Pediatrics

Thin GBM disease

OVERVIEW: What every practitioner needs to know

Thin glomerular basement membrane (GBM) disease is a benign hereditary disorder presenting with persistent microscopic hematuria. Renal biopsy confirms the diagnosis of thinning of the GBM. Prognosis of thin GBM disease is generally favorable with no evidence of proteinuria or progressive renal insufficiency.

Are you sure your patient has thin GBM disease? What are the typical findings for this disease?

  1. Asymptomatic, microscopic hematuria (intermittent or persistent)

  2. Family history of microscopic hematuria (30%-50% of cases)

  3. No evidence of proteinuria

  4. Normal blood pressure

  5. Normal serum creatinine

Nomenclature

Thin glomerular basement membrane (GBM) disease is also known as thin basement membrane nephropathy and benign familial hematuria.

Rare presentation

Some patients present with episodes of gross hematuria and flank pain.

What other disease/condition shares some of these symptoms?

1. IgA nephropathy - often presents with painless gross hematuria shortly following a viral upper respiratory infection (URI)

2. Alport syndrome (hereditary nephritis) - generally presents with sensorineural hearing loss, lens defect, renal insufficiency or failure

3. Idiopathic hypercalciuria - asymptomatic, microscopic hematuria with urine calcium-to-creatinine ratio >0.2

What caused this disease to develop at this time?

  • Presumed autosomal dominant inheritance of a defective gene that encodes for abnormal collagen production, which then results in thinning of the glomerular basement membrane. The thinning of the GBM results in increased episodes of spontaneous GBM ruptures, which then allows the red blood cells to be excreted into the urine. Mutations in type IV collagen genes COL4A3 and COL4A4 have been identified in some, but not all, patients with thin GBM disease. Because the same genes—type IV collagen genes COL4A3 and COL4A4—are involved in thin GBM disease and Alport syndrome, both diseases are now grouped together under Type IV Collagen Nephropathies.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Serum chemistry to monitor renal function

  • Manual blood pressure measurement to monitor for hypertension

  • Urinalysis to verify hematuria – urine dipstick detects hemoglobin and myoglobin

  • First morning random urine sample to monitor for proteinuria (normal urine protein-to-creatinine <0.2)

  • Urine calcium-to-creatinine ratio to rule out hypercalciuria (normal urine calcium-to-creatinine <0.2)

  • Diagnosis of thin GBM disease is confirmed by renal biopsy, as the measurement of the GBM can only be seen at the electron microscopy level. Under electron microscopy, thin GBM width is ~150-225 nM versus normal GBM width between 300-400 nM. However, if the child does not have proteinuria (protein >200 mg/day or urine protein-to-creatinine ratio >0.2), hypertension, and/or renal insufficiency AND has a parent with documented history of asymptomatic, microscopic hematuria, then renal biopsy is not indicated. It is recommended that renal biopsy be pursued for parental reassurance, future family planning when the patient is of age, or if the patient is to be considered for kidney donation as an adult.

Would imaging studies be helpful? If so, which ones?

  • Renal and bladder ultrasound is recommended to rule out anatomical abnormalities of the genitourinary system.

Confirming the diagnosis

  • To differentiate between thin GBM disease and Alport syndrome, ask about family history of sensorineural hearing loss, ocular defects, renal failure, dialysis, and/or kidney transplantation. However, since some children with Alport syndrome can present initially with only asymptomatic, microscopic hematuria, and renal biopsy may only identify thin basement membranes and normal immunostaining for type IV collagen during the early disease course of Alport syndrome, children with asymptomatic, microscopic hematuria should be followed closely with annual first morning urine samples to identify for the presence of proteinuria.

  • Monitoring of these patients can be performed by the primary care provider if he/she feels comfortable. Once there is proteinuria, these children need to be referred to a pediatric nephrologist, and a renal biopsy should be performed if proteinuria persists.

If you are able to confirm that the patient has thin GBM disease, what treatment should be initiated?

  • Prognosis for thin GBM disease is generally favorable with minimal to no evidence of proteinuria and no renal failure. However, a small proportion of patients may develop persistent proteinuria and progressive renal insufficiency. Once persistent proteinuria is confirmed, these children should be placed on anti-proteinuric agents, such as an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). These children should be referred to pediatric nephrology for long-term management.

  • Once proteinuria has been identified, anti-proteinuric agents should be initiated to prevent progression of renal disease.

  • There are no prospective, randomized, placebo-controlled trials evaluating the efficacy of therapy in patients with thin GBM disease. The general consensus in the nephrology community is that reducing proteinuria will delay the progression of renal dysfunction.

What are the adverse effects associated with each treatment option?

Both ACE inhibitors and ARBs are teratogenic, so teenage females and their parents must be informed to stop the medication if the patient is pregnant. Furthermore, ACE inhibitors and ARBs may cause acute kidney injury (elevated BUN and creatinine) in the setting of volume depletion, so these patients must maintain adequate hydration.

What are the possible outcomes of thin GBM disease?

Because some children with Alport syndrome can present initially with only asymptomatic, microscopic hematuria and have no family history of Alport syndrome, it can be difficult to differentiate between thin GBM disease and early Alport Syndrome. For this reason, it is imperative to screen first degree relatives for hematuria, as up to 50% of first degree relatives with thin GBM disease will have hematuria. Furthermore, children with asymptomatic, microscopic hematuria and a negative family history of hematuria must be followed closely for any signs of renal disease (proteinuria, elevated serum creatinine, and hypertension).

Anti-proteinuric agents will reduce proteinuria and delay progression of renal disease. However, they are teratogenic and in the setting of volume depletion may cause acute kidney injury. Thus, avoiding pregnancy and maintaining adequate hydration will reduce the side effects of these pharmacological agents.

What causes this disease and how frequent is it?

  • Incidence: 5%-9%

  • Presumed autosomal dominant inheritance of a defective gene that encodes for abnormal collagen production, which then results in thinning of the glomerular basement membrane. The thinning of the GBM results in increased episodes of spontaneous GBM ruptures, which then allows the red blood cells to be excreted into the urine. Mutations in type IV collagen genes COL4A3 and COL4A4 have been identified in some, but not all, patients with thin GBM disease.

How do these pathogens/genes/exposures cause the disease?

  • Presumed autosomal dominant inheritance of a defective gene that encodes for abnormal collagen production, which then results in thinning of the glomerular basement membrane. The thinning of the GBM results in increased episodes of spontaneous GBM ruptures, which then allows the red blood cells to be excreted into the urine. Mutations in type IV collagen genes COL4A3 and COL4A4 have been identified in some, but not all, patients with thin GBM disease.

Other clinical manifestations that might help with diagnosis and management

What complications might you expect from the disease or treatment of the disease?

1. Minimal to moderate proteinuria (<1.5 grams/day)

2.. Renal insufficiency.

3. Anti-proteinuric agents, such as ACE inhibitors and ARBs, may cause fetal renal failure in pregnant patients and acute kidney injury in volume-depleted patients. Usually, the acute kidney injury is reversible once the agent is temporarily discontinued and euvolemia has been achieved.

Are additional laboratory studies available; even some that are not widely available?

A skin biopsy may help to differentiate between thin GBM disease and X-linked Alport syndrome. In thin GBM disease, the staining for the alpha-5 chain of type IV collagen is normal, whereas no staining is detected in most patients with X-linked Alport syndrome. However, some patients with X-linked Alport syndrome do have normal staining for alpha-5 chain of type IV collagen, so a skin biopsy can confirm a suspected diagnosis of Alport syndrome, but cannot exclude the diagnosis.

How can thin GBM disease be prevented?

Thin GBM disease cannot be prevented because it is a hereditary disease with a gene defect.

What is the evidence?

There are no prospective, randomized, placebo-controlled trials evaluating the efficacy of therapy in patients with thin GBM disease. The general consensus in the nephrology community is that reducing proteinuria will delay progression of dysfunction.

http://www.alportsyndrome.org/what-is-alport-syndrome/alport-syndrome-diagnosis/ (On the main website, the last paragraph discusses thin basement membrane nephropathy..

(This website lists contact information on Alport Syndrome and Thin Basement Membrane Nephropathy. Dr. Clifford E. Kashtan, a pediatric nephrologist, is one of the world's experts and a very useful resource if physicians have questions.)

Kashtan, CE. "Familial hematuria due to type IV collagen mutations: Alport syndrome and thin basement membrane nephropathy". Curr Opin Pediatr. vol. 16. 2004. pp. 177-81.

Carasi, C, Van't Hoff, WG, Rees, L. "Childhood thin GBM disease: review of 22 children with family studies and long-term follow-up". Pediatr Nephrol. vol. 20. 2005. pp. 1098-105.

Tryggvason, K, Patrakka, J. "Thin basement membrane nephropathy". J Am Soc Nephrol. vol. 17. 2006. pp. 813-22.

Deltas, C. "Thin basement membrane nephropathy: is there genetic predisposition to more severe disease?". Pediatr Nephrol. vol. 24. 2009. pp. 877-9.

Ongoing controversies regarding etiology, diagnosis, treatment

Some patients with biopsy-proven thin basement membrane nephropathy do develop focal segmental glomerulosclerosis (FSGS) over time. It is uncertain whether the thinning of the GBM is the main factor in the development of FSGS or an incidental finding in patients with underlying FSGS. Regardless, the therapy is the same – antiproteinuric agents to reduce persistent proteinuria and delay the progression of renal disease.

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