Download Cystic and Inherited Kidney Diseases

Inherited Kidney Diseases
Zehra Eren M.D.
Nephrology Department
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
LEARNING OBJECTIVES
• Alport’s Syndrome
• Thin basement membrane disease
• Anderson-Fabry disease
• Nail-Patella Syndrome
• Sicle Cell Nephropathy
AUTOSOMAL DOMINANT POLYCYSTIC
KIDNEY DISEASE (ADPKD)
• 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
• 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
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 4,304amino-acid protein (polycystin 1)
- Mutations in the PKD2 gene:15%, located on
chromosome 4 (4q.21.2), codes for a 968amino-acid protein (polycystin 2)
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
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
Ravine Criteria for Diagnosing ADPKD
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
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)
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.
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
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
bilateral angiomyolipomas
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
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
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
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
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 nephronsparing approach to remove lesions that
are 3 cm or larger whenever possible
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
Alport syndrome
• Pathogenesis
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
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
ANDERSON-FABRY DISEASE (AFD)
• X-linked lysosomal storage disease
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:
 cardiomyopathy
 Valvular disease
 Coronary artery disease
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 LIMhomeodomain type that plays an important
role for limb and renal development
-incidence:22 per million
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)
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
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
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
S. Berns, Allen R. Nissenson
Edgar V. Lerma, Jeffrey