Nephritic syndrome and Glomerulonephritis Flashcards
NEPHRITIC SYNDROME
Clinical / Urinary manifestations
- hematuria / urinary casts
- hypertension
- edema
- minimal/mild proteinuria
± kidney failure
Nephritic syndrome /Nephritis
Definition
Common appearance
Etiology
is a nonspecific term that covers different kidney diseases
Common appearance: alteration of the kidney filtering membrane
Etiology: infectious or non-infectious
Acute nephritic syndrome
develops
suddenly (RPGN) or over a
short time period ( APSGN)
Chronic nephritic syndrome develops
and progress slowly ( IgA GN)
Acute Glomerulonephritis ( AGN )- ex
post - streptococcal, proliferative, endocapilary- glomerulonephritis
Crescentic glomerulonephritis
glomerulonephritis- extracapilary GN ; RPGN
- anti GMB antibody - (Goodpasture syndrome)
- immune complexe (lupus nephritis, PSAGN)
- pauci- immune GN (Wegener′ s granulomatosis-ANCA+)
Mesangial proliferative GN
( Henoch-Schonlein purpura)
Membrano proliferative GN(MPGN)
idiopatic or secondary
ACUTE ENDOCAPILARY GN(AGN)
- Begins abruptly in children 3-14 years age old
- Main etiological factor is a prior throat or cutaneos streptococcal infection; staphylococcus, pneumococcus, viral and parasitic infections are also AGN responsible.
- Gross or microscopic hematuria is always present ( nephritic syndrome! )
- Fever is not necessarily a clinical sign in AGN
- Blood presure increases as kidney function becames impaired
C3↓, C4↓ in the first 6-8 weeks,** ASO titre↑** ,mild increase in plasma creatinine - Good prognosis, complete recovery of renal function, in majority of patients, particularly in child
ACUTE ENDOCAPILARY GN
When RPGN develops ( in AGN evolution),
weakness, fatigue and fever are the most obvious
early symptoms
Loss of appetite , nausea, vomiting, abdominal pain and joint pain, edema, and usually oliguria
/ anuria ( AKI or AKF !) are also common
About 50% of people had a “flu-like” disease in the month before kidney failure started to
develop
AGN treatment
Largelly supportive; diet light in protein and sodium, until kidney function recovers
Management of the associated hypertension: diuretic therapy, hydralazine or a calcium channel blocker
Antibiotics are usually ineffective because nephritis begins 1-6 weeks after the streptococcal infection
If RPGN in AGN evolution, promptly treatment shoud be started
Henoch-Schönlein purpura (HSP)
Conforming ISKD - child classification, in HSP there are 6 grades histological nephritis patterns
♦ st I : minimal changes
♦ st II: pure mesangial proliferation without crescents, a.focal b. diffuse
♦ st III: mesangial proliferative GN with less than 50% crescents, a.focal b.diffuse
♦ st IV: mesangial proliferative GN with 50-75% crescents, a. focal b. diffuse
♦ st V: mesangial proliferative Gn with more than 75% crescents
♦ st VI: membranoproliferative( mesangioproliferative) GN
Henoch-Schönlein purpura (HSP)
Crescent definition
proliferation of the epithelial parietal cells, the monunuclear phagocytes, and fibroblasts in the urinary space
Percentage of crescents is important in appreciate severity and evolution , in any type of GN
Renal involvment in HSP
♦ microscopic/macroscopic hematuria
♦ proteinuria ± up to nephrotic range
♦ hypoalbuminemia
♦ severe hypertension
♦ abnormal renal function up AKF
The hypercellularity of post-infectious glomerulonephritis is due to
increased numbers of
epithelial,
endothelial,
and mesangial cells as well as neutrophils in, and around the
glomerular capillary loops.
Patients who have had a strep infection typically have an
elevated anti-streptolysin O (ASO) titer.
By electron microscopy, the immune deposits of post-infectious
glomerulonephritis are
predominantly subepithelial, with electron dense
subepithelial “humps” above the basement membrane and below the
epithelial cell. The capillary lumen is filled with a leukocyte cytoplasmic
granules.
AGN treatment
Largelly supportive; diet light in protein and sodium,
until kidney function recovers
Management of the associated hypertension: diuretic therapy, hydralazine or a calcium channel blocker
Antibiotics are usually ineffective because nephritis begins 1-6 weeks after the streptococcal infection
If RPGN in AGN evolution, promptly treatment shoud be started
Management in HSP
♦ st I, IIa,IIb – no treatment ± ACE inhibitor if persistent
proteinuria
♦ st.IIIa, IIIb – pulsed Methilprednisolone 600mg/m2 for three
days , oral prednisolone 2mg/kg/day( max 60 mg) for 1 month
than taper; consider Cyclophosphamide 2,5 mg/kg/day, for 8
weeks, ± ACE inhibitor if persistent proteinuria
♦ st. IVa,IVb, Va,Vb &VI necesitate steroids as above ,
Cyclophosphamide 8 weeks, consider plasmapheresis, ± ACE
inhibitor
SLE glomerulonephritis
Renal manifestations are present in nearly two thirds of children with SLE, and may be present with a combination of symptomatic signs/syndromes
- hypertension
- nephrotic syndrome
- gross hematuria
SLE glomerulonephritis
(SLEGN)
A wide range of extrarenal manifestations is
commonly present
The choice therapy is influenced by potential renal or
extrarenal complications
There is a wide variation in the histological
appearances in lupus nephritis
SLE-GN histology ( WHO clasif.)
♦ st 1. normal glomeruli ( a. negative IF& EM b. deposits on IF
& EM)
♦ st 2. mesangial alterations ( a. mild mesangial hypercellularity
b. moderate mesangial hypercellularity)=
diffuse mesangial deposits on IF&EM
♦ st 3. focal proliferative GN+ diffuse mesangial &
subendothelial/subepithelial deposits on IF & EM
♦ st 4. diffuse proliferative GN, presents mesangial,
subendotelial &subepitelial deposits on IF & EM
♦ st 5. membranous GN with diffuse subepithelial & few
mesangial and focal subendothelial deposits on IF & EM
Glomerular disease with systemic lupus erythematosus (SLE) is common, and lupus
nephritis can have many morphologic manifestations as seen on renal biopsy;
the more immune complex deposition and the more cellular proliferation, the worse the disease. In this case, there is extensive immune complex deposition in the thickened glomerular capillary loops, giving a so-called ” wire loop appearance”
SLE – GN treatment
- Renal involvment in children is often well controlled with
corticosteroids alone - FSGN &mild SN : corticosteroids, diuretic,antihypertensive
agents if necessary - If not DPGN , prednisolone 1mg/kg, preferably by alternate
days - Stage IV – Methilprednisolone (600mg/m2, in severe
SLE-GN →good anti-inflammatory effect, but not for long
term control - In severe SLE-GN, corticosteroid unresponsive, intermitent
IV cyclophosphamide →dramatically improves evolution
SLE – severe GN treatment
1.Prednisolone + Azathioprine /Mychophenolat –Mofetil
could be a satisfacatory alternative
2.IV- Cyclophosphamide is given by monthly IV infusion,
500-1000mg/m2; in comparison with daily oral therapy, the immunosuppresive effects appears to be greater, and the
toxicity( especially bladder toxicity) appears to be less
- The optimal duration of IV treat - Cyclophosphamide
therapy has not conclusively established; once 7 doses of
therapy has been completed, continued administration at three month intervals, or alternatively oral Azathioprine may be substituted
Familial Hematuria
The major forms
- Thin Basement Membrane Nephropathy ( TBMN)
- Alport syndrome
are caused by mutations in type IV collagen
Since 1990 four genetic loci, have been identified as sites of mutations in famillies transmitting hematuria
A critical type IV collagen nettwork is located in specialized BM of the kidney, cochlea and eye
Alport nephropathy evolution can be broken down into 4 phases
Familial Hematuria/ Alport syndrome
Histology
Phase I: from birth until late childhood / early adolescence: mild mesangial proliferation & GMB attenuation, with focal areas of lamellation and normal
podocyte foot processes
Phase II: overt proteinuria in addition to hematuria ; GFR is normal. Mesangial proliferation by light microscopy, FSG, tubulointerstitium is spared.
EM: diffuse thickening and lamellation of the GBM, and extensive foot processes fusion
Phase III: declining renal function, interstitial fibrosis and tubular atrophy
Phase IV: clinical & histological features of ESRD
hereditary nephritis:
Alport syndrome in which patients may also manifest
nerve deafness, and eye problems. The renal tubular cells appear foamy because of the accumulation of neutral fats and mucopolysaccharides. The glomeruli show irregular thickening and splitting of basement membranes.
Alport syndrome – treatment
- No specific treatment to alter the natural history of
human Alport syndrome - Alport syndrome is primarly a glomerulopathy; loss of
renal function is tightly correlated with expansion and
fibrosis in the interstitial compartment - Early ACE inhibition has no effect on the onset of
proteinuria but could delay ESRD. Angiotensin
blockade, initiated early in the course of the disease may
be beneficial in human Alport syndrome - Cyclosporine appeared to supress proteinuria &
stabilize renal function
MEMBRANOPROLIFERATIVE
GLOMERULONEPHRITIS (MPGN)
Epidemiology and types
Affects children & young adults, mean age of onset
between 8-30 years
It has been classified as idiopatic & secondary
Idiopatic MPGN is subdivided into types 1-3, based
on biopsy morphological patterns
MPGN Type I electron miograph
splitting and reduplication of basement membrane that is piled up above the mesangial cytoplasm in this micrograph.
- These changes occur when the mesangial cell (which has a macrophage-like function) goes after subendothelial immune deposits, but makes a mess of the basement membrane in the process.
MPGN Type II
The bright deposits scattered along capillary walls and in the mesangium by
immunofluorescence microscopy with antibody to complement component C3 are typical for membranoproliferative glomerulonephritis, type II. MPGN type II, known as dense deposit disease, produces a nephritic syndrome. Most patients have detectable circulating C3 nephritic factor, an IgG autoantibody.
MPGN - treatment
**If plasma albumin >2,5g/L **± hypertension, no specific therapy
If hypertension is present, an ACE inhibitor should be used
If plasma albumin <2,5g/L ± normal/elevated plasma creatinine:
prednisolone 40mg/m2 , on alternate days,
6-12 months+aspirin1mg/kg, 3 times/week+
dipyridamole 1,5 mg/kg, 3 times/day
If there is improvement or clinical/biochimical stability, the prednisolon regimen could be continued, on alternate days, with progressive
tapering, for the next 30 months ( e.g. 20mg/m2, 15mg/m2, 10 mg/m2)
PRIMARY IgA NEPHROPATHY
IGAN ( Berger disease)
The disease occors at all ages; affects males more often than
females
Five different clinical syndromes can be identified at onset
- Recurrent macroscopic hematuria
- Asymptomatic microscopic recurrent hematuria &
proteinuria - Acute nephritic syndrome
- Nephrotic syndrome
- Nephritic/nephrotic syndrome
The commonest presentation of IGAN in children is
recurrent macroscopic hematuria + reccurent respiratoy
infections
IGAN
high power microscopy
IgA nephropathy (Berger disease). The IgA is deposited mainly within the mesangium, which
then increases mesangial cellularity as shown at the arrow. Patients with IgA nephropathy usually
present with hematuria.
IGAN
fluoroscopy
This immunofluorescence pattern demonstrates positivity with antibody to IgA. The pattern is that of mesangial deposition in the glomerulus.
IGA NEPHROPATHY
The interval between precipitating URI and the appearance of hematuria ranges from 1-2 days
Serum IgA levels are increased in 16 – 18 % of children
Serum complement concentrations are usually normal
Difuse mesangial IgA deposits may be also observed in HSP, SLE ,and chronic liver disease
The prophylactic antibiotics and tonsillectomy may reduce the frequency of episodes of macroscopic hematuria; the long term benefit remains questionable
IGA NEPHROPATHY
treatment
Glucocorticoids : in nephrotic syndrome and minimal mesangial
lesions but long term glucocorticoid and immunosupresant
treatmens does not confer any benefit
- Patients with mild/moderate proteinuria ( PCR : 20-200
mg/mmol) and diminished GFR : fish oil & ACE inhibitor - Glucocorticoid therapy should be considered in patients who
have nephrotic range proteinuria & a normal GFR
FOCAL GLOMERULOSCLEROSIS
FSGS
Diagnosis based on the presence of focal & glomerular
segmental scarrring on biopsy&steroid resistant nephrotic
syndrome
May also be present with asymptomatic proteinuria and/or
hematuria
In nephrotic syndrome steroid resistance, FSGS is definied
by the persistence of proteinuria following at least 4 weeks of
60 mg/m2 of oral prednisone administration
FSGS
microscopy
An area of collagenous sclerosis runs
across the middle of this glomerulus. In contrast to minimal change disease, patients with FSGS are more likely to have non-selective proteinuria, hematuria, progression to chronic renal failure, and poor response to corticosteroid therapy.
FSGS
treatment (1)
Mendosa protocol has been advocated in FSGS
Cyclophosphamide has been used more often than
Chlorambucil in FSGS ( 2,5 mg/kg/day for 90 days)
**Cyclosporin **has given in FSGS, in doses of 5mg/kg/day
with low dose alternate day steroids; found to be effective in
reducing urinary protein excretion & delaying the progression
to ESRD
FSGS
treatment (2)
Malignant clinical course FSGS defines rapid deterioration in renal function completely unresponsive to all therapies; in these cases regular salt poor albumin infusion with diuretics are helpful
Patients with malignant course have a significant risk of recurrence post renal transplantation
RAPIDLY PROGRESSIVE
GLOMERULONEPHRITIS( RPGN)
RPGN is a clinical definition, usually associated with a
crescentic GN on renal biopsy
- Severe proliferation that results in circumferential layers of
fibroblasts, macrophages &epithelial cells within Bowman′s
space described as crescents - Primary- crescentic GN: Idiopathic, Anti- GMB disease,
IgA- nephropathy, Membranous -GN - Secondary-crescentic GN: PSAGN, Shunt nephritis,
Infective endocarditis, SLE, HSP, PAN, Wegener′s
granulomatosis, Cryoglobulinemia
RPGN / Crescentic GN - histology
three IF staining patterns on renal biopsy
a . Immune complexe : (e.g. PSAGN, HSPGN, SLE, MPGN, MGN ,Mixed Cryoglobulinemia). This condition have granular immune deposition on IF ( the commonest observed pattern)
b . Pauci – immune : Vasculitis ( e.g.PAGN, Wegener)& Idiopathic GN. These conditions are typified by the absence of immune deposits on IF & ANCA positivity
c . Anti- GMB antibody disease: (e.g. Goodpasture syndrome). This condition is typified by linear GMB staining &the presence of circulating anti-GMB antibody. May be associated with anti-alveolar MB
antibody staining ,and pulmonary hemorrhage
RPGN with crescents
light microscopy
Crescents are composed of proliferating epithelial cells. Crescentic glomerulonephritis is known as rapidly progressive glomerulonephritis (RPGN) There are several causes, and in this case is
due to SLE. Note in the lower left glomerulus that the capillary loops are markedly thickened (the so-called “wire loop” lesion of lupus nephritis).
RPGN with crescents
fluoroscopy
This immunofluorescence micrograph of a glomerulus demonstrates positivity with antibody to fibrinogen. With a rapidly progressive GN, the glomerular damage is so severe that fibrinogen leaks into Bowman’s space, leading to proliferation of the epithelial cells and formation of the bright
crescent shown here.
RPGN with crescents
light microscopy in Goodpasture syndrome
Another glomerulus with epithelial crescents squashing the glomerular tufts from all sides. RPGN may be idiopathic or may result from SLE, post-infectious GN (as in some cases of post-infectious GN), from various types of vasculitis, and from Goodpasture syndrome.
RPGN / CRESCENTIC GN
Clinical presentation /Treatment
Children with crescentic GN present oliguria, a significant & rapid elevation in plasma creatinine, hypoproteinemia, nephrotic range proteinuria in
association with other signs of acute GN
Patients with immune complex crescentic GN should be managed according to their specific underlying condition.
Pulse Methylprednisolone will be considered
RPGN / CRESCENTIC GN
Treatment
The following regime should be considered in patients
who are ANCA ±
Methylprednisolone 600 mg/m2/day for 3 days ; oral
Cyclophosphamide 2,5 mg/kg/day, for 6 – 8 weeks
begining day 4, alternate day oral Prednisolone 2mg/kg
begining day 5, with a slow tailoring over 6 months
Other regime recommend : monthly boluses
Cyclophosphamide for 6 months or Mychophenolate-
Mophetil introduced progressively untill the full dose of
1g/1,73m2, twice daily, for 1 year, with fewer adverse
events
NEPHRITIC SYNDROME (GN)
CONCLUSIONS
Nephritic syndrome defines a clinical presentation reflecting different pathological patterns ( GN) that some are progressive to ESRD
In the case of a severe, or unfavourable nephritic syndrome course, especially if nephrotic syndrome is associated , a renal biopsy should be considered
A severe clinical acute GN ( RPGN) presentation often correlates with a severe underlying histological pattern, e.g.crescentic GN
