29. ACUTE AND CHRONIC GLOMERULONEPHRITIS + 30. NEPHROTIC SYNDROME

Question 1

Nephritic syndrome (NS) is a clinical syndrome, which is defined as:

Answer 1

the association of hematuria,
proteinuria, and arterial hypertension with or without renal failure.

Question 2

Proteinuria values seen in nephrotic syndrome:

Answer 2

• Proteinuria is non-nephrotic proteinuria (<3 g/24 h), usually without deviations of serum levels of total protein and albumin.

Peripheral oedema is also present and is caused by sodium and water retention.
NS is caused by glomerular injury and glomerular inflammation.

Question 3

When does acute post-streptococcal glomerulonephritis occur?

Answer 3

Develops around 5-21 days (avg. 10 days) after pharyngitis, or 4-6 weeks after impetigo

Question 4

Etiology of acute GN:

Answer 4

Acute post-infectious GN can occur following infections with other bacterial and viral pathogens e.g.
Various bacteria (Streptococcus group A, C; G, Streptococcus viridans, Staphylococcus aureus, and
Viruses like EBV, CMV.

Group A beta-hemolytic streptococci!!!!!!!!!

Question 5

Pathogenesis of acute poststreptococcal glomerulonephritis:

Answer 5

Infection with nephritogenic strains of group A beta-hemolytic streptococci → immune complexes containing the streptococcal antigen deposit within the glomerular basement membrane; → complement activation (↑ consumption of complement factors) → destruction of the glomeruli → immune complex-mediated glomerulonephritis and nephritic syndrome

• implantation of the nephritogenic antigen into glomerular structures.
• molecular mimicry between streptococcal antigens and normal glomerular antigens that react with
  antibodies against streptococcal antigens
• initiates inflammatory response with infiltration of neutrophils and macrophages, with release
  of cytokines, proteases, C3 complement etc that damage the podocytes and the GBM
• damage to the podocytes allow larger molecules to filter through the glomerulus such as proteins
  and RBCs = proteinuria and hematuria
• this makes the urine darker, and oliguria occurs as the GFR is decreasing (due to glomerular
  inflammation and leukocyte infiltration)
• with oliguria, less fluid is excreted so more
  fluid is retained results in peripheral
  oedema
• with sodium and water retention, there is
  also hypertension

Question 6

Pathology of acute poststreptococcal glomerulonephritis:

Answer 6

Pathology:The most typical teature observed via light microscopy is diffuse enlargement of all glomeruli
due to hypercellularity. There is a swelling of the endothelial cells that leads to the obstruction of the
capillary loops.

Question 7

Clinical features of acute poststreptococcal glomerulonephritis:

Answer 7

Clinical features present after a latent period of 10-14 days after pharyngitis and 2-3 weeks after
pyoderma.
1. sudden onset with development of nephritic syndrome (oedema, oliguria, azotemia, hematuria and
hypertension).
2.Non-specific symptoms also may present as pallor, malaise, low-grade fever, lethargy, anorexia and
headache.
3. Gross hematuria is present in 30-70% of cases, while microscopic haematuria is present in all patients.
Macroscopic hematuria is monotonous and is described as being smoky,
cola coloured, tea coloured or rusty. It persists for 1-2 weeks and after that transforms into microscopic
hematuria.
4.Oedema usually manifest in the morning as periorbital, but also may be located in the pretibial area and
can progress to generalized oedema (anasarca) with presence of ascites and pleural effusions.
5.Hypertension
6. Bradycardia is a life-threatening clinical symptom, resulting from both swelling of the sinus node and
the brain stem heart’s regulation center.

Question 8

Complications of acute poststreptococcal glomerulonephritis:

Answer 8

1.Circulatory congestion is the most common complication in hospitalized children with APSGN. If
severe, it can lead to pulmonary oedema which represents an emergency state and requires prompt and
appropriate therapy.
- The signs of circulatory congestion are tachycardia, dyspnea, cough and orthopnoea. On auscultation,
pulmonary rales may be audible. Chest radiograph is required and shows signs of congestion.
2.Hypertensive encephalopathy is another serious complication.
- The most common clinical signs are nausea, vomiting, headache and impairment of consciousness that
varies from somnolence to coma.
Additionally, seizures, hemiparesis, amaurosis and aphasia may be observed.

Question 9

Diagnosis of acute poststreptococcal glomerulonephritis:

Answer 9

• Low-grade proteinuria and hematuria with red blood cell casts and dysmorphic erythrocytes points to the
  glomerular origin of hematuria.
  -In the initial phase, due to retention of water and salt, dilutional anemia may be seen.
• Acute renal injury presents with azotemia, dyselectrolytemia, and metabolic acidosis.
• cultures of the throat or skin should be obtained depending on the site of the initial
  infection.
• AST (ASO, streptozyme) should be measured to define the presence of pre-existing streptococcal
  infection.
  -There is a marked depression of serum hemolytic complement CH50 and C3 due to activation of the
  alternative complement pathway, which normalies in 6 to 8 weeks.
  -Additional tests are required in particular cases:
  1. chest radiography (suspected pulmonary congestion/oedema, pericardial effusions);
  2. ECG (in bradycardia/hyperkalemia);
  3. ultrasonography (kidneys with increased parenchymal echogenicity and prominent pyramids with or
  without increased size).

Question 10

Pharmacological treatment of acute poststreptococcal glomerulonephritis:

Answer 10

1.Loop diuretic (Furosemide 1-2 mg/kg/day, in anasarca 5-10 mg/kg/ 24-hour
infusion) to control the oedema syndrome and circulatory congestion;
2.Calcium channel blockers 1 mg/kg/day in hypertension after the hyperhydration correction;
3. Labetalol 0.5-1 mg/kg/h, diazoxide 2-3 mg/kg or nitropruside 0.5-2 ug/kg/min in hypertensive
encephalopathy
1.Loop diuretic (Furosemide 1-2 mg/kg/day, in anasarca 5-10 mg/kg/ 24-hour
infusion) to control the oedema syndrome and circulatory congestion;
2.Calcium channel blockers 1 mg/kg/day in hypertension after the hyperhydration correction;
3. Labetalol 0.5-1 mg/kg/h, diazoxide 2-3 mg/kg or nitropruside 0.5-2 ug/kg/min in hypertensive
encephalopathy

Question 11

Pathophysiology of IgA nephropathy:

Answer 11

an increased number of defective, circulating IgA antibodies are synthesized (often triggered by mucosal infections, i.e., upper respiratory tract and gastrointestinal infections) → IgA antibodies form immune complexes that deposit in the renal mesangium → mesangial cell and complement system activation → glomerulonephritis (type III hypersensitivity reaction)PA

Question 12

Pathology of IgA nephropathy:

Answer 12

Histology shows focal or diffuse hypercellularity with mesangial proliferation and extracellular matrix
expansion to semi-lunar structures and glomerular sclerosis.

Question 13

Treatment of IgA nephropathy:

Answer 13

-In proteinuria 0.5-1 g/24 h with/without microscopic hematuria – ACE inhibitors or angiotensin Il
receptor blockers (ARB).
-In proteinuria 1-3 g/24 h ACE inhibitors with or without ARB,
if treatment is ineffective - methylprednisolone pulses.

Question 14

Pathophysiology of rapidly progressing glomerulonephritis:

Answer 14

Breaks in the glomerular capillary wall and dysfunction of the glomerular basement membrane (GBM) → leakage of plasma proteins (e.g., coagulation factors) and passage of inflammatory cells (macrophages, T cells) into Bowman space
Release of inflammatory cytokines → damage to the membrane of Bowman space and passage of cells from the interstitium into Bowman space
This causes the formation of fibrin clots and proliferation of cells (e.g., macrophages, fibroblasts, neutrophils, epithelial cells) → crescent moon formation → compression of the glomerulus → renal dysfunction

Question 15

PSGN under electron microscopy:

Answer 15

Dome-shaped subendothelial and subepithelial antigen-antibody complexes between the capillary endothelium and the basal membrane, referred to as “humps”

Question 16

Treatment of RPGN:

Answer 16

methylprednisolone (15-20 mg/kg, max 1 g i.v. for 3 days),
cyclophosphamide (500-750 mg/m? i.v. monthly for 6 months),
plasmapheresis, prednisolone (1.5-2 mg/kg/24 h for 4 weeks with a gradual decrease) and subsequent
maintenance therapy with azathioprine, alternate intake of prednisolone,
mycophenolate mofetil (Cellcept).

Question 17

Classification of glomerulonephritis:

Answer 17

Primary glomerulonephritis:
- IgA nephropathy
- Membranoproliferative glomerulonephritis
- Goodpasture syndrome
- Idiopathic crescenticglomerulonephritis

Secondary glomerulonephritis:
- Post-infection glomerulonephritis (post-streptococcal, in endocarditis, shunt nephritis)
- Henoch-schonlein nephritis
- Systemic lupus erythematosus
- Granulomatosis with polyangitis
- Microscopic polangitis

Question 18

Nephrotic syndrome is characterized by…

Answer 18

generalized oedema, hypoalbuminuria <25g/L and massive proteinuria >40mg/m2/h or a protein/creatinine ratio in urine >2.0g/mmol

Question 19

Clinical features of APSGN appear ______ after pharyngitis and _______ after pyoderma

Answer 19

10-14 days
2-3 weeks

Question 20

Pathologic sign of RPGN:

Answer 20

Glomerular crescents in more than 50% of the glomeruli
+ nephritic syndrome with rapid deterioration of the GFR (>50%) within days or weeks

Question 21

Membranoproliferative glomerulonephritis (MPGN) definition:

Answer 21

Definition: Membranoproliferative glomerulonephritis (MPGN) is a combination of morphologically
similar, but pathogenetically different diseases characterized by glomerular hypercellularity, increased
mesangial matrix and thickening of the peripheral capillary walls . It is associated with functional
impairment of the glomerular basement membrane (GBM), leading to progressive decrease in renal
function, often to end stage renal disease.

Question 22

3 types of membranoprolifertaive glomerulonephritis disorders:

Answer 22

-Type I presents with interposition of mesangial cells and matrix between glomerular basement membrane
and endothelial cells, leading to double contour (tram lines-like)
of subendothelial electronic dense deposits.
- In type Ill, similar dense subendothelial and subepithelial deposits are observed.
- In type Il - or dense deposit disease, complement-containing solid deposits in the lamina densa of
glomerular basement membrane are found .

Question 23

Treatment of membranoproliferative glomerulonephritis:

Answer 23

• In type l and Ill MPGN, concomitant infection treatment, antiproteinuric agents : ACE inhibitors/ARB,
  antihypertensive therapy, statins, prednisolone (2 mg/kg/48 h for 1 year with subsequent dose reduction),
  pulse therapy with methylprednisolone,
  calcineurin inhibitors (cyclosporine A, tacrolimus), mycophenolate mofetil (Cell-cept), plasmapheresis are
  used. Plasmapheresis, eculizumab (antibody against
  C5).
• transfusion of fresh frozen plasma, substitution of factor H are applied in type II MPGN.

Question 24

Nephrotic syndrome is characterized by…

Answer 24

generalized oedema, hypoalbuminemia <25 g/L and
massive proteinuria >40 mg/m 2 /h or a protein/creatinine ratio in urine >0.2 g/mmol.

Question 25

Minimal change disease:

Answer 25

Light microscopy shows normally-appearing glomeruli (patent capillary loops, thin glomerular capillary
walls).
Sometimes mild mesangial hypercellularity and limited tubular lesions and interstitial fibrosis
may be seen. The immunofluorescence usually is negative.
Electron microscopy detects ultrastructural changes in podocytes and mesangium, marked effacement
of the foot processes, the cytoplasm of the cells may be enlarged, with clear vacuoles and prominence
of organelles, endothelial cell edema. Mesangial cells may also be slightly enlarged with increased
mesangial matrix. Blood vessels and basement membrane have a normal appearance.

Question 26

FOcal Segmental glomerular sclerosis:

Answer 26

Light microscopy shows sclerosis that are segmental (involving only a portion of the tuft) and focal
(involving some but not all glomeruli). The lesions preferentially and early involved the deep
juxtamedullary glomeruli. They contain hyaline material.
Synechiae are also observed. The uninvolved portion of the glomerular tuft should appear essentially
normal or finding similar to those in MCD or diffuse mesangial proliferation are observed.
Tubular atrophy and interstitial fibrosis are proportional to glomerular damage.
Electron microscopy reveals changes in the podocytes - cytoplasm degeneration, destruction of the cell
membrane, effacement of the foot processes.
Cell debris remains in their place. Paramesangial and subendothelial finely granular osmophilic deposits,
endothelial edema and increased mesangial matrix, detachment of epithelial cells from the basement
membrane are described.
5 histologic variants exist: Classic (the most frequent), perihilar, tip (the most benign), cellular and
collapsing (with the worst prognosis). FSGS is an irreversible process of sclerosis.

Question 27

Common location of edema in childhood?

Answer 27

Genital area - penis, scrotum, labia

Question 28

Nephrotic range proteinuria:

Answer 28

The nephrotic rage proteinuria is defined as protein >50 mg/kg/24 h, >40 mg/m°/h in 24 h urine
collection or protein/creatinine ratio (Uprot/Ucreatinin) in untimed urine specimens (in small children)
>0.2 g/mmol.

Question 29

Blood-chemistry changes:

Answer 29

1. Hypoproteinemia, hypoalbuminemia and dysproteinemia - increased a2- and -globulins, decreased -
   globulins. Fibrinogen is increased, antithrombin III is reduced.
   2.Hyperlipidemia - increased cholesterol, LDL and triglycerides.
2. Serum electrolytes - hypoproteinemia leads to low total calcium, but normal levels of ionized calcium.
3. BUN, creatinine, and uric

Question 30

Symptomatic therapy:

Answer 30

Mild edema could be successfully treated by limiting fluid intake up to 2/3 of the daily needs and taking
Na+ <2 mEq/kg/24 h.
Upright hypotension, serum albumin <20 g/L, GFR >75% of age and sex normal values, FeNa <0.2% are
found in hypovolemic patient. They are treated with 20% human albumin (1 g/kg for 4 hours) and loop
diuretic (Furosemide 1 mg/kg).
Hypertension, serum albumin >20 g/L, GFR <50% of age and sex normal values, FeNa >0.2% are found in
hypervolemic patient. Treatment consists of loop diuretic and potassium-sparing diuretic
(Spironolactone 2-3 mg/kg) without human albumin.
Antiproteinuric agents: ACE inhibitors (Enalapril 0.2-0.5 mg/kg/24 h) and ARB (Losartan 0.4-1.3
mg/kg/24 h) reduce the pressure in glomeruli by affecting capillary hydrostatic pressure and
permeability. In this way they reduce the proteinuria.
Treatment of dyslipidemia is required if lipid changes persist after remission. HMG-CoA reductase
inhibitors (statins) and fibrates are used along with a fat-poor diet.
Arterial hypertension (AH) treatment: AH is observed in about 19% of children with NS. Calcium
channel blockers are used for treatment in acute phase. The treatment of persistent AH requires
addition of ACE Inhibitors and/or ARB.
Treatment of hypocalcemia: Hypocalcemia is caused by the loss of 25-hydroxycholecalciferol and its
binding protein. Treatment with calcium preparation in combination with vitamin D is applied.
Prevention of thrombotic complications includes regular ambulation, avoidance of hemoconcentration
and hypovolemia, early treatment of infections, administration of warfarin (or low molecular weight
heparin) if serum albumin level is <20 g/L, fibrinogen level is>6 g/L, ATIll is >70%, and D-dimers are
>1000 ng/mL.

Question 31

Initial teatment of nephrotic syndrome:

Answer 31

Initial treatment with corticosteroids (CSs): prednisone is given in maximal dose 60 mg/m2/24 h (max.
80 mg/24 h) for 4 weeks. Remission is usually achieved between 10 and 14 days (three consecutive days
with protein-negative urine).

Question 32

When is treatment steroid resistant?

Answer 32

SRNS is characterized by a lack of urinary remission following 4 weeks of prednisone 60 mg/m2/day
followed by three intravenous pulses of methylprednisolone 1000 mg/1.73 m2/dose.

Question 33

SSNS types:

Answer 33

Steroid-dependent NS (SDNS- two consecutive relapses during corticosteroid therapy or within 14 days
of ceasing therapy),

Frequently relapsing NS (FRNS - two or more relapses within 6 months of initial
response or four or more relapses in any 12-month period).

Question 34

SSNS teatment:

Answer 34

Medications of first choice are the CNIs (cyclosporine A 3-5 mg/kg/24 h, tacrolimus 0.05-0.2 mg/kg/24
h).
Their immunosuppressive effect is caused by inhibition of calcineurin - an enzyme activating a nuclear
factor in T lymphocytes, leading to IL-2 gene expression. CNIs are T lymphocyte-selective
immunosuppressants. Nephrotoxicity is their main side effect. A second immunosuppressant could be
added if this treatment is not effective.
Usually antimetabolite is used: mycophenolate mofetil 1200 mg/m2/24 h.This drug suppresses the T and
B lymphocyte proliferation. In recent years, a very good effect of treatment with rituximab (375 mg/m2
i.v. once a week for 4 weeks) has been reported in case of resistance to previous medications.

Question 35

SRNS teatment:

Answer 35

Genetic forms of SRNS/ A monogenic defect accounts for about 66% of SRNS in the first year of life and
up to 25% in cases with onset under 25 years of age.
Genetic defects mostly affect the proteins responsible for the podocyte structure and function. More
than 50 gene mutations, leading to syndrome and non-syndrome SRNS are currently known.
Most common autosomal recessive (AR) forms of SRNS are caused by mutations in the NPHS1 gene
(nephrin-encoding gene) and in the NPHS2 gene (podocin-encoding gene).
Mutations in nephrin gene are responsible for almost all cases of congenital NS. Mutations in podocin
gene account for about 37.5% of cases of SRNS in the first 6 months of life and 10-30% of sporadic forms
of SRNS.
Most common autosomal dominant (AD) forms of SRNS are caused by mutations in the ACTN4 gene (a-
actinin-4-encoding gene) and in the TRPC6 gene (cation channel-encoding gene).
Treatment of the genetic forms of SRNC is performed with antiproteinuric agents, adequate nutrition,
prevention of complications, and improvement of lipid status.

Question 36

Complications with nephrotic syndrome:

Answer 36

Complications/Acute kidney injury most often results from hypovolemia, infection, or thrombosis. It is
often reversible. Infections are observed in about 1-2% of patients annually.
They are the leading cause of death in children with NS. The most common infections are cellulitis,
peritonitis, respiratory or urinary tract infections, non-localized bacteremia. Main pathogen is
Streptococcus pneumoniae, but E. coli, Streptococcus group B, Haemophilus influenza and other Gram-
negative microorganisms can also cause infections. The incidence of clinically manifested thrombosis is
close to 3% and this is the second most common cause of death in children with NS.
Hypercoagulability (increased platelet count with increased aggregability, increase in procoagulant
proteins such as fibrinogen and factors V and VIll, decreased level of the anticoagulant protein -
antithrombin Il), hypovolemia, reduced physical activity and infections are factors that increased the risk
for thromboembolic complications. Deep vein thrombosis (97%) is most commonly seen, but arterial
thrombosis is also possible.