Nephritic syndrome and Glomerulonephritis

Question 1

NEPHRITIC SYNDROME

Answer 1

Clinical / Urinary manifestations
- hematuria / urinary casts
- hypertension
- edema
- minimal/mild proteinuria
± kidney failure

Question 2

Nephritic syndrome /Nephritis
Definition
Common appearance
Etiology

Answer 2

is a nonspecific term that covers different kidney diseases

Common appearance: alteration of the kidney filtering membrane

Etiology: infectious or non-infectious

Question 3

Acute nephritic syndrome
develops

Answer 3

suddenly (RPGN) or over a
short time period ( APSGN)

Question 4

Chronic nephritic syndrome develops

Answer 4

and progress slowly ( IgA GN)

Question 5

Acute Glomerulonephritis ( AGN )- ex

Answer 5

post - streptococcal, proliferative, endocapilary- glomerulonephritis

Question 6

Crescentic glomerulonephritis

Answer 6

glomerulonephritis- extracapilary GN ; RPGN
- anti GMB antibody - (Goodpasture syndrome)
- immune complexe (lupus nephritis, PSAGN)
- pauci- immune GN (Wegener′ s granulomatosis-ANCA+)

Question 7

Mesangial proliferative GN

Answer 7

( Henoch-Schonlein purpura)

Question 8

Membrano proliferative GN(MPGN)

Answer 8

idiopatic or secondary

Question 9

ACUTE ENDOCAPILARY GN(AGN)

Answer 9

• 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

Question 10

ACUTE ENDOCAPILARY GN
When RPGN develops ( in AGN evolution),

Answer 10

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

Question 11

AGN treatment

Answer 11

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

Question 12

Henoch-Schönlein purpura (HSP)
Conforming ISKD - child classification, in HSP there are 6 grades histological nephritis patterns

Answer 12

♦ 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

Question 13

Henoch-Schönlein purpura (HSP)
Crescent definition

Answer 13

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

Question 14

Renal involvment in HSP

Answer 14

♦ microscopic/macroscopic hematuria
♦ proteinuria ± up to nephrotic range
♦ hypoalbuminemia
♦ severe hypertension
♦ abnormal renal function up AKF

Question 15

The hypercellularity of post-infectious glomerulonephritis is due to

Answer 15

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.

Question 16

By electron microscopy, the immune deposits of post-infectious
glomerulonephritis are

Answer 16

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.

Question 17

AGN treatment

Answer 17

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

Question 18

Management in HSP

Answer 18

♦ 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

Question 19

SLE glomerulonephritis

Answer 19

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

Question 20

SLE glomerulonephritis
(SLEGN)

Answer 20

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

Question 21

SLE-GN histology ( WHO clasif.)

Answer 21

♦ 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

Question 22

Glomerular disease with systemic lupus erythematosus (SLE) is common, and lupus
nephritis can have many morphologic manifestations as seen on renal biopsy;

Answer 22

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”

Question 23

SLE – GN treatment

Answer 23

1. Renal involvment in children is often well controlled with
   corticosteroids alone
2. FSGN &mild SN : corticosteroids, diuretic,antihypertensive
   agents if necessary
3. If not DPGN , prednisolone 1mg/kg, preferably by alternate
   days
4. Stage IV – Methilprednisolone (600mg/m2, in severe
   SLE-GN →good anti-inflammatory effect, but not for long
   term control
5. In severe SLE-GN, corticosteroid unresponsive, intermitent
   IV cyclophosphamide →dramatically improves evolution

Question 24

SLE – severe GN treatment

Answer 24

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

3. 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

Question 25

Familial Hematuria The major forms

Answer 25

- 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

Question 26

Familial Hematuria/ Alport syndrome Histology

Answer 26

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

Question 27

hereditary nephritis:

Answer 27

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.

Question 28

Alport syndrome – treatment

Answer 28

* 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

Question 29

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN) Epidemiology and types

Answer 29

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

Question 30

MPGN Type I electron miograph

Answer 30

**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.

Question 31

MPGN Type II

Answer 31

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.

Question 32

MPGN - treatment

Answer 32

**If plasma albumin >2,5g/L **± hypertension, no specific therapy If **hypertension is present,** an **ACE inhibitor s**hould 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)

Question 33

PRIMARY IgA NEPHROPATHY IGAN ( Berger disease)

Answer 33

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

Question 34

IGAN high power microscopy

Answer 34

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.

Question 35

IGAN fluoroscopy

Answer 35

This immunofluorescence pattern demonstrates positivity with antibody to IgA. The pattern is that of mesangial deposition in the glomerulus.

Question 36

IGA NEPHROPATHY

Answer 36

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

Question 37

IGA NEPHROPATHY treatment

Answer 37

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

Question 38

FOCAL GLOMERULOSCLEROSIS FSGS

Answer 38

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

Question 39

FSGS microscopy

Answer 39

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.

Question 40

FSGS treatment (1)

Answer 40

**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

Question 41

FSGS treatment (2)

Answer 41

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

Question 42

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS( RPGN)

Answer 42

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

Question 43

RPGN / Crescentic GN - histology three IF staining patterns on renal biopsy

Answer 43

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

Question 44

RPGN with crescents light microscopy

Answer 44

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).

Question 45

RPGN with crescents fluoroscopy

Answer 45

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.

Question 46

RPGN with crescents light microscopy in Goodpasture syndrome

Answer 46

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.

Question 47

RPGN / CRESCENTIC GN Clinical presentation /Treatment

Answer 47

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

Question 48

RPGN / CRESCENTIC GN Treatment

Answer 48

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

Question 49

NEPHRITIC SYNDROME (GN) CONCLUSIONS

Answer 49

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