Hematuria & Nephritis Flashcards
nephritic syndrome - defined
*clinical syndrome resulting from inflammatory lesions in the glomerulus
*hallmarks:
-hematuria
-hypertension
-decreased GFR with azotemia (AKI)
-oliguria
hematuria - defined
*blood in the urine
*macroscopic (gross) - visible as a red or brown discoloration to the urine
*microscopic: red blood cells visible only under the microscope (3+ RBCs per high powered field)
*evaluation: goal is to determine:
-transient vs. persistent
-glomerular vs. non-glomerular
macroscopic hematuria
*visible as a red or brown discoloration to the urine
*after centrifugation:
-if supernatant is clear + sediment is red/brown, color change is due to hematuria
-if supernatant is red/brown: color change is due to pigment in the urine (hemoglobin, myoglobin, drugs/foods)
*urine dipstick detects reducing substances + positive for either RBCs or pigment
common causes of TRANSIENT hematuria
*contamination from menses
*vigorous exercise
*sexual activity
*fever
*infection (cystitis, prostatitis)
*trauma
*instrumentation (foley)
approach: repeat urinalysis; transient hematuria is typically benign
risk factors that warrant further workup for transient hematuria
*females > 50 yo / males > 40 yo
*smoking history (> 10 pack-years)
*other
glomerular vs. non-glomerular hematuria
*findings suggestive of glomerular source:
-dysmorphic RBCs
-cellular casts
-proteinuria
-other signs/symptoms of glomerular disease
*blood clots are suggestive of NON-glomerular disease
diseases that cause nephritic syndrome
- post-infectious glomerulonephritis
- membranoproliferative glomerulonephritis
- IgA nephropathy
- Alport Syndrome
- thin basement membrane
note - these can all be primary/idiopathic or secondary to another source
post-infectious glomerulonephritis (PIGN) - light microscopy findings
*diffuse, exudative proliferative glomerulonephritis, endocapillary hypercellularity with numerous neutrophils
*enlarged and hypercellular glomeruli
post-infectious glomerulonephritis (PIGN) - immunofluorescence findings
*subendothelial deposits with prominent IgG and C3 along the GBM, as well as mesangium deposits
*granular (“starry sky”) appearance (“lumpy-bumpy”) due to IgG, IgM, and C3 deposition along GBM and mesangium
post-infectious glomerulonephritis (PIGN) - electron microscopy findings
*scattered subepithelial hump shaped deposits without BM reaction, occasional mesangial and subendothelial deposits
post-infectious glomerulonephritis (PIGN) - etiology / mechanism
*immune complex deposition (type III hypersensitivity reaction) causing exudative hypercellularity; with consumptive hypocomplementemia
*nephritogenic infectious antigens thought to be the cause of immune complex formation (ex. erythrogenic toxin type B from streptococci)
*most common cause is STREPTOCOCCAL INFECTION
post-infectious glomerulonephritis (PIGN) - epidemiology
*more common in children and in developing countries
*children: seen 2-4 weeks after group A streptococcal pharyngitis or skin infection
*adults: Staph is an additional causative agent
post-infectious glomerulonephritis (PIGN) - clinical presentation
*sudden onset edema, hematuria, HTN, and azotemia 2-3 weeks after strep pharyngitis or cellulitis
*streptozyme test looks for extracellular strep products
*LOW COMPLEMENT (SERUM C3)
post-infectious glomerulonephritis (PIGN) - treatment
*supportive care
post-infectious glomerulonephritis (PIGN) - prognosis
*good - most have rapid, full recovery in 1-4 weeks
*may have increased risk for proteinuria, CKD, and HTN later
membranoproliferative glomerulonephritis (MPGN) - light microscopy findings
*endocapillary hypercellularity, “tram-track” appearance due to GBM splitting from mesangial infiltration, mesangial expansion/hypercellularity
*mesangial ingrowth → GBM splitting →”tram track” on H&E and PAS stains
membranoproliferative glomerulonephritis (MPGN) - immunofluorescence findings
*immune complex deposition with GRANULAR staining in GBM and mesangium IgG, C3, C1q/C4
membranoproliferative glomerulonephritis (MPGN) - electron microscopy findings
*subendothelial immune complexes
membranoproliferative glomerulonephritis (MPGN) - pathogenesis
*hallmark: GRANULAR immune complex deposition in the subendothelial and mesangial compartments
*results in GBM alterations, endocapillary proliferation, leukocyte infiltration, mesangial proliferation → new inner basement membrane laid down as a reaction to subendothelial deposits, resulting in double contour
*circulating antigens likely result in immune complex formation
membranoproliferative glomerulonephritis (MPGN) - PRIMARY etiology
*inciting antigens unknown
membranoproliferative glomerulonephritis (MPGN) - SECONDARY etiology
*infection: HEP C (usually with cryoglobulinemia) > hep B; endocarditis; other
*alpha 1 antitrypsin deficiency
*lupus nephritis
*malignancy: CLL, lymphoma, dysproteinemias
membranoproliferative glomerulonephritis (MPGN) - epidemiology
*rare
*children or young adults
*older adults with chronic infections
membranoproliferative glomerulonephritis (MPGN) - clinical presentation
*MIXED nephrotic/nephritic syndrome
*low complement: low C3 and LOW C4 (classic)
membranoproliferative glomerulonephritis (MPGN) - treatment
*secondary: treatment of underlying disease
*primary: corticosteroids and immunosuppresive agents
membranoproliferative glomerulonephritis (MPGN) - prognosis
*more than 50% progress to ESRD by 10 years
C3 glomerulopathies - defined
*glomerular diseases caused by abnormalities in complement regulation
- glomerulonephritis with dominant C3 (C3GN)
-MPGN-like appearance
-C3 deposition dominant on immunofluorescence -
dense deposit disease (DDD)
-MPGN-like appearance
-irregular, RIBBON-LIKE electron dense deposit in GBM
dense deposit disease (DDD) - etiology/pathogenesis
*disorder of complement activation
*alternate pathway is being constantly activated due to pathologic stabilization of the C3 convertase by two ways;
1. C3 nephritic factor (C3NeF): circulating autoantibody which binds and stabilizes C3 convertase
2. genetic defect in factor H, factor I, MCP: usually degrades C3/C5 convertase
*glomerular damage occurs due to recruitment of inflammatory cells similarly to MPGN type 1
dense deposit disease (DDD) - epidemiology
*rare
*usually seen in young adults
dense deposit disease (DDD) - clinical presentation
*variable, mixed nephrotic/nephritic syndrome
*low C3 levels and normal C4 (not always)
dense deposit disease (DDD) - treatment
*eculizumab (binds and inhibits C5)
*plasma exchange
*immunosuppression
dense deposit disease (DDD) - prognosis
*high rate of recurrence in kidney transplant
IgA nephropathy (IGAN) - light microscopy findings
*varies; minimal mesangial expansion to diffuse proliferative lesions
*mesangial proliferation
IgA nephropathy (IGAN) - immunofluorescence findings
*diffuse global IgA deposits in the mesangium
*lambda > kappa light chains + C3
IgA nephropathy (IGAN) - electron microscopy findings
*electron dense deposits in mesangium
*subendothelial deposits with endocapillary hypercellularity
*occasional subepithelial with intramembranous
IgA nephropathy (IGAN) - pathogenesis
*generation of abnormally glycosalated IgA (galactose-deficient IgA1)
*impaired clearance of these defective IgA from circulation
*IgA1 immune complexes form in circulation and favor deposition in the mesangium → inflammatory mesangial cell reaction to immune complexes
*occurs CONCURRENTLY with respiratory or GI tract infections
IgA nephropathy (IGAN) - epidemiology
*most common cause of glomerulonephritis worldwide
*patient ancestry: asians > caucasion > african
IgA nephropathy (IGAN) - clinical presentation
*present with GROSS HEMATURIA concurrently with MUCOSAL INFECTION (syn-pharyngitic)
*asymptomatic hematuria, proteinuria, HTN
*can cause RPGN
*isolated kidney involvement or part of a syndrome:
-Henoch-Schonlein Purpura (HSP): IgA Vasculitis (systemic form) - abdominal pain, GI bleeding, palpable purpura, and hematuria
IgA nephropathy (IGAN) - treatment
*supportive: ACEi/ARB, SGLT2
*for higher creatinine, more proteinuria: immnuosuppression + corticosteroids
IgA nephropathy (IGAN) - prognosis
*worst for: elevated creatinine, HTN, proteinuria > 1 g/day
Alport Syndrome - overview
*genetic defect in type IV collagen (mostly X-linked)
*hallmarks:
-hematuria
-low level proteinuria
-progressive loss of GFR with progression to ESRD
*other sx: eye problems, hearing problems
Alport Syndrome - light microscopy findings
*for the most part unremarkable
*can have early periglomerular fibrosis and tubulointerstitial fluid
*irregular thinning and thickening and splitting of glomerular basement membrane
Alport Syndrome - immunofluorescence findings
*negative, but staining to demonstrate ABSENCE of alpha 5 type IV collagen can help make the diagnosis
Alport Syndrome - electron microscopy findings
*thickening of GBM
*mottled “basket-weave” appearance of GBM due to irregular thickening and longitudinal splitting of GBM
Alport Syndrome - etiology
*inherited mutation of type IV collagen
*classical Alport Syndrome: X-linked dominant mutation of alpha 5 subunit of type IV collagen
*other types: autosomal recessive mutation of alpha 3 subunit; autosomal dominant mutation of alpha 4 subunit
*result: abnormal incorporation of alpha 3, 4, 5 subunits of type IV collagen into the GBM causing compromise of GBM integrity
Alport Syndrome - clinical presentation
*males (X-linked) with hematuria in childhood with progression to ESRD
*HEARING LOSS AND OCULAR DEFECTS IN ADULTHOOD
*female carriers may have hematuria without progressive renal disease
Alport Syndrome - treatment
*supportive care
*BP control
*RAAS blocking drugs
Alport Syndrome - prognosis
*chronic hematuria & scarring with 905 of X-linked cases are ESRD by age 30
*depends on the type of mutation in the gene
*TRANSPLANT KIDNEYS can develop de-novo anti-glomerular basement membrane antibodies (anti-GBM disease) with glomerulonephritis because normal GBM is recognized as foreign
thin basement membrane (TBM) - light microscopy findings
*no specific lesion
thin basement membrane (TBM) - immunofluorescence findings
*negative
thin basement membrane (TBM) - electron microscopy findings
*thinning of the lamina densa of the GBM
thin basement membrane (TBM) - etiology
*on a continuum of the Alport Syndrome
*familial inheritance pattern: AD and AR both seen
thin basement membrane (TBM) - clinical presentation
*hematuria, either microscopic or macroscopic, intermittent or persistent
thin basement membrane (TBM) - treatment and prognosis
*tx: monitor
*prognosis: good; aka benign familial hematuria
