria/Proteinuria

A

manifestation of subtle or mild glomerular abnormalities.

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8
Q

Acute Renal Failure

A

features: oliguria or anuria, recent onset azotemia from glomerular, interstitial, or vascular injury or acute tubular injury. frequently reversible.

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9
Q

Chronic Renal Failure

A

prolonged signs and symptoms of uremia. is end result of all chronic renal parenchymal diseases.

major cause of death from renal disease.

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10
Q

Renal Tubular Defects

A

features: polyuria, nocturia, electrolyte disorders (metabolic acidosis).

from direct effect on tubular structure or from defects in tubular functions (can be inherited or acquired).

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11
Q

UTI

A

features: bacteriuria and pyuria.

symptomatic or asymptomatic.

may affect kidney or bladder

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12
Q

Nephrolithiasis

A

aka renal stones

features: severe spasms of pain (renal colic) and hematuria.

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13
Q

Urinary Tract Obstruction

A

includes renal tumors.

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14
Q

4 Stages of Chronic Renal Failure

A
  1. diminished renal reserve: GFR = 50%, serum BUN and creatinine are normal, patients asymptomatic but susceptible to azotemia.
  2. renal insufficiency: GFR = 20-50%, azotemia with anemia and HTN, polyuria, nocturia. sudden stress can ⇒ uremia.
  3. chronic renal failure: GFR < 20-25%, edema, metabolic acidosis, hyperkalemia. cannot regulate volume and solute composition. overt uremia with neurologic, GI, and cardiovascular complications.
  4. end-stage renal disease: GFR < 5%. terminal stage of uremia.
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15
Q

Systemic Diseases Associated with Glomerular Disease

A

diabetes mellitus, SLE, vasculitis, amyloidosis, Goodpasture syndrome, microscopic polyarteritis/polyangiitis, Wegener granulomatosis, Henoch-Schonlein purpura, bacterial endocarditis

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16
Q

Glomerulus Anatomy

A

capillaries

endothelium: thin, fenestrated.

glomerular basement membrane: thick electron-dense central layer (lamina densa), thinner electron-lucent peripheral layers (lamina rara externa and interna). made of type IV collagen, laminin, proteoglycans (heparan sulfate), fibronectin, entactin, glycoproteins.

visceral epithelium: aka podocytes. interdigitating processes adherent to lamina rara externa. foot processes are separated by filtration slits which have a thin diaphragm.

mesangial cells: lies in mesangial matrix. mesenchymal origin. contractile, phagocytic, and can proliferate, lay down matrix and collagen, and secrete mediators.

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17
Q

Normal Glomerular Filtration Barrier Characteristics

A
  • highly permeable to water and small solutes. impermeable to proteins like albumin (70kD) or larger.
  • charge selector: more cationic can pass, anionic do not. determined by proteoglycans of GBM and sialoglycoproteins of epithelial/endothelial cell coats (glycocalyx)
  • slit diaphragm allows for size selection. important proteins in diaphragm: nephrin, podocin, CD2AP.
  • nephrin connects foot processes by attaching to podocin, CD2AP, and the actin cytoskeleton.
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18
Q

Albumin

A
  • has PI of 4.5.
  • completely excluded from filtrate by size-charge barrier
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19
Q

Nephrin

A
  • part of the slit diaphragm.
  • connects foot processes by attaching to podocin, CD2AP, and the actin cytoskeleton.
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20
Q

Podocin

A
  • part of the foot process of podocytes.
  • via nephrin, helps link foot processes at slit diaphragm.
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21
Q

CD4AP

A
  • part of the foot process of podocytes.
  • via nephrin, helps link foot processes at slit diaphragm.
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22
Q

Hypercellularity

A
  • in inflammatory diseases of kidney.
  • characterized by: cellular proliferation of mesangial or endothelial cells, leukocytic inflitration (neutrophils, monocytes, lymphocytes), and/or formation of crescents
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23
Q

Crescents

A
  • accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes.
  • fibrin may elicit the crescentic response. find it in glomerular tufts and urinary spaces.
  • others that elicit crescentic formation: tissue factor, IL-1, TNF, IFN-gamma
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24
Q

Basement Membrane Thickening

A
  • on PAS stain: see thickening of capillary walls
  • EM: has two forms:
    1. immune complex deposits on endothelial or epithelial side of GBM or within the GBM. fibrin, amyloid, cryoglobulins, and fibrillary proteins can deposit in GBM.
    1. increased synthesis of protein components (see in diabetic glomerulosclerosis).
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25
Q

Hyalinosis

A
  • accumulation of material that is homogenous and eosinophilic by light microscopy.
  • EM: hyalin is extracellular and amorphous.
  • made of plasma proteins insudated from circulation
  • extensive ⇒ obliteration of capillary lumens of glomerular tuft.
  • consequence of endothelial or capillary wall injury, end result of glomerular damage.
  • found in focal segmental glomerulosclerosis
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26
Q

Sclerosis

A
  • accumulations of extracelular collagenous matrix, confined to mesangial areas (diabetic glomerulosclerosis) or involving capillary loops.
  • can ⇒ obliteration of capillary lumens ⇒ form fibrous adhesions between sclerotic portions and parietal epithelium and Bowman capsules.
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27
Q

Primary Glomerulopathy Categories

A
  • diffuse = involving all glomeruli
  • global = involving entire glomerulus
  • focal = involves only a portion of the glomeruli
  • segmental = affects part of each glomerulus
  • capillary loop or mesangial = affects predominantly the capillary or mesangial regions.
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28
Q

Antibody-associated Injury

A
    1. antibodies reacting in situ within glomerulus, binding to insoluble fixed glomerular antigens or to molecules planted within glomerulus.
    1. deposition of circulating antigen-antibody complexes in glomerulus.
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29
Q

Heymann Nephritis

A
  • on EM: presence of numerous discrete electron-dense deposits along subepithelial aspect of GBM.
  • IF: granular lumpy deposition.
  • results from rxn of antibody with antigen comlex on basal surface of visceral epithelial cells and cross-reacting with brush border antigen. then complement activation and shedding of aggregates to form subepithelial deposits.
  • antigen = megalin = lipoprotein receptor (in rats)
  • anti-GBM antibody induced disease = autoimmune.
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30
Q

Antibodies against Planted Antigens

A
  • Ab react in situ with antigens that are not normally present in glomerulus but planted there.
  • planted antigens: cationic molecules binding to anionic components of glomerulus; DNA, nucleosomes, nuclear proteins (affinity for GBM); bacterial products; immunoglobulins; immune complexes
  • induce Ig deposition
  • IF: granular deposition
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31
Q

Anti-GBM Antibody-induced Glomerulonephritis

A
  • Ab directed against intrinsic fixed antigens that are normal components of GBM proper.
  • IF: diffuse linear pattern
  • cross-reactivity in the lungs ⇒ simultaneous lung and kidney lesions = Goodpasture syndrome
  • GBM antigen = component of noncollagenous domain of the alpha3 chain of collagen type IV (for GBM suprastructure). also the antigen in Goodpasture syndrome.
  • features: severe crescentic glomerular damage and rapidly progressive glomerulonephritis.
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32
Q

Circulating Immune Complex Glomerulonephritis

A
  • caused by trapping of circulating Ag-Ab complexes within glomeruli.
  • localize not from affinity but from the physicochemical properties and hemodynamic factors of the glomerulus.
  • antigens can be endogenous or exogenous
  • microbial antigens: Hep B, Hep C, T. pallidum, Plasmodium falciparum.
  • glomerular lesions have leukocytic infiltrate and proliferation of mesangial and endothelial cells
  • EM: immune complexes in mesangium = subendothelial deposits, or subepithelial deposits = outer surface of GBM and podocytes.
  • IF: granular deposits
  • highly cationic antigen ⇒ subepithelial deposit;
  • highly anionic antigen ⇒ subendothelial deposit.
  • neutral ⇒ mesangial deposits
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33
Q

Antibodies to Glomerular Cells

A
  • Ab to mesangial cell ⇒ mesangiolysis then mesangial cell proliferation.
  • Ab to endothelial cell ⇒ endothelial injury and intravascular thrombosis
  • Ab to visceral epithelial cell ⇒ proteinuria.
  • IF: granular deposits along GBM or in mesangium.
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34
Q

Role of Cell Mediated Immunity in Glomerulonephritis

A
  • sensitized T cells may injure glomerulus.
  • clues: activated macrophages and T cells, injury by transpanting T cells.
  • T lymphocytes propogate the inflammation.
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35
Q

Membranoproliferative Glomerulonephritis

A
  • aka MPGN type II or dense deposit disease.
  • through activation of alternative complement pathway
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36
Q

Cell causing Glomerular Injury

A
  • neutrophils/monocytes: from activating complement and from Fc-mediated adherence/activation. release proteases ⇒ GBM degradation; O2 free radicals; arachidonic acid metabolites.
  • macrophages/T lymphocytes/NK cells: in Ab and cell mediated rxn.
  • platelets: in immune-mediated injury. release eicosanoids and growth factors.
  • resident glomerular cells: mesangial cells. make: ROS, cytokines, chemokines, growth factors, eicosanoids, NO, and endothelin.
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37
Q

Soluble Mediators of Glomerular Injury

A
  • chemotactic complement components: cause leukocyte influx ⇒membrane attack complex ⇒ stimulate mesangial cells to make oxidants, proteases, etc. without neutrophils ⇒ proteinuria.
  • eicosanoids/NO/angiotensin/endothelin: cause hemodynamic changes.
  • cytokines: IL-1 and TNF ⇒ leukocyte adhesion, etc.
  • chemokines: monocyte chemoattractant protein 1 and CCL5 promote monocyte and lymphocyte influx.
    • PDGF in mesangial cell proliferation.
    • TGF-beta, CTGF, and FBGF important for ECM deposition and hyalinization ⇒ glomerulosclerosis.
    • VEGF maintains endothelial integrity, helps regulate capillary permeability.
  • coagulation system: fibrin stimulates parietal epitheial cell proliferation (crescent formation). mediated by macrophage procoagulant activity.
    • **Plasminogen activator inhibitor-1 **⇒ ↑ thrombosis and fibrosis, inhibits degradation of fibrin and matrix proteins.
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38
Q

Tubulointerstitial Fibrosis

A
  • tubular damage and interstitial inflammation.
  • from ischemia downstream of sclerotic glomeruli, acute/chronic inflammation, loss of peritubular capillary blood supply.
  • proteinuria ⇒ direct injury to and activation of tubular cells from iron, Ig, complement products, cytokines, lipid moieties, oxidated plasma proteins.
  • active tubular cells ⇒ cytokines, chemokines, growth factors ⇒ interstitial fibrosis
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39
Q

Acute Proliferative Glomerulonephritis

A
  • includes Poststreptococcal and Postinfectious glomerulonephritis.
  • diffuse proliferation of glomerular cells, influx of leukocytes.
  • caused by immune complexes
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40
Q

Poststreptococcal Glomerulonephritis

A
  • appears 1-4 weeks after beta hemolytic strep infection of pharynx or skin. identify by M protein.
  • usually kids 6-10 yrs.
  • low serum complement levels (used up), elevated titers of antibodies against strep.
  • IF: granular deposits IgG, IgM, and C3 in mesangium and along GBM. focal and sparse.
  • EM: discrete, amorphous, electron-dense deposits on epithelial side of GBM, look like humps. Subendothelial and intramembranous deposits common.
  • antigens: NAPlr, strep pyogenic exotoxin (SpeB), zSpeB.
  • morphology: enlarged hypercellular glomeruli from infiltration by leukocytes, proliferation of mesangial and endothelial cells, crescent formation in severe cases. involves all glomeruli. swelling of endothelial cells. interstitial edema, inflammation, red cell casts.
  • prognosis: most kids recover. 1% ⇒ rapidly progressive glomerulonephritis. some ⇒ chronic glomerlonephritis. 60% adults recover, the rest have persistent proteinuria, hematuria, and HTN which may ⇒ chronic glomerulonephritis or rapidly progressive glomerulonephritis.
  • bad prognosis: prolonged and persistent heavy proteinuria and abnormal GFR.
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41
Q

Clinical Case:

Young child presents with: malaise, fever, nausea, oliguria, and hematuria. Had sore throat 1-2 weeks ago. Red cell casts in urine, mild proteinuria, periorbital edema, mild-mod HTN.

What does this child have?

A

Poststreptococcal Glomerulonephritis

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42
Q

Clinical Case:

Adult presents with sudden appearance of HTN or edema with an elevated BUN. He is found to have a decreased serum concentration of C3 complement and other complement factors and upon microscopic examination of his urine he has hematuria.

What does this patient have?

A

Poststreptococcal Glomerulonephritis

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43
Q

Rapidly Progressive (Crescentic) Glomerulonephritis

A
  • rapid and progressive loss of renal function with severe oliguria and nephritic syndrome.
  • most commonly has crescents in most glomeruli.
  • group 1: anti-GBM antibody induced disease.
    • IF: linear deposits of IgG and C3 in GBM.
    • Goodpasture’s Syndrome if also cross-react with pulmonary alveolar basement membrane.
    • tx: plasmapheresis
  • group 2: immune complex deposition. like from IgA nephropathy, lupus nephritis, postinfectious GN, Henoch-Schonlein purpura.
    • IF: granular pattern
    • cellular proliferation within glomerulus tuft and crescent formation.
    • tx: treat underlying disease.
  • group 3: pauci-immune type. lack of anti-GBM or immune complexes. have circulating antineutrophil cytoplasmic antibodies (ANCAs) ⇒ cytoplasmic or perinuclear staining patterns.
    • play a role in vasculitides. ex: Wegener granulomatosis or microscopic polyangiitis
  • morphology: kidneys enlarged and pale, petechial hemorrhages.
    • can have focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation.
    • have crescents = proliferating parietal cells with monocytes and macrophages in urinary space. eventually obliterate Bowman space and compress glomerular tuft. later undergo sclerosis but can go away with early aggressive treatment.
    • prominent fibrin strands between layers in crescents.
    • EM can show rupture in GBM ⇒ leukocytes, proteins, and inflammatory mediators into urinary space for crescent formation.
  • features: hematuria, RBC casts in urine, mod proteinuria, variable HTN and edema.
  • tx: steroids and cytotoxic agents. may require chronic dialysis or transplantation
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44
Q

Goodpasture Syndrome

A
  • rapidly progressive glomerulonephritis with anti-GBM antibody and C3 deposits that affect both the kidney and lungs ⇒ pulmonary hemorrhage with renal failure.
  • antigen = peptide in noncollagenous portion of the alpha3 chain of type IV collagen
  • features: recurrent hemoptysis or life-threatening pulmonary hemorrhage.
  • tx: plasmapheresis and steroids.
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45
Q

Clinical Case:

A 40 y/o man presents to the ER for bloody urine and puffy legs. Upon examination he is found to have 2+ edema to his knees and a BP of 145/85. His U/A showed 2+ proteinuria and RBC casts. On H&E stain, crescents are visible from the biopsy sample.

What does he have? What further tests need to be run to confirm the diagnosis?

A
  • Rapidly Progressive GN.
  • to differentiate we need to run anti-GBM antibody tests, ANCA tests, and antinuclear antibodies (immune complexes as well).
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46
Q

Clinical Case:

A 24 y/o male presents to the ER with shortness of breath and coughing up blood for the past few days. On U/A he is found to have 1+proteinuria, hematuria, and rare RBC casts. Kidney biopsy was done and he was found to have crescents in 65% of his kidneys.

What is his diagnosis?

A

Goodpasture Syndrome that is rapidly progressive.

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47
Q

Membranous Nephropathy

A
  • in adults. has diffuse thickening of glomerular capillary wall from accumulation of electron-dense, Ig deposits along subepithelial GBM.
  • 2° membranous glomerulopathy when in association to other systemic diseases: SLE, infections (Hep B/C, syphilis, schistosomiasis, malaria), autoimmune disorders, malignant tumors, drugs (penicillamine, captopril, gold, NSAIDs).
  • 85% is idiopathic.
  • paucity of neutrophils, monocytes, platelets in glomeruli. MAC (C5b-C9) activates glomerular epithelial and mesangial cells ⇒ proteases and oxidants ⇒ capillary wall injury and ↑ protein leakage.
  • morphology: light microscopy = normal or diffuse thickening of glomerular capillary wall.
    • EM: thickening from irregular dense deposits of immune complexes between GBM and epithelial cells with effaced foot processes. irregular spikes of matrix protein from GBM on silver stain. thicken to domelike protrusions and close over deposits.
    • IF: granular deposits containing Ig and complement
    • sclerosis can occur, proximal tubules have protein reabsorption droplets, may be considerable interstitial mononuclear cell inflammation.
  • features: insidious onset nephrotic syndrome. hematuria and mild HTN, proteinuria not fixed by steroids, ↑ sclerosis, ↑ serum creatinine.
  • prognosis: sclerosis = bad, non-nephrotic proteinuria = good, women = good.
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48
Q

Clinical Case:

35 y/o female presents to the ER with hematuria with no past medical history. On examination she is found to have a BP of 155/90, hypercholesterolemia, hyperlipidemia, and 3+ proteinuria (>3.5mg/day). EM shows domelike protrusions and spikes as well as a thickened glomerular capillary wall.

What is the diagnosis?

A

Membranous glomerulopathy.

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49
Q

Minimal Change Disease

A
  • most frequent cause of nephrotic syndrome in children (peak btw 2-6).
  • diffuse effacement of foot processes of visceral epithelial cells in glomeruli on light microscopy.
  • absence of immune deposits.
  • associations: mostly visceral epithelial cell injury
    • sometimes follows respiratory infection or immunization.
    • has a dramatic response to corticosteroid therapy.
    • associated with atopic disorders (rhinitis, eczema)
    • ↑ certain HLA haplotypes
    • ↑ incidence of Hodgkin’s lymphoma (defects in T-cell mediated immunity)
    • proteinuria-inducing factors in plasma or lymphocyte supernatants
  • morphology: normal on light microscopy and EM.
    • visceral epithelial cells show uniform and diffuse effacement of foot processes
    • rim of cytoplasm showing vacuolization, swelling, and hyperplasia of villi = fusion of foot processes
    • cells of proximal tubules laden with lipid and protein = lipoid nephrosis
  • features: massive proteinuria but good renal function. protein is mostly albumin.
  • tx: corticosteroids
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50
Q

Clinical Case:

A 6 y/o girl presents today for a routine physical and upon U/A was found to have high levels of urine protein, predominantly albumin. Kidney function appears normal on analysis. Biopsy shows normal glomerular anatomy with lipid deposits in some tubular cells.

What does this child have?

A

Minimal Change Disease

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51
Q

Focal Segmental Glomerulosclerosis (FSGS)

A
  • sclerosis of some glomeruli (focal) and in the glomeruli only part of the capillary tuft is involved.
  • types: primary disease
    • associated with HIV, heroin addiction, sickle-cell disease, massive obesity
    • secondary event, scarring of previously active necrotizing lesions
    • adaptive to loss of renal tissue from reflux nephropathy, HTN nephropathy, unilateral renal agenesis.
    • inherited forms: like with slit diaphragm proteins.
  • initiated by adaptive change in unaffected glomeruli: compensatory hypertrophy.
  • hemodynamic changes = ↑ glomerular blood flow, filtration, and transcapillary pressure (glomerular HTN), systemic HTN.
  • podocytes can’t proliferate ⇒ can’t maintain filtration barrier ⇒ abnormal protein filtration and loss of support of GBM ⇒ segmental loop dilation and fibrous attachment to Bowman capsule and sclerosis.
  • sequence: endothelial/epithelial cell injury, ↑ glomerular permeability to proteins, accumulation of proteins in mesangial matrix, proliferation of mesangial cells, infiltration by macrophages, ↑ accumulation of ECM, segmental and global sclerosis of glomeruli, ↓ nephron mass, activate compensatory mechanisms.
  • proteinuria and sclerosis ⇒ uremia and sclerosis.
  • tx: renin-angiotensin inhibitors
  • idiopathic FSGS: 10% nephrotic cases in kids, 35% in adults. ↑ incidence in Hispanics and African Americans.
    • ↑ incidence hematuria, ↓ GFR, HTN, non-selective proteinuria, poor response to steroids, progression to chronic kidney disease.
    • hallmark is epithelial damage from cytokines, genetic defects of slit diaphragm.
    • hyalinosis and sclerosis from entrapment of plasma proteins in hyperpermeable foci and ↑ ECM deposition.
  • morphology: initially involve juxtamedullary glomeruli. sclerotic areas have collapsed capillary loops, ↑ matrix, segmental deposition of plasma proteins along capillary wall (hyalinosis).
    • lipid droplets and foam cells.
    • light microscopy: ↑ matrix.
    • EM: diffuse effacement of foot processes, denudation of underlying GBM.
    • IF: IgM and C3 in sclerotic areas or mesangium
    • profuse hyalinosis and thickening of afferent arterioles.
    • leads to profuse sclerosis, tubular atrophy, and interstitial fibrosis.
    • collapsing glomerulopathy - variant of FSGS with retraction or collapse of entire glomerular tuft. has proliferation and hypertrophy of glomerular visceral epithelial cells.
      • characteristic of HIV nephropathy.
      • prominent tubular injury with cyst formation.
  • genetic basis: NPHS1 (nephrin); NPHS2 (podocin) ⇒ kid onset steroid resistant nephrotic syndrome aut recessive. alpha actinin 4 mutation is aut dominant. TRPC6 mutation affects podocytes.
  • renal ablation FSGS = complication of glomerular diseases (reflux nephropathy, unilateral agenesis). may ⇒ progressive glomerulosclerosis and renal failure.
  • features: kids better prognosis. 20% pts have rapid course with intractable proteinuria and failure in 2 yr.
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52
Q

Clinical Case:

A 45 y/o Hispanic male presents to his primary care physician with a complaint of bloody urine. Physical exam reveals a blood pressure of 145/88. U/A reveals gross hematuria, and severe proteinuria. He was previously seen for the same reason and has not responded to corticosteroid therapy. A biopsy was performed which revealed sclerosis with IgM and C3 deposits. Light microscopy shows sporadic involvement of glomeruli that are only partially affected.

What does this patient have?

A

FSGS.

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53
Q

HIV-associated Nephropathy

A
  • occurs with: acute renal failure, acute interstitial nephritis from drugs/infection, thrombotic microangiopathies, postinfectious glomerulonephritis, collapsing variant of FSGS (most common).
    • more frequent in African Americans.
  • EM: large numbers of tuberloreticular inclusions within endothelial cells caused by IFN-alpha.
  • caused by HIV products: vpr and nef.
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54
Q

1° Membranoproliferative Glomerulonephritis

A
  • alterations in GBM, proliferation of glomerular cells, and leukocyte infiltration.
  • aka mesangiocapillary glomerulonephritis.
  • 1° MPGN: type I and type II.
    • type I MPGN: evidence of immune complexes in glomerulus, activation of both classic and alternative complement pathways.
      • antigens unknown. associated with Hep C and B.
    • type II MPGN: aka dense-deposit disease. rare. abnormalities suggest activation of alternative complement pathway. ↓ serum C3, normal C1 and C4. ↓ factor B and properdin.
      • C3 and properdin deposited in glomeruli.
      • 70% have C3 nephritic factor (C3NeF) - circulating antibody that binds to alternate pathway C3 convertase ⇒ ↑ C3 activation and hypocomplementemia. ↓ synthesis C3 from liver
  • morphology: light microscopy: large, hypercellular glomeruli from proliferation of mesangial cells and capillary endothelial cells and infiltrating leukocytes. may have crescents. lobular appearance from proliferating mesangial cells and ↑ mesangial matrix. GBM thickened, glomerular capillary wall looks ‘double-contour’ or ‘tram-track’ on silver or PAS stain.
    • type I: presence of subendothelial electron-dense deposits.
      • IF: granular pattern. C3 deposits, some IgG and early complement (C1q and C4).
    • type II: lamina densa is irregular, ribbon-like, extremely electron-dense with dense deposits in GBM.
      • IF: C3 deposits irregular granular or linear foci in GBM but not in dense deposits. also in mesangium = mesangial rings. IgG absent as well as C1q and C4.
  • presentation: kid or young adult with nephrotic syndrome, hematuria, mild proteinuria, mixed nephrotic-nephritic component. slowly progressive. some get crescents and look like RPGN. 50% ⇒ chronic renal failure. high recurrence in transplant kidneys.
  • tx: steroids, immunosuppressive agents, antiplatelet drugs (none effective)
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55
Q

2° MPGN

A
  • more common in adults.
  • found with: chronic immune comlex disorders (SLE, Hep B, Hep C, endocarditis, chronic visceral abscesses, HIV, schistosomiasis); alpha1 antitrypsin deficiency; malignant diseases; hereditary deficiencies of complement regulatory proteins.
  • presentation: nephrotic syndrome.
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56
Q

IgA Nephropathy

A
  • aka Berger Disease
  • prominent IgA deposits in mesangial regions on IF.
  • frequent cause of recurrent gross or microscopic hematuria, most common type of glomerulonephritis****
  • 2° IgA nephropathy in pts with liver and intestinal diseases.
  • ↑ plasma polymeric IgA, circulating IgA immune complexes. IgA1 ⇒ nephritogenic deposits in mesangium. uses alternative pathway (C3 with no C1q or C4).
  • genetic influence.
  • ⇒ ↑ IgA synthesis ⇒ trapped in mesangium ⇒ activate alternative complement pathway ⇒ glomerular injury
  • more common with gluten enteropathy (Celiac disease) and liver disease
  • morphology: can look normal, have mesangial widening and endocapillary proliferation, or rarely have crescents. may have leukocytes.
    • healing ⇒ 2° focal segmental sclerosis.
    • IF: mesangial depositition of IgA, some C3 and properdin, less IgG and IgM.
    • EM: presence of electron-dense deposits in mesangium.
  • presentation: older children and young adults, gross hematuria after respiratory, GI, or urinary tract infection, microscopic hematuria with or without proteinuria, few have acute nephritic syndrome. hematuria lasts a few days and returns every few months.
    • slow progression to chronic renal failure over 20yrs.
    • ↑ risk of progression: old age, heavy proteinuria, HTN, ↑ glomerulosclerosis.
    • recurs in transplants.
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57
Q

Clinical Case: A 20 year old male presents to the ER with a complaint of blood in his urine. Blood analysis shows 4+ proteins, hyperlipidemia, ↓ C3, ↓ factor B, and normal levels of C1 and C4. He is C3NeF positive. On light microscopy of a renal biopsy crescents are visible, and there is a tram-track appearance on silver stain. IF shows irregular ribbon-like deposits in the GBM.

What does this patient have?

A

Type II MPGN

58
Q

Clinical Case: An 18 y/o female presents to the ER with a lot of blood in her urine. She was seen here last week for a UTI. She complains that this has been occuring on and off for the past year with the hematuria lasting a few days each time. IF showed mesangial deposition of IgA. Mesangial widening was also noted.

What does she have?

A

IgA Nephropathy

59
Q

Alport Syndrome

A
  • a hereditary nephritis. X-linked.
  • females typically limited to hematuria.
  • due to abnormal alpha3 (COL4A3), alpha4 (COL4A4), or alpha5 (COL4A5) of type IV collagen.
    • COL4A5 is the X-linked. COL4A3 and COL4A4 are autosomal recessive.
    • defective assembly type IV collagen, defective assembly of collagen network
  • morphology: early lesion EM: diffuse GBM thinning, interstitial foam cells filled with neutral fats and mucopolysaccharides.
    • later see focal segmental and global glomerulosclerosis, vascular sclerosis, tubular atrophy, interstitial fibrosis.
    • EM late: irregular foci of thickening alternates with thinning and splitting of lamina densa ⇒ basket-weave appearance.
    • antibodies to alpha3, alpha4, alpha5 don’t stain both glomerular and tubular basement membranes. alpha5 staining absent in skin biopsy specimens.
  • presentation: onset age 5-20 year, gross hematuria with progression to chronic renal failure, red cell casts, nerve deafness, eye disorders (lens dislocation, posterior cataracts, and corneal dystrophy).
60
Q

Clinical Case: A 10 year old male presents to his local PCP with substantial hematuria. U/A reveiled proteinuria with red blood cell casts. His history is significant for deafness and vision problems. Renal biopsy revealed a pattern of thickening and thinning of the GBM consistent with ‘basket-weave’ appearance. A skin biopsy revealed a lack of alpha5 staining.

What does this child have?

A

Alport Syndrome

61
Q

Thin Basement Membrane Lesion (Benign Familial Hematuria)

A
  • manifested clinically as familial asymptomatic hematuria.
  • mutation in alpha3 or alpha 4 of type IV collagen. autosomal recessive.
  • homogenous pts may appear like Alport syndrome and may progress to renal failure.
  • found on routine U/A
  • morphology: diffuse thinning of GBM to 150-250nm.
  • renal function normal but may have mild to mod proteinuria. good prognosis.
  • needs to be distinguished from IgA nephropathy and Alport syndrome.
62
Q

Chronic Glomerulonephritis

A
  • can come from IgA nephropathy, membranous nephropathy, MPGN, FSGS, crescentic GN, poststreptococcal GN, or unknown.
  • morphology: cortex is thinned, granular cortical surfaces, ↑ peripelvic fat.
    • obliteration of glomeruliacellular eosinophilic masses.
    • accompanied by HTN, arterial and arteriolar sclerosis, atrophy of associated tubules, irregular interstitial fibrosis, mononuclear leukocytic infiltration.
    • dialysis ⇒ arterial intimal thickening, extensive deposition of calcium oxalate crystals, acquired cystic disease
    • uremic changes: pericarditis, secondary hyperparthyroidism, LV hypertrophy, uremic pneumonitis, uremic gastroenteritis.
  • presentation: develops insidiously then slowly goes to renal insufficiency or death from uremia. have nonspecific complaints like loss of appetite, anemia, vomiting, or weakness.
    • most pts HTN, have cerebral or cardiovascular manifestations.
    • relentlessly progressive.
      • nephrotic pts: glomeruli obliterated ⇒ ↓ GFR, protein loss in urine ↓.
    • if don’t get dialysis or transplant, will die.
63
Q

Clinical Case:

A 65 y/o male presents to his PCP with a complaint of feeling weak and vomiting. He has a history of FSGS and HTN. Biopsy of his kidneys shows cortical thinning and obliteration of the glomeruli as well as arterial sclerosis.

What does he have?

A

Chronic Glomerulonephritis

64
Q

Lupus Nephritis

A
  • presentation: recurrent microscopic or gross hematuria, nephritic syndrome, nephrotic syndrome, chronic renal failure, and HTN.
65
Q

Clinical Case:

A 26 y/o female presents to her PCP with a complaint of periodic hematuria. She is found on U/A to have hypercholesterolemia, heavy proteinuria. On U/A she si found to have fatty casts. She is ANA positive.

What does she have?

A

Lupus nephritis

66
Q

Henoch-Schönlein Purpura

A
  • presentation: purpuric skin lesions on extensor surfaces of arms and legs and buttocks, abdominal pain, vomiting, intestinal bleeding, nonmigratory arthralgia, renal abnormalities.
    • renal problems = gross or microscopic hematuria, nephritic syndrome, nephrotic syndrome or a combo.
    • adults may get rapidly progressive GN with crescents.
    • mostly kids 3-8 yrs but may be in adults (renal more severe)
    • strong background of atopy in 1/3 pts, onset follows upper resp infection
  • IgA deposited in glomerular mesangium similar to IgA nephropathy
  • morphology: vary from mild focal mesangial proliferation to diffuse mesangial proliferation or endocapillary to crescentic GN.
    • IF: deposition of IgA, some IgG and C3 in mesangial region.
    • lesions: subepidermal hemorrhages and necrotizing vsculitis of small vessels in dermis.
    • vasculitis can be in other organs such as GI or rarely kidney.
  • prognosis: excellent in kids, worse if have diffuse lesions, crescents or nephrotic syndrome.
67
Q

Clinical Case:

A 5 year old girl presents to her pediatrician with purplish lesions on her buttocks and the front of her arms. Her mother reports that she has reddish urine on and off for the past 2 months. She is allergic to pollen and cat dander. Biopsy of her kidney reveals IgA deposits in the mesangium on IF.

What does this girl have?

A

Henoch-Schönlein Purpura

68
Q

Bacterial Endocarditis-Associated Glomerulonephritis

A
  • an immune complex nephritis initiated by complexes of bacterial antigen and antibody. occurs with bacterial endocarditis.
  • presentation: hematuria and proteinuria. can have acute nephritic presentation or RPGN.
  • IF: glomerular immune deposits.
69
Q

Clinical Case:

A 32 year old male was found to have a systolic ejection murmur following a serious skin infection one month earlier. He was placed on antibiotics but showed up to the ER with complaints of blood in his urine after 1 day. U/A revealed proteinuria and biopsy of the kidneys revealed immune complexes.

What does this patient have?

A

Bacterial Endocarditis-Associated GN

70
Q

Diabetic Nephropathy

A
  • a leading cause of chronic renal failure.
  • most common lesions of glomeruli: non-nephrotic proteinuria, nephrotic syndrome, chronic renal failure.
  • causes hyalinizing arteriolar sclerosis, papillary necrosis, and tubular lesions.
  • morphology: capillary basement membrane thickening, diffuse mesangial sclerosis, nodular glomerulosclerosis. appear same in type I and type II diabetes.
  • caused by metabolic defect = insulin deficiency, hyperglycermia, or glucose intolerance. ⇒ ↑ type IV collagen and fibronectin and ↓ heparan sulfate proteoglycan
  • nonenzymatic glycosylation of proteins causes glomerulopathy
  • end stage characterized by ↑ GFR, ↑ glomerullar capillary pressure, glomerular hypertrophy, ↑ glomerular filtration area.
  • two processes: metabolic defect ⇒ thickened GBM and ↑ mesangial matrix; hemodynamic effects help develop glomerulosclerosis. both ⇒ loss of podocytes.
71
Q

Clinical Case:

A 65 year old female presents to the ER with hematuria and mild proteinuria. She was diagnosed with type II diabetes ten years ago. Renal biopsy shows thickening of the GBM, mesangial sclerosis, and nodular glomerulosclerosis.

What does this woman have?

A

Diabetic Nephropathy

72
Q

Amyloidosis

A
  • deposition of light-chain AA in the glomeruli.
  • stains on Congo red in mesangium and capillary walls. can be in interstitium and blood vessel walls
  • obliterates glomerulus.
  • presentation: nephrotic syndrome, die of uremia. kidney size normal or increased.
73
Q

Clinical Case:

A 50 year old male presents to the ER with hematuria and proteinuria. A biopsy of his kidney on Congo red stain revealed deposits in the glomeruli.

What does this patient have?

A

Amyloidosis

74
Q

Fibrillary Glomerulonephritis

A
  • fibrillar deposits in mesangium and glomerular capillary walls. resemble amyloid but don’t stain on Congo, also are larger in diameter than amyloid fibrils.
  • light microscopy: shows membranoproliferative or mesangioproliferative patterns
  • IF: selective deposition of polyclonal IgG of IgG4 subclass, complement C3, and Igkappa and Iggamma light chains.
  • presentation: nephrotic syndrome, hematuria, progressive renal insufficiency.
    • recurs in kidney transplants.
75
Q

Clinical Case:

A 60 year old female presents to her PCP with a complaint of bloody urine. U/A shows massive proteinuria and hematuria. Blood analysis shows hypercholesterolemia and hyperlipidemia. Biopsy shows fibrils in the mesangium that do not stain Congo red and reveals deposits of IgG, complement C3, and light chain Iggamma.

What does this patient have?

A

Fibrillary Glomerulonephritis

76
Q

Immunotactoid Glomerulopathy

A
  • microtubular deposits, 30-50 nm in width. have circulating paraproteins or monoclonal Ig deposition in glomeruli.
77
Q

Clinical Case:

A 72 year old male presents to her PCP with complaints of bloody urine. U/A shows hematuria and proteinuria. Biopsy of the kidney reveals Ig deposition in the glomeruli that are microtubular in shape.

What does this man have?

A

Immunotactoid Glomerulopathy

78
Q

Essential Mixed Cryoglobulinemia

A
  • deposits of cryoglobulins made of IgG-IgM complexes induce cutaneous vasculitis,, synovitis, and proliferative GN (mostly MPGN type I).
  • associated with hep C
79
Q

Plasma Cell Dyscrasias

A
  • can induce glomerular lesions
80
Q

Multiple Myelomas

A
  • produce circulating monoclonal Ig associated with amyloidosis, deposition of monoclonal Ig in GBM, distinctive nodular glomerular lesions ⇒ depositionn of nonfibrillar light chains
  • aka monoclonal Ig deposition disease
  • characterized by deposition of Igkappa or Iggamma light chains in glomeruli, PAS-pos mesangial nodules, lobular accentuation, and mild mesangial hypercellularity.
  • presentation: proteinuria or nephrotic syndrome, HTN, progressive azotemia.
81
Q

Clinical Case:

A 58 year old female presents to her PCP with a complaint of bloody urine. Upon U/A proteinuria and hematuria were noticeable as well as lipids in the urine. Her creatinine and BUN were elevated while her GFR was decreased. She has a history of hypertension. Upon biopsy of the kidney, deposits of Igkappa were found in the glomeruli.

What does this patient have?

A

Multiple myeloma

82
Q

Acute Tubular Injury (AKI)/ Acute Tubular Necrosis (ATN)

A
  • characterized by acute diminution of renal function and often has tubular injury. reversible lesion.
  • most common cause of acute renal failure (rapid ↓ renal function and urine flow, <400mL per day) from ischemia, toxic injury to tubules, acute tubulointerstitial nephritis, and urinary obstruction.
  • ischemic AKI - from poor blood flow with hypotension and shock.
  • nephrotoxic AKI - from drugs, contrast, poisons, organic solvents.
  • hemolytic crises ⇒ hemoglobinura; skeletal muscle injuries ⇒ myoglobinuria.
    • ⇒ intratubular hemoglobin or myoglobin casts
  • critical events: tubular injury, disturbed blood flow.
    • tubule cell injury - sensitive to ischemia and toxins.
      • reversible changes = loss of polarity/brush border from redistribution of membrane proteins, ↑ Na delivery to distal tubules ⇒ ↑ tubuloglomerular feedback ⇒ vasoconstriction; injured cells detach ⇒ luminal obstruction, ↑ intratubular pressure, ↓ GFR
      • irreversible changes = necrosis and apoptosis ⇒ tubular back-leak ⇒** ↓ tubular flow.**
    • disturbed blood flow - intrarenal vasoconstriction ⇒ ↓ glomerular blood flow, ↓ oxygen delivery to outer medulla tubular cells
      • vasoconstriction caused by ↓ NO, ↓ PGI2, ↑ Renin-angiotensin, ↑ endothelin
  • re-epithelization depends on growth factors and cytokines from tubular cells or inflammatory cells.
    • TGF-alpha, insulin-like growth factor 1, and hepatocytes growth factor important
  • morphology: focal tubular epithelial necrosis, large skip areas btw necrotic points with rupture of basement membrane and occlusion by casts. mostly in proximal tubule and thick ascending limb in renal medulla.
    • tubular damage = loss of brush borders, simplification of cell structure, cell swelling, vacuolization, sloughing of non-necrotic tubular cells into lumen.
    • eosinophilic hyaline casts and granular casts in distal tubules and collecting ducts. made of Tamm-Horsfall protein and plasma proteins.
    • ischemic AKI - interstitial edema and leukocytes in dilated vasa recta. flattened epithelial cells with hyperchromatic nuclei and mitotic figures.
    • toxic AKI - acute tubular injury mostly proximal convoluted tubules.
      • mercury chloride causes acidophilic inclusions then necrosis, desquamate, and calcify.
      • carbon tetrachoride accumulates neutral lipids in injured cells causes fatty change then necrosis.
      • ethylene glycol causes ballooning and hydropic or vacuolar degeneration of proximal convoluted tubules ⇒ calcium oxalate crystals.
  • presentation: 3 stages.
      1. initiation: 36 hrs long, slight ↓ urine output with ↑ BUN. oliguria from ↓ blood flow and ↓ GFR.
      1. maintenance: urine output btw 40-400 mL/day (oliguria), salt and water overload, ↑ BUN, hyperkalemia, metabolic acidosis, uremia. tx: dialysis.
      1. recovery: ↑ urine volume (up to 3L/day), ↑ urinary loss of water sodium and potassium, hypokalemia, ↑ risk infection.
  • 50% do not have oliguria = nonoliguric AKI usually with nephrotoxins.
83
Q

Clinical Case:

A 72 year old female presents to her PCP with complaints of prolonged bloating and decreased urine production. Blood analysis shows her to be acidotic and hyperkalemic with an ↑ BUN. Biopsy revealed focal areas of necrosis in her thick ascending limb with large areas of normal tubular cells inbetween.

What does she have?

A

AKI/ATN

84
Q

Acute vs Chronic Tubulointerstitial Nephritis

A
  • acute = rapid onset with interstitial edema, leukocyte infiltration (eosinophils and neutrophils) of interstitium and tubules, and focal tubular necrosis.
  • chronic = infiltration with mononuclear leukocytes, interstitial fibrosis, widespread tubular atrophy.
  • presentation of tubular defects: impaired concentration of urine, polyuria or nocturia, salt wasting, diminished ability to excrete acids (metabolic acidosis), isolated defects in tubular reabsorption or secretion.
85
Q

Acute Pyelonephritis

A
  • caused by bacterial infection, associated with UTI. usually gram (-) bacilli: E. coli, Proteus, Klebsiella, Enterobacter. Also Strep faecalis and staph.
    • in immunocompromised can be from viruses: Polyomavius, CMV, adenovirus.
  • from bacteremia or ascending spread (most common)
    • starts in distal urethra and introitus, then moves to bladder, and can be aided by urinary tract obstruction and stasis or urine.
    • incompetence of vesicoureteral reflex allows ascension to kidney, allows reflux into ureter.
      • usually from congenital absence or shortening of intravesical portion of ureter
    • intrarenal reflux = infected bladder urine propelled upward to renal pelvis and into renal parenchyma through open ducts at tips of papillae.
      • common in upper and lower poles of kidney
  • morphology: patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, and tubular necrosis. damage mostly in upper and lower poles.
    • early = limited to interstitium.
    • glomeruli usually okay until late but are affected in fungal varieties.
    • complications:
      • papillary necrosis in diabetics and pts with urinary tract obstruction. distal 2/3 of pyramid is gray-white to yellow necrosis. has coagulative necrosis with preservation of tubule outlines
      • pyonephrosis: with total or almost complete obstruction high in urinary tract. suppurative exudate fills rnal pelvis, calyces, and ureter with pus.
      • perinephric abscess: extnsion of pus through renal capsule into perinephric tissue
    • healing: macrophages, plasma cells, and lymphocytes come in and cause irregular scars = fibrous depressions on cortical surface. have tubular atrophy, interstitial fibrosis, lymphocytic infiltrate in patchy, jigsaw pattern with preserved parenchyma around it = pyelonephritic scar.
      • associated with inflammation, fibrosis, and deformation of underling calyx and perlvis.
  • presentation: predisposing factors = urinary tract obstruction, catheters, vesicoureteral reflux, pregnancy, female, preexisting renal lesions, diabetes mellitus, immunosuppression/deficiency.
    • sudden pain at costovertebral angle with fever and malaise, dysuria, frequency, urgency, pyuria, pus casts (leukocyte casts).
    • usually recovers in a few days with antibiotics. may persist with bacteremia for years.
      • superimposition of papillary necrosis ⇒ acute renal failure.
  • polyomavirus nephropathy: usually in allograft pts. viral infection of tubular epithelial cell nuclei ⇒ nuclear enlargement and intranuclear inclusions made of virions.
86
Q

Clinical Case:

A 30 year old female presents to the ER for fever and tiredness. She also complains that she needs to urinate more frequently than normal and has a hard time making it to the bathroom. She has a medical history that includes DM type I and HTN. U/A shows pus casts and pyuria. Biopsy reveals coagulative necrosis with preserved tubules.

What does she have?

A

Acute Pyelonephritis

87
Q

Chronic Pyelonephritis

A
  • caused by bacterial infection, associated with UTI. usually gram (-) bacilli: E. coli, Proteus, Klebsiella, Enterobacter. Also Strep faecalis and staph.
  • in immunocompromised can be from viruses: Polyomavius, CMV, adenovirus.
  • from bacteremia or ascending spread (most common)
    • starts in distal urethra and introitus, then moves to bladder, and can be aided by urinary tract obstruction and stasis or urine.
    • incompetence of vesicoureteral reflex allows ascension to kidney, allows reflux into ureter.
    • usually from congenital absence or shortening of intravesical portion of ureter
    • intrarenal reflux = infected bladder urine propelled upward to renal pelvis and into renal parenchyma through open ducts at tips of papillae.
      • common in upper and lower poles of kidney
  • chronic tubulointerstitial inflammation and renal scarring associated with pathologic involvement of the calyces and pelvis.
  • ⇒ end-stage kidney disease
  • 2 forms:
      1. Reflux Nephropathy: more common form. in early childhood from UTI on top of congenital vesicoureteral reflux and intrarenal reflux ⇒ uni or bilateral damage (scarring and atrophy) ⇒ chronic renal insufficiency.
      1. Chronic Obstructive Pyelonephritis: recurrent infections on top of diffuse or localized obstructive lesions ⇒ inflammation and scarring ⇒ chronic pyelonephritis.
        * parenchymal atrophy, can be bilateral ⇒ renal insufficiency.
        • unilateral when occurs with calculi and unilateral obstructive anomalies of ureter.
  • morphology: kidneys irregularly scarred, asymmetric (when bilateral).
    • hallmarks: coarse, discrete, corticomedullary scars overlying dilated, blunted, or deformed calyces, flattening of papillae.
    • mostly upper and lower poles.
    • tubules have atrophy as well as hypertrophy or dilation. can have colloid casts.
    • chronic interstitial inflammation and fibrosis in cortex and medulla.
    • can have pus casts.
    • obliterative intimal sclerosis in scarred areas, pts with HTN have hyaline arteriosclerosis.
    • Xanthogranulomatous pyelonephritis: rare form of chronic pyelonephritis with accumulation of foamy macrophages with plasma cells, lymphocytes, polymorphonuclear leukocytes, and giant cells.
      • associated with Proteus infections and obstructions.
      • produce large, yellowish orange nodules that can be confused with renal cell carcinoma.
  • presentation: insidious in onset or present as recurrent acute pyelonephritis with back pain, fever, pyuria, bacteriuria.
    • with reflux may be silent and present with renal insufficiency and HTN or find pyuria/bacteriuria as random finding.
    • reflux discovered when kids have HTN.
    • have polyuria and nocturia.
    • **asymmetrically contracted kidneys with coarse scars, and blunting and deformity of calyceal system. **
    • proteinuria is mild, may develop secondary FSGS. poor prognosis.
88
Q

Clinical Case:

A 8 year old male presents to his PCP for a routine physical and HTN is discovered. He has had issues with bed wetting recently and frequent trips to urinate. U/A shows low levels of proteinuria as well as a few colloid casts and pus casts. Imaging shows asymmetrically scarred kidneys.

What does this child have?

A

Chronic Pyelonephritis

89
Q

Acute Drug-Induced Interstitial Nephritis

A
  • occurs with sulfonamides, synthetic penicillins, synthetic antibiotics (Rifampin), diuretics (thiazides), NSAIDs, and others (allopurinol, cimetidine).
  • begins 15 days after exposure with fever, eosinophilia, rash, and renal abnormalities (hematuria, mild proteinuria, and leukocyturia).
    • 50% have ↑ serum creatinine level or acute renal failure with oliguria. see in elderly.
  • immune response idiosyncratic and not dose-related.
  • tubulitis = infiltration of tubules by lymphocytes. very common.
  • serum IgE levels ↑, IgE plasma cells and basophils in lesions ⇒ involves late phase IgE-mediated hypersensitivity (type I).
  • mononuclear or granulomatous infiltrate and positive for drug haptens = type IV hypersensitivity (T cell).
  • morphology: interstitium has pronounced edema and infiltration by mononuclear cells (lymphocytes and macrophages). Eosinophils and neutrophils in clusters.
    • interstitial non-necrotizing granulomas = have giant cells. with thiazides and methicillin.
    • glomeruli unaffected except with NSAIDs with minimal change disease and nephrotic syndrome.
  • presentation: may have irreversible damage in elderly.
90
Q

Clinical Case:

A 81 year old man presents to his PCP with complaints of frequent urination, rash, and fever. Blood labs show eosinophilia. U/A shows proteinuria. Imaging shows edema and lymphocytes inside the tubules. The patient notices that the rash appears whenever he takes his thiazide diuretic.

what does this man have?

A

Acute Drug-Inducd Interstitial Nephritis

91
Q

Analgesic Nephropathy

A
  • chronic renal disease caused by excessive intake of analgesic mixtures and having chronic tubulointerstitial nephritis and renal papillary necrosis.
    • usually phenacetin, aspirin, caffeine, acetaminophen, and codeine. usually two of them.
  • sequence of events: papillary necrosis, then cortical tubulointerstitial nephritis from impeded urine flow. also water depletion
    • phenacetin’s metabolite = acetaminophen ⇒ depletes cells of glutathione ⇒ oxidative metabolites
    • aspirin ⇒ inhibits vasodilation from prostaglandins ⇒ ischemia for papillae
  • morphology: kidneys normal or slightly small, depressed areas of cortex = cortical atrophy over necrotic papillae.
    • papillae show stages of necrosis, calcification, fragmentation, and sloughing.
    • early = patchy necrosis. late = entire papilla necrotic ⇒ ghosts of tubules and foci of dystrophic calcification.
    • cortical changes = atrophy of tubules, interstitial fibrosis and inflammation. cortical columns of Bertin are spared atrophy.
  • presentation: more common in women (5:1). prevalent in people with recurrent headaches and muscle plain, psychoneurotic patients, and factory workers.
    • early findings = hyposthenuria (can’t concentrate urine) and distal tubular acidosis ⇒ kidney stones.
    • symptoms = headache, anemia, GI symptoms, and HTN. 50% have UTI. can have hematuria or renal colic if ureter obstructed.
    • MRI and CT show papillary necrosis and calcifications.
    • can progress to transitional papillary carcinoma of the renal pelvis.
  • tx: drug withdrawal can cause stabilization or improvement.
92
Q

Clinical Case:

A 46 year old female presents to her PCP with a complaint of prolonged diarrhea and stomach ache and a headache for the past week. She has a history of recurrent headaches and kidney stones. She is currently taking phenacetin and aspirin but it is not reducing her pain level very much. U/A shows a specific gravity of 1.010. CT shows calcification and necrosis in the papillae. Biopsy reveals the papillae are at varying stages of necrosis, calcification, and sloughing.

What does this patient most likely have?

A

Analgesic Nephropathy

93
Q

Nephropathy Associated with NSAIDs

A
  • adverse effects related to ability to inhibit COX-dep PG synthesis. COX-2 is in kidney.
  • related syndrome: acute renal failure from ↓ blood flow; acute hypersensitivity interstitial nephritis; acute interstitial nephritis and minimal change disease; membranous nephropathy.
94
Q

Aristolochic Nephropathy

A
  • chronic tubulointerstitial nephritis from aristolochic acid found in herbal remedies.
  • forms adducts with DNA ⇒ renal failure and interstitial fibrosis associated with paucity of infiltrating leukocytes.
  • increased incidence of carcinoma of kidney and urinary tract.
95
Q

Clinical Case:

A 62 year old female presents to the ER for sudden appearance of blood in her urine. She takes herbal supplements and teas every winter to ward off the flu and any colds. U/A reveals hematuria and moderate proteinuria. Biopsy of her kidney reveals interstitial fibrosis but few leukocytes.

What does she have?

A

Aristolochic Nephropathy

96
Q

Urate Nephropathy

A
  • 3 types:
      1. acute uric acid nephropathy = from precipitation of uric acid crystals in renal tubules, mostly collecting duct ⇒ obstruction of nephrons ⇒ acute renal failure
        * common in those with leukemias and lymphomas with chemo
      1. chronic urate nephropathy = gouty nephropathy = protracted forms of hyperuricemia. deposition of monosodium urate crystals in acidic milieu of distal tubules and collecting ducts and interstitium. may form birefrinent needle-like crystals in tubular lumens or interstitium.
        * ⇒ tophus = made of foreign-body giant cells, mononuclear cells, firbotic rxn.
        * tubular obstruction ⇒ cortical atrophy and scarring.
        * renal arterial and arteriolar thickening from HTN.
        * may have increased exposure to lead from moonshine.
      1. nephrolithiasis = uric acid stones. in 22% of those with gout, 42% of those with secondary hyperuricemia.
97
Q

Clinical Case:

A 38 year old male presents to the ER with pain and swelling in his joints. He says he has gout and has had this many times before. He has also been complaining of weakness and nausea. He was diagnosed with HTN a few years ago. U/A shows microscopic hematuria and proteinuria. Biopsy of the kidneys reveals deposits of monosodium urate crystals in the distal tubules, collecting ducts, and interstitium. On IF there are birefringent needle-like crystals in the interstitium.

What does he have?

A

Chronic Urate Nephropathy

98
Q

Nephrocalcinosis

A
  • associate with hypercalcemia as found in hyperparathyroidism, multiple myeloma, vitamin D intoxication, metastatic cancer, and excess calcium intake (milk-alkali syndrome).
  • is deposition of calcium in kidney’s or calcium stones.
  • can cause chronic tubulointerstitial disease and renal insufficiency.
  • earliest damage done to tubular epithelial cells from mitochondrial distortion.
  • then deposits appear in mitochondria, cytoplasm, basement membrane.
    • can obstruct tubular lumen ⇒ atrophy of nephrons and 2° interstitial fibrosis and inflammation.
    • have alternating areas of scarred and normal parenchyma.
  • earliest functional defect is inability to concentrate urine. can also get tubular acidosis and salt-losing nephritis.
  • slowly progresses to renal insufficiency
99
Q

Acute Phosphate Nephropathy

A
  • excessive accumulation of calcium phosphate crystals in tubules.
    • in patients consuming high doses oral phosphate (for colonoscopy)
    • NOT HYPERCALCEMIC. have excess phosphate load. dehydration can ⇒ precipitation of calcium phosphate ⇒ renal insufficiency a few weeks later.
  • only partially recover renal function.
100
Q

Clinical Case:

A 55 year old male presents to his PCP with a complaint of ongoing nausea and urinating less than normal. He has been feeling this way for the last 2 weeks, since he had his colonoscopy done. Renal biopsy reveals accumulations of calcium phosphate crystals in his tubules.

what does he have?

A

Acute Phosphate Nephropathy

101
Q

LIght-Chain Cast Nephropathy

A
  • aka myeloma kidney.
  • is tubulointerstitial from tumor (hypercalcemia, hyperuricemia, obstruction of ureters) or therapy (irradiation, hyperuricemia, chemo, infections).
  • in multiple myeloma:
    • Bence Jones proteinuria and cast nephropathy. failure = amount Bence Jones protein. combine with Tamm-Horsfall protein in kidney under acidic conditions to form large distinct tubular casts that obstruc tubular lumens and cause inflammation around casts.
    • amyloidosis - AL type
    • light-chain deposition disease: kappa type light chains deposit in GBMs and mesangium in nonfibrillar forms, ⇒ glomerulopathy, or in tubular basement membrane ⇒ tubulointerstitial nephritis.
    • hypercalcemia and hyperuricemia.
  • morphology: pink or blue amorphous masses (Bence Jones tubular casts) distend lumen. surrounding multinucleate giant cells from phagocytes. interstitial tissue has nonspecific inflammation and fibrosis. sometimes get granulomatous rxn.
  • presentation: chronic renal failure develops insidiously (most common).
    • acute renal failure with oliguria.
    • precipitating factors: dehyrdation, hypercalcemia, acute infection, treatment with nephrotoxic antibiotics.
    • Bence Jones proteinuria in 70% multiple myeloma.
    • non-light-chain proteinuria suggests amyloidosis or light-chain deposition disease.
102
Q

Clinicl Case:

A 47 year old female presents to her PCP for routine followup of her multiple myeloma. Her U/A reveals Bence Jones proteinuria.

What does she hae and what would you expect her biopsy to reveal?

A

She has Light-Chain Cast Nephropathy.

Expect her biopsy to show interstitial inflammation and fibrosis, Bence Jones casts with multinucleate giant cells around them.

103
Q

Benign Nephrosclerosis

A
  • renal pathology associated with sclerosis of renal arterioles and small arteries.
  • focal ischemia by vessels with thickened walls and narrowed lumens
  • parenchymal effects: glomerulosclerosis, chronic tubulointerstitial injury ⇒ ↓ functional renal mass.
  • more frequent in blacks, HTN, diabetes mellitus.
  • have medial and intimal thickening and hyaline deposition in arterioles from extravasation of plasma proteins in injured endothelium and ↑ deposition of basement membrane matrix.
  • morphology: kidneys normal or slightly smaller, fine granularity (grain leather) of cortex.
    • hyaline arteriolosclerosis of small arteries and arterioles
    • microscopic subcapsular scars with sclerotic glomeruli and tubular dropout.
    • fibroelastic hyperplasia = interlobular and arcuate arteries have medial hypertrophy, reduplication of elastic lamina, and ↑ myofibroblastic tissue in intima ⇒ narrowed lumen.
    • narrowing ⇒ patchy ischemic atrophy
      • foci of tubular atrophy and interstitial fibrosis
      • collapse of GBM, deposition of collagen in Bowman space, periglomerular fibrosis, and total sclerosis of glomeruli.
  • Presentation: moderate ↓ renal blood flow, normal GFR or slightly reduced. may have mild proteinuria
    • ↑ risk renal failure in: African Americans, HTN, diabetes mellitus
104
Q

Malignant Nephrosclerosis

A
  • associated with malignant or accelerated phase of HTN.
    • often superimposed on preexisting essential benign HTN, 2° forms HTN, or underlying chronic renal disease (GN or reflux nephropathy)
    • frequenct cause of death from uremia in pts with scleroderma.
    • usually young, men, black.
  • pathogenesis: initial insult is vascular damage to kidney (long-standing HTN, arteritis, coagulopathy)
    • ⇒ ↑ permeability of small vessels to fibrinogen and plasma proteins, endothelial injury, focal death of vascular wall cells, platelet deposition ⇒ fibrinoid necrosis of arterioles and small arteries, swelling of vascular intima, intravascular thrombosis.
    • PDGF, plasma, and other cells ⇒ hyperplasia of intimal smooth muscle cells ⇒ hyperplastic arteriolosclerosis.
    • kidney becomes very ischemic ⇒ very ↑ plasma renin levels, ↑ aldosterone levels.
    • all adds up to cuse malignant arteriolosclerosis
  • morphology: small pinpoint petechial hemorrhages on cortical surfaces = ‘flea-bitten’ appearance.
    • fibrinoid necrosis of arterioles - eosinophilic granular change in blood vessel wall.
    • onion-skinning = intimal thickening by proliferating smooth muscle cells and accumulation of plasma protein and proteoglycans around blood vessel = hyperplastic arteriolitis
  • presentation: systolic pressure > 200 and diastolic > 120, papilledema, retinal hemorrhages, encephalopathy, cardovascular abnormalities, renal failure.
    • early symptoms: headaches, nausea, vomiting, visual impairments (scotomas aka spots)
    • HTN crises: loss of consciousness or convulsions.
    • marked proteinuria and hematuria
  • tx: anti-HTN drugs, this is a medical emergency.
105
Q

Clinical Case:

A 24 year old African American male presents to the ER after suddenly losing consciousness in a grocery store. He currently complains of a headache, nausea, and seeing spots. His b/p is 210/125. His U/A reveals proteinuria and microscopic hematuria. Blood labs reveal ↑ levels of renin and aldosterone. Biopsy of his kidney reveals onion-skinning around the arterioles as well as fibrinoid necrosis.

What does this man have?

A

Malignant Nephrosclerosis

106
Q

Renal Artery Stenosis

A
  • unilateral = 2-5% HTN
  • from stimulation of renin secretion by JGA and production of angiotension II
  • morphology: 70% from occlusion by atheromatous plaque at origin of renal artery. more in men and increases with age and diabetes mellitus. concentrically placed with superimposed thrombosis.
    • 2nd type = fibromuscular dysplasia of renal artery. fibrous and fibromuscular thickening involving intima, media, or adventitia. medial is most common. more common in women, age 20-40. usually medial or distal part of renal artery. can involve segmental branches and be bilateral.
    • ischemic kidney is small with atrophy, crowded glomeruli, atrophic tubules, interstitial fibrosis, focal inflammatory infiltrates. unaffected kidney has more severe arteriolosclerosis from HTN.
  • presentation: resemble essential HTN. may hear bruit in affected kidneys. ↑ plasma or renal vein renin.
107
Q

Thrombotic Microangiopathies

A
  • characterized by microangiopathic hemolytic anemia, throbocytopenia, renal failure, thrombotic lesions in capillaries and arterioles in tissue beds.
  • have schistocytes in blood smear. normal coagulation profile, normal fibrin split products.
  • two main forms: HUS and TTP.
  • two pathogenic triggers: endothelial injury, and platelet activation and aggregation.
    • endothelial injury ⇒ platelet activation and aggregation, thrombosis from ↓ PGI2 and NO production, ↑ endothelin ⇒ vasoconstriction. adhesion molecules also recruit leukocytes which promote thrombosis.
    • platelet aggregation from ↑ large vWF from a deficiency of ADAMTS13 caused by Ab (common) or inherited (not common) ⇒ activate platelet spontaneously
  • tissue dysfunction from microthrombi, vascular obstruction, and tissue ischemia.
108
Q

Typical Hemolytic-Uremic Syndrome (HUS)

A
  • aka epidemic, classic, diarrhea-positive.
  • follows infection with O157:H7 E. coli ⇒ Shiga-like toxin. from ground hamburger, drinking water, raw milk, person-person transmission.
  • usually kids or elderly
  • prodrome = influenza-like or diarrheal symptoms. then sudden onselt hematemesis and melena, severe oliguria, hematuria, associated with microangiopathic hemolytic anemia, thrombocytopenia, and prominent neurologic changes. HTN in 50%.
  • Shiga-like toxin damages endothelium↑ leukocytes adhesion molecules, ↑ endothelin, ↓ NO, with TNF have endothelial apoptosis ⇒ platelet activation and vasoconstriction
  • schistocytes on blood smear, normal coagulation times, normal fibrin split products.
  • morphology: acute = patchy or diffuse cortical necrosis, thickened capillary walls, subendothelial deposits of fibrin and cell debris, fibrinoid necrosis of interlobular arteries and arterioles, occlusive thrombi
  • tx: dialysis
109
Q

Clinical Case:

A 9 year old male presents to the ER with sudden onset bloody vomiting and bloody urine. Mother states he had been feeling achey during the morning. On presentation he is not very lucid. Culture of the stool is positive for E. coli O157:H7. Biopsy reveals microthrombi and thrombi in the kidney along with capillary wall thickening.

What does this child have?

A

typical HUS

110
Q

Atypical Hemolytic-Uremic Syndrome (HUS)

A
  • aka non-epidemic, diarrhea-negative.
  • in adults.
  • 50% have inherited deficiency of complement factors (ex. factor H). a few have mutated factor I or CD46.
  • 50% have relapses and progress to end-stage renal disease.
  • associated conditions: antiphospholipid syndrome, pregnancy/postpartum, vascular diseases of kidney, chemo and immunosuppressive drugs, irradiation of kidney.
  • can have neurologic symptoms.
  • have schistocytes on blood smear, normal coagulation times, and normal fibrin split products.
  • morphology: acute = patchy or diffuse cortical necrosis and subcapsular petechiae, glomeruli occluded by thrombi, capillary walls thickened, subendothelial deposits of cell debris and fibrin, interlobular arteries and arteriols have fibrinoid necrosis and occlusive thrombi.
    • chronic = varying degrees of scarring.
      • LM: glomerli hypercellular with thickened capillary walls with splitting ‘tram-track’ basement membrane, onion-skinning of arteries and arterioles
      • manifests as renal failure and HTN.
111
Q

Thrombotic Thryombocytopenic Purpura (TTP)

A
  • ****pentad: fever, neurologic symptoms, microangiopathic hemolytic anemia, thrombocytopenia, and renal failure.
  • caused by Ab or genetic defects ⇒ functional deficits in ADAMTS13
    • most commonly by inhibitory autoantibodies.
  • present as adults <40yrs.
    • CNS involvement is dominant feature, renal present in 50%.
  • tx: exchange transfusions and immunosuppressive therapy
  • have schistocytes on blood smear, normal coagulation times, and normal fibrin split products.
  • morphology: acute = patchy or diffuse cortical necrosis and subcapsular petechiae, glomeruli occluded by thrombi, capillary walls thickened, subendothelial deposits of cell debris and fibrin, interlobular arteries and arteriols have fibrinoid necrosis and occlusive thrombi.
    • chronic = varying degrees of scarring.
      • LM: glomerli hypercellular with thickened capillary walls with splitting ‘tram-track’ basement membrane, onion-skinning of arteries and arterioles
      • manifests as renal failure and HTN.
112
Q

Atherosclerotic Ischemic Renal Disease

A
  • atherosclerotic unilateral renal artery stenosis ⇒ HTN
  • bilateral renal artery disease common cause of chronic ischemia with renal insufficiency in older adults
  • tx: surgical revascularization.
113
Q

Atherembolic Renal Disease

A
  • embolization of atheromatous plaques from aorta or renal artery **into intraparenchymal renal vessels in elderly patients with severe atherosclerosis. **
    • contain cholesterol crystals which you see as rhomboid clefts.
  • usually of no consequence.
  • in elderly with compromised renal function may ⇒ acute renal failure usually after abd surgery on atherosclerotic aneurysms.
114
Q

Sickle-Cell Disease Nephropathy

A
  • seen with Sickle-Cell disease or trait.
  • presentation: hematuria and diminished concentrating ability (hyposthenuria), proteinuria.
  • from accelerated sickling in hypertonic hypoxic renal medulla. hyperosmolarity dehydrates RBC and ↑ intracellular HbS concentrations.
  • have patchy papillary necrosis.
115
Q

Diffuse Cortical Necrosis

A
  • usually after an obstetric emergency like abruptio placentae, septic shock, or extensive surgery.
  • bilateral and symmetric = fatal without supportive therapy.
  • morphology: massive ischemic necrosis limited to cortex. looks like acute ischemic infarct.
    • glomerular and arteriolar microthrombi usually focal.
    • acute necroses of small arterioles and capillaries
    • lesions patchy with coagulative necrosis
    • hemorrhages into glomeruli with formation of fibrin plugs in glomerular capillaries.
  • sudden anuria, terminating rapidly in uremic death.
116
Q

Renal Infarcts

A
  • has limited collateral circulation, is ‘end-organ’, and gets 1/4 CO.
  • most are due to emboli from left atrium and ventricle after an MI.
    • less frequently from vegetative endocarditis, aortic aneurysm, aortic atherosclerosis.
  • morphology: infarcts in kidney are white. ** After 24hrs are sharply demarcated, pale, yellow-white areas** with small irregular foci of hemorrhagic discoloration.
    • ringed by zone of intense hyperemia.
    • wedge-shaped, apex points towards medulla.
    • undergo progressive fibrous scarring ⇒ V shaped depressed, pale, gray-white scars. undergo ischemic coagulative necrosis.
  • presentation: usually silent. can have pain with tenderness at CVA with red cells in urine.
117
Q

Agenesis of the Kidney

A
  • have bilateral agenesis in stillborn kids.
    • associated with limb defects and hypoplastic lungsearly death.
  • unilateral agenesis is uncommon. can live as long as no other abnormalities.
    • opposite kidney enlarged from compensatory hypertrophy.
    • can develop glomerular sclerosis from adaptive changes in hypertrophied nephrons.
118
Q

Hypoplasia

A
  • bilaterally ⇒ renal failure in early childhood.
  • unilateral = acquire scarring from vascular, infectious, or parenchymal diseases.
  • truly hypoplastic kidney has no scarring and has ↓ number renal lobes and pyramids (<6)
  • oligomeganephronia = small kidney with fewer nephrons that are hypertrophied.
119
Q

Ectopic Kidney

A
  • lie just above pelvic brim or within the pelvis.
  • normal or slightly small kidneys.
  • kinking or tortuosity of ureters ⇒ obstruction to urinary flow ⇒ ↑ risk bacterial infections.
120
Q

Horseshoe Kidney

A
  • fusion of upper or lower poles of kidneys ⇒ horseshoe-shaped structure continuous across midline anterior to great vessels.
    • most fused at lower pole (90%).
121
Q

Multicystic Renal Dysplasia

A
  • persistence in the kidney of abnormal structures: cartilage, undifferentiated mesenchyme, and immature collecting ductules: and by abnormal lobar organization.
  • associatead with ureteropelvic obstruction, ureteral agenesis or atresia, and anomalies of lower urinary tract.
  • dysplasia is uni or bilateral and cystic.
    • enlarged, irregular, and multicystic.
    • cysts vary in size and lined by flattened epithelium.
    • presence of islands of undifferentiated mesenchyme with cartilage and immature collecting ducts.
  • unilateral dysplasia discovered by appearance of flank mass, opposite kidney is normal.
  • bilateral multicystic renal dysplasia will go to renal failure.
122
Q

Adult Polycystic Kidney Disease

A
  • autosomal dominant. multiple expanding cysts of both kidneys that destroy renal parenchyma and cause renal failure. systemic disease = cysts happen in other organs.
  • 1/400-1000 births. need mutation of both alleles of PKD gene.
  • bilateral. initially involve portions of nephrons ⇒ renal function good until 30-50yrs.
  • mutations of chromosome 16p13.1 (PKD1) and 4q21 (PKD2).
    • PKD1 is 85%. severe disease, end-stage renal disease or death by age 53.
    • age 69 for PKD2.
  • PKD1 encodes polycystin-1 an integral membrane protein in tubular epithelial cells in distal nephron.
  • PKD2 encodes polycystin-2, integral membrane protein in all segments of renal tubules and some extrarenal tissues. functions as Ca-permeable cation channel so a defect ⇒ disrupted intracellular Ca level regulation.
  • defects in mechanosensing, Ca flux, and signal transduction underlie cyst formation.
  • polycystin 1 and 2 are located on primary cilium of tubular cells. bending cilia allows Ca channels to open.
    • defect ⇒ no opening of Ca channels ⇒ changes in cellular proliferation, basal levels of apoptosis, interactions with ECM, and secretory function of epithelia.
    • ↑ proliferation and ↑ intraluminal fluid from ↑ secretion ⇒ cyst formation
  • morphology: bilaterally enlarged kidneys. ** mass of cysts with no obvious parenchyma btw**.
    • cysts filled with clear, serous fluid or turbid, red-brown hemorrhagic fluid.
    • arise from tubules and move toward calyces and pelvis ⇒ pressure defects.
    • lining of epithelium.
  • presentation: asymptomatic until renal insufficiency.
    • or pain from hemorrhage or dilation of cysts, hematuria, urinary tract infection, renal stones, HTN.
    • dragging sensation.
    • sometimes insidious onset hematuria with progressive chronic kidney disease (proteinuria, polyuria, HTN).
    • progression accelerated in blacks, males, and pts with HTN.
    • 40% have polycystic liver disease.
    • also can have intracranial berry aneurysms, mitral valve prolapse
    • 40% die of coronary of HTN heart disease, 25% of infection, 15% ruptured berry aneurysm or HTN intracerebral hemorrhage.
123
Q

Childhood Polycystic Kidney Disease

A
  • autosomal recessive. perinatal, neonatal, infantile, and juvenile forms.
    • perinatal and neonatal most common
  • caused by mutations of PKHD1 gene encoding fibrocystin. highly expressed in adult/fetal kidney and liver and pancreas.
    • localized to primary cilium of tubular cells
  • morphology: kidneys enlarged with smooth surface. numerous small cysts in cortex and medulla, looks spongelike.
    • dilated elongated channels perpendicular to cortical surface. cylindrical dilation of collecting tubules.
    • cysts have uniform lining of cuboidal cells.
    • liver has cysts with portal fibrosis and proliferation of portal bile ducts.
  • survive infantile or juvenile form may ⇒ hepatic fibrosis with bland periportal fibrosis and proliferation of well-differentiated biliary ductules = congenital hepatic fibrosis.
  • may develop portal HTN with splenomegaly
124
Q

Medullary Sponge Kidney

A
  • restricted to lesions consisting of multiple cystic dilations of collecting ducts in medulla.
  • in adults, incidental finding or from secondary complications: calcifications in dilated ducts, hematuria, infection, urinary calculi. renal function normal.
  • gross inspection: papillary ducts in medulla dilated, small cysts present.
    • cysts lined by cuboidal epithelium or transitional epithelium.
    • cortical scarring absent unless have pyelonephritis.
  • features: hematuria, UTI, recurrent renal stones.
125
Q

Nephronophthisis

A
  • variable number of cysts in medulla, concentrated at corticomedullary junction.
  • cortical tubulointerstitial damage causes renal insufficiency.
  • most genetic cause of end-stage renal disease in children and young adults.
  • juvenile form - NPH1, NPH2, NPH3 mutated.
    • present in primary cilia, basal bodies of the cilia, or centrosome organelle.
    • NPH1, NPH3-NPH6 = nephrocystins
    • NPH2 = inversin, mediates left-right patterning during embryogenesis
  • 3 forms:
      1. sporadic/nonfamilial
      1. familial juvenile nephronophthisis = most common.
        * autosomal recessive, manifest in childhood or adolescence.
      1. renal-retinal dysplasia = as ocular lesions.
  • morphology: small kidneys with contracted granular surfaces and cysts in medulla (corticomedullary junction). small cysts in cortex.
    • lined by flattened or cuboidal epithelium, surrounded by inflammatory cells or fibrous tissue.
    • widespread atrophy and basement membrane thickening of proximal and distal tubules in cortex. interstitial fibrosis.
  • in children or adolescents with unexplained chronic renal failure, family history, and chronic tubulointerstitial nephritis.
  • features: salt wasting, polyuria, growth retardation, anemia. defect in concentrating ability, tubular acidosis. can have ocular motor abnormalities, retinal dystrophy, liver fibrosis, and cerebellar abnormalities. terminal renal failure in 5-10 yrs.
126
Q

Adult-Onset Medullary Cystic Disease

A
  • variable number of cysts in medulla, concentrated at corticomedullary junction.
  • cortical tubulointerstitial damage causes renal insufficiency.
  • autosomal dominant. mutation in MCKD1 and MCKD2. progresses to end-stage kidney disease in adult life.
  • morphology: small kidneys with contracted granular surfaces and cysts in medulla (corticomedullary junction). small cysts in cortex.
    • lined by flattened or cuboidal epithelium, surrounded by inflammatory cells or fibrous tissue.
    • widespread atrophy and basement membrane thickening of proximal and distal tubules in cortex. interstitial fibrosis.
  • features: salt wasting, polyuria.
127
Q

Acquired (Dialysis-Associated) Cystic Disease

A
  • pts have end-stage renal disease, are on dialysis, and show numerous cortical and medullary cysts.
    • contain clear fluid, lined by hyperplastic or flattened tubular epithelium, contain calcium oxalate crystals.
    • form from obstruction of tubules by interstitial fibrosis or oxalate crystals.
  • presentation: mostly asymptomatic. may have hematuria. 7% develop renal cell carcinoma.
128
Q

Simple Cysts

A
  • multiple or single cortical cystic spaces usually 1-5cm in diameter.
  • translucent, lined by gray, glistening, smooth membrane, filled with clear fluid. single layer of cuboidal or flattened cuboidal epithelium. can be atrophic.
  • usually post mortem findings.
  • if hemorrhage ⇒ sudden distension and pain, and bizarre radiographic shadows.
    • have smooth contours, are avascular, and show as fluid on ultrasound.
129
Q

Obstructive Uropathy

A
  • ⇒ ↑ susceptibility to infection and stone formation.
  • unrelieved ⇒ hydronephrosis/obstructive uropathy = permanent renal atrophy.
  • can be sudden/insidious, partial/complete, uni/bilateral.
  • common causes:
    • congenital anomalies: posterior urethral valves and structures, meatal stenosis, bladder neck obstruction, ureteroplevic junction narrowing, vesicoureteral reflux.
    • urinary calculi
    • benign prostatic hypertrophy
    • tumors
    • inflammation
    • sloughed papillae or blood clots
    • pregnancy
    • uterine prolapse and cystocele
    • functional disorders: spinal cord damage, diabetic nephropathy, abnormalities or ureter or bladder.
  • hydronephrosis = dilation of renal pelvis and calyces associated with progressive atrophy of kidney from obstruction to outflow of urine.
    • high pressure in pelvis causes renal atrophy and causes dimunition in inner medullary blood flow.
    • also get interstitial fibrosis.
    • GFR decreases later on, have impaired concentrating ability.
  • morphology: sudden and complete obstruction ⇒ **↓ GFR, mild dilation of pelvis/calyces, atrophy of renal parenchyma. **
    • subtotal/intermittent ⇒ normal GFR, progressive dilation.
    • kidney enlargred. interstitial inflammation
    • chronic = cortical tubular atrophy with diffuse interstitial fibrosis. progressive blunting of apices of pyramids, become cupped.
    • advanced = kidney thin-walled cystic structure with parenchymal atrophy, total obliteration of pyramids, thinning of cortex.
  • presentation:
    • acute = pain from distention, renal colic, prostatic enlargment ⇒ bladder symptoms.
    • unilateral complete/partial hydronephrosis = silent. diagnose by ultrasound.
    • bilateral partial obstruction = inabiity to concentrate urine, polyuria, nocturia, distal tubular acidosis, salt wasting, secondary renal calculi, chronic tubulointerstitial nephritis with scarring and atrophy of papilla and medulla. HTN.
    • complete bilateral obstruction = oliguria or anuria ⇒ death. if relieved can have postobstructive diuresis (lose lots of sodium chloride).
130
Q

Urolithiasis

A
  • men>women, ages 20-30yrs. family predisposition.
  • 4 types:
      1. calcium stones (70%)
      1. triple stones/struvite stones (15%)
      1. uric acid stones (5-10%)
      1. cystine stones (1-5%)
  • mucoprotein matrix in all stones.
  • could also be caused by deficiency in inhibitors of crystal formation in urine: pyrophosphate, diphosphate, citrate, glycosaminoglycans, osteopontin, nephrocalcin.
  • determinant = ↑ urinary concentration of constituent, supersaturated. can have low urine volume as well.
  • morphology: 80% unilateral. usually in renal calyces and pelves and bladder.
    • renal pelvies - small stones, smooth or jagged.
  • presentation: smaller stones produce colic with intense pain and ureteral obstruction.
    • larger stones remain silent in renal pelvis.
      • manifest by hematuria
131
Q

Calcium Oxalate Calculi

A
  • 70% of calculi
  • calcium oxalate or mixed with calcium phosphate
  • 5% have hypercalcemia and hypercalciuria; 55% have hypercalciuria without hypercalcemia; 20% have hyperuricosuric calcium nephrolithiasis (↑ uric acid secretion).
  • 5% have hyperoxaluria from ↑ absorption; hypocitraturia with acidosis and chronic diarrhea ⇒ stones.
  • radiopaque
132
Q

Magnesium Ammonium Phosphate Calculi

A
  • 15% of all calculi
  • Magnesium ammonium phosphate.
  • from bacteria (Proteus) which convert urea to ammonium ⇒ alkaline urine ⇒ precipitation.
  • forms large stones = staghorn calculi. take up large part of renal pelvis.
133
Q

Uric Acid Calculi

A
  • 5-10% of calculi
  • common with hyperuricemia (gout).
  • 50% have neither hyperuricemia nor ↑ uric acid secretion. have urine pH <5.5 ⇒ precipitate uric acid.
  • radiolucent.
134
Q

Cystine Calculi

A
  • 1-5% of calculi
  • from genetic defects in renal absorption of amino acids ⇒ cystinuria.
  • get stones at low urinary pH.
135
Q

Renal Papillary Ademona

A
  • small adenoma arising from renal tubular epithelium.
  • benign, usually found at autopsy.
  • usually papillary
  • morphology: <0.5cm in diameter, in cortex, pale yellow-gray, discrete, well-circumscribed nodules.
    • made of complex, branching, papillomatous structues with complex fronds.
    • can grow as tubules, glands, cords, and sheets.
    • cuboidal to polygonal cells in shape, regular small central nuclei, scanty cytoplasm, no atypia.
    • have trisomy 7 and 17.
    • 3cm is cutoff for metastases.
136
Q

Angiomyolipoma

A
  • benign, made of vessels, smooth muscle, and fat.
  • in 25-50% pts with tuberous sclerosis = loss of function mutation in TSC1 or TSC2 tumor suppressor genes.
  • lesions of cerebral cortex ⇒ epilepsy, mental retardation, skin abnormalities, and benign tumors.
  • susceptible to spontaneous hemorrhage.
137
Q

Oncocytoma

A
  • benign epithelial tumor of large eosinophilic cells with small round nuclei and large nucleoli.
  • numerous mitochondria.
  • gross: tan or mahogany brown, homogeneous, well encapsulated. up to 12cm in diameter.
  • can be familial = multicenteric.
138
Q

Renal Cell Carcinoma

A
  • in older people (50-70yrs), 2:1 men:women.
  • arise from tubular epithelium.
  • risk factors: tobacco**, obesity, HTN, estrogen therapy, asbestos, petroleum, heavy metals, tuberous sclerosis, acquired cystic disease, chronic renal failure.
  • usually sporadic but can be autosomal dominant.
    • Von Hippel-Lindau syndrome - in familial and sporadic clear cell tumors.
    • Familial clear cell carcinoma
    • Hereditary papillary carcinoma -multiple bilateral tumors with papillary histology. mutated MET.
  • types:
    • clear cell carcinoma (70-80%)
    • papillary carcinoma (10-15%)
    • chromophobe renal carcinoma (5%)
    • collecting duct (Bellini duct) carcinoma (<1%)
  • morphology: usually at the poles. tendency to invade the renal vein and grow as solid column of cells in vessel. can extend to right side of heart.
  • presentation: costrovertebral pain, palpable mass, and hematuria seen in 10% of cases. hematuria most reliable.
    • general symptoms: fever, malaise, weakness, weight loss.
    • paraneoplastic syndromes: polycythemia, hypercalcemia, HTN, hepatic dysfunction, feminization or masculinization, Cushing syndrome, eosinophilia, leukomoid rxn, amyloidosis.
    • tendency to metastasize widely before have symptoms.
      • metastasizes to: lungs, bones, regional lymph nodes, liver, adrenal, and brain.
  • prognosis: 5 year survival 45%. 15-20% with renal vein invasion. 70% without distant metastases.
  • tx: nephrectomy.
139
Q

Clear Cell Carcinoma

A
  • 70-80% renal cell carcinomas
  • nonpapillary cells, clear or granular cytoplasm. 95% sporadic. associated with VHL on chromosome 3 (deletion or somatic mutation or hypermethylation)
  • VHL encodes protein in ubiquitin ligase complex, mutation ⇒ ↑ HIF-1 ⇒ ↑ VEGF, PDGF, TGF-alpha, TGF-beta. upregulation of insulin-like growth factor 1.
  • arises from proximal tubular epithelium.
  • solitary unilateral lesion, spherical. bright yellow-gray-white tissue, distorts renal outline. yellow = prominent lipid accumulation in tumor cells.
  • large areas of ischemic, opaue, gray-white necrosis and foci of hemorrhage.
  • margins sharply defined and confined in capsule.
  • growth pattern can be trabecular or tubular.
  • tumor cells rounded or polygonal shape with clear or granular cytoplasm (glycogen and lipids).
  • branching vasculature, cysts, and solid areas.
  • most are well differentiated but some have nuclear atypia with bizarre nuclei and giant cells.
140
Q

Papillary Carcinoma

A
  • 10-15% renal cell carcinomas
  • papillary growth pattern, familial and sporadic.
  • sporadic = trisomies 7, 16, 17, and loss of Y in males
  • familial = trisomy 7.
  • MET on chromosome 7 = receptor for hepatocyte growth factor.
  • multifocal in origin, bilateral.
  • from distal convoluted tubules.
  • hemorrhagic and cystic.
  • most common type in those with acquired cystic disease.
  • cuboidal or low columnar cells in papilary formations.
  • interstitial foam cells in papillary cores. psammoma bodies.
  • little stroma but highly vascularized.
141
Q

Chromophobe Renal Carcinoma

A
  • 5% renal cell carcinomas
  • made of cells with prominent cell membranes and pale eosinophilic cytoplasm with halo around nucleus.
  • arranged in solid sheets with concentration of largest cells around blood vessels.
  • multiple chromosome losses and extreme hypodiploidy.
  • grow from intercalaed cells of collecting ducts.
  • good prognosis.
  • hard to distinguish from oncocytoma.
142
Q

Collecting Duct Carcinoma

A
  • <1% renal cell carcinomas
  • from collecting duct cells in medulla.
  • characterized by nests of malignant cells enmeshed within prominent fibrotic stroma (medullary).
  • irregular channels lined by atypical epithelium with hobnail pattern.
143
Q

Urothelial Carcinomas of Renal Pelvis

A
  • 5-10% of renal tumors come from urothelium of renal pelvis.
  • produce hematuria quickly, small when discovered.
  • block urinary outflow and cause palpable hydronephrosis and flank pain.
  • can involve pelvis, ureters, bladder.
    • 50% have preexisting bladder urothelial tumor.
  • foci of atypia or carcinoma in situ in urothelium remote from renal pelvis and bladder in pts with analgesic nephropathy and Balkan nephropathy.
  • infiltration of pelvic wall and calcyes is common.
  • presentation: flank pain, hydronephrosis, hematuria.
  • poor prognosis.