Thin Basement Membrane Nephropathy

Etiology

Mutations in COL4A3 and COL4A4 cause TBMN. These genes are located on chromosome 2 at 2q35-37 and encode for 2 different chains of type IV collagen.[2][3][10] The mutations are heterozygous, involving a single allele, and can include various types such as splice variants, missense mutations, or frameshift mutations.[2]

One-half to two-thirds of patients with TBMN have an identifiable family history, typically inherited in an autosomal dominant pattern.[3][9] Patients without an identifiable family history may have a de novo mutation. The disease can also exhibit incomplete penetrance, which might explain a negative family history in some cases.[1][10]

Epidemiology

TBMN is a common cause of glomerular hematuria in both children and adults, with age at presentation varying widely. The median age at diagnosis in adults is 37, while in children, it is 7.[1] Most case series indicate that TBMN is more common in females and shows no predilection for any particular ethnicity.[1][11]

The exact prevalence of TBMN is difficult to determine due to its variable clinical presentation, with many cases likely going unrecognized. However, estimates from one biopsy series of kidneys that were transplanted indicated the incidence of thin basement membrane morphology in about 5% to 9% of the general population.[12] More conservative estimates place the incidence of TBMN between 1% and 2%.[1][10][13]

Pathophysiology

The GBM is the acellular middle layer of the glomerular filtration barrier, situated between the 2 cellular layers—the endothelial cells on one side and the epithelial foot processes on the other.[14][15] The GBM comprises extracellular matrix proteins, with type IV collagen being the most abundant.[14][15]

Type IV collagen in the GBM of adults is composed of a complex assembly of 3 chains—α-3, α-4, and α-5, which form a triple helix.[2][16] Each α-chain is encoded by a distinct gene—the α-5 chain is encoded by COL4A5 on the X chromosome, while the α-3 and α-4 chains are encoded by COL4A3 and COL4A4 on chromosome 2, respectively.[2][16] The α-1 and α-2 chains of type IV collagen are typically present only during embryonic development.[2][16]

Heterozygous mutations in COL4A3 and COL4A4 are the most commonly reported genetic abnormalities in TBMN.[1][3][9] These mutations lead to abnormal folding and assembly of the collagen chains, resulting in their early degradation. This degradation interferes with the normal developmental transition from the α-1 and α-2 chains to the α-3, α-4, and α-5 chains.[2] The embryonic forms of type IV collagen chains are more susceptible to degradation, which causes structural changes and thinning of the GBM.[2]

The thin GBM is fragile and sensitive to disruption by proteases, causing transient, localized ruptures of the membrane. These protease-induced ruptures of the glomerular filtration barrier allow red blood cells (RBCs) to escape from the capillary space into the Bowman space of the glomerulus. Once in the Bowman space, the RBCs appear in the urine as hematuria.[17][18]

A similar pathogenic process is observed in Alport syndrome, which is most commonly caused by mutations in COL4A5 on the X chromosome.[3] However, Alport syndrome can also result from mutations in COL4A3 and COL4A4, inherited in either autosomal dominant or autosomal recessive patterns.[3][10][19] Please see StatPearls' companion resource, "Alport Syndrome," for further information. Therefore, distinguishing between TBMN and Alport syndrome can be challenging due to significant overlap in clinical presentation. Both conditions are now considered part of the spectrum of type IV collagen disorders.[3][20]

Histopathology

The pathognomonic finding of TBMN is uniform thinning of the GBM, which is revealed by electron microscopy of a renal biopsy.[4][5][6]

Light Microscopy

In cases of TBMN, light microscopy typically does not reveal any specific findings. The glomeruli may appear normal or show mild mesangial cell proliferation or mild mesangial matrix expansion. In rare instances, slight attenuation of the GBM, indicative of thinning, can be observed using Jones methenamine silver or periodic acid-Schiff staining (see Image. Light Microscopy of Renal Parenchyma in Thin Basement Membrane Nephropathy).[4] 

Global or focal segmental glomerulosclerosis is not typically associated with TBMN. If present, it may suggest additional pathologies or nonspecific manifestations of kidney disease progression. Similarly, interstitial fibrosis and tubular atrophy are nonspecific indicators of advancing kidney dysfunction.[1][4][5]

Immunofluorescence

Immunofluorescence is usually negative in TBMN. However, nonspecific staining of the mesangium for immunoglobulin M (IgM) and C3 can occasionally be observed, and, more rarely, staining for IgG or IgA may be positive.[1][4][6]

Unlike X-linked Alport syndrome, immunohistochemistry for collagen staining is not always helpful in diagnosing TBMN. In X-linked Alport syndrome, biopsies consistently lack staining for the α-5 chain. However, a normal staining pattern may be observed depending on the specific mutations in the autosomal forms of type IV collagen disorders involving the α-3 and α-4 chains.[5]

Electron Microscopy

The pathognomonic feature of TBMN is the uniform and extensive (>50%) thinning of the GBM, which can be visualized using electron microscopy (see Image. Electron Microscopy of Renal Parenchyma in Thin Basement Membrane Nephropathy).[1][21] Importantly, unlike in Alport syndrome, the electron microscopy features of TBMN do not show progressive irregularity in the thickness of the GBM, nor do they exhibit the splitting and layering characteristic of Alport syndrome.[5][22][23] Please see StatPearls' companion resource, "Alport Syndrome," for further information.

The thickness of the GBM normally varies with age. At birth, the GBM is approximately 150 nm thick and continues to increase throughout childhood. Around the age of 11, the thickness of the GBM approaches adult measurements. The mean normal GBM thickness in adult males is 370 ± 50 nm, while in adult females, it is 320 ± 50 nm.[4][21] The World Health Organization (WHO) has proposed the most commonly used threshold for determining a thin basement membrane, which is 250 nm for adults and 180 nm for children between the ages of 2 and 11.[4][21]

History and Physical

Most cases of TBMN initially present with isolated, asymptomatic microscopic hematuria that is often identified incidentally. The medical history and physical examination of these patients are typically otherwise unremarkable, and a family history of hematuria may or may not be present.

Gross hematuria, or "cola-colored" urine, which is frequently seen in other glomerulonephropathies, is less common in TBMN, occurring in only 5% to 22% of cases, often following infection or exercise. When gross hematuria does occur, it is more common in children with TBMN.[1][4] Proteinuria is uncommon but becomes more likely with advancing age. When present, proteinuria is typically subnephrotic, defined as less than 3000 mg of protein per 24 hours.[1][4] The primary extrarenal manifestation of TBMN is hypertension.[1][4][21]

The medical history and physical examination should concentrate on identifying any potential or obvious causes of microscopic hematuria. The medical history must focus on excluding other common causes, such as urological conditions, nephrolithiasis, and IgA nephropathy. A comprehensive review of systems is essential to rule out systemic manifestations of autoimmune diseases, such as systemic lupus erythematosus, which can also present with microscopic hematuria.

Most patients with TBMN will report a family history of hematuria without progressing to end-stage renal disease (ESRD). A family history of hematuria combined with a negative urological workup strongly suggests TBMN. Additionally, a specific history of hearing loss and ocular lesions can help distinguish TBMN from Alport syndrome.[3] Please see StatPearls' companion resource, "Alport Syndrome," for further information.

The family medical history is crucial in evaluating TBMN as it helps identify potential familial cases, differentiate TBMN from X-linked Alport syndrome, and establish prognosis.[3] Key questions should address instances of microscopic or gross hematuria, hearing or vision loss, and, most importantly, any history of progressive kidney disease or dialysis dependence in other family members. The physical examination should focus on measuring blood pressure, assessing for edema indicative of proteinuria, and conducting a careful evaluation of vision and hearing. Additionally, it should check for other systemic signs, such as rash or joint involvement, which could suggest alternative causes of glomerular hematuria.

Notably, geographic clusters of TBMN patients can exhibit variable clinical manifestations. For instance, a cohort in Cyprus was found to have a progressive variant of TBMN, with 14% of 127 patients developing ESRD. These geographic clusters should be considered when evaluating and managing TBMN.[4][21]

Evaluation

Initial Diagnostic Evaluation

The initial diagnostic evaluation for suspected TBMN includes urinalysis, microscopic examination of urinary sediment, and laboratory assessment of kidney function.

In patients with TBMN, dipstick urinalysis typically reveals microscopic hematuria without proteinuria.[1][4][21] If proteinuria is detected on dipstick testing, it must be quantified. Urine protein quantification is most commonly performed using a spot urine sample to measure the urine protein-to-creatinine ratio. A ratio of less than 0.2 is considered normal, while a ratio of 0.3 or higher is abnormal. Although a 24-hour urine protein quantification is the gold standard for assessing proteinuria, it is less practical and more cumbersome.[24] Please see StatPearls' companion resource, "Proteinuria," for more information. 

Microscopic examination of urine sediment can help identify dysmorphic red blood cells (RBCs) or RBC casts, which are indicative of glomerular hematuria.[25] Dysmorphic RBCs are thought to result from passage through gaps in the GBM, while RBC casts form when RBCs enter the tubular lumen and become trapped in the tubular protein matrix.[26] However, the absence of dysmorphic RBCs or RBC casts does not exclude glomerular hematuria.

Kidney function is assessed through measurements of serum creatinine and blood urea nitrogen. Serum albumin levels should also be measured to rule out nephrotic syndrome if proteinuria is present.

Renal Biopsy

Beyond the initial investigations, the primary decision to evaluate TBMN is whether to proceed with a kidney biopsy. When the presentation and course of the disease are benign, characterized by isolated microscopic hematuria without proteinuria, hypertension, or laboratory evidence of kidney dysfunction, and there is no family history of progressive kidney dysfunction or ESRD, a biopsy is typically not recommended. In such cases, the diagnosis is inferred clinically.[1][4] However, a kidney biopsy can be considered in the following circumstances:

• The presence of additional features, such as laboratory evidence of kidney injury, proteinuria, or hypertension, particularly in individuals aged 50 or younger.

• The presence of extrarenal manifestations such as hearing and ocular defects or family history suggestive of kidney disease such as Alport syndrome, particularly X-linked Alport syndrome.

• If the individual is considering a kidney donation.

Genetic Testing

Genetic testing is generally not required to diagnose TBMN.[9] The genes involved in the pathogenesis of TBMN are COL4A3 and COL4A4 on chromosome 2.[1][2] The rate of detection of mutations is low in TBMN in patients with only microscopic hematuria as the clinical manifestation.[1] The likelihood of detecting a pathogenic variant is higher if there is kidney function impairment or an associated family history.[27]

In cases where biopsy-proven thin GBM is present along with kidney dysfunction and family history suggestive of X-linked inheritance, screening for COL4A5 mutations to rule out X-linked Alport syndrome becomes more pertinent.[9][27]

Treatment / Management

A specific, evidence-based management strategy does not exist for TBMN.[1][9] Most patients with isolated microscopic hematuria have a benign clinical course and do not require any specific therapy.[4]

Once diagnosed, management involves regular clinical monitoring for the development of hypertension, including routine blood pressure measurements. Laboratory studies should include serum creatinine and blood urea nitrogen tests, as well as urinalyses with urine protein-to-creatinine ratio assessments to monitor for renal impairment and proteinuria. These routine evaluations can be conducted by the primary care practitioner, with referrals made as necessary.

If proteinuria or hypertension is noted, management strategies for TBMN include:

• Blood pressure management, with a goal of less than 130/80 mm Hg, which is in line with the 2017 American College of Cardiology/American Heart Association Guidelines for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults.[28]
• Salt intake minimization, with a target sodium intake of less than 2000 mg daily.
• Moderate-intensity physical activity for a total duration of at least 150 min/week.
• Pharmacological therapy, involving the use of the maximum tolerated doses of renin-angiotensin-system inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).[1][9][21]
(A1)

Immunosuppression is not indicated in the management of TBMN.

Once treatment for hypertension or proteinuria is initiated, or if kidney dysfunction is noted, more frequent monitoring and management of associated complications—such as progression of chronic kidney disease (CKD), anemia due to CKD, CKD-related mineral and bone disorder, and ESRD—are necessary. The frequency of monitoring depends on blood pressure control, the degree of proteinuria, and the level of kidney dysfunction or stage of CKD, which is best managed under the guidance of a nephrologist.

Genetic Counseling

Counseling for patients with TBMN and their families is recommended. Counseling should include the diagnosis, the likely inherited nature of the disease, and the need for monitoring for microscopic hematuria, along with proteinuria, hypertension, and kidney function impairment.[9][27]

Renal Transplant Donation

Historically, potential renal transplant donors with TBMN were considered acceptable, as some recipients with TBMN have maintained kidney function without significant issues or complications.[29] However, with an increased understanding of the overlap between TBMN and autosomal forms of Alport syndrome and recognizing the higher risk of progressive kidney disease, it is now recommended that individuals with a heterozygous mutation in COL4A3 or COL4A4 should not be considered kidney donors.[27]

Differential Diagnosis

Alport Syndrome

The condition most closely related to TBMN that requires differentiation is Alport syndrome. Differentiating between these 2 conditions is crucial due to differences in prognosis.[3][20][22][23][30] Please see StatPearls' companion resource, "Alport Syndrome," for further information.

The salient differences between the 2 conditions include:

• Mutations and inheritance: The most well-recognized form of Alport syndrome is inherited in an X-linked fashion and is caused by mutations in COL4A5. However, Alport syndrome can also follow autosomal recessive or autosomal dominant inheritance patterns due to homozygous or heterozygous mutations in COL4A3 and COL4A4. In contrast, TBMN is most commonly inherited in an autosomal dominant pattern, typically due to heterozygous mutations in COL4A3 or COL4A4.

• Histopathology: The characteristic finding of TBMN on renal biopsy is uniform thinning of the GBM, observed in more than 50% of the membrane on electron microscopy.[17][31][32] In contrast, the pathognomonic biopsy feature of Alport syndrome includes progressive irregularity and uneven thickness of the GBM, with electron microscopy revealing splitting, layering, and small, dense "breadcrumb" inclusions between the layers.[33][34][35] A combination of electron microscopy and immunohistology for α-3 and α-5 collagen subtypes can facilitate a definitive diagnosis from a renal biopsy, even in challenging cases.[23]

• Presentation: X-linked Alport syndrome is more commonly seen in males and typically presents at a young age with hearing loss, vision changes, and a high risk of progression to ESRD. Female carriers of X-linked Alport syndrome generally have a milder clinical presentation and a lower risk of progression to ESRD. The autosomal dominant forms of Alport syndrome and TBMN present similarly, usually without extra-renal features, and the risk of progression to ESRD depends on the presence of proteinuria and a positive family history of renal disease.

• Management: Neither Alport syndrome nor TBMN are curable. The only approved pharmacological therapies for either condition are ACE inhibitors or ARBs when proteinuria is present. There is no role for immunosuppression in either condition. Novel agents currently under evaluation for Alport syndrome but not yet approved include bardoxolone methyl, a semi-synthetic triterpenoid molecule that activates the transcription factor nuclear factor erythroid 2-related factor 2 (CARDINAL trial); sparsentan, a dual endothelin type A receptor and angiotensin II type 1 receptor antagonist (EPPIK trial); and atrasentan, an endothelin type-A receptor antagonist (AFFINITY trial).[36] Currently, no agents are being studied for the treatment of TBMN.

• Prognosis: The X-linked form of Alport syndrome carries a poor prognosis, with approximately 50% of affected males reaching ESRD by age 30 and about 90% by age 40. Females with X-linked Alport syndrome have a better prognosis, with a 25% lifetime risk of progression. Autosomal recessive forms of Alport syndrome also have a poor prognosis, with most patients reaching ESRD by age 30. In contrast, autosomal dominant forms of Alport syndrome and TBMN nephropathy share a similar prognosis, with less than a 1% estimated risk of progression to ESRD, unless proteinuria and significant family history are present, which can increase the risk for progression to ESRD to up to 20%.

In summary, due to their shared molecular pathophysiological basis and overlapping clinical presentation, it has been proposed that both Alport syndrome and TBMN be classified as forms of type IV collagen disorders.[3]

Other Conditions

Additional conditions that should be considered in the differential diagnosis of TBMN include:

• IgA nephropathy (Please see StatPearls' companion resource, "IgA Nephropathy (Berger Disease)," for further information.)
• Postinfectious glomerulonephritis (Please see StatPearls' companion resources, "Poststreptococcal Glomerulonephritis" and "Glomerulonephritis," for further information.)
• Lupus nephritis (Please see StatPearls' companion resource, "Lupus Nephritis," for further information.)
• Medullary sponge kidney (Please see StatPearls' companion resource, "Medullary Sponge Kidney," for further information.)

Urological conditions, including malignancies and nephrolithiasis, should always be considered in the differential diagnosis of isolated microscopic hematuria. For patients aged 50 or younger with asymptomatic microscopic hematuria and no identified urological cause, a nephrology consultation is advisable. This is particularly important if the patient shows persistent proteinuria, abnormal serum creatinine, red cell casts or dysmorphic RBCs on urinalysis, worsening hypertension, increasing edema, or has a family history of kidney disease.

Prognosis

The long-term prognosis for most patients with TBMN is generally favorable.[1][21] The condition usually does not lead to the progression of kidney disease or ESRD. However, as the genetic basis of TBMN and its overlap with other type IV collagen disorders involving mutations in COL4A3 and COL4A4—such as Alport syndrome, variants of IgA nephropathy, and focal segmental glomerulosclerosis—have become clearer, TBMN is no longer considered a universally benign condition requiring no monitoring.[3][20] Therefore, the term "benign familial hematuria" is no longer recommended for this condition, and "thin basement membrane disease/nephropathy" or "TBMN" are preferred.[3]

The estimated risk of progression to ESRD in individuals with heterozygous mutations in COL4A3 or COL4A4, inherited in an autosomal dominant fashion as seen in TBMN, is less than 1% in the absence of associated risk factors.[3] However, in those with risk factors such as proteinuria, evidence of renal dysfunction, specific biopsy features (eg, focal segmental glomerulosclerosis, GBM thickening, and lamellation), and a family history of kidney disease progression, the risk of ESRD can increase up to 20%.[3]

Complications

The complications of TBMN include hypertension, proteinuria, and ESRD, although these are rare. Equally important are the psychosocial impacts, such as anxiety related to the diagnosis, especially in young individuals, and the potential issues arising from genetic testing without appropriate counseling. Additionally, complications related to investigations, such as kidney biopsy, should be considered.

Mitigating these complications involves obtaining a comprehensive medical history, including family history, providing genetic counseling, and carefully selecting patients for genetic testing and biopsy.