Thin Basement Membrane Nephropathy (TBMN)

Overview

Epidemiology

• The frequency may be approximately 5%‒9%.
• However, TBMN is clinically diagnosed in < 1% of the general population.
• Most common cause of persistent hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma

Etiology

• Autosomal dominant inheritance Autosomal dominant inheritance Autosomal Recessive and Autosomal Dominant Inheritance
• In some families, TBMN appears to be caused by mutations in:
  • COLA4A3 → encodes the alpha-3 chains of type IV collagen Type IV collagen A non-fibrillar collagen found in the structure of basement membrane. Collagen type IV molecules assemble to form a sheet-like network which is involved in maintaining the structural integrity of basement membranes. The predominant form of the protein is comprised of two alpha1(IV) subunits and one alpha2(IV) subunit, however, at least six different alpha subunits can be incorporated into the heterotrimer. Alport Syndrome
  • COLA4A4 → encodes the alpha-4 chains of type IV collagen Type IV collagen A non-fibrillar collagen found in the structure of basement membrane. Collagen type IV molecules assemble to form a sheet-like network which is involved in maintaining the structural integrity of basement membranes. The predominant form of the protein is comprised of two alpha1(IV) subunits and one alpha2(IV) subunit, however, at least six different alpha subunits can be incorporated into the heterotrimer. Alport Syndrome
• Similar to Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. Alport Syndrome

Pathophysiology

• Alpha-3 and alpha-4 chains combine with alpha-5 chain → type IV collagen Type IV collagen A non-fibrillar collagen found in the structure of basement membrane. Collagen type IV molecules assemble to form a sheet-like network which is involved in maintaining the structural integrity of basement membranes. The predominant form of the protein is comprised of two alpha1(IV) subunits and one alpha2(IV) subunit, however, at least six different alpha subunits can be incorporated into the heterotrimer. Alport Syndrome molecule (an important structural component of the glomerular basement membrane Glomerular basement membrane The layer of extracellular matrix that lies between the endothelium of the glomerular capillaries and the podocytes of the inner or visceral layer of the bowman capsule. It is the product of these two cell types. It acts as a physical barrier and an ion-selective filter. Goodpasture Syndrome (GBM))
• Abnormalities in type IV collagen Type IV collagen A non-fibrillar collagen found in the structure of basement membrane. Collagen type IV molecules assemble to form a sheet-like network which is involved in maintaining the structural integrity of basement membranes. The predominant form of the protein is comprised of two alpha1(IV) subunits and one alpha2(IV) subunit, however, at least six different alpha subunits can be incorporated into the heterotrimer. Alport Syndrome → thinning of the GBM

Clinical Presentation

• Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are asymptomatic.
• Classic presentation: asymptomatic, microscopic hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma (may be present or intermittent)
• Episodes of gross hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma may occur.
  • Sometimes preceded by upper respiratory tract infection (URTI)
  • Can be associated with flank pain Flank pain Pain emanating from below the ribs and above the ilium. Renal Cell Carcinoma
• Blood pressure:
  • Typically normal in most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Some may develop hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension.

Diagnosis and Management

Diagnosis

• A diagnosis is suggested by:
  • Benign Benign Fibroadenoma presentation and course 
  • Positive family history Family History Adult Health Maintenance of hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
  • Negative family history Family History Adult Health Maintenance of kidney failure
• Laboratory findings:
  • Microscopic hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma may be incidentally seen on routine urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children.
    • Intermittent or persistent
    • Dysmorphic red cells and RBC casts
  • Urine protein
    • Usually normal
    • Mild-to-moderate proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children occurs in some individuals.
  • Creatinine
    • Usually normal
    • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome may develop in rare cases.
• Renal biopsy Renal Biopsy Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis:
  • Generally not performed
  • Limited to patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with suspected TBMN who also have proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
  • Light microscopy is insufficient for diagnosis.
  • Electron microscopy is necessary to show diffuse GBM thinning.

Management and prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Most cases are benign Benign Fibroadenoma and require no treatment.
• ACE inhibitors ACE inhibitors Truncus Arteriosus or ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication:
  • May be used for: 
    • Frequent gross hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
    • Proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children 
    • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • ↑ Creatinine
  • May ↓ intraglomerular pressure
• Long-term prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas is good in most cases.
• Individuals with heterozygous COL4A3/COL4A4 mutations are at ↑ risk for chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease.

Differential Diagnosis

• Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. Alport Syndrome: a genetic disorder similar to TBMN characterized by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure encoding for alpha chains of type IV collagen Type IV collagen A non-fibrillar collagen found in the structure of basement membrane. Collagen type IV molecules assemble to form a sheet-like network which is involved in maintaining the structural integrity of basement membranes. The predominant form of the protein is comprised of two alpha1(IV) subunits and one alpha2(IV) subunit, however, at least six different alpha subunits can be incorporated into the heterotrimer. Alport Syndrome. Individuals present with glomerulonephritis (GN), hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, and hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may also have sensorineural hearing loss Sensorineural hearing loss Hearing loss resulting from damage to the cochlea and the sensorineural elements which lie internally beyond the oval and round windows. These elements include the auditory nerve and its connections in the brainstem. Hearing Loss and ophthalmic symptoms, which help differentiate the condition from TBMN. Diagnosis is by history, including family history Family History Adult Health Maintenance, urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children, and renal or skin biopsy Skin Biopsy Secondary Skin Lesions. Treatment is focused on limiting disease progression with ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication and ACE inhibitors ACE inhibitors Truncus Arteriosus.
• IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions nephropathy: a renal disease characterized by the deposition of IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions immune complexes Immune complexes The complex formed by the binding of antigen and antibody molecules. The deposition of large antigen-antibody complexes leading to tissue damage causes immune complex diseases. C3 Deficiency in the mesangium Mesangium The thin membranous structure supporting the adjoining glomerular capillaries. It is composed of glomerular mesangial cells and their extracellular matrix. IgA Nephropathy. The disease may manifest as slowly progressive hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, and renal insufficiency. Diagnosis is done by urinalysis Urinalysis Examination of urine by chemical, physical, or microscopic means. Routine urinalysis usually includes performing chemical screening tests, determining specific gravity, observing any unusual color or odor, screening for bacteriuria, and examining the sediment microscopically. Urinary Tract Infections (UTIs) in Children and renal biopsy Renal Biopsy Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Treatment options include ACE inhibitors ACE inhibitors Truncus Arteriosus, ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication, corticosteroids Corticosteroids Chorioretinitis, and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants.
• C3 glomerulopathies: rare forms of GN that include dense deposit disease and C3 GN. The conditions result from abnormal regulation of the alternative complement pathway. The clinical presentation is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables and can include proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma, renal insufficiency, and/or hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension. The diagnosis is made by low complement levels and renal biopsy Renal Biopsy Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Since the condition is uncommon, there is a paucity of information to guide therapy. However, management may include ACE inhibitors ACE inhibitors Truncus Arteriosus, ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication, and immunosuppressive agents.
• Poststreptococcal glomerulonephritis Poststreptococcal Glomerulonephritis Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis ( PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Postinfectious Glomerulonephritis): a self-limited type of GN that occurs most commonly in children. The condition is an immune complex–mediated condition, often preceded by group A beta-hemolytic streptococcal pharyngitis Streptococcal Pharyngitis Rheumatic Fever or skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease. Laboratory results show decreased complement levels, elevated antistreptolysin-O and anti-DNase B levels. Immunofluorescence reveals granular immune complex deposition along the GBM. Management is supportive.