Thin Basement Membrane Nephropathy (TBMN)

Thin basement membrane nephropathy (TBMN), also called benign familial hematuria, is a type of nephritic syndrome Nephritic syndrome Nephritic syndrome is a broad category of glomerular diseases characterized by glomerular hematuria, variable loss of renal function, and hypertension. These features are in contrast to those of nephrotic syndrome, which includes glomerular diseases characterized by severe proteinuria, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephritic Syndrome caused by diffuse thinning of the glomerular basement membrane (GBM). The syndrome is often familial and due to mutations of alpha chains of type IV collagen. Clinical presentation can range from asymptomatic microscopic hematuria to gross hematuria, flank pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, proteinuria, 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. Diagnosis is by clinical evaluation. Renal biopsy is rarely required but will show diffuse thinning of the GBM on electron microscopy. Most cases are benign, but ACE inhibitors and ARBs may be used in certain cases.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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

Etiology

  • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance
  • In some families, TBMN appears to be caused by mutations in:
    • COLA4A3 → encodes the alpha-3 chains of type IV collagen
    • COLA4A4 → encodes the alpha-4 chains of type IV collagen
  • 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: TBMN patients with heterozygous COL4A3/COL4A4 mutations are considered “carriers” of autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance 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 molecule (an important structural component of the glomerular basement membrane (GBM))
  • Abnormalities in type IV collagen → thinning of the GBM

Clinical Presentation

  • Most patients are asymptomatic.
  • Episodes of gross hematuria may occur.
    • Sometimes preceded by upper respiratory tract infection (URTI)
    • Can be associated with flank pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Blood pressure:
    • Typically normal in most patients
    • 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 presentation and course 
    • Positive family history of hematuria
    • Negative family history of kidney failure
  • Laboratory findings:
    • Microscopic hematuria may be incidentally seen on routine urinalysis.
      • Intermittent or persistent
      • Dysmorphic red cells and RBC casts
    • Urine protein
      • Usually normal
      • Mild-to-moderate proteinuria occurs in some individuals.
    • Creatinine
      • Usually normal
      • Renal failure may develop in rare cases.
  • Renal biopsy:
    • Generally not performed
    • Limited to patients with suspected TBMN who also have proteinuria
    • Light microscopy is insufficient for diagnosis.
    • Electron microscopy is necessary to show diffuse GBM thinning.

Management and prognosis

  • Most cases are benign and require no treatment.
  • ACE inhibitors or ARBs:
    • May be used for: 
      • Frequent gross hematuria
      • Proteinuria 
      • Hypertension
      • ↑ Creatinine
    • May ↓ intraglomerular pressure
  • Long-term prognosis is good in most cases.

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 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 encoding for alpha chains of type IV collagen. Patients present with glomerulonephritis (GN), hematuria, proteinuria, 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 may also have sensorineural hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss and ophthalmic symptoms. Diagnosis is by history, including family history, urinalysis, and renal 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. Structure and Function of the Skin biopsy. Treatment is focused on limiting disease progression with ARBs and ACE inhibitors.
  • IgA nephropathy IgA nephropathy IgA nephropathy (Berger's disease) is a renal disease characterized by IgA deposition in the mesangium. It is the most common cause of primary glomerulonephritis in most developed countries. Patients frequently present in the second and third decades of life and, historically, with a preceding upper respiratory or GI infection. IgA Nephropathy: a renal disease characterized by the deposition of IgA immune complexes in the mesangium. The disease may manifest as slowly progressive hematuria, proteinuria, and renal insufficiency. Diagnosis is done by urinalysis and renal biopsy. Treatment options include ACE inhibitors, ARBs, corticosteroids, 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.
  • Complement component 3 glomerulopathy: a rare form of GN that includes dense deposit disease and complement component 3 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, hematuria, 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. Since the condition is uncommon, there is a paucity of information to guide therapy. However, management may include ACE inhibitors, ARBs, 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. Poststreptococcal 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. Poststreptococcal Glomerulonephritis): a self-limited type of GN that occurs in children. The condition is an immune complex–mediated condition, often preceded by group A beta-hemolytic streptococcal pharyngitis Pharyngitis Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis 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. Structure and Function of the Skin infections. 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.

References

  1. Glassock, RJ, et al. (Ed.). (2020). Thin basement membrane nephropathy (benign familial hematuria). UpToDate. Retrieved August 10, 2021, from https://www.uptodate.com/contents/thin-basement-membrane-nephropathy-benign-familial-hematuria
  2. O’Brien, F. (2021). Thin basement membrane disease. MSD Manual Professional Version. Retrieved August 10, 2021, from https://www.msdmanuals.com/professional/genitourinary-disorders/glomerular-disorders/thin-basement-membrane-disease
  3. Kashtan, CE, et al. (2020). Isolated and persistent glomerular hematuria in adults. Glassock, RJ, et al. (Eds.), UpToDate. Retrieved August 11, 2021, from https://www.uptodate.com/contents/isolated-and-persistent-glomerular-hematuria-in-adults
  4. Boyer, OG. (2020). Evaluation of microscopic hematuria in children. In Niaudet, P, et al. (Eds.), UpToDate. Retrieved on August 11, 2021, from https://www.uptodate.com/contents/evaluation-of-microscopic-hematuria-in-children

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