Glomerular Diseases (Based on Kaplan Pathology 2018, MKSAP, Up To Date) 9.11.

19
NEPHRITIC SYNDROME
General dysmorphic hematuria +/- RBC casts; variable proteinuria; leukocytes; systemic findings: edema, HTN,
Characteristics kidney failure (azotemia and oliguria)
Nephritic Conditions Clinical Presentation/Pathogenesis Renal Biopsy Treatment Prognosis
Anti-GBM antibody disease Presents with nephritic picture. A LM - proliferative GN steroids, cytotoxic poor due to
common cause of RPGN (kidney function (hypercellularity) with fibrin drugs life-
may deteriorate rapidly over days to deposition in glomeruli and (cyclophosphamide threatening
weeks) is an antibody-mediated crescentic many crescents or rituximab), daily pulm hem
GN with peak incidence age 20-40, IF - smooth, linear pattern of plasmapheresis to and renal
males>females; if lung is affected it is IgG and C3 deposition along remove circulating failure; early
called Goodpasture Syndrome - GBM; see linear insitu IgG antibodies. aggressive tx
pulmonary hemorrhage and hemoptysis. deposition because of even may prevent
Pathogenesis: autoimmune disease distribution of IgG along ESRD
caused by antibodies directed against the GBM
noncollagenous domain of type IV EM - no immune complex
collagen. Labs: nml complement levels, deposits; + GBM disruption
increased anti-GBM antibody levels; CXR: (rents)
diffuse alveolar infiltrates in GP syndrome.
Pauci-Immune GN Presents with range of minimal kidney LM - range of mild focal and combination variable
disease to RPGN. Most common cause of segmental GN to a diffuse therapy with prognosis;
RGPN. Systemic symptoms may be necrotizing and crescentic steroids and worse if older
nonspecific: low grade fever, myalgia, GN. Granulomas imply a dx cyclophosphamide or if severe
fatigue, and arthritis; may see of GPA. Variable interstitial (or rituximab) with pulmonary
leukocytoclastic vasculitis (with palpable inflammation and vasculitis or without involvement
purpura) as well as pulm disease. of arterioles and venules. plasmapheresis and severe
Pathogenesis: caused by microscopic kidney
vessel vasculitis affecting kidney, resulting disease at
in necrotizing lesions in the glomeruli with presentation
few or no immune deposits. ANCA IF - neg for immunoglobulin
encourages vascular destruction by PMN. and complement deposition
GBM destruction releases fibrin into
urinary space which causes reactive
proliferation by parietal cells. Renal
lesions may occur alone or as part of a
systemic vasculitis. Three forms of
systemic vasculitis associate with pauci-
immune GN: granulomatosis with
polyangiitis (GPA, aka Wegener
granulomatosis), microscopic polyangiitis EM - neg for
(MPA), and eosinophilic granulomatosis immunoglobulin and
with polyangiitis (EGPA, aka Churg-Strauss complement deposition
syndrome-asthma, pulm infiltrates,
eosinophilia). Labs: most patient have
circulating ANCA (antineutrophilic
cytoplasmic antibodies); nml complement
levels
Immune-complex mediated GN
1. Infection related GN/ Presentation: Young child with fever, LM - infiltrate of neutrophils Supportive care most children
Postinfectious GN/ malaise, periorbital edema, hypertension, in glomerulus, diffuse (all (95%) have
Poststreptococcal GN smoky urine, oliguria beginning approx glomeruli involved) good
two weeks after strep infection; Staph GN prognosis;
typically associated with ongoing 15-50% of
IF - granular deposits of IgG
infection. Labs: cultures for nonstrep adults
or IgA and C3 in mesangium
shows responsible organism; with PSGN: develop
and Bowman's capsule side
depressed complement levels (usually C3 ESRD.
of capillary wall
which signifies activation of alternate
(subepithelial)
complement pathway), antibodies to
EM - subepithelial immune
streptococcal antigens (antistreptolysin-O
complex deposits (humps,
and DNAse B)
dome shaped)
2. IgA Nephropathy Presents: In adults see microscopic LM - nml glomeruli or Those with usually
hematuria with or without proteinuria. mesangial proliferation proteinuria should benign
Recurrent gross hematuria which may get ACEI or ARB and course, unless
follow a respiratory illness is another 6 month steroid has more
presentation. May see HTN, edema and course. otherwise kidney
kidney failure with RPGN. Affects children can observe involvement
and young adults mostly. Can be IF - mesangial deposits of and
associated with Celiac sprue and HSP (IgA IgA and C3 dysfunction
vasculitis) and liver disease. Pathogenesis:
autoantibodies against abnormal IgA form
immune complexes and deposit in the
kidney and extra renal sites (HSP). Labs:
EM - mesangial immune
serologic tests for systemic diseases and
complex deposits
complements are nml. Kidney bx required
for dx.
3. Lupus Nephritis Presents with extrarenal symptoms of SLE Microscopy depends on Aggressive depends on
at the time of diagnosis of LN. Many will which class: Has 5 different combination of which class
have varying degrees of nephritic classes: Minimal mesangial immunosuppressive
syndrome. Pathogenesis: LN is the LN, Mesangial proliferative rx (steroid with
archetypal immune complex disease with LN, Focal proliferative LN, cyclophosamide)
immune deposits in all areas of the Diffuse proliferative LN,
glomerulus. Labs: active serologies (ANA, Membranous LN GN,
dsDNA), low C3 and C4 complement Advanced sclerosing LN.
levels. IF - granular pattern
EM - discrete deposits
4. Membranoproliferative Presents as nephritic, nephrotic or both. LM - lobulated appearance slowly
GN Occurs in children or young adults. of glomerulus due to progressive
mesangial and endothelial course
cell proliferation and resulting in
thickening of the GBM from chronic renal
deposition of subendothelial failure over
immune complex or 10 years.
complement factor deposits.
Splitting of BM (tram-
tracking)
a. Type I aka Immune Caused by infections (Hep C/B), IF - granular pattern of C3 Treat causative
Complex-mediated MPGN autoimmune dz (SLE), monoclonal with IgG, C1q, C4 infection,
gammopathy. Labs: May show serologic EM - subendothelial and autoimmune
evidence of Hep C or SLE. Intermittently mesangial immune complex disease or
low serum complement levels. deposits monogammapthy.
b. Type II or Two types: dense deposit disease (DDD) IF - granular and linear No specific tx for C3
Complement- mediated and C3 GN: associated with uncontrolled pattern of C3 deposition glomerulopathies:
MPGN activation of the alternative complement tapering dose of
EM - dense deposits within
pathway. Labs: Reduced C3 levels. steroids have
the GBM
varying results.
Alport Syndrome Presents: Gross hematuria begins in LM - ? No specific progressive
childhood. Hearing loss and various ocular therapies except disease the
IF - ?
abn of the lens and cornea can occur. ACEI and ARB's to ultimately
Proteinuria, HTN, CKD usually develop EM - alternating thickening control the ends in renal
over time. Pathogenesis: Rare X-linked and thinning of BM with proteinuria. Kidney failure. ESKD
disorder caused by defect in type IV splitting of the lamina densa transplant is the occurs
collagen. causing a "basket weave" optimal treatment. between
appearance. teens and 4th
decade of life.
Rapidly Progressive GN Clinical syndrome characterized by rapid LM: glomerular high dose IV steroids, variable
progression of kidney failure within crescents and cyclophosphamide or depending on
weeks. May be idiopathic or associated inflammation of rituximab in case of pauci- initial cause
immune GN. Plasmapheresis
with any etiology of GN but particularly glomerular capillaries. of RPGN. See
if pulm hemorrhage or severe
common in anti-GBM antibody disease or IF: helps to make kidney failure to remove above.
pauci-immune small vessel vasculitis. definitive dx; granular circulating antibody. Rapid dx
immune complex , is critical. Delay may result in
linear anti-GBM irreversible kidney failure or
antibody staining, or death from pulm
pauci immune GN hemorrhage.
 NEPHROTIC SYNDROME
General nephrotic range proteinuria (>3.5gms/24 hours); hypoalbuminemia; edema; hyperlipidemia; dysmorphic hematuria +/-
RBC casts; variable proteinuria; leukocytes; systemic findings: edema, HTN, kidney failure (azotemia and oliguria); maybe
Characteristics occur as a primary (idiopathic) or secondary cause.
Nephritic
Clinical Presentation/Pathogenesis Renal Biopsy Treatment Prognosis
Conditions
Minimal Change Presents with acute onset of edema and LM - nml glomeruli with corticosteroids Excellent prognosis
Disease weight gain. Most common cause of lipid accumulation in with majority
idiopathic nephrotic disease in children. proximal tubule cells (lipid completely
Peak incidence age 2-6. Secondary causes nephrosis) recovering. Some do
include meds (NSAIDs, lithium, interferons, IF - negative with no relapse and are more
etc) and malignancies (Hodgkin’s and immune deposits difficult to treat.
thymoma). May occur after URI or after EM - nml GBM,
immunization. Pathogenesis not fully effacement of epithelial
understood but ? related to production of (podocyte) processes,
cytokines by immune cells that lead to microvillous
podocyte dysfunction. Labs: Complement transformation, no
levels of are normal and serologies are immune complex deposits
negative for systemic disease.
Membranous Presents with typical nephrotic syndrome, LM - diffuse thickening of primary dz - Clinical course is
Nephropathy but increase propensity for thromboembolic the cap walls without alternating variable and may lead
events (particularly renal vein thrombosis). proliferative lesions; see steroids with to spontaneous
Most common cause of idiopathic nephrotic GBM projections "spikes" cyclophosphamide remission, persistent
syndrome in white adults. Most cases are with silver staining or calcineurin proteinuria or ESRD.
idiopathic (85%) - mediated by immune inhibitors
complexes: Pathogenesis: Autoantibodies IF - granular and linear (cyclosporine or
cross-react with podocyte surface antigens pattern of IgG and C3 tacrolimus);
(phospholipase A2 receptor [PLA2R], subepithelial deposition secondary dz -
activate complement and damage the GBM. EM - subepithelial treatment of
May be secondary to drugs (penicillamine, deposits along the GBM infection; steroids
gold, NSAIDs), infections (Hep B, C, syphilis) with effacement of the do not help; stop
and systemic diseases (SLE, DM), podocyte foot processes offending drugs;
malignancies of the lung or colon, treat malignancy;
lymphoma. May have a genetic immunosuppressiv
predisposition. Labs: elevated PLA2R levels e treatment for
in idiopathic MG. lupus MG.
Focal segmental Present with either asymptomatic LM - focal segmental primary dz - primary dz - may see
glomerulosclerosis proteinuria or edema or fully nephrotic. Can sclerosis and hyalinization steroids or partial or complete
see HTN, microscopic hematuria and of glomeruli calcineurin remission in 40-60% if
variable renal failure. Occurs in all ages inhibitors treated. In refractory
particularly in African Americans. May be IF - IgM and C3 deposits in secondary dz - disease (poor
from genetic mutation of podocyte proteins, the sclerotic segments remove offending response to steroids)
direct podocyte injury etc. Can be primary drug; treat most progress to renal
(idiopathic) or secondary and related to EM - effacement of foot infection; loss of failure secondary dz -
variety of predisposing conditions (renal processes in nonsclerotic wt in obese pts; treatment may halt
tissue loss, chronic HTN, diabetes, IgA regions and without ACEI and ARB's to progression of disease
immune deposits;
nephropathy, sickle cell anemia, heroin use, help with and improve
AIDS, morbid obesity, meds - interferon). increased mesangial proteinuria symptoms
Labs: Serologic tests for systemic disease are matrix in sclerotic
neg and complement activity is nml. segments
Diabetic Present with albuminuria 5-15 years after LM: expansion of the BP and Glycemic see clinical
nephropathy diagnosis of DM Type I and less predictable mesangium and control helps delay presentation.
with Type II; overt nephropathy occurs 10-15 thickening of the GBM, progression. Use
years after disease onset in 50% of pts and followed by focal ACEI or ARBs.
progresses to ESRD in most. Pathogenesis (nodular) sclerosis (the
involves early reversible phase of kidney Kimmelstiel-Wilson lesion)
hyperfiltration mediated by hyperglycemia then global sclerosis of
associated elevation of angiotensin. This phase
the glomerulus; interstitial
is followed by activation of inflammatory and
fibrosis; tubular atrophy
profibrotic pathways, resulting in laying down
of extracellular matrix in all compartments of
with thickened tubular
the kidney followed by fibrosis and eventually BM and arteriolosclerosis
ESRD. Labs: Serologic tests for systemic disease
are negative and compliment activity is nml.
Abbreviations: LM = light microscopy, IF = immunofluorescence, EM = electron microscopy, ESRD = end stage renal disease, GBM = glomerular basement membrane,
HSP = Henoch-Schonlein purpura, SLE = systemic lupus erythematosus, DM = diabetes mellitus, GN = glomerulonephritis
TUBULAR DISEASES
Tubular interstitial nephritis
Disorder Clinical Presentation/Pathogenesis Renal Biopsy Treatment Prognosis
General info Acute or chronic inflammation of tubules and LM - neutrophilic rapid treatment of Tx may lead to
interstitium. Can be due to meds, infections, acute interstitial underlying causes; slowing of
pyelonephritis, SLE, lead, urate nephropathy, infiltrate, Discontinue offending drugs progression of
multiple myeloma, sarcoidosis, Sjogren syndrome, parenchymal and toxins. Use ACE and kidney dysfunction
malignancy (lymphoma, leukemia). abscesses, ARBs to control BP if and slight reversal.
neutrophil casts in proteinuria present;
tubules. consider
immunosuppressive rx.
Acute Bacterial infection involving the renal pelvis,
Pyelonephritis tubules and interstitium. Caused by E Coli, Proteus,
Klebsiella and Enterobacter. Predisposing factors
include urinary obstruction, vesicoureteral reflux.
Pregnancy, urethral instrumentation, DM, BPH. Sxs
include: fever, chills, malaise, dysuria, frequency,
urgency, CVAT. UA shows pyuria and WBC casts.
Chronic Occurs from chronic obstruction or in the setting LM - interstitial Some develop
Pyelonephritis of vesicoureteral reflux. Scarring at the upper and fibrosis and glomerulosclerosis.
lower poles of the kidney with associated calyceal inflammation with Renal insufficiency
blunting. thyroidization of develops gradually.
the tubule.
Drug induced Caused by penicillins, other antibiotics, diuretics, LM - interstitial recovery after
Tubular NSAIDs. hypersensitivity reaction occurs a couple inflammation and withdrawal of drug
interstitial of weeks after exposure to the drug: fever, granulomas
nephritis eosinophilia, rash hematuria, minimal proteinuria.
Urate Caused by deposition of urate crystals (secondary
nephropathy to leukemia treatment, lead poisoning, gout) in
tubules and interstitium. May produce acute renal
failure

Acute tubular injury/ Necrosis (ATN)

Ischemic ATN Most common cause of ATN. Due to decreased Excellent if survives
blood flow caused by severe hemorrhage, severe the underlying
renal vasoconstriction, hypotension, dehydration, disease and if
or shock. patient has no
Nephrotoxic Causes include: drugs (polymyxin, methicillin, preexisting kidney
ATN gentamicin, sulfonamides), radiographic contrast disease
agents, heavy metals (mercury, lead, gold), organic
solvents (carbon tetrachloride, chloroform, methyl
alcohol), ethylene glycol (antifreeze), mushroom
poisoning, pesticides, myoglobin. Sxs: oliguria with
elevation of BUN and Cr; metabolic acidosis and
hyperkalemia, and dirty brown granular casts and
epithelial casts on urinalysis.