Heritable Kidney Diseases

The hallmark of ADPKD is gradual kidney cyst growth that results in massive kidney enlargement, which leads to loss of kidney function.

• Kidney manifestations of ADPKD include massive kidney enlargement, back and flank pain, kidney stones, urinary tract infections, hypertension, and hematuria.
• Proteinuria in patients with ADPKD is associated with a greater risk for end-stage kidney disease (ESKD).
• Overt proteinuria is uncommon, and a urine protein-creatinine ratio above 1 mg/mg suggests the presence of another kidney disease.
• Larger kidney size is associated with loss of kidney function, and most patients with ADPKD develop kidney failure by the fifth or sixth decade of life.

• Extrarenal manifestations of ADPKD include cysts in the liver, pancreas, spleen, thyroid, seminal vesicles, and arachnoidea mater. By age 35 years, most patients with ADPKD have liver cysts detectable on MRI, and severe hepatic cystic disease occurs predominantly in women.
• Intracranial aneurysms occur in approximately 5% of these patients, and 50% of these cysts may rupture.
• The most important risk factor for the development of intracranial aneurysms in patients with ADPKD is a family member with an intracranial aneurysm.

Hypertension in patients with ADPKD is common, develops early, and is associated with poor kidney outcomes. The blood pressure target in patients with ADPKD is less than 125/75 mm Hg. An angiotensin-converting enzyme inhibitor or angiotensin receptor blocker should be used as first-line therapy to achieve this goal.

• Infection of kidney cysts may manifest as flank pain and fever accompanied by a bland urinalysis and a negative urine culture.
• The treatment of cyst infection in patients with ADPKD requires antibiotics that are capable of penetrating the cyst, including fluoroquinolones, chloramphenicol, and trimethoprim-sulfamethoxazole; therapy should be continued for at least 2 to 4 weeks.

Patients with ADPKD who have cyst hemorrhage commonly develop low-grade fever and gross hematuria. These episodes are most often self-limited, and bed rest and increased fluid intake shorten the duration of gross hematuria. Cyst hemorrhage in the absence of gross hematuria is often painful due to acute cyst expansion.

• Major Features
• 1. Facial angiofibromas or forehead plaque
• 2. Nontraumatic ungual or periungual fibroma
• 3. Hypomelanotic macules (three or more)
• 4. Shagreen patch (connective tissue nevus)
• 5. Multiple retinal nodular hamartomas
• 6. Cortical tubera
• 7. Subependymal nodule
• 8. Subependymal giant cell astrocytoma
• 9. Cardiac rhabdomyoma, single or multiple
• 10. Lymphangiomyomatosis^b
• 11. Renal angiomyolipoma^b

• Minor Features
• 1. Multiple, randomly distributed pits in dental enamel
• 2. Hamartomatous rectal polyps^c
• 3. Bone cysts^d
• 4. Cerebral white matter radial migration lines^{a, d, e}
• 5. Gingival fibromas
• 6. Nonrenal hamartoma^c
• 7. Retinal achromic patch
• 8. “Confetti” skin lesions
• 9. Multiple renal cysts

• ^cDefinite Tuberous Sclerosis Complex
• Either two major features or one major feature plus two minor features
• Probable Tuberous Sclerosis Complex
• One major plus one minor feature
• Possible Tuberous Sclerosis Complex
• Either one major feature or two or more minor features

Tuberous sclerosis is an autosomal-dominant disorder caused by mutations in the TSC1 and TSC2 genes. A definitive diagnosis of tuberous sclerosis entails the presence of any two major features or one major feature and two minor features

• Major Features
• 1. Facial angiofibromas or forehead plaque
• 2. Nontraumatic ungual or periungual fibroma
• 3. Hypomelanotic macules (three or more)
• 4. Shagreen patch (connective tissue nevus)
• 5. Multiple retinal nodular hamartomas
• 6. Cortical tubera
• 7. Subependymal nodule
• 8. Subependymal giant cell astrocytoma
• 9. Cardiac rhabdomyoma, single or multiple
• 10. Lymphangiomyomatosis^b
• 11. Renal angiomyolipoma^b

• Minor Features
• 1. Multiple, randomly distributed pits in dental enamel
• 2. Hamartomatous rectal polyps^c
• 3. Bone cysts^d
• 4. Cerebral white matter radial migration lines^{a, d, e}
• 5. Gingival fibromas
• 6. Nonrenal hamartomac
• 7. Retinal achromic patch
• 8. “Confetti” skin lesions
• 9. Multiple renal cysts

Kidney angiomyolipomas occur in 70% to 80% of affected patients and are detected by CT or MRI based on their fat content. Complications of these lesions include pain and hemorrhage and commonly occur once lesions reach 4 cm (1.6 in) in diameter. Hemorrhage from these lesions is the most common cause of kidney failure and death in adults with tuberous sclerosis.

Case reports have demonstrated significant reductions in kidney angiomyolipomas over a short period of time with use of rapamycin. Arterial embolization is a frequently used kidney-sparing measure to reduce the size of kidney angiomyolipomas, and successful embolization prevents regrowth of these tumors.

• Alport syndrome
• Fabry disease
• Thin basement membrane nephropathy

Alport syndrome, also known as hereditary nephritis, is an X-linked disorder in approximately 80% of patients and an autosomal-recessive disorder in about 10% of patients. Mutations in the α5 chain of type IV collagen on chromosome Xq22 cause the X-linked, or classic, form of this disease, whereas mutations in the α3 and α4 chains of type IV collagen cause the autosomal-recessive form.

• Alport syndrome commonly manifests as nephrotic-range proteinuria and progressive kidney insufficiency.
• Disruption in the basement membrane of the middle ear and the ocular lenses also causes sensorineural hearing loss and visual abnormalities associated with anterior lenticonus.
• Men with Alport syndrome develop hematuria, proteinuria, and progressive chronic kidney disease early, usually in the second or third decade of life. Women with X-linked Alport syndrome have a milder disease course that usually manifests as microscopic hematuria. Age of onset of ESKD is highly variable in women and can be in the fifth or sixth decade of life.

The lack of normal α5 type IV collagen on skin biopsy is diagnostic of Alport syndrome in affected men; however, in affected women, the presence of α5 type IV collagen is less consistent due to lyonization of the X chromosome and is therefore less accurate.

Thin basement membrane nephropathy, also known as benign familial hematuria, is an inherited disorder caused by mutations in the α3 and α4 chains of type IV collagen. Unlike Alport syndrome, thin basement membrane nephropathy usually does not cause kidney failure. This condition usually initially manifests during childhood and is characterized by microscopic or gross hematuria, and a family history of hematuria is suggestive of the condition.

Fabry disease is an X-linked disorder caused by deficiency of the α-galactosidase A enzyme. This condition causes globotriaosylceramide to accumulate in multiple tissues throughout the body.

Clinical manifestations of Fabry disease include mild nephrotic-range proteinuria, slow deterioration in kidney function, cutaneous angiokeratomas, painful paresthesias of the hands, and premature coronary artery disease. Progression to ESKD during the third or fourth decade of life is the most common complication in affected men and the primary cause of premature death in all patients with Fabry disease.

Biochemical or genetic screening for Fabry disease is recommended for family members of affected patients. Intravenous replacement with recombinant human α-galactosidase A is effective in treating Fabry disease.