Nephritic syndrome

Tbilisi referral hospital, Tbilisi, Georgia

Nephrologist
Nino Maglakelidze
 Nephritic syndrome

Definition of nephritic syndrome

Acute nephritis is sudden onset of:

•Haematuria (macroscopic/microscopic ) with red cell casts or
dysmorphic RBCs
•Proteinuria in the non-nephrotic range ( <3.5g)

It is often accompanied by:

Hypertension
Edema, (peri orbital, leg and sacral)
Temporary oliguria and
Decrease glomerular filtration rate or sudden increase serum
creatinine
Pathegeneses

Acute nephritic syndrome comprise of a specific set or renal diseases

where an immune mechanism triggers inflammation causing damage
to the basement membrane, messangium or capillary endothelium
of the glomerulus.

Acute nephritic syndrome is often caused by an immune response

 triggered by an infection or other disease.
Causes of nephritic syndrome in children and adolescents:

•Hemolitic uremic syndrome (disorder that occurs when an infection

In the digestive system produces toxic substances that destroy
red blood cells and cause kidney injury)

•IgA nephropathy 

•Post-streptococcal glomerulonephritis (kidney disorder that occurs

after infection with certain strains of streptococcus bacteria)

•Goodpasture syndrome (disorder in which the immune system attacks

the glomeruli)
 Causes of nephritic syndrome in children and adolescents:

•Endocarditis (inflammation of the inside lining of the heart chambers

and heart valves caused by a bacterial or fungal infection)
•Membranoproliferative glomerulonephritis (disorder that involves
inflammation and changes to kidney cells)
•Rapidly progressive (crescentic) glomerulonephritis (a form of
glomerulonephritis that leads to a rapid loss of kidney function)
•Lupus nephritis (kidney complication of systemic lupus erythematosus)
•Vasculitis (inflammation of the blood vessels)
 Poststreptococcal glomerulonephritis

Poststreptococcal glomerulonephritis (PSGN) is caused by prior

infection with specific nephritogenic strains of group A beta-hemolytic
streptococcus.

Epidemiology:
PSGN is the most common cause of acute nephritis in children,
it primarily occurs in developing countries. 

•new annual cases of PSGN worldwide, 97 percent occur in regions of

the world with poor socioeconomic status, with an annual incidence that
ranges from 9.5 to 28.5 per 100,000 individuals

•In more developed and industrialized countries, the incidence has

continued to decrease; the estimated annual incidence was 0.3 per
100,000 individuals between 2005 and 2015
PATHOGENESIS:

PSGN appears to be caused by glomerular immune complex disease

induced by specific nephritogenic strains of group A beta-hemolytic
streptococcus (GAS). The resulting glomerular immune complex disease
triggers complement activation and inflammation.

Mechanisms for the immunologic glomerular injury induced by

beta-hemolytic streptococcus infection:
●Deposition of circulating immune complexes with streptococcal
antigenic components.
●In situ immune complex formation resulting from deposition of
streptococcal antigens within the glomerular basement membrane
(GBM) and subsequent antibody binding.
●In situ glomerular immune complex formation promoted by
antibodies to streptococcal antigens that cross-react with glomerular
components (molecular mimicry).
 Morphology of postinfective glomerulonephritis:

Light microscope:

•Light microscopy shows prominent endocapillary proliferation and

hypercelluraty with neutrophils 
 Morphology of postinfective glomerulonephritis:

Immunofluorescence microscopy 
 Immunofluorescence (IF) microscopy reveals :
A characteristic pattern of deposits of immunoglobulin G (IgG) and C3
distributed in a diffuse granular pattern within the mesangium and
glomerular capillary walls;
 Morphology of postinfective glomerulonephritis:

Electron microscopy :
The most characteristic feature detected by
electron microscopy (EM) are the dome-shaped subepithelial
electron-dense deposits that are known as humps.
CLINICAL MANIFESTATIONS:

●Edema − Generalized edema is present in approximately two-thirds

of patients due to sodium and water retention. In severe cases, fluid
overload leads to respiratory distress due to pulmonary edema.

●Gross hematuria − is present in approximately 30 to 50 percent of

patients. The urine looks smoky and tea or colacolored.

●Hypertension − Hypertension is present in 50 to 90 percent of

patients and varies from mild to severe. It is primarily caused by salt
and fluid retention.
CLINICAL MANIFESTATIONS:

●Subclinical cases of PSGN are primarily characterized by microscopic

hematuria. Such patients were often detected during epidemics.

●Some patients present with clinical symptoms related to hypertensive

crisis or edema with minor urine abnormalities.
Laboratory findings:

Renal function — PSGN is associated with a variable decline in

glomerular filtration rate (GFR) that is detected by a rise in serum
creatinine. Acute renal failure requiring dialysis is uncommon.

Urinalysis and urinary protein excretion — in patients

with PSGN reveals hematuria (some of the red cells are typically
dysmorphic) with or without red blood cell casts, varying degrees of
proteinuria, and often pyuria. Nephrotic range proteinuria is
uncommon and occurs in approximately 5 percent of cases at
presentation.
 Laboratorial finding
Complement  Factors :
In approximately 90 percent of patients, C3 and
C4 are significantly depressed in the first two weeks of the disease
course.

Serology:

•Anti-streptolysin (ASlO)

•Anti-hyaluronidase (AHase)

•Anti-streptokinase (ASKase)

•Anti-nicotinamide-adenine dinucleotidase (anti-NAD)

•Anti-DNase B antibodies.
 Indications for renal biopsy 

Kidney biopsy is usually performed in patients in whom other

glomerular disorders are being considered.

•Persistently low C3 levels beyond six weeks are suggestive of a

diagnosis of membranoproliferative glomerulonephritis as C3 levels
typically normalize in patients with PSGN by this timeframe.

•Recurrent episodes of hematuria are suggestive of IgA nephropathy

and are rare in PSGN.

•A persistent or progressive increase in serum creatinine is

uncharacteristic of PSGN, but there are occasional patients whose renal
function does not fully recover.
 ACUTE MANAGEMENT

Supportive care :

•No specific therapy is indicative for PSGN.

•Management is supportive and is focused on treating the clinical

manifestations of the disease, particularly complications due to
volume overload.

•General measures include sodium and water restriction and loop

diuretics.

•Loop diuretics generally provide a prompt diuresis with reduction

of blood pressure and edema.
 ACUTE MANAGEMENT

•Infrequently, patients have hypertensive encephalopathy due to severe

hypertension. 
These patients should be treated urgently to reduce the blood pressure.
Oral nifedipine or parenteral nicardipine are effective.

•angiotensin-converting enzyme (ACE) inhibitors should be used with

caution due to the risk of hyperkalemia. 

•Patients with PSGN have variable reductions in renal function and some
patients require dialysis during the acute episode. 
Dialysis indications:

•For patients with serious renal impairment

•Life-threatening fluid overload (pulmonary edema, heart failure,

and hypertension) that is refractory to medical therapy.

•Hyperkalemia (serum or plasma potassium >6.5 mmol/l) unresponsive

to medical therapy
Prognosis:

Most patients have an excellent outcome.

This patients who present with acute renal failure and may have
crescents on the initial renal biopsy  their kidney function recovers
totally.
 anti-GBM antibody (Goodpasture's) disease

Anti-GBM antibody disease is a disorder in which circulating antibodies

are directed against an antigen intrinsic to the glomerular basement
membrane (GBM), thereby resulting in acute or rapidly progressive
glomerulonephritis that is typically associated with crescent formation.
PATHOGENESIS 

There is short-lived production of circulating autoantibodies, which are

directed against an antigen intrinsic to the glomerular basement
membrane (GBM), in response to an unknown inciting stimulus.

The development of anti-GBM antibodies may precede the onset of

clinical signs and symptoms by many months. The principal target for
the anti-GBM antibodies (which are typically immunoglobulin G
(IgG) 1 and 3 but sometimes IgA or IgM) is the NC1 domain of the
alpha-3 chain of type IV collagen (alpha-3(IV) chain), one of six
genetically distinct gene products found in basement membrane
collagen.

The epitope of type IV collagen specifically recognized by anti-GBM

antibodies may correlate with the prognosis of the disease. 
EPIDEMIOLOGY

Acute glomerulonephritis due to anti-GBM antibody disease is rare,

estimated to occur in fewer than one case per million population;

Crescentic glomerulonephritis due to anti-GBM antibody disease

accounted for fewer than 3 percent of all kidney biopsies.
 EPIDEMIOLOGY

The diagnosis of anti-GBM disease is made in older children and in

adults of all ages. However, younger patients (<30 years) are more
likely to present with the full constellation of Goodpasture's syndrome
(eg, with pulmonary hemorrhage), and older patients (>50 years)
with isolated glomerulonephritis.

There appears to be a slight male predominance in the younger age

group, and a female predominance in the older age group.
 CLINICAL PRESENTATION 

•Hematuria

•Nephritic range proteinuria

•Nephritic sediment - dysmorphic red blood cells, red blood cell casts.

•Rapidly progressive renal failure over weeks

•With or without pulmonary hemorrhage

 Pulmonary manifestation:
•Pulmonary involvement, generally consisting of alveolar hemorrhage,

•affects approximately 40 to 60 percent of patients; 

•Pulmonary manifestations include shortness of breath,

•cough,

•sometimes overt hemoptysis,

•pulmonary infiltrates on chest x-ray.

Pulmonary CT scan of Goodpasture syndrome
 CLINICAL PRESENTATION

Iron deficiency anemia, possibly due to prolonged pulmonary bleeding,

may be seen. 

A rare variant of anti-GBM antibody disease, known as "atypical

anti-GBM nephritis," has been reported in a series of 20 patients who
presented with hematuria, proteinuria, and mild renal insufficiency,
without pulmonary hemorrhage.

Renal biopsy in these patients demonstrated bright linear

immunoglobulin G (IgG) deposition along the GBM but without features
of crescentic glomerulonephritis.

These atypical cases accounted for approximately 12 percent of

anti-GBM patients.
DIAGNOSIS

The presence of anti-GBM antibody disease should be

suspected in any patient with acute glomerulonephritis, particularly if
accompanied by rapid progression and/or pulmonary (alveolar)
hemorrhage. 

The diagnosis of anti-GBM antibody disease requires demonstration

of anti-GBM antibodies either in the serum or the kidney biopsy. 
Kidney biopsy 

Light microscopy usually shows crescentic glomerulonephritis.

Kideny biopsy 

Immunofluorescence microscopy demonstrates the virtually

pathognomonic finding of linear deposition of immunoglobulin G (IgG)
along the glomerular capillaries and occasionally the distal tubules.
Kidney biopsy

Electron microscope show granular deposits of antigen-antibody

complexes along the glomerular basement membrane.
Serologic testing

•anti-GBM antibodies; (using a direct enzyme-linked immunoassay

ELISA)

•In 10 and 50 percent of patients with anti-GBM antibody disease

also test positively for ANCA 
Treatment:

•it is recommended to begin treatment with high-dose corticosteroids

1.0 mg/kg maximum dose 60-80mg per day;

•in combination with cyclophosphamide 0.5 -1.0 mg/m2 monthly

•plus plasmapheresis 14 sessions or until serum anti-GBM antibodies

become undetectable in serum;

•It is not recommended no maintenance immunosuppressive therapy

for anti-GBM GN;
PROGNOSIS 

Renal and patient survival correlates closely with the degree of renal
impairment at presentation.

Patients with moderate to severe disease who do not require dialysis

upon presentation generally respond to therapy

Patients who require immediate dialysis at presentation does not

escape the need for maintenance dialysis.
 Hemolytic - uremic syndrome

The hemolytic uremic syndrome (HUS) is defined by the simultaneous

occurrence of

hemolytic anemia,

thrombocytopenia,

and acute kidney injury.

 Classification of hemolytic uremic syndrome:

HUS had been divided into:

diarrhea-positive (resulted from Shiga toxin-producing Escherichia coli

(STEC) infections and less frequently from Shigella dysenteriae
type 1 infection).

and diarrhea-negative HUS.  (such as cases due to complement

dysregulation (also referred to as atypical HUS)

Complement gene mutations

Antibodies to complement factor H
 Gene affected gene for non-STEC-HUS cases

Complement factor H (CFH, 20 to 30 percent)

CD46, previously known as membrane cofactor protein

(5 to 15 percent)

Complement factor I (CFI, 4 to 10 percent)

Complement factor 3 (C3, 2 to 10 percent)

Complement factor B (CFB, 1 to 4 percent)

Thrombomodulin gene (THBD, 3 to 5 percent)

Thrombotic thrombocytopenic purpura 

Thrombotic thrombocytopenic purpura (TTP) is due to deficient

activity of the Von Willebrand factor cleaving protease.

TTP can be congenital and acquired.

TTP is usually due to mutations of the ADAMTS13 gene.

Affected children usually present at birth with hemolytic anemia and

thrombocytopenia. Nervous system is affected, the patient may have
Confusion, seizures and etc. Renal involvement often occurs.

TTP is distinguished from HUS by abnormally low ADAMTS13 activity.

DIAGNOSIS — The diagnosis of hemolytic uremic syndrome (HUS)
is clinically based on the presence of the classical triad of
microangiopathic hemolytic anemia, thrombocytopenia and acute
kidney injury.

•The microangiopathic hemolytic anemia is established by a

hemoglobin level less than 8 g/dL with a negative Coomb's test and a
peripheral blood smear demonstrating a large number of schistocytes
(up to 10 percent of red cells).

•Thrombocytopenia is characterized by a platelet count below 

140,000/mm3 and is usually approximately 40,000/mm3. Despite the
low platelet count, there is typically no purpura or active bleeding.
The degree of thrombocytopenia is unrelated to the severity of renal
dysfunction.
DIAGNOSIS 

•Elevated lactate dehydrogenase level and low level of haptoglobine.

•Acute kidney injury − The severity of renal involvement ranges from

hematuria and proteinuria to severe renal failure (usually identified by
abnormally elevated serum creatinine and blood urea nitrogen [BUN]
levels) and oligoanuria. Severe renal failure occurs in one-half of cases.

•Hypertension is common, particularly after the administration of excess

fluids or blood transfusions.

•Most patients have microscopic hematuria on urinalysis, although

macroscopic hematuria may be observed. Red blood cell casts are
occasionally seen, but are not a typical feature.
DIAGNOSIS 

•Screening for Shiga toxin-producing bacterial strains to differentiate

STEC HUS from other forms of HUS. This includes testing for Shiga toxins
(eg, ELISA) in the stool, stool cultures, and serologic testing for IgM and
anti-lipopolysaccharide antibodies against the most frequent STEC
serotypes. 

•Assessing ADAMTS 13 function to differentiate HUS from thrombotic

thrombocytopenic purpura (TTP).
Kidney biopsy
Renal histology typically demonstrates glomerular thrombotic
microangiopathy in patients with STEC HUS, characterized by a thickening
of the capillary walls, with a double-contour appearance due to a
widening of the subendothelial space. In patients with complement-
mediated HUS, the renal histological lesion is most often arteriolar
thrombotic microangiopathy.
TREATMENT
 The management of hemolytic uremic syndrome (HUS) is supportive.
Use of the following interventions is primarily based on data from
observational studies of patients with Shiga toxin-producing
E. coli (STEC) HUS.

•Red blood cell transfusions for anemia when clinically indicated;

(eg, hemoglobin level reaches 6 to 7 g/dL or hematocrit <18 percent).

•Platelet transfusion for patients who have significant clinical bleeding.

•Appropriate fluid and electrolyte management to maintain adequate
intravascular volume and correct/avoid electrolyte abnormalities.

•Initiation of dialysis therapy in patients with symptomatic uremia,

severe fluid overload, or electrolyte abnormality that is refractory
to medical therapy.

•Provision of adequate nutrition.

TREATMENT

Treatment of complement-mediated HUS

•Plasma exchange or infusion

•Eculizumab, a monoclonal antibody to C5 that blocks the terminal

complement cascade

•Renal or combination renal-hepatic transplantation.

Treatmemt of Thrombotic thrombocytopenic purpura

 Fresh frozen plasma infusion

Plasma exchange

Steroids