1. Inherited Kidney Diseases Zehra Eren M.D. Nephrology Department

2. LEARNING OBJECTIVES Recognize Renal cystic disorders -Autosomal dominant polycystic kidney disease -Autosomal recessive polycystic kidney disease -Medullary sponge kidney -Medullary cystic kidney disease -Tuberous sclerosis cpmplex -von Hippel-Lindau disease

3. LEARNING OBJECTIVES Alport’s Syndrome Thin basement membrane disease Anderson-Fabry disease Nail-Patella Syndrome Sicle Cell Nephropathy

6. Epidemiology The most common renal hereditary disease, affects 1 in 400 to 1,000 live births Affects all races with equal frequence AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

7. Autosomal dominant polycystic kidney disease Prevalence: 1:300 to 1:1000 90% of cases are inherited, 10% are sporadic Only1 to 5% nephrons developed cysts Cysts are in medulla and cortex ADPKD causes symptoms in third or fourth decade 50% of patients developing ESRD by age 60

9. AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) Inheritance - Mutations in the polycystic kidney disease (PKD)1 gene:85%, located on the short arm of chromosome 16 (16p.3.3), codes for a 4,304- amino-acid protein (polycystin 1) - Mutations in the PKD2 gene:15%, located on chromosome 4 (4q.21.2), codes for a 968- amino-acid protein (polycystin 2)

10. ADPKD Pathology - massive enlargement of the kidneys secondary to cyst growth and development Diagnosis -Radiologic Radiological imaging is required (ultrasound is the current imaging modality of choice in at-risk individuals (positive family history in a parent). - Genetic

13. ADPKD Pathology - massive enlargement of the kidneys secondary to cyst growth and development Diagnosis -Radiologic Radiological imaging is required (ultrasound is the current imaging modality of choice in at-risk individuals (positive family history in a parent). - Genetic

14. Ravine Criteria for Diagnosing ADPKD

18. Clinical Manifestations Renal Chronic flank pain Acute pain indicates: infection (pyelonephritis- pyocyst) urinary tract obstruction sudden hemorrhage into cysts Hematuria Impaired renal concentrating ability Nephrolitiasis in 15%to 20% Hypertension in 75% adults

19. Clinical Manifestations Extrarenal Hepatic cysts: Liver cysts present approximately 10 years after renal cysts Intracranial aneurysms:Occur in 4% to 8% of symptomatic ADPKD patients Cardiac disease:Mitral and aortic prolapse and regurgitation Diverticular disease: Hernias:abdominal and inguinal hernias (up to 45% of ADPKD patients)

21. AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD) Epidemiology -Affects 1/10,000 to 1/40,000 individuals Inheritance -Autosomal recessive disorder -Mutations in a single gene on the short arm of chromosome 6p 21.1 Pathology -The protein encoded by the PKHD1 gene is called polyductin or fibrocystin.

25. Diagnosis and Clinical Manifestations ● Prenatally: Oligohydramnios, enlarged kidneys, and lung hypoplasia with resultant Potter facies ● Infancy: Pneumomediastinum, pneumothorax, HTN, cardiac hypertrophy,endomyocardiofibrotic congestive heart failure, and renal failure ● Older children: Hepatic fibrosis, portal HTN, and complications of variceal bleeding, thrombocytopenia, and anemia predominate

26. TUBEROUS SCLEROSIS COMPLEX (TSC ) Genetics -autosomal dominant pattern -high rate of spontaneous mutations (65% to 75% of patients) TSC1 → 9 (9q34), its protein product is called Hamartin TSC2 → 16 (16p13.3), its protein product is named Tuberin

33. bilateral angiomyolipomas

35. MEDULLARY CYSTIC KIDNEY DISEASE (MCKD) Rare inherited cystic disease, autosomal dominant inheritance: - MCKD1 was mapped to chromosome 1 (1q21) and accounts for the minority of cases - MCKD2 was mapped more recently to chromosome 16 (16p12) and accounts for mutations in most cases

36. MEDULLARY CYSTIC KIDNEY DISEASE (MCKD) Pathology -normal- to small sized kidneys -cysts located at the corticomedullary junction and in the medulla. However, the presence of cysts is not universal -Microscopically: diffuse tubulointerstitial inflammation, hypertrophied and dilated tubules. Glomeruli are usually normal

37. Diagnosis and Clinical Course Clinical features with a family history The presence of cysts supports the diagnosis but is not essential Computed tomography scan is the most sensitive technique for cyst detection Polyuria and polydipsia Progressive renal failure ultimately leads to ESRD

40. von Hippel-Lindau disease autosomal dominant syndrome manifested by a variety of benign and malignant tumors VHL gene abnormality is present in about 1 in 36,000 newborns

43. von Hippel-Lindau disease Clear cell RCCs occur in approximately 70 percent of VHL patients who survive to 60 years of age. Annual imaging of the kidneys with MRI or CT is indicated to establish the diagnosis For patients in whom an RCC is diagnosed, we recommend a nephron- sparing approach to remove lesions that are 3 cm or larger whenever possible

47. ALPORT’S SYNDROME OR HEREDITARY NEPHRITIS Genetics -Prevalence of genetic mutation estimated at 1 in 5,000 to 1 in 10,000. -Accounts for 1% to 2% of ESRD cases. -X-linked inheritance in almost all cases (85%) -Of the non–X-linked cases, most are autosomal recessive

48. Alport syndrome Pathogenesis

49. ALPORT SYNDROME Renal Manifestations -Hematuria: the characteristic clinical feature of Alport’s syndrome -Proteinuria Extrarenal Manifestations -Sensorineural hearing loss -Ocular defects: anterior lenticonus -Leiomyomatosis of the esophagus and genitalia

50. THIN BASEMENT MEMBRANE DISEASE (TBMD) Inherited renal disease of the GBM clinically characterized by persistent microscopic hematuria inherited in an autosomal dominant fashion, is not accompanied by extrarenal manifestations, and has a benign course The diagnosis is established by renal biopsy and electron microscopy

52. ANDERSON-FABRY DISEASE (AFD) X-linked lysosomal storage disease

53. ANDERSON-FABRY DISEASE (AFD) Diagnosis: measurement of plasma or leukocyte α-GALAactivity, skin biopsy, examination of urine sediment, or sequencing of the defective gene Clinical Manifestations ▫ Renal ▫ Cardiac:  c ardiomyopathy  Valvular disease  Coronary artery disease

60. Nail-Patella syndrom (NPS) osteo-onychodysplasia Genetics -mutations of the LMX1B gene located at the distal end of the long arm of chromosome 9 -LMX1B is a transcription factor of the LIM- homeodomain type that plays an important role for limb and renal development -incidence:22 per million

61. Nail-Patella syndrom (NPS) Renal manifestations: present in one-half of patients -proteinuria (sometimes nephrotic range proteinuria) -Hematuria -Hypertension -Impaired urinary concentration About 30 percent of patients with renal manifestations will develop end-stage renal disease (ESRD)

64. Sickle Cell Nephropathy Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of sickle cell disease The primary event leading to renal involvement appears to be sickling of erythrocytes in the vasa recta capillaries leading to microthrombotic infarction and extravasation of blood in the medulla Renal failure may ensue in over 10 percent of affected patients, but other clinically significant renal manifestations occur much more frequently

65. Renal Findings in SCN Hematuria -medullary congestion -renal papillary necrosis -medullary calcification -medullary carcinoma Tubular Dysfunction -concentration defect -increased sodiım and phosphate reabsorption -decreased proton and potassium secretion -increased urate secretion Glomerular sclerosis -hyperfiltration -glomerular hypertrophy -proteinuria/nephrotic syndrome -Focal segmental glomerulosclerosis

67. SUGGESTED READING Goldman's Cecile Medicine, Goldman L, Schafer AI Case files Internal Medicine, Toy Patlan Current Medical Diagnosis and Treatment, Maxine A. Papadakis, Stephen J. McPhee, Eds. Michael W. Rabow, Associate Ed. Current Diagnosis & Treatment: Nephrology & Hypertension Edgar V. Lerma, Jeffrey S. Berns, Allen R. Nissenson