Evaluation of the adult patient with isolated and persistent glomerular hematuria*

ANA: antinuclear antibody; NGS: next-generation sequencing; ESRD: end-stage renal disease; RBCs: red blood cells; IgA: immunoglobulin A.

* Isolated hematuria is defined as hematuria that occurs in an asymptomatic patient who has a normal rate of albumin excretion, a normal serum creatinine concentration, and normal blood pressure. Persistent hematuria is hematuria that is present on repeat urinalyses over a period of 1 to 4 weeks. Signs of glomerular hematuria include a dysmorphic appearance of some RBCs, RBC casts, and, in patients with gross hematuria, a brown, cola-colored urine.

¶ Patients should be evaluated for a personal history of gross hematuria, acute kidney injury, sensorineural hearing loss, flank pain during an acute respiratory infection, or kidney stones. In addition, patients should be assessed for a family history of Alport syndrome, hematuria, and/or renal failure of unclear etiology. Physical exam should include an evaluation for ocular findings characteristic of Alport syndrome (eg, lenticonus, fleck retinopathy). Referral to an ophthalmologist may be required to properly evaluate these ocular features.

Δ Refer to UpToDate topics on the evaluation of hematuria in adults. Patients with evidence of glomerular hematuria by urine microscopy (eg, RBC casts, dysmorphic appearance of some RBCs) may not need to be evaluated for potentially serious urologic disease unless the patient has clinical risk factors for a urologic cause of microscopic hematuria.

◊ Molecular genetic testing for mutations in COL4A3, COL4A4, and COL4A5 is the diagnostic procedure of choice to confirm that a patient's hematuria is associated with a COL4 mutation. Genetic testing for COL4 mutations can be performed by NGS, which enables simultaneous analysis of the COL4A3, COL4A4, and COL4A5 genes, or by targeted mutational analysis, which focuses on a specific variant or mutation in one of the COL4 genes.

§ A kidney biopsy can help to distinguish between the most common causes of isolated and persistent glomerular hematuria. However, the risks of kidney biopsy should be weighed against the potential benefits of establishing a diagnosis (eg, predicting prognosis and genetic counseling in patients found to have Alport syndrome) and potential therapies. Since there are no specific therapies for patients with Alport syndrome, thin basement membrane nephropathy, or IgA nephropathy with isolated hematuria, patients should be informed that conservative monitoring (ie, urinalysis and measurement of serum creatinine and urine protein excretion on an annual basis) is also an option, and a kidney biopsy can be deferred until the patient develops signs of progressive renal disease (eg, increasing serum creatinine or urine albumin excretion >30 mg/day). However, a kidney biopsy is indicated if the patient is being actively evaluated as a potential living donor for kidney transplantation.

¥ If a kidney biopsy cannot be performed (ie, not available or contraindicated), an alternative test to confirm the diagnosis of X-linked Alport syndrome is to perform a skin biopsy with immunostaining for the alpha-5 chain of type IV collagen. Normal skin expression of the alpha-5(IV) chain does not, however, exclude a diagnosis of Alport syndrome.

‡ Hemizygous or heterozygous mutations in COL4A5 are consistent with X-linked Alport syndrome. Mutations in both alleles of COL4A3 or COL4A4 are consistent with autosomal recessive Alport syndrome. Heterozygous mutations in COL4A3 or COL4A4 are consistent with autosomal dominant Alport syndrome or thin basement membrane nephropathy.