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Genetic Disorders and Kidney Disease mutations are inherited as an autosomal dominant trait, with spontaneous germline mutations accounting for the e Patients with monoclonal gammopathy of renal signifi- remaining cases. cance can present with proteinuria, hematuria, and ele- vated serum creatinine; kidney biopsy is necessary to Screening and Diagnosis make the diagnosis. Ultrasonography is the most common and least costly screen- ¢ Kidney disease in amyloidosis is most commonly ing method for ADPKD. Ultrasonography criteria for diagnos- caused by AL amyloid composed of monoclonal A or « ing APKD are based on the number of visible cysts that are light chains or AA amyloid formed by serum amyloid A more than expected for the patient’s age. Family history of protein; patients frequently present with nephrotic- ADPKD may also be considered. Direct DNA sequencing of the range proteinuria, and treatment is aimed at the under- PKD1 and PKD2 genes may be used to confirm the diagnosis lying disorder. or, in some cases, is performed in lieu of imaging. Gene linkage e Kidney involvement in cryoglobulinemia occurs most testing, which identifies DNA markers in several members of a frequently with type II (mixed) cryoglobulins; treat- family, can also be used in patients with a family history of ment is directed at eradication of commonly associated ADPKD. hepatitis C virus. Clinical Manifestations Early in the disease course, there are generally no symptoms. Diagnosis is therefore often delayed in patients without a Genetic Disorders and known family history of ADPKD. The first sign of ADPKD is

mutations are inherited as an autosomal dominant trait, with spontaneous germline mutations accounting for the e Patients with monoclonal gammopathy of renal signifi- remaining cases. cance can present with proteinuria, hematuria, and ele- vated serum creatinine; kidney biopsy is necessary to Screening and Diagnosis make the diagnosis. Ultrasonography is the most common and least costly screen- ¢ Kidney disease in amyloidosis is most commonly ing method for ADPKD. Ultrasonography criteria for diagnos- caused by AL amyloid composed of monoclonal A or « ing APKD are based on the number of visible cysts that are light chains or AA amyloid formed by serum amyloid A more than expected for the patient’s age. Family history of protein; patients frequently present with nephrotic- ADPKD may also be considered. Direct DNA sequencing of the range proteinuria, and treatment is aimed at the under- PKD1 and PKD2 genes may be used to confirm the diagnosis lying disorder. or, in some cases, is performed in lieu of imaging. Gene linkage e Kidney involvement in cryoglobulinemia occurs most testing, which identifies DNA markers in several members of a frequently with type II (mixed) cryoglobulins; treat- family, can also be used in patients with a family history of ment is directed at eradication of commonly associated ADPKD. hepatitis C virus. Clinical Manifestations Early in the disease course, there are generally no symptoms. Diagnosis is therefore often delayed in patients without a Genetic Disorders and known family history of ADPKD. The first sign of ADPKD is Kidney Disease often hypertension; other early signs and symptoms include hematuria (macroscopic or microscopic), pain in the back or Genetic Cystic Kidney Disorders abdomen, urinary tract infection, or kidney stones. In patients without a family history, these presentations usu- Genetic cystic kidney disorders include autosomal dominant ally lead to imaging studies that reveal ADPKD. CT or MRI polycystic kidney disease and tuberous sclerosis complex. may be used to evaluate for complications in patients with known ADPKD, such as bleeding into a cyst or a suspected Autosomal Dominant Polycystic Kidney Disease kidney stone. Autosomal dominant polycystic kidney disease (ADPKD) is Extrarenal manifestations include hepatic cysts (detected the leading genetic cause of end-stage kidney disease in >80% of patients over their lifetime), mitral valve prolapse, (ESKD) and the fourth leading cause of ESKD. ADPKD inguinal and umbilical hernias, and intracranial aneurysms manifests as large kidneys with multiple kidney cysts (detected in 5% to 10% of patients, with a strong familial (Figure 17). Genetic mutations in PKD1 and PKD2, which pattern). encode for proteins that regulate differentiation and prolif- eration of renal tubular epithelial cells, account for approxi- Management mately 85% and 15% of cases, respectively. More than 90% of Patients with ADPKD have a >50% chance of progressing to ESKD by age 70 years. Management primarily focuses on controlling blood pressure with renin-angiotensin system blockade and addressing complications of disease. Vasopressin V2 blockade with tolvaptan slows kidney func- tion decline in adults at risk for rapidly progressing ADPKD. Risk factors associated with rapid disease progression include male sex; onset of hypertension before age 35 years; urologic events (such as gross hematuria, cyst infection, and/or flank pain) before age 35 years; total kidney volume greater than expected for age; truncating PKD1 mutations; estimated glo- merular filtration rate decline >5 mL/min/1.73 m? within 1 year; and a family history of ESKD at or before age 58 years. Tolvaptan carries an FDA-mandated safety warning for pos- sible irreversible liver injury. Therefore, patients with ADPKD receiving tolvaptan require frequent laboratory monitoring of liver tests. Patients with ADPKD should be offered screen- FIGURE 17. Autosomal dominant polycystic kidney disease with multiple ing for cerebral aneurysms by CT or MR angiography, par- bilateral cysts, which replace the normal smooth architecture of the kidneys and lead to markedly increased kidney size. Image from the CDC Public Health Image ticularly those with a family history of intracranial aneurysm Library. or hemorrhage.

Kidney Disease often hypertension; other early signs and symptoms include hematuria (macroscopic or microscopic), pain in the back or Genetic Cystic Kidney Disorders abdomen, urinary tract infection, or kidney stones. In patients without a family history, these presentations usu- Genetic cystic kidney disorders include autosomal dominant ally lead to imaging studies that reveal ADPKD. CT or MRI polycystic kidney disease and tuberous sclerosis complex. may be used to evaluate for complications in patients with known ADPKD, such as bleeding into a cyst or a suspected Autosomal Dominant Polycystic Kidney Disease kidney stone. Autosomal dominant polycystic kidney disease (ADPKD) is Extrarenal manifestations include hepatic cysts (detected the leading genetic cause of end-stage kidney disease in >80% of patients over their lifetime), mitral valve prolapse, (ESKD) and the fourth leading cause of ESKD. ADPKD inguinal and umbilical hernias, and intracranial aneurysms manifests as large kidneys with multiple kidney cysts (detected in 5% to 10% of patients, with a strong familial (Figure 17). Genetic mutations in PKD1 and PKD2, which pattern). encode for proteins that regulate differentiation and prolif- eration of renal tubular epithelial cells, account for approxi- Management mately 85% and 15% of cases, respectively. More than 90% of Patients with ADPKD have a >50% chance of progressing to ESKD by age 70 years. Management primarily focuses on controlling blood pressure with renin-angiotensin system blockade and addressing complications of disease. Vasopressin V2 blockade with tolvaptan slows kidney func- tion decline in adults at risk for rapidly progressing ADPKD. Risk factors associated with rapid disease progression include male sex; onset of hypertension before age 35 years; urologic events (such as gross hematuria, cyst infection, and/or flank pain) before age 35 years; total kidney volume greater than expected for age; truncating PKD1 mutations; estimated glo- merular filtration rate decline >5 mL/min/1.73 m? within 1 year; and a family history of ESKD at or before age 58 years. Tolvaptan carries an FDA-mandated safety warning for pos- sible irreversible liver injury. Therefore, patients with ADPKD receiving tolvaptan require frequent laboratory monitoring of liver tests. Patients with ADPKD should be offered screen- FIGURE 17. Autosomal dominant polycystic kidney disease with multiple ing for cerebral aneurysms by CT or MR angiography, par- bilateral cysts, which replace the normal smooth architecture of the kidneys and lead to markedly increased kidney size. Image from the CDC Public Health Image ticularly those with a family history of intracranial aneurysm Library. or hemorrhage. 58

Genetic Disorders and Kidney Disease Tuberous Sclerosis Complex Collagen Type IV-Related Nephropathies Tuberous sclerosis complex (TSC) is a genetic disorder with Type IV collagen is an integral component of the glomerular mutations in the tumor-suppressing genes TSC1 or TSC2 and basement membrane (GBM). Structural defects in this protein, resulting tumors in many organs, primarily in the brain, eyes, due to genetic variations, can result in manifestations span- heart, kidney, skin, and lungs. Although TSC is most fre- ning from GBM thinning to progressive glomerular injury. quently diagnosed in the pediatric population, mild disease There is a subgroup of adult patients with focal segmental may escape detection until adulthood. glomerulosclerosis and type IV collagen mutations (see Renal angiomyolipomas occur in 75% of patients with TSC Glomerular Diseases). and can be detected by CT, ultrasonography, or MRI. Renal cell carcinoma occurs in 1% to 2% of adults with TSC, and therefore Hereditary Nephritis screening with abdominal MRI is recommended every 1 to Hereditary nephritis (Alport syndrome) is a glomerular dis- 3 years. Kidney cysts may also develop. The features of TSC ease associated with sensorineural hearing loss and charac- that most strongly affect quality of life are generally associated teristic ocular findings. There are three genetic variants: with the brain: seizures, developmental delay, intellectual dis- X-linked (80%), autosomal recessive (15%), and autosomal ability, and autism. dominant (5%). Females with the X-linked variant can be Surgery or related interventions (radiofrequency ablation, asymptomatic carriers or can develop kidney disease depend- selective arterial embolization) may be required for large ing on activity of the X chromosome in somatic renal cells. (>5 cm) or hemorrhagic renal angiomyolipomas. Diagnosis has traditionally been made by kidney biopsy with electron microscopy. In patients with a well-documented family history and microscopic hematuria, diagnosis is increas- e Autosomal dominant polycystic kidney disease is char- ingly being made by genetic testing. Genetic testing is also the acterized by large kidneys with multiple kidney cysts, most reliable way to identify heterozygote carriers of type IV hypertension, hematuria, pain in the back or abdomen, collagen mutations. Proteinuria, hypertension, and CKD usually urinary tract infection, or kidney stones. progress to ESKD between the late teenage years and the fourth e Patients with autosomal dominant polycystic kidney decade of life. Management is supportive, including blood pres- disease should be offered screening for cerebral aneu- sure control with renin-angiotensin system blockade. rysm with CT or MR angiography.

Tuberous Sclerosis Complex Collagen Type IV-Related Nephropathies Tuberous sclerosis complex (TSC) is a genetic disorder with Type IV collagen is an integral component of the glomerular mutations in the tumor-suppressing genes TSC1 or TSC2 and basement membrane (GBM). Structural defects in this protein, resulting tumors in many organs, primarily in the brain, eyes, due to genetic variations, can result in manifestations span- heart, kidney, skin, and lungs. Although TSC is most fre- ning from GBM thinning to progressive glomerular injury. quently diagnosed in the pediatric population, mild disease There is a subgroup of adult patients with focal segmental may escape detection until adulthood. glomerulosclerosis and type IV collagen mutations (see Renal angiomyolipomas occur in 75% of patients with TSC Glomerular Diseases). and can be detected by CT, ultrasonography, or MRI. Renal cell carcinoma occurs in 1% to 2% of adults with TSC, and therefore Hereditary Nephritis screening with abdominal MRI is recommended every 1 to Hereditary nephritis (Alport syndrome) is a glomerular dis- 3 years. Kidney cysts may also develop. The features of TSC ease associated with sensorineural hearing loss and charac- that most strongly affect quality of life are generally associated teristic ocular findings. There are three genetic variants: with the brain: seizures, developmental delay, intellectual dis- X-linked (80%), autosomal recessive (15%), and autosomal ability, and autism. dominant (5%). Females with the X-linked variant can be Surgery or related interventions (radiofrequency ablation, asymptomatic carriers or can develop kidney disease depend- selective arterial embolization) may be required for large ing on activity of the X chromosome in somatic renal cells. (>5 cm) or hemorrhagic renal angiomyolipomas. Diagnosis has traditionally been made by kidney biopsy with electron microscopy. In patients with a well-documented family history and microscopic hematuria, diagnosis is increas- e Autosomal dominant polycystic kidney disease is char- ingly being made by genetic testing. Genetic testing is also the acterized by large kidneys with multiple kidney cysts, most reliable way to identify heterozygote carriers of type IV hypertension, hematuria, pain in the back or abdomen, collagen mutations. Proteinuria, hypertension, and CKD usually urinary tract infection, or kidney stones. progress to ESKD between the late teenage years and the fourth e Patients with autosomal dominant polycystic kidney decade of life. Management is supportive, including blood pres- disease should be offered screening for cerebral aneu- sure control with renin-angiotensin system blockade. rysm with CT or MR angiography. e Tolvaptan delays decline in kidney function in adults at Thin Glomerular Basement Membrane Disease risk for rapidly progressive autosomal dominant poly- Thin glomerular basement membrane disease (benign famil- cystic kidney disease. ial hematuria) is associated with type IV collagen variants ¢ Kidney manifestations of tuberous sclerosis complex causing GBM thinning, which results in hematuria without

e Tolvaptan delays decline in kidney function in adults at Thin Glomerular Basement Membrane Disease risk for rapidly progressive autosomal dominant poly- Thin glomerular basement membrane disease (benign famil- cystic kidney disease. ial hematuria) is associated with type IV collagen variants ¢ Kidney manifestations of tuberous sclerosis complex causing GBM thinning, which results in hematuria without include renal angiomyolipomas, renal cell carcinoma, significant proteinuria or ensuing glomerulosclerosis. Up to and cysts. 5% of the population may be affected. Although diagnosis can be made using electron microscopy of kidney biopsy material, thin glomerular basement membrane disease is usually a clinical diagnosis based on benign presentation and Genetic Noncystic Kidney course (normal kidney function with microscopic hematuria Disorders and little or no proteinuria) and positive family history of Genetic noncystic kidney disorders include autosomal similarly benign phenotype (family history of isolated hema- dominant tubulointerstitial kidney disease, collagen type turia without kidney failure). The disease has excellent long- IV-related disease, Fabry disease, and apolipoprotein L1 term prognosis with rare progression to CKD. Management is nephropathy. supportive.

and cysts. 5% of the population may be affected. Although diagnosis can be made using electron microscopy of kidney biopsy material, thin glomerular basement membrane disease is usually a clinical diagnosis based on benign presentation and Genetic Noncystic Kidney course (normal kidney function with microscopic hematuria Disorders and little or no proteinuria) and positive family history of Genetic noncystic kidney disorders include autosomal similarly benign phenotype (family history of isolated hema- dominant tubulointerstitial kidney disease, collagen type turia without kidney failure). The disease has excellent long- IV-related disease, Fabry disease, and apolipoprotein L1 term prognosis with rare progression to CKD. Management is nephropathy. supportive. Autosomal Dominant Tubulointerstitial Fabry Disease Kidney Disease Fabry disease is an X-linked recessive inborn error of gly- Autosomal dominant tubulointerstitial kidney disease cosphingolipid metabolism caused by deficiency of (ADTKD) should be suspected in patients with slowly progres- a-galactosidase A. The enzyme deficiency leads to defective sive chronic kidney disease (CKD), a bland urine sediment, storage of sphingolipid and progressive endothelial accumula- small kidneys, and a family history of ESKD. Mutations in tion, causing abnormalities in the skin (telangiectasias and UMOD are the most commonly identified variants in ADTKD, angiokeratomas), eye, kidney, heart (premature coronary but variants in REN, MUC1, and HNF1B have also been identi- artery disease), brain, and peripheral nervous system (severe fied in families with a history of ADTKD. Gout and anemia neuropathic pain). that appear earlier than expected for CKD stage have been Diagnosis can be made by kidney biopsy but also can associated with ADTKD. be made noninvasively with measurement of leukocyte

Autosomal Dominant Tubulointerstitial Fabry Disease Kidney Disease Fabry disease is an X-linked recessive inborn error of gly- Autosomal dominant tubulointerstitial kidney disease cosphingolipid metabolism caused by deficiency of (ADTKD) should be suspected in patients with slowly progres- a-galactosidase A. The enzyme deficiency leads to defective sive chronic kidney disease (CKD), a bland urine sediment, storage of sphingolipid and progressive endothelial accumula- small kidneys, and a family history of ESKD. Mutations in tion, causing abnormalities in the skin (telangiectasias and UMOD are the most commonly identified variants in ADTKD, angiokeratomas), eye, kidney, heart (premature coronary but variants in REN, MUC1, and HNF1B have also been identi- artery disease), brain, and peripheral nervous system (severe fied in families with a history of ADTKD. Gout and anemia neuropathic pain). that appear earlier than expected for CKD stage have been Diagnosis can be made by kidney biopsy but also can associated with ADTKD. be made noninvasively with measurement of leukocyte 59