Renal Disease: Glomerular Disorders and Glomerulonephritis

• Renal diseases are conditions that affect renal function.
• They can be classified as glomerular, tubular, or interstitial.

Glomerular Disorders

• The main cause of glomerular disorders is immune complexes.

• Deposition of immune complexes triggers an immune reaction that produces changes/damages in the glomerular membrane.

• This results in thickening of the glomerular membrane or complement activation.

• Non-immunologic causes of glomerular disorders:

  • Exposure to chemicals and toxins
  • Disruption of the negative charge of the membrane, leading to nephrotic syndrome
  • Deposition of amyloid material
  • Thickening of the membrane caused by diabetic nephropathy

• Two categories of glomerular disorders include glomerulonephritis and nephrotic syndrome.

Glomerulonephritis

• Glomerulonephritis is characterized by sterile inflammation.
• There is presence of blood, protein, and casts in the urine
• Can progress from acute to chronic to nephrotic syndrome and eventually end-stage renal disease (ESRD).

Acute Post-streptococcal Glomerulonephritis

• Acute glomerulonephritis (AGN) has a sudden onset of symptoms due to glomerular damage.

• Symptoms include fever, edema (most noticeably around the eyes), fatigue, nausea, hypertension, oliguria, proteinuria, and hematuria.

• Main cause is infection by B-hemolytic streptococcus, and M protein is the virulence factor.

• An Antibody + organism complex deposited in the glomerular membrane causes inflammation reaction.

• Main findings:

  • Marked hematuria; this only disappears when glomerular damage is repaired
  • Proteinuria
  • Oliguria
  • RBC casts, which are a hallmark of AGN
  • Dysmorphic RBCs
  • Hyaline & Granular Casts

• Other findings:

  • Increased BUN
  • (+) ASO
  • (+) Anti-DNAse B, which are diagnostic tests for Streptococcal infection

Rapidly Progressive Glomerulonephritis

• Rapidly progressive (crescentic) glomerulonephritis is more serious and has a poorer prognosis.
• Main cause is deposition of immune complexes as a result of complication of another glomerulonephritis or immune disorders.
• Immune complexes attract macrophages to damage capillary walls.
• Damaged capillary walls release cells and plasma to Bowman's capsule.
• Cells & plasma proteins lead to crescentic formation, which destroys capillaries and is irreversible.
• Findings include being similar to AGN but worsens as the disease progresses
• There is marked proteinuria, decreased GFR, increased fibrin degradation products and IgA deposition in the glomerular membrane.

Good Pasteur Syndrome

• Autoimmune disorder is caused by anti-glomerular membrane antibody.
• Autoantibody binds to glomerular membrane, causing complement activation.
• Complement damages the membrane and surrounding capillaries.
• Diagnosis is made by a (+) anti-glomerular membrane antibody in patient’s serum.
• Findings include hemoptysis and dyspnea followed by hematuria, proteinuria and presence of RBC casts.
• This can progress to chronic glomerulonephritis and end-stage renal disease if left unmanaged.

Granulomatosis with Polyangiitis

• Formerly Wegener’s Granulomatosis
• Caused by anti-neutrophilic cytoplasmic antibody (autoantibody).
• ANCA binds to neutrophils, causing them to activate and leading to granuloma formation.
• Findings include initial respiratory symptoms and later renal involvement, hematuria, proteinuria, RBC casts and increased creatinine & BUN levels.
• Diagnosis includes (+) ANCA in patient’s serum.
  • Incubate patient’s serum + ethanol or formalin-fixed neutrophils
  • Indirect immunofixation is done to detect ANCA
  • Results in:
    • Ethanol-fixed neutrophils: perinuclear pattern (p-ANCA)
    • Formalin-fixed neutrophils: granular pattern in the cytoplasm (c-ANCA)

Henoch-Schonlein Purpura

• Occurs in children following upper respiratory infections.
• Decreased platelets cause vascular problems
• Findings include respiratory & gastrointestinal symptoms.
• Renal Involvement is a serious complication.
  • Heavy proteinuria
  • Hematuria
  • RBC Casts
• Complete recovery occurs in over 50% of patients.
• Some may progress to a more serious form of glomerulonephritis and renal failure.

Membranous Glomerulonephritis

• The deposition of IgG complexes causes thickening of the glomerular membrane.
• Disease is associated with deposition of IgG complex.
  • SLE
  • Sjogren syndrome
  • Hepatitis B
  • Secondary syphilis
  • Mercury treatments
  • Malignancy
• 70% of cases are idiopathic
• Disease slowly progresses and can develop to nephrotic syndrome.
  • Hematuria
  • RBC Casts (rare)

Membranoproliferative Glomerulonephritis

• There are changes in cellularity of the glomerulus and capillaries.
• Very poor prognosis
• It can be 1 of 3 types:
  • Type 1:
    • Increased cellularity in Bowman’s capsule leads to thickening of the membrane
    • Progresses to nephrotic syndrome
  • Type 2:
    • A "dense deposit disease"
    • Dense deposits in basement membrane, tubules and Bowman’s capsule
    • Exhibits symptoms of chronic glomerulonephritis
  • Type 3
    • Has endothelial and sub-endothelial deposits

Chronic Glomerulonephritis

• It is caused by significant damage to the glomerulus from acute glomerulonephritis.
• Findings include fatigue, anemia, hypertension, edema, and oliguria, increased serum creatinine and BUN levels, proteinuria and hematuria with various casts.
• Broad cast means chronic glomerulonephritis is already progressing to end-stage renal disease (ESRD).

IgA Nephropathy

• The disease is also known as Berger’s Disease.
• Mucosal infection with increased IgA complexes gets deposited in the glomerular membrane.
• Spontaneous/periodic macroscopic hematuria is a key finding
• Disease may remain asymptomatic for 20 years or more.
• Progresses to chronic glomerulonephritis and end-stage renal disease if unmanaged.

Nephrotic Syndrome

• Damage to shield of negativity and podocytes
• Albuminuria & Lipiduria
• Decreased blood albumin can result in:
  • Edema
  • Decreased coagulation factors & immunoglobulins
    • Prone to infection & coagulation disorders
• Urinary findings include:
  • Marked proteinuria (>3.5g/day)
  • Lipiduria
  • Oval fat bodies
    • These are a hallmark of nephrotic syndrome
  • there are lipid droplets inside RTE cells
  • Results in Maltese cross formation under a polarizing microscope

Minimal Change Disease

• Can also be called Lipid nephrosis or Nil Disease.
• Damage occurs to shield of negativity and podocytes but with minimal cellular changes in the glomerulus.
• Is the most common cause of nephrotic syndrome in children.
• Idiopathic; associated with HLA-B12 (postulated as T-cell disorder).
• Has a good prognosis: and responds well to corticosteroid treatment.

Focal Segmental Glomerulosclerosis

• Only affects certain areas of podocytes.
• Is the most common cause of primary glomerulonephritis in adults.
• May be primary (idiopathic) or secondary (diseases, or drugs)
  • Diseases (HIV & Hepatitis) or drugs (analgesic & heroin abuse)
• The finding is similar to nephrotic syndrome with moderate to heavy proteinuria and hematuria.

Tubular Disorders

• Causes include damage in the renal tubules that disrupts tubule function.
• Hereditary and metabolic disorders can also affect the functions of the tubules

Acute Tubular Necrosis

• Primary disorder of damage to tubules, causing death of renal epithelial cells.

• Death of renal epithelial cells results from:

  • Ischemia
    • Decrease blood flow or lack of oxygen to renal cells
    • Shock; general decrease of blood flow throughout the body
      • Can result from cardiac failures, sepsis involving toxigenic bacteria, anaphylaxis, massive hemorrhage, and electrocution
  • Exposure to toxic chemicals/substances
    • Aminoglycosides, Amphotericin B (antifungal), Cyclosporine, radiographic dye, Ethylene glycol, Heavy metals, and Toxic mushrooms
    • Myoglobin is toxic to renal tubules

• Urinary findings

  • Mild proteinuria and microscopic hematuria
  • RTE cells are a noticeable finding
  • RTE casts and other types of casts

Hereditary & Metabolic Disorders

• Systemic conditions that affect tubular reabsorptive capacity of the tubules
• Lack of genes for reabsorption

Fanconi Syndrome

• The most common disorder affecting tubular function
• Generalized failure of PCT to reabsorb solutes due to:
  • Impaired transport across the membrane
  • Disruption of cellular energy need for transport
  • Changes in membrane permeability
• Can be inherited or acquired:
  • Inherited, associated with cystinosis and Hartnup diseases
  • Acquired, exposure to toxic agents (heavy metals & outdated tetracycline), complication from multiple myeloma or renal transplant
• Urinary findings include renal glycosuria, very acidic pH (below 5.5), and failure to reabsorb bicarbonate ions.

Alport Syndrome

• Inherited genetic disorder that affects collagen production
  • X-linked or autosomal
  • Males with X-linked genes are more affected
  • Glomerular membrane: lamellated with thin areas
• Urinary findings include mild symptoms/ persistent hematuria, proteinuria and renal insufficiency.
• May progress to nephrotic syndrome and ESRD

Uromodulin-Associated Kidney Disease

• Uromodulin refers to only protein produced by kidneys (RTE cells) and its primary protein in urine
• The kidney disease deals with a production of abnormal uromodulin due to mutation
• Accumulation of abnormal uromodulin leads to death of renal cells
• Mutation also increases serum uric acid; Young people develop gouty arthritis before renal abnormalities are manifested.

Diabetic Nephropathy

• The most common cause of End-Stage Renal Disease (ESRD)
• It is a complication of uncontrolled DM.
  • Deposition of glycosylated proteins in the glomerular membrane impairs glomerular function
  • Vascular sclerosis affects renal tubular function
• Early onset can be detected by microalbuminuria, which can prevent progression of disease

Diabetes Insipidus

• Caused by a Defect in Anti-Diuretic Hormone (ADH)
• 2 types:
  • Neurogenic/Type 1; Hypothalamus cannot produce ADH
  • Nephrogenic/Type 2; Renal tubules are unresponsive to ADH and is inherited as a sex-linked recessive gene or acquired from exposure of tubules to Lithium and Amphotericin B
• Urine Findings showIncreased urine volume, low specific gravity, and very dilute urine that causes false negative to chemical analysis

Renal Glycosuria

• Affects reabsorption of glucose; (+) glucose in urine without hyperglycemia
• Can be inherited as autosomal recessive
  • Decreased in number
  • Decreased affinity of GLUT to glucose

Interstitial Disorders

• Conditions that affect the renal interstitium.
• Tubulointerstitial disorders: interstitial disorders affect renal tubular function due to proximity producing urine abnormalities.
• Most tubulointerstitial disorders are due to infection (urinary tract infection) and inflammation.

Urinary Tract Infection

• Most common renal disease
• Infections can be:
  • Lower Urinary Infection; Bladder to urethra and includes Cystitis, most common type of UTI, infection of the bladder and may progress to an upper UTI if left untreated.
  • Upper Urinary Infection; Renal pelvis, renal tubules and the interstitium are affected. Generally called pyelonephritis and can be acute or chronic
• Urinary findings include bacteriuria, pyuria, hematuria, proteinuria, increased pH and presence of casts
  • Casts differentiate an upper UTI from lower UTI.

Acute Pyelonephritis

• Common cause is untreated lower UTI
• Infection ascends to the kidneys
• Ascending movement of bacteria from the bladder to the kidneys can be promoted by:
  • Conditions that interfere with urinary flow from the ureters to the bladder
  • Incomplete emptying of bladder during urination
  • Examples: Renal calculi, pregnancy and vesicoureteral reflux (VUR)
• Rapid onset of symptoms like increased urinary frequency, burning sensation, and lower back pain.
• Urinary Findings include findings in urinary tract infection as well as WBC Casts that indicate pyelonephritis.

Chronic Pyelonephritis

• More serious and can result in permanent damage to the kidneys
• Usually caused by congenital structural defects that allow the reflux of urine
• Is diagnosed in children
• Urinary findings are similar to acute pyelonephritis.
• Various types of casts (granular, broad, waxy) as the disease progresses as well as increased proteinuria, hematuria with decreased GFR

Acute Interstitial Nephritis (AIN)

• Inflammation due to allergic reaction to medications, such as Penicillin, Methicillin, Ampicillin, Cephalosporins, Rifampin, Sulfonamides, NSAIDs, and Thiazide diuretics
• Symptoms appear around 2 weeks after the intake or administration of medications
• Urinalysis Findings include:
  • Microscopic & Macroscopic hematuria
  • Proteinuria
  • Pyuria without bacteriuria
  • Eosinophils
    • The main leukocyte is involved and a differential stain can be used for eosinophil for diagnosis
  • WBC Casts

Renal Failure

• End-Stage Renal Disease (ESRD) due to untreated or unmanaged renal disorders

• Characterized by:

  • Marked decrease of GFR (below25ml/min)
  • Increased serum BUN & creatinine (azotemia)
  • Electrolyte imbalance
  • Constant isosthenuria
  • Proteinuria
  • Glycosuria

• It is also characterized by Telescope Urine Sediments with presence of abundant variety of advanced casts (granular, broad and waxy)

• Can be chronic or acute:

  • Acute; sudden loss of renal function; reversible
    • Pre-renal; decrease of blood flow
    • Renal; acute glomerular and tubular diseases
    • Post-renal; renal calculi, tumor or obstructions

Renal Lithiasis

• Formation of renal stones in the tubules, depending on a favorable environment
  • pH of urine
  • Chemical concentration
  • Urine stasis
• Lithotripsy; Procedure using high-energy shock waves to break the stones
• Common urinary calculi include:
  • Calcium oxalate or calcium phosphate.Major cause of renal calculi (75%)
  • Magnesium ammonium phosphate (struvite); is associated with urinary infections involving urea-splitting bacteria
  • Uric acid
  • Cystine
• Prevention is maintaining the urinary pH incompatible to the formation of particular renal calculi