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Glomerulonephritis and
Chronic Renal
insufficiency in Children

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By NGARE ANGELA
Group 3
Anatomy:
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Anatomy:
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Anatomy:
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Glomerulonephritis
Glomeulonephritis is an immune-mediated renal disease induced by two
mechanisms:
1- Antibody-mediated immunity:
 In situ immune complexes: Antibodies (autoantibodies) that bind to
planted (exogenous) antigens, or interact with intrinsic glomerular
cell surface antigens, as a result of changes to the cell surface ( antiGBM antibody nephritis, membranous glomerulonephritis).
 Circulating immune complex: Pre-formed immune complexes from
the circulation that trapped by glomerulous. Regardless of whether
they are endogenous (lupus nephritis),
or exogenous (acute post streptococcal GN), the antigens are
not glomerular in origin.
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Glomerulonephritis
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2- Cell-mediated immunity :
Caused by sensitized T-cells, cytotoxic action of T cells which
may damage the intrinsic glomerular cells or alter glomerular
filtration barrier (e. In pauci-immune glomerular diseases, such as
ANCA-related crescentic glomerulonephritis).
Then, Activation of classical or alternative complement pathway,
followed by secretion of secondary inflammatory mediators,
including cytokines and chemical mediators, derived from
activated leukocytes. Following the initiation of immune-mediated
glomerular injury, various cytokines, chemokines, and growth
factors are significantly involved in the promotion of glomerular
injury as second messengers.
Complement Cascade:
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Terminology
 Glomerulonephritis : inflammation of the glomeruli
 Glomerulopathy : disease of the glomeruli
 All glomeruli are involved: Diffuse (generalized)
 Some glomeruli are involved: Focal
In one glomerulus:
 if the whole glomerulus is involved : Global
 if only a part of the glomerulus is involved: Segmental
Other terminologies in common use:
 Proliferative: increase in the number of cells
 Sclerosing: Hardening of the tissue
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Glomerular lesion
The lesion Consists of:
 Infilteration of leucocytes.
 Proliferation of endothelial, mesangial and epithelial cell.
 Formation of deposits.
 Also immunoglobulins and complements form deposits (granular
deposits).
The formed deposits lie at three sites:

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In the mesangium (mesangial deposits ).
Between the endothelial cells and glomerular basement
membrane (GBM ) (subendothelial deposits ).
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Between the outside of GBM and podocytes (subepithelial
deposits).
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Glomerular injury
 Glomerulonephritis arises from the responses of intrinsic glomerular
cells to inflammatory reactions. Glomerular deposition,
hypercellularity (intrinsic and inflammatory cells), and capillary
destruction are typical features of glomerular injury.
 Extensive inflammatory damage to glomeruli → Impairment of
selective filtering properties of the kidney leading to a decreased
GFR and eventually produce uremic symptoms with salt and water
retention, leading to edema and hypertension.
 Molecules normally not filtered such as constituents of the blood,
pass into the urine and are excreted.
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 Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft,
the capillary lumens are open, the thickness of the glomerular capillary wall (long
arrow) is similar to that of the tubular basement membranes (short arrow), and the
mesangial cells and mesangial matrix are located in the central or stalk regions of the
tuft (arrows). Courtesy of Helmut G Rennke.
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Electron microscopy
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Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes
(arrow). The GBM is thin and no electron dense deposits are present. Two normal platelets are seen in the capillary lumen. Courtesy of Helmut Rennke, MD.
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Possible Clinical Manifestations:
 Proteinuria: asymptomatic
 Haematuria: asymptomatic (especially dysmorphic red
cells, red cell casts)
 Hypertension
 Nephrotic syndrome
 Nephritic syndrome
 Acute renal failure
 Rapidly progressive renal failure
 End stage renal failure
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Dysmorphic erythrocytes in the
scanning electron microscope
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Red blood cell cast
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Acute Nephritic Syndrome:
Syndrome characterised in typical cases by:
haematuria
oliguria
oedema
hypertension
reduced GFR
proteinuria
fluid overload
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Phase contrast microscopy showing dysmorphic red cells in a patient with glomerular bleeding. Acanthocytes can be recognized as ring forms with vesicle-shaped protrusions (arrows). Courtesy of Hans Köhler, MD.
Clinical Features of the Acute Nephritic
Syndrome:
haematuria is usually macroscopic with smoky brown
urine (like coca cola)
oliguria may be overlooked or absent in milder cases
oedema is usually mild and is often just peri-orbital,
weight gain may be detected
hypertension common and associated with raised urea
and creatinine
proteinuria is variable but usually less than in the
nephrotic syndrome
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Etiology of the Nephritic Syndrome
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Most common cause is Acute Poststreptococcal Glomerulonephritis
Subacute Bacterial Endocarditis
Lupus Nephritis (SLE)
Anti-glomerular Basement Membrane Disease
IgA Nephropathy
ANCA-related glomerulonephritis(Wegener's granulomatosis)
Henoch-Schonlein purpura
Membranoproliferative Glomerulonephritis
Crescentic glomerulonephritis
Management issues in the nephritic
syndrome
Appropriate investigations: skin and throat swabs,strep
serology, complement, urea, creatinine, electrolytes,
urinalysis and CXR
BP, urine output and daily weight
Fluid and diet management
Treat hypertension and fluid overload
Treat infection
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Complications of the Nephritic Syndrome
Hypertensive encephalopathy (seizures, coma)
Heart Failure (pulmonary oedema)
Uraemia requiring dialysis
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Prognosis in the Nephritic Syndrome
More than 95% of children make a complete recovery.
Chronic renal impairment in the longer term is
uncommon in children.
Bad prognostic features include severe renal
impairment at presentation and continuing heavy
proteinuria and hypertension.
Adults more likely to have long term sequelae than
children.
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Acute Post-Streptococcal
Glomerulonephritis(APSGN)
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Post-streptococcal glomerulonephritis is an immunemediated disease involving:
- Streptococcal antigens (endostreptosin)
- Circulating (and in situ) immune complexes
- Activation of complement, and glomerular
infiltration of lymphocytes and macrophages in
association with cell-mediated immunity .
Poststreptococcal glomerulonephritis is prototypical
for acute endocapillary proliferative
glomerulonephritis.
APSGN: Pathogenesis
It is caused by an exogenous antigen (endostreptosin)
following infection of the pharynx or skin with strain
of group A β-hemolytic streptococcus.
Specific M proteins in group A streptococci were
initially considered “nephritogenic,”
Host susceptibility factors (HLA-DR)
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APSGN: Pathogenesis
 Studies in epidemics revealed that APSGN was
associated with pyodermitis due to Group A
streptococci of M types 47, 49, 55, 57 and 60,
and with upper respiratory infections due to
streptococci of M types 1, 2, 4, 12, 18 and 25.
 Immune complexes formed against nephritogenic
streptococcal antigen(s) may be formed in circulation,
and deposited in the glomeruli, or formed in situ
against antigenic fractions planted in the glomeruli.
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APSGN: Clinical Characteristics
 Children from 4 to 14 years are more frequently
affected by APSGN, It is rare below the age of 2
and above the age of 20.
 Twice more frequent in males than in females.
 The latent period between infection and nephritis
is longer after skin infections (3–5 weeks) than
after upper respiratory infections (1–2 weeks).
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APSGN: Clinical Characteristics
 The classic presentation is an acute nephritic syndrome with
hematuria (usually gross and the urine looks smoky brown),
pyuria, red blood cell casts, edema, hypertension, and oliguric
renal failure, which may, exceptionally, be severe enough to
appear as RPGN (crescentic GN). and more rarely with heavy
proteinuria (nephrotic).
 Systemic symptoms of slight fever, headache, nausea, malaise,
anorexia, and flank pain (due to swelling of the renal capsule) are
reported in as many as 50% of cases.
 Subclinical disease is characterized by a reduction of serum
complement, microscopic hematuria and normal or increased
blood pressure in asymptomatic patients.
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APSGN: Serological Findings
 The most constant serological finding is the reduction in serum
complement levels that occurs in more than 90% of the cases. The
activation of the complement system is usually via the alternative
complement pathway and reduced C3 with normal C1 and C4.
 IgG and IgM serum levels are elevated in 80–90% of the patients
with APSGN.
 Rising antistreptococcal antibody titers are the usual clinical
indication of a preceding streptococcal infection since positive
cultures are obtained in only 20–25% of the cases.
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APSGN: Serological Findings
 Antistreptolysin O titers and anti-DNAse B titers
are the most frequently elevated antibody titers
after streptococcal throat infections and after
streptococcal skin infection, respectively.
 Throat cultures are usually negative by the time patient
presents with GN, but ASLO, anti-DNAse B should be high
along with low complements.
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APSGN: Pathology
Renal biopsy is usually not done in patients with APSGN.
If the clinical presentation is atypical or resolution of the
disease delayed, then renal biopsy is mandatory:
1- The serum complement is normal
2- The serum complement remains low after 8 weeks
3- Proteinuria in the nephrotic range
4- Depressed GFR > 3 – 4 weeks
5- Gross hematuria > 2 - 3 weeks.
6- Persistent proteinuria > 3 - 6 months
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7- Hypertension > 2 – 3 weeks
8- Severe anuria and rapid progressive course
APSGN: Pathology
 Biopsy findings in APSGN are those of endocapillary proliferative
glomerulonephritis. glomeuli enlarged due to swelling and
hypercellularity ( mesangial and endothelial cell proliferation).
Glomerular basement membrane is normal. Macrophages and
lymphocytes can be found in increased numbers in the glomeruli
and in tubulointerstitial areas.
 the more remarkable histologic characteristics are found in the
glomeruli that present a diffuse increment in cellularity.
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 The immunofluorescent appearance: Glomerular granular
subendothelial immune deposits C3, IgG and IgM are usually present
and they may be demonstrated in the mesangium and in the
glomerular basement membrane.
APSGN: Pathology
The hallmark of APSGN is the electron microscopy findings
of large subepithelial deposits ( humps ), believed to be
immune complexes formed in situ against antigenic fractions
planted in the glomeruli.
Follow-up studies performed several years after the initial
episode of acute poststreptococcal glomerulonephritis,have
revealed immune deposits and a variable degree of mesangial
sclerosis and obliteration, even in the absence of clinical
manifestations of renal disease.
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APSGN: Pathology
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APSGN: Pathology
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APSGN: Diagnosis
 The clinical presentation is that of a child of 4–15 years
who suddenly develops dark and scanty urine and
swelling of the face and legs.
 History and physical examination determines a high blood
pressure and the absence of a systemic illness.
 A history of a precedent upper respiratory infection and/or
skin infections suggests a post-streptococcal etiology that
maybe confirmed by a positive culture or rising antistreptococcal antibody titers.
 The serum complement C3 is low.
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APSGN: Differential Diagnosis
The complement is a first line diagnostic test that permits
consideration of acute glomerulonephritis that present low (C3):
 APSGN
 Lupus nephritis
 shunt nephritis
 endocarditis
 cryoglobulinemia
 membranoproliferative glomerulonephritis
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The reduction of C1, C4 and C3 levels, indicating activation
of the classic pathway of complement, is characteristic of
lupus erythematosus.
APSGN: Treatment
Antibiotic treatment for streptococcus: Even without infection
(penicillin or, in allergic individuals, erythromycin) should be
given to all patients and their cohabitants.
Antibiotic treatment after the onset of APSGN does not alter
the course of the disease. Antibiotic prophylaxis given to
family members may reduce the risk of spread of APSGN.
Treatment of the Acute Nephritic Syndrome: Supportive
 Restrictions of fluid and sodium intake are the cornerstones
of the treatment.
 Cases that present significant edema, hypertension and
circulatory congestion benefit from the administration of
loop diuretics.
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APSGN: Treatment
 Antihypertensive treatment in cases of severe hypertension:
Nifedipine, Parenteral hydralazine may be required with close
observation. Angiotensin converting enzyme inhibitors carry the
risk of hyperkalemia.
 Hemodialysis or peritoneal dialysis may be required
occasionally in children for the treatment of hyperkalemia,
uremia or severe circulatory congestion.
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 Steroids are not generally indicated but are used in patients who
have renal failure or rapidly progressive GN, which is usually
associated with crescentic APSGN.
There are reports of beneficial effects of pulse
methyprednisolone therapy.
APSGN: Prognosis
Majority of children with APSGN are believed to make a full
recovery without significant long-term consequences.
Recurrences of APSGN are rare.
Progression to chronic kidney disease (CKD) and end-stage
renal disease (ESRD) may occur in exceptionally severe
cases of APSGN.
Complete resolution of the hematuria and proteinuria in
children occurs within 3–6 weeks of the onset of nephritis.
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APSGN: Follow-up
Follow-up of APSGN is important to document full recovery.
 Proteinuria usually resolves by 6–8 weeks. Prolonged
proteinuria for more than 3 months may indicate irreversible renal
injury.
 Gross hematuria usually improves within 1–3 weeks.
 Microscopic hematuria can persist for up to 1 year and is not an
indicator of poor prognosis.
 Recovery of serum complement C3 to normal usually takes 6–8
weeks. Persistent hypocomplementemia beyond 8 weeks requires
a careful search for other diagnoses, such as MPGN and SLE
nephritis.
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Other acute post-infectious GN
Acute GN follows other infections:
 Bacterial sepsis
 Acute or subacute bacterial endocarditis
 Visceral abscess
 Infected ventriculoperitoneal shunt
 Osteomyelitis
Treatment is aimed at eradicating the primary
disease.
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IgA Nephropathy (Berger’s Disease)
IgA nephropathy (IgA N) is the most frequent type of chronic
glomerulonephritis in children.
Pathogenesis:
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IgA N is generally considered to be an immune complexmediated or aggregated IgA - mediated glomerulonephritis.
Genetic factors have been suggested as important in
the development of IgA Nephropathy.
Because of the frequent association between upper respiratory
tract or gastrointestinal infection and the onset of macroscopic
hematuria, It has been suggested that certain viral or bacterial
infections may lead to IgA nephropathy.
IgA Nephropathy: Pathogenesis
Many antigens, including herpes simplex virus, cytomegalovirus,
Epstein-Barr virus, adenovirus and milk antigen, have been
Identified.
Circulating IgA immune complexes have been detected, often
associated with IgG immune complex.
Serum levels of IgA are increased in 50–70% of patients with IgA
nephropathy,
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IgA production is T cell-dependent, and the increased production
in IgA nephropathy may indicate altered T cell function.
IgA Nephropathy: Pathology
Light microscopic findings: are quite variable, often
mild to moderate mesangial cell proliferation.
The most characteristic abnormality is mesangial
enlargement, caused by various combinations of
hypercellularity and increase in matrix.
Progression of IgA nephropathy leads to gradual
resolution of mesangial hypercellularity and an
increase of matrix associated with The development
of sclerosis.
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IgA Nephropathy:
Pathology
Immunofluorescence (IF):
- The diagnostic immunopathological pattern of IgAN
is the presence of IgA in the glomerular mesangium
as the sole or predominant Ig (IgA1 deposits).
- There are also deposits of IgG and/or IgM with the
same staining pattern as IgA but with lesser intensity
and frequency.
- C3 deposits were observed in a similar distribution
pattern in 64% of cases.
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IgA Nephropathy: Clinical Features
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IgA N occurs at all ages but is most common during the second
and third decades of life.
Male > Females 2 to 1
The clinical presentation varies:
 Some patients have asymptomatic persistent microscopic hematuria
with or without proteinuria.
 Another classic presentation is recurrent episodes of macroscopic
haematuria typically occur during a URI (less frequently, in association
with other infections) and clearing after a period of 2–4 days. The
interval between the precipitating infection and the appearance of
hematuria ranges from 1 to 2 days compared with 1 or 2 weeks in acute
postinfectious glomerulonephritis.
IgA Nephropathy: Clinical Features
 The blood pressure and renal function at onset are normal.
 Hypertension is infrequent and usually mild to moderate.
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 Some patients present with acute nephritic syndrome or nephrotic
syndrome.
 Renal function is usually normal but occasionally a patient will present
with acute renal failure due to acute tubular necrosis secondary to the
gross haematuria.
 Less than 5% have chronic renal insufficiency (CRI) at diagnosis
 Some patients develop extensive crescents and arapidly progressive
course.
IgA Nephropathy: Diagnosis
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 There is no specific serologic marker for IgA
Nephropathy.
 Diagnosis depends on IF examination:
The presence of IgA as the sole or predominant Ig in the
glomerular mesangium.
 Serum concentrations of C3 and C4 are normal.
 Although serum IgA level is usually above the mean and
often significantly elevated,
the sensitivity and specificity are too low for its use
as a diagnostic test.
IgA Nephropathy: Management
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 There is no clear guidelines for the treatment of pediatric IgA N.
 Aggressive control of blood pressure and proteinuria with
ACEI’s or AR2B’s.
 Combination therapy with ACEI and AR2B has an additive
dose-dependent antiproteinuric effect compared to
monotherapies.
 Corticosteroid therapy is indicated for pediatric patients with IgA N
who have the nephrotic syndrome.
 Rapidly progressive or severe crescentic IgA N are usually
treated with high-dose intravenous methylprednisolone pulses
followed by oral corticosteroids and sometimes other
immunosuppressive agents such as cyclophosphamide.
IgA Nephropathy: Prognosis
 The outcome for pediatric patients with IgA N ranges from complete
resolution of all clinical signs of disease to ESRD.
 Slowly progressive.
 By 20 years, 50% have end stage kidney disease.
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 Clinical markers at diagnosis that associate with worse
prognosis and progression to CRI and/or ESRD are:
1- proteinuria >1g/day
2- severe histologic features such as the presence of
crescents and/or segmental sclerosis, glomerular fibrosis.
3- hypertension.
4- increased creatinine.
Rapidly Progressive GN (RPGN)
Rapidly progressive glomerulonephritis (RPGN), or crescentic
glomerulonephritis, is a clinicopathologic condition that is
characterized by a rapid deterioration of renal function and
demonstration of ‘crescents’ affecting at least 50% of the
glomeruli in an adequate biopsy specimen.
Severely affected glomeruli may eventually progress to global
sclerosis.
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The crescents are believed to be the result of severe nonspecific glomerular injury, with numerous underlying causes.
RPGN: Classification
Current classification of RPGN is based on the nature of
immune deposits seen in the renal biopsy. It is categorized as:
 Immune complex-mediated: MPGN, IgA nephropathy, SLE
nephritis, Henoch–Schönlein purpura nephritis, APSGN.
 Anti-glomerular basement membrane (anti-GBM) antibody
mediated: Binding of circulating autoantibodies to the GBM.
 Pauci-immune: Extensive glomerular crescent formation
without evidence of immune complex or anti-GBM antibody
deposition, such as Wegener’s granulomatosis ( ANCA related).
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Anti-GBM antibody mediated RPGN is the most aggressive form of
RPGN, and accounts for approximately 12% of pediatric cases.
RPGN: Clinical manifestations
The manifestations of RPGN can vary from asymptomatic
proteinuria and hematuria, or increased serum creatinine, to lifethreatening renal failure or hypertensive crisis.
Nephritic features such as hypertension, oliguria, hematuria, or
nephrotic syndrome are also frequently present.
Renal failure, requiring dialysis, may be present at the time of
initial diagnosis, or develop subsequently over days to weeks.
Even in asymptomatic cases, progressive renal disease and
declining kidney function is common.
Indicators of poor renal prognosis are: impaired renal function at
onset, and large percentage fibrous crescents on renal biopsy.
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RPGN: Diagnosis
 Nephritic urinary sediment : red cells, white cells, red cell casts, white
cell casts, hyaline casts.
 Serology: depends on underlying disease.
 Immediate hospitalisation and biopsy:
 Crescentic GN : Proliferation of epithelial cells surrounding the
glomerulus, but within Bowman’s space.
 If IgG present in linear stain along the GBM, consistent with anti GBM
antibiodies, which is a marker of Goodpasture’s syndrome.
 Presence of IgG and complement in a granular staining on the
capillary wall suggests an immune complex associated disease such as
lupus, IgA nephropathy or APSGN.
 Absence of immune deposition suggests a vasculitic process such as
Wegener’s granulomatosis or microscopic polyangiitis.
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RPGN: Treatment
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The standard treatment of RPGN consists of glucocorticoids and
cytotoxic drugs.
Intravenous methylprednisolone pulses: 20 mg/kg on alternate
days for six doses. followed by oral prednisone: 2 mg/kg/day
gradually tapered over 1 year .
Monthly intravenous cyclophosphamide infusions at a dose of
500-1000 mg/m2/dose for 6 months.
Maintenance therapy with azathioprine (2 mg/kg/day) was
recommended for 12 months after remission.
The combination of high-dose steroids and cyclophosphamide is
effective in inducing remission in up to 90% of adult patients with
RPGN.
RPGN: Goodpasture’s Syndrome
Autoimmune
Commonly 2nd-3rd decade and second peak in
60 years age group.
 Some present with renal involvement
(Goodpasture’s disease).
 Some present with pulmonary haemorrhage
and nephritis (Goodpasture’s syndrome).
 Rarely some present with only pulmonary
involvement.
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Goodpasture’s Syndrome
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RPGN: Goodpasture’s Syndrome
 Classic : haemoptysis after upper respiratory
infection and have nephritic urinary sediment.
 History of smoking or hydrocarbon exposure is
common.
 CXR: pulmonary haemorrhage.
 Lab: iron deficiency anaemia and renal dysfunction,
circulating anti-GBM antibodies.
 Kidney biopsy: crescentic GN with linear staining IgG
and C3 along the glomerular basement membrane.
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RPGN: Goodpasture’s Syndrome
 Treatment:
 High dose IV methylprednisolone pulses:
(20 mg/kg daily for 3 days) followed by oral
prednisolone and cyclophosphamide.
 Plasma exchange every other day until anti-GBM Ab
titer is negative.
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Membranous nephropathy
Membranous nephropathy (MN) is the most common cause of
nephrotic syndrome in older adults, and although more common
in the adult population, has been described in children, and even
in the newborn.
The disease is defined by the presence of subepithelial immune
deposits (between the GBM and the podocyte).
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In childhood: Idiopathic MN is a relatively rare cause of nephrotic
syndrome. By contrast, MN in children is more often due to
secondary causes such as SLE, hepatitis B, drugs and toxins.
MN: Pathogenesis
The presence of immune complexes in the subepithelial space
suggests in situ formation of immune complexes involving
podocyte antigens, or planted exogenous antigens, because the
layer of endothelial cells and the GBM provide an effective barrier
to the passage of pre-formed circulating immune complexes.
In idiopathic MN: the autoantibodies react to an endogenous
antigen on the podocyte foot process.
In secondary MN: reaction of antibody to an exogenous antigen
which has trapped in the subepithelial space (planted antigen).
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MN: Pathogenesis
Common secondary causes of MN:
 Infections: Hepatitis B, rarely Hepatitis C, syphilis.
 Drugs: Penicillamine, gold, captopril, NSAID’s.
 Autoimmune diseases : SLE
 Malignancies
MN is an example of Immune-mediated podocyte injury,
which results from complement activation (alternate pathway).
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The podocyte and GBM abnormalities can largely explain the
marked proteinuria that typically develops in MN.
MN: Pathology
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Light Microscopy:
Diffuse thickening of the GBM. Glomerular cellularity is typically
normal. The presence of mesangial hypercellularity or leukocyte
infiltration suggests a secondary form of MN.
Immunofluorescence:
Finely granular deposits of IgG in a subepithelial distribution on
the outer surface of the GBM.
Complement C3 is present in about 50% of adult patients.
Electron Microscopy:
Effacement of podocyte foot processes overlying the areas of
electron dense deposits, new layers of GBM are laid down over
this electron-dense deposits.
MN: Clinical manifestations
Age at presentation can vary from neonatal to young
adulthood, but the mean age is typically 8–10 years.
MN in childhood affects males and females fairly equally.
Typically presents with either asymptomatic proteinuria, or
with features of nephrotic syndrome.
Proteinuria is typically within the nephrotic range (90%).
Microhematuria is common (80%).
Gross hematuria occurs in approximately 40%.
Hypertension at onset is uncommon.
Renal function is typically normal at presentation.
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Treatment of Idiopathic MN
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Exclusion of secondary causes of the disease.
Non-Immunosuppressive Therapy :
 Angiotensin converting enzyme (ACE) inhibitor or angiotensin
receptor blocker (ARB) therapy are renoprotective.
 Blood pressure should be controlled.
 Lipid lowering therapy (statins) for hypercholesterolaemia.
 Low dose aspirin therapy may be used, if increased risk of
venous thrombosis.
Immunosuppressive therapy:
Usually reserved for those with risk factors for disease
progression. Steroid therapy in children with nephrotic syndrome.
If steroid resistant: addition of cyclophosphamide or cyclosporin.
MN: Prognosis
The prognosis in children is much better than in adults,
however, overall about 25% progress to chronic kidney disease.
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 The most important prognostic indicator in children is the
presence of nephrotic syndrome.
Other adverse risk factors:
 The renal biopsy findings: degree of glomerular sclerosis and
Interstitial fibrosis.
 Age: older than 10 years.
 Hypertension at onset.
 The presence of renal vein thrombosis.
Membranoproliferative
Glomerulonephritis(MPGN)
MPGN is uncommon histologic lesion associated with the
childhood nephrotic syndrome.
While primary (idiopathic) MPGN is more common, MPGN has
also been described as a consequence of other disorders.
Pathogenesis: MPGN I: Circulating immune complexes composed of
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[IgG (antibody)-unknown antigen-C3] which deposit in the
subendothelial glomerular space, giving rise
to a response that includes marked mesangial proliferation.
MPGN II (Dense Deposit Disease: DDD): Circulating IgG autoantibody
(nephritic factor) that activates complement via the alternative
pathway. Excessive activation of C3 by unregulated C3 convertase
(mutations in factor H?)
MPGN III: Uncertain
MPGN: Classification
MPGN type I:
 Idiopathic ( primary): familial
 Secondary: - Malignancy (B-cell lymphoma, Non-Hodgkin’s lymphoma)
- Immunologic (Cryoglobulinemia, SLE, Complement
deficiencies)
- Infectious (Hepatitis C, rarely Hepatitis B, HIV)
- Other (Heroin abuse, Partial lipodystrophy )
MPGN type II (Dense Deposit Disease: DDD):
 Idiopathic( primary): familial
 Complement deficiencies
 Partial lipodystrophy
MPGN type III:
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Idiopathic( primary): familial
MPGN: Pathology
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On light microscopy: all forms of MPGN are characterized by
an increased mesangial matrix and cellularity, capillary wall
thickening, a splitting of the GBM (double contour called tramtracking), and a characteristic lobular appearance of the glomeruli.
Immunofluorescence: IF staining is positive for C3 and IgG in
MPGN types I and III, and C3 alone are seen in dense deposit
disease (MPGN type II).
Electron microscopy: Based on the nature and location of the
electron-dense deposits, MPGN is classified into three subtypes.
Subendothelial deposits are seen in MPGN type I, whereas
intramembranous electron-dense deposits characterize dense
deposit disease or MPGN type II .
 Light micrograph in membranoproliferative glomerulonephritis showing a
lobular appearance of the glomerular tuft with focal areas of increased
glomerular cellularity (large arrows), mesangial expansion (*), narrowing of the
capillary lumens, and diffuse thickening of the glomerular capillary walls (small
arrows). Courtesy of Helmut Rennke, MD.
73
MPGN: Clinical Manifestation
Characteristic clinical features included an older age at
presentation, a slight female predominance.
74
The presentation of MPGN generally falls into three
categories:
 Asymptomatic micro-hematuria and proteinuria:
50% of patients.
 Nephrotic syndrome: 1/3 of patients.
 Acute nephritic syndrome with gross hematuria :
25% of patients.
MPGN: Clinical Manifestation
 Systolic hypertension in approximately 50%.
 Nearly 60% had microscopic hematuria at onset.
 75% had persistently low serum complement C3.
 50% had azotemia, relatively preserved renal
function.
 Rare patients may develop rapidly progressive
glomerulonephritis.
75
 Antecedent constitutional complaints, including
fatigue, lassitude, and weight loss, characterize the
onset in about 25% of patients with MPGN type I.
MPGN: Treatment
 Manage hypertension, ACEI/AR2B, salt restriction, diuretics,
treat HCV.
 Steroids (high dose): 2 mg/Kg (to a maximum of 80 mg),
alternate day prednisone for a minimum of 2 years.
Dose reduction thereafter is based on improvement of clinical
parameters (urinalysis, serum albumin, serum C3 level),
and glomerular morphology (degree of mesangial proliferation,
number of open capillary lumens).
76
Long-term, prednisone dose is slowly reduced if there is no
evidence for disease reactivation (increase in proteinuria,
and/or hematuria and/or decrease in serum C3 level).
MPGN: Treatment
Most patients will continue with at least some degree of
proteinuria as a result of chronic glomerular damage.
Absence of microhematuria appears to be the best clinical
indicator of disease remission.
Most patients have continued on alternate day steroids for at
least 5 years and many for much longer periods.
In the most recent report using the same alternate day
prednisone regimen, renal survival was 80% at 10 years in
those with MPGN type I.
77
 Other therapies (in patients resistant to steroids):
Cyclosporine, tacrolimus, mycophenolate.
Conclusions
 Take a history.
 Do a urine test.
 If haematuria with (proteinuria,
dysmorphic RBCs, RBC casts) → GN ?
 Exclude secondary causes.
 Biopsy is the definitive way to diagnose.
78
Acute Renal Failure
 is a rapidly progressive loss of renal function, generally
characterized by oliguria (decreased urine production,
quantified as less than 400 mL per day in adults, less than
0.5 mL/kg/h in children or less than 1 mL/kg/h in infants);
and fluid and electrolyte imbalance. AKI can result from a
variety of causes, generally classified as prerenal, intrinsic,
and postrenal. An underlying cause must be identified and
treated to arrest the progress, and dialysis may be
necessary to bridge the time gap required for treating
these fundamental causes
Causes of ARF
 Prerenal causes of AKI are those that decrease effective blood flow to the
kidney. These include systemic causes, such as low blood volume, low blood
pressure, and heart failure, as well as local changes to the blood vessels
supplying the kidney (clots, stenosis…)
 Sources of damage to the kidney itself are dubbed intrinsic. Intrinsic can be
due to damage to the glomeruli, renal tubules, or interstitium. Common
causes of each are glomerulonephritis, acute tubular necrosis (ATN), and
acute interstitial nephritis (AIN), respectively
 Postrenal is a consequence of urinary tract obstruction. This may be related
to benign prostatic hyperplasia, kidney stones, obstructed urinary catheter,
bladder stone, bladder, ureteral or renal malignancy
Chronic Renal Failure
 The most common causes of CKD are diabetes
mellitus, hypertension, and
glomerulonephritis.Together, these cause
approximately 75% of all adult cases
 http://www.youtube.com/watch?v=ikGl7DPXUK0&fea
ture=related
Chronic Renal Failure
 Presence of markers of kidney damage for three
months, as defined by structural or functional
abnormalities of the kidney with or without
decreased GFR, manifest by either pathological
abnormalities or other markers of kidney damage,
including abnormalities in the composition of blood
or urine, or abnormalities in imaging tests.
 The presence of GFR <60 mL/min/1.73 m2 for three
months, with or without other signs of kidney
damage as described above.
Am J Kidney Dis 2002; 39:S1
Diabetes
 A group of metabolic diseases in which a person has high blood sugar, either
because the body does not produce enough insulin, or because cells do not
respond to the insulin that is produced. This high blood sugar produces the
classical symptoms of polyuria (frequent urination), polydipsia (increased
thirst) and polyphagia (increased hunger).
 There are three main types of diabetes:
 Type 1 diabetes: results from the body's failure to produce insulin, and
presently requires the person to inject insulin.
 Type 2 diabetes: results from insulin resistance, a condition in which cells fail
to use insulin properly, sometimes combined with an absolute insulin
deficiency.
 Gestational diabetes: is when pregnant women, who have never had
diabetes before, have a high blood glucose level during pregnancy. It may
precede development of type 2 DM.
GFR
 Volume of fluid filtered from the renal glomerular capillaries into
the Bowman's capsule per unit time.
 Glomerular filtration rate (GFR) can be calculated by measuring
any chemical that has a steady level in the blood, and is freely
filtered but neither reabsorbed nor secreted by the kidneys. The
rate therefore measured is the quantity of the substance in the
urine that originated from a calculable volume of blood
 The GFR test measures how well your kidneys are filtering a
waste called creatinine, which is produced by the muscles. When
the kidneys aren't working as well as they should, creatinine
builds up in the blood.
Stages of CKD
 Stage 1*: GFR >= 90 mL/min/1.73 m2
 Normal or elevated GFR
 Stage 2*: GFR 60-89 (mild)
 Stage 3: GFR 30-59 (moderate)
 Stage 4: GFR 15-29 (severe; pre-HD)
 Stage 5: GFR < 15 (kidney failure)
Am J Kidney Dis 2002; 39 (S2): S1-246
Epidemiology
 19 million Americans have CKD
 Approx 435,000 have ESRD/HD
 Annual mortality rate for ESRD: 24%
Am J Kidney Dis 2002; 39(S2): S1-246
Signs & Symptoms
 General
 Fatigue & malaise
 Edema
 Ophthalmologic
 AV nicking
 Cardiac





HTN
Heart failure
Hyperkalemia
Pericarditis
CAD
 GI
 Anorexia
 Nausea/vomiting
 Dysgeusia
 Skin
 Pruritis
 Pallor
 Neurological
 MS changes
 Seizures
Uremia
 Is the clinical and laboratory syndrome, reflecting
dysfunction of all organ systems as a result of
untreated or undertreated acute or chronic renal
failure
Changes in the blood
 The kidneys work to filter toxins and waste products
out of the blood. When kidney function declines,
waste products begin to build up within the blood.
Creatine and urea build up. Phosphate also
accumulates in the blood. A build up of hydrogen ions
may also occur, leading to acidosis.
Changes in electrolytes
 Because of the resulting changes to the blood
chemistry, the electrolyte balance of the blood and
cells is disrupted. Fluid retention also results. Often
fluid retention is the first noticeable sign that the
kidneys are beginning to shut down. The resulting
water weight gain and edema in the hands and feet
signal that the kidneys are not removing waste
products and fluids as they should.
Pulmonary Edema
 as acute renal failure worsens, fluids continue
to build within the body and may begin to
collect in the air sacs of the lungs. This
condition, known as pulmonary edema, can
result in difficulty breathing, restlessness,
anxiety and wheezing. Untreated pulmonary
edema can ultimately lead to respiratory
failure. Most deaths that occur in cases of
renal failure are due to either a systemic
Why does edema occur in
patients with kidney disease?
 Edema forms in patients with kidney disease for two
reasons:
1.
a heavy loss of protein in the urine, or
2. impaired kidney (renal) function.
Heavy loss of protein in the urine
 The heavy loss of protein in the urine (over 3.0
grams per day) with its accompanying edema
is termed the nephrotic syndrome. Nephrotic
syndrome results in a reduction in the
concentration of albumin in the blood
(hypoalbuminemia). Since albumin helps to
maintain blood volume in the blood vessels, a
reduction of fluid in the blood vessels occurs.
The kidneys then register that there is
Heavy loss of protein in the urine
 The treatment of fluid retention in these patients is to
reduce the loss of protein into the urine and to
restrict salt in the diet. The loss of protein in the urine
may be reduced by the use of ACE inhibitors and
angiotensin receptor blockers (ARB's). Both
categories of drugs, which ordinarily are used to
lower blood pressure, prompt the kidneys to reduce
the loss of protein into the urine.
Impaired kidney (renal) function
 Patients who have kidney diseases that impair
renal function develop edema because of a
limitation in the kidneys' ability to excrete
sodium into the urine. Thus, patients with
kidney failure from whatever cause will
develop edema if their intake of sodium
exceeds the ability of their kidneys to excrete
the sodium. The more advanced the kidney
failure, the greater the problem of salt
Management
 Identify and treat factors associated with progression




HTN
Proteinuria
Glucose control
Treat pulmonary edema (Bipap)
Hypertension
 Target BP
 <130/80 mm Hg
 Consider several anti-HTN medications with
different mechanisms of activity




ACEs/ARBs
Diuretics
CCBs
HCTZ (less effective when GFR < 20)
Metabolic changes with CKD






Hemoglobin/hematocrit 
Bicarbonate 
Calcium
Phosphate 
PTH 
Triglycerides 
Metabolic changes…
 Monitor and treat biochemical abnormalities





Anemia
Metabolic acidosis
Mineral metabolism
Dyslipidemia
Nutrition
Anemia
 Common in CRF
 HD pts have increased rates of:
 Hospital admission
 CAD/LVH
 Reduced quality of life
 Can improve energy levels, sleep, cognitive function,
and quality of life in HD pts
Treating Anemia
 Epoetin alfa (rHuEPO; Epogen/Procrit)
 HD: 50-100 U/kg IV/SC 3x/wk
 Non-HD: 10,000 U qwk
 Darbepoetin alfa (Aranesp)
 HD: 0.45 g/kg IV/SC qwk
 Non-HD: 60 g SC q2wks
Metabolic acidosis
 Muscle catabolism
 Metabolic bone disease
 Sodium bicarbonate
 Maintain serum bicarbonate > 22 meq/L
 0.5-1.0 meq/kg per day
 Watch for sodium loading
 Volume expansion
 HTN
Mineral metabolism
 Calcium and phosphate metabolism abnormalities
associated with:
 Renal osteodystrophy
 Calciphylaxis and vascular calcification
 14 of 16 ESRD/HD pts (20-30 yrs) had calcification on
CT scan
 3 of 60 in the control group
NEJM 2000; 342(20): 1478-83
Nutrition
 Think about uremia
 Catabolic state
 Anorexia
 Decreased protein intake
 Consider assistance with a renal dietician
CV disease
 70% of HD patients have concomitant CV disease
 Heart disease leading cause of death in HD patients
 LVH can be a risk factor
Kidney Int 1995; 47(1): 186-92
Acid Base Balance
 http://www.youtube.com/watch?v=i_pTaTveCCo&feat
ure=related