Disorders of glomerular functions, nephritic and nephrotic syndrome

The **Nephritic and Nephrotic syndromes** (ICD-10: Template:MKN) represent the two primary clinical manifestations of glomerular dysfunction. While they share some features, they differ significantly in their pathophysiology, diagnostic criteria, and clinical presentation.

Nephritic Syndrome

Nephritic syndrome is characterized by a set of symptoms resulting from an inflammatory process within the glomeruli.

1.  Hematuria (dysmorphic erythrocytes in the urine).
2.  Oliguria and  azotemia.
3.  Hypertension.
4. Mild  proteinuria and edema may occur, but are not as pronounced as in nephrotic syndrome.

Lesions caused by nephritic syndrome share common features: cell proliferation within the glomerulus accompanied by a leukocytic infiltrate. The reaction resulting from inflammation destroys capillary walls, allowing erythrocytes to escape into the urine, leading to hemodynamic changes and a subsequent decrease in GFR (glomerular filtration rate). This manifests clinically as oliguria, fluid retention, and azotemia. Acute nephritic syndrome can occur secondarily (SLE) or as a result of primary glomerular disease (e.g., Post-infectious glomerulonephritis).

Acute Post-infectious Glomerulonephritis

Histology of post-infectious GN

• Synonym: Post-streptococcal glomerulonephritis.
• One of the most frequent glomerular disorders caused by immune complex (IC) deposits; common in children and young adults.
• Initial antigens can be:

• Endogenous (e.g., in SLE).
• Exogenous – β-hemolytic group A streptococci, pneumococci, staphylococci, viruses (mumps, measles, chickenpox, Hepatitis B, C).

• Classically develops 1 to 4 weeks after recovery from a group A streptococcal infection.
• Only certain (nephritogenic) strains of β-hemolytic streptococci are capable of inducing the disorder.

Pathogenesis

Deposition of IC occurs (circulating and "in situ" complexes – e.g., C3 component of complement, IgG binding to bacterial antigens trapped on the glomerular basement membrane, GBM). Subsequently, typical signs of immune complex disease, such as hypocomplementemia, develop.

Schematic representation of subepithelial "humps" (black).

Morphology

Uniform increase in cellularity of the glomerular tuft (diffuse GN) is observed due to increased proliferation and edema of mesangial and endothelial cells. Additionally, neutrophils and monocytes migrate to the site. A typical feature in electron microscopy is the presence of subepithelial humps nestled against the GBM. Immunofluorescence shows granular deposits, especially subepithelially.

Clinical Course

Onset is sudden; patients suffer from malaise, nausea, and low-grade fever. Urine has a brownish tint (gross hematuria), and mild proteinuria occurs. Serum tests show low complement levels, while serum anti-streptolysin O antibody levels are elevated. Children experience relatively frequent remissions; however, some may develop Rapidly Progressing GN (due to severe glomerular damage with "crescent" formation).

IgA Nephropathy

 For more information see IgA nephropathy.

IgA staining in a patient with Henoch-Schönlein purpura

• Synonym: Berger's disease.
• Common in children and young adults.
• It is the most common glomerular disease identified by renal biopsies worldwide.

Pathogenesis

Increased IgA synthesis in the bone marrow (response to respiratory or GIT infection) and elevated serum levels are observed in 50% of patients. Faulty glycosylation may also occur. IgA immune complexes subsequently deposit in the mesangium and activate complement via the alternative pathway.

Morphology

Lesions vary considerably (segmental inflammation, diffuse mesangial proliferation). IF displays IC IgA in the mesangium, often with a minor presence of C3, IgG, or IgM. Components required for the classical complement pathway (C1q and C4) are absent.

Clinical Course

The disease begins as gross (microscopic in 30–40% of patients) hematuria during a non-specific upper respiratory tract infection. This lasts for several days, then subsides, only to return every few months. Some experts consider IgA nephropathy a localized variant of Henoch-Schönlein purpura. Patients with celiac disease and liver disorders (secondary IgA nephropathy) are at increased risk. Chronic renal failure may develop within 20 years of onset in 25–50% of patients.

Hereditary Nephritis

• Synonym: Hereditary glomerulonephritis.
• A group of congenital diseases caused by mutations in GBM proteins, such as Alport syndrome.

Pathogenesis

Caused by a mutation in type IV collagen (found in basement membranes; necessary for the function of glomeruli, the lens, and the cochlea). It is a heterotrimer (α3, α4, α5 chains); mutations can occur in any monomer.

Morphology

Glomeruli appear normal until late stages, when secondary sclerosis may develop. Interstitial cells accumulate neutral lipids and glycosaminoglycans. As the disease progresses, glomerulosclerosis, vascular sclerosis, tubular atrophy, and interstitial fibrosis increase. Electron microscopy reveals irregular thickening of the GBM in late stages.

Clinical Course

Inheritance can be X-linked (defect in the α5 gene), AD, or AR (defect in the α3 or α4 genes). Renal failure typically appears between ages 20 and 50. It presents with hematuria and slowly progressing proteinuria.

Nephrotic Syndrome

Nephrotic syndrome (NS) is defined as a severe disorder of the glomerular basement membrane leading to massive protein loss in the urine.

NS is characterized by proteinuria followed by hypoproteinemia, hypoalbuminemia, hypercholesterolemia, and edema. It is dangerous primarily due to potential complications: infections, thromboembolic events, accelerated atherosclerosis, and protein malnutrition. Persistent nephrotic syndrome can progress to chronic renal failure. It is particularly common in children (15 times more frequent than in adults). In children, the most common cause is minimal change disease (MCD).

Diagnostic Criteria

• Proteinuria > 3.5 g/24 hours (more than 2 g/m²/day), (50 mg/kg weight);
• Decreased plasma albumin (below 30 g/l);
• Peripheral edema;
• Hypercholesterolemia > 8 mmol/l.

Pediatric Criteria:

• Proteinuria > 1 g/1 m²/24 hours;
• Serum albumin < 25 g/l.

Etiopathogenesis

Intact glomerulus

Proteinuria is caused by damage to the capillary wall of the glomerulus, resulting in increased permeability for protein macromolecules. If protein loss exceeds the liver's proteosynthetic capacity, hypoproteinemia, hyperlipidemia, and edema develop.

The glomerular capillary wall consists of:

1. Fenestrated endothelia;
2. Glomerular basement membrane (collagen IV, laminin, entactin) – blocks proteins > 100–150 kD;
3. Glomerular epithelial cells (podocytes) – the most selective barrier.

The electrostatic repulsion barrier (anionic filter) ensures selectivity by charge (prevents albumin passage). Its damage leads to selective proteinuria (albuminuria), typical for **minimal change nephrotic syndrome**. Extensive damage leads to non-selective proteinuria (loss of larger molecules like immunoglobulins).

Pathophysiological Mechanisms

• **Edema**: Loss of albumin leads to hypoalbuminemia, decreasing oncotic pressure and shifting fluid into the interstitium.
• **Infections**: Loss of immunoglobulins in urine.
• **Thrombophilia**: Caused by decreased intravascular volume, loss of antithrombin III, and thrombocytosis.
• **Hyperlipoproteinemia**: Liver stimulation due to low protein and decreased lipoprotein lipase activity.

Diseases Associated with Nephrotic Syndrome

Focal segmental glomerulosclerosis

Diabetic glomerulosclerosis

• **Primary Glomerulopathies**:
  • Minimal change disease (MCD) – common in children; 95% corticosteroid-sensitive.
  • Focal segmental glomerulosclerosis (FSGS) – only 30% corticosteroid-sensitive.
  • Membranous nephropathy.
  • Hereditary (Finnish type, Denys-Drash syndrome).
• **Secondary Glomerulopathies**:
  • Diabetic nephropathy, amyloidosis, Alport syndrome, hemolytic-uremic syndrome.
  • Lupus nephritis, Henoch-Schönlein purpura, Goodpasture syndrome.
  • Infections (Toxoplasmosis, CMV, EBV, measles).
  • Medications (NSAIDs, D-penicillamine).

Clinical Presentation

• Oliguria, edema of upper eyelids and genitals → progress to limbs, ascites, hydrothorax.
• Weight gain, thirst, foaming urine.
• Fatigue, overall malaise.
• Blood pressure is usually normal.

Complications

• **Infections**: Defective immune response; often Gram-positive (S. pneumoniae).
• **Thromboembolic events**: Especially renal vein thrombosis.
• **Lipid metabolism disorders**: High cholesterol and triglycerides; lipiduria.
• **Protein malnutrition**: Masked by edema; patients are in a severe catabolic state.

Diagnostics

• **Urinalysis**: Proteinuria > 3.5 g/24h; proteinuria/creatinine ratio; electrophoresis (selective vs. non-selective).
• **Blood tests**: Hypoproteinemia, hypoalbuminemia (< 20 g/l), hypercholesterolemia. Elevated hematocrit and platelets. High ESR.
• **Renal biopsy**: Indicated if features suggest something other than MCD (e.g., age <1 or >15, hematuria, hypertension, low C3). In MCD, EM shows podocyte foot process effacement.

Therapy

• **Symptomatic**: Fluid and salt restriction; Vit D and Calcium; anticoagulation (Aspirin); infection treatment.
• **Causal**: Prednisone (60 mg/m²/day for 6 weeks, then 40 mg/m² every other day for 6 weeks).
• **Edema**: Diuretics (Furosemide, Spironolactone); I.V. albumin in case of severe hypovolemia.
• **Refractory cases**: Cytostatics (Cyclophosphamide) or immunosuppressants (Cyclosporin A).

Prognosis

Good for MCD (95% steroid-sensitive). FSGS is often steroid-resistant, with 50% developing renal failure within 10 years.

Links

Related articles

• Nephrotic syndrome
• Nephritic syndrome
• Glomerulonephritis
• Alport syndrome

External links

• [[16](http://www.urologiepropraxi.cz/pdfs/uro/2010/03/06.pdf) Merta: Nephrotic syndrome (2010)]
• Template:Kamera[[17](https://youtube.com/watch?v=SN7uhC2JySo?&t=55) Nephritic-Nephrotic Spectrum] - YouTube

Sources

• Kumar, V., Abbas, A., Fausto, N. Robbins Basic Pathology. 8th ed. 2007. ISBN 978-1-4160-2973-1.
• Hrodek, O., Vavřinec, J. Pediatrie. Galén, 2002. ISBN 80-7262-178-5.