Renal Cystic Diseases, Part I Flashcards
MultiCystic Kidney Disease and Von Hippel–Lindau Disease
Multicystic Kidney Disease
Background
Multicystic kidney disease (MCDK) is a congenital abnormality of the kidney and urinary tract (CAKUT) where irregular cysts replace normal renal parenchyma, leading to a nonfunctional kidney.
Multicystic Kidney Disease
Epidemiology
0.1%; male-to-female ratio: 1.3 to 1.9:1
Multicystic Kidney Disease
Pathogenesis
Known mutations account for <20% of cases and predominantly include genes involved in glomerular development, ureteric branching, and metanephric mesenchyme
May be seen with fetal alcohol syndrome
Multicystic Kidney Disease
Clinical Manifestations of MCDK
Age of onset: in utero, may present with oligohydramnios
Multicystic Kidney Disease
Clinical Manifestations of MCDK
Thirty percent of patients have other CAKUT: vesicoureteral reflux in contralateral kidney, neurogenic bladder, duplicating collecting systems, ectopic kidney.
Multicystic Kidney Disease
Clinical Manifestations of MCDK
Ultrasound: typically only involves one kidney. Spontaneous involution with cystic collapse may occur. Higher rate of involution by 10 years is seen with kidney size < 5 cm and more commonly for right than left kidney. Adults may thus present with single functioning kidney, which may be confirmed with a dimercaptosuccinic acid scan (DMSA).
Multicystic Kidney Disease
Clinical Manifestations of MCDK
MCDK is not associated with HTN or malignancy.
Long-term follow-up for vesicoureteral reflux, albuminuria, and kidney injury is recommended.
Autosomal Dominant Tubulointerstitial Kidney Disease
Background
Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is a form of nephronophthisis (chronic tubulointerstitial disease that progresses to ESRD) that is associated with various mutations (UMOD, MUC1, REN, HNF-1b).
Autosomal Dominant Tubulointerstitial Kidney Disease
Clinical Manifestations Common to Various ADTKD
Small kidneys with or without corticomedullary cysts
Renal insufficiency, bland urine; ESRD by third decade of life with UMOD and sixth decade of life with MUC1 mutations.
Autosomal Dominant Tubulointerstitial Kidney Disease
Clinical Manifestations Common to Various ADTKD
Hyperuricemia and gout may be seen in patients with UMOD and REN mutations.
HTN is uncommon prior to ESRD.
Genetic testing is indicated for living related kidney donors.
Autosomal Dominant Tubulointerstitial Kidney Disease
Pathogenesis of ADTKD
ADTKD—UMOD (a.k.a. uromodulin kidney disease, familial juvenile hyperuricemic nephropathy, medullary cystic kidney disease type 2)
Autosomal Dominant Tubulointerstitial Kidney Disease
Pathogenesis of ADTKD
Mutation of UMOD which encodes for uromodulin = Tamm Horsfall proteins (THF). Mutated THF proteins are trapped in tubular epithelial cells which lead to tubular cell apoptosis, reactive interstitial fibrosis, and cyst formation.
Autosomal Dominant Tubulointerstitial Kidney Disease
Pathogenesis of ADTKD
Renal insufficiency, bland urine, ESRD: early third decade of life
Early-onset hyperuricemia and gout
Autosomal Dominant Tubulointerstitial Kidney Disease
Pathogenesis of ADTKD
ADTKD—MUC1 (a.k.a. Mucin-1 kidney disease, medullary cystic kidney disease type 1)
Mutation of MUC1 which encodes for Mucin-1
Autosomal Dominant Tubulointerstitial Kidney Disease
Pathogenesis of ADTKD
Age to ESRD: sixth decade of life
ADTKD—REN (a.k.a. familial juvenile hyperuricemic nephropathy type 2)
Autosomal Dominant Tubulointerstitial Kidney Disease
Pathogenesis of ADTKD
Mutation of REN which encodes for preprorenin. Mutated preprorenin results in defective translocation to endoplasmic reticulum (ER) and lysozymes for processing into renin. Cytoplasmic accumulation of preprorenin in renin producing cells leads to tubular dilation and fibrosis.
Autosomal Dominant Tubulointerstitial Kidney Disease
Pathogenesis of ADTKD
Associated with anemia, hyporenin, hypovolemia, early onset hyperuricemia, gout
Autosomal Dominant Tubulointerstitial Kidney Disease
Pathogenesis of ADTKD
ADTKD—HNF-1b (a.k.a. maturity-onset diabetes mellitus of the young type 5, renal cyst and diabetes syndrome)
Mutation of HNF-1b which encodes for the hepatocyte nuclear factor-1b
Associated with diabetes mellitus
Autosomal Recessive Tubulointerstitial Disease
Background:
Rare nephronophthisis with similar histopathology as the autosomal-dominant forms of tubulointerstitial disease. NPHP1-3 are the most common types of NPHP.
Epidemiology
1 in 5,000 live births
Autosomal Recessive Tubulointerstitial Disease
Pathogenesis:
Multiple single-gene mutations have been implicated in the pathogenesis of NPHP. Responsible genes are those encoding proteins localized to the cilium, basal body, and centrosome in tubular epithelial cells. Causal gene is not known in two-third of NPHP cases.
Genetic testing is indicated for living related kidney donors.
Autosomal Recessive Tubulointerstitial Disease
Clinical Manifestations:
Age of onset: in utero
Growth retardation
ESRD by age 30s in general; ESRD by age 3 in NPHP2
Autosomal Recessive Tubulointerstitial Disease
Clinical Manifestations:
Ultrasound findings are similar to those seen in ADTKD: Kidneys are small to normal size, with increased echogenicity and loss of corticomedullary differentiation. Corticomedullary or medullary cysts may be present. Thin section CT may identify corticomedullary junction cysts.
Autosomal Recessive Tubulointerstitial Disease
Histopathology:
Classic triad of tubular basement membrane irregularities, tubular atrophy with cyst formation, and interstitial fibrosis with cell infiltration
Vasopressin-resistant urinary concentration defect with associated polyuria and polydipsia
Autosomal Recessive Tubulointerstitial Disease
Histopathology:
Histology with tubular atrophy, interstitial fibrosis, and corticomedullary microcystic dilation of renal tubules.
Clinical manifestations other than kidney disease in NPHP 1, 2, and 3: retinitis pigmentosa, coloboma, strokes.
Autosomal Recessive Tubulointerstitial Disease
Management:
Blood pressure control if applicable, preferably with renin–angiotensin–aldosterone system (RAAS) inhibitors; consider salt, fluids, with or without fludrocortisone if hypotension/hypovolemia.
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Background:
Autosomal-dominant (or sporadic) tumor-suppressor gene syndrome associated with benign hamartomas of brain, eyes, heart, lung, liver, kidney, skin: angiomyolipomas (AML), oncocytomas, lymphangiomatous cyts; others: renal cysts, glomerulocystic kidney disease (GCKD), RCC (often bilateral and multifocal), FSGS with interstitial fibrosis.
Epidemiology
1 in 6,000 live births
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Pathogenesis:
Sporadic mutations occur in approximately 70% of cases.
Mutations in tumor suppressor genes TSC1 or TSC2 encoding for hamartin and tuberin respectively. Both normally form a hamartin–tuberin complex which antagonizes an insulin-signaling pathway and downstream mammalian target of rapamycin (mTOR) that normally regulates cell size and growth rate.
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Pathogenesis:
Compared with TSC1, TSC2-linked disease is typically more severe. TSC2 mutations are five times more common than TSC1 with sporadic mutations. Familial mutations involve TSC1 and TSC2 equally.
Genetic analysis is positive in 75% to 90%. False-negative genetic testing may occur with de novo somatic mutations.
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Clinical Manifestations:
Classic Vogt triad (< 30% of TSC): seizures, mental retardation, facial angiofibromas.
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Clinical Manifestations:
Most common associated findings: renal AML (60% to 70%) and cysts (20% to 30%). AML may be more severe in women with increased rupture risk during pregnancy and length > 3 cm. Prophylactic surgery or vascular coiling/thrombosis may be considered if >4 cm
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Clinical Manifestations:
Lymphangioleiomyomatosis AML may occur almost exclusively in women with or without spontaneous pneumothorax.
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Clinical Manifestations:
Others: brain: mental retardation, seizures, autism; skin: angiofibromas, hypomelanotic macules; lungs: interstitial disease; RCC (often bilateral and multifocal)
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Management:
Management:
Annual renal ultrasound screening is recommended.
mTOR inhibitor everolimus for TSC-related renal AML.
Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex
Management:
Surgical decompression of large symptomatic cysts refractory to medical therapy
Nephron-sparing surgical resection of renal carcinoma
Bilateral nephrectomies are recommended at ESRD (dialysis or transplant).
TSC/PKD1 Contiguous Gene Syndrome
Deletion mutation involving both TSC2 and PKD1 genes resulting in severe polycystic kidney disease.
TSC/PKD1 Contiguous Gene Syndrome
Occurs in 2% to 3% of patients with TSC; age of onset: first year of life; ESRD by age 20s
Ultrasound: large kidneys similar to autosomal-dominant polycystic kidney disease (ADPKD)
Von Hippel–Lindau Disease
Background
Multiorgan predisposition to malignancy due to a germ-line mutation and a subsequent somatic mutation of the VHL gene.
Epidemiology
1 in 36,000 live births involving all ethnicities
Von Hippel–Lindau Disease
Pathogenesis:
Autosomal-dominant mutation of VHL gene encoding two VHL proteins. VHL protein is part of the ubiquitin–ligase complex involved in ubiquitination and subsequent degradation of the α subunit of the hypoxia-inducible-factor HIF-1 and HIF-2. Accumulated HIF-α binds to HIF-β, translocate to nucleus, bind to the hypoxia response element to induce transcriptions of vascular endothelial growth factor, erythropoietin, tumor growth factor-β1, platelet-derived growth factor, among others.
Von Hippel–Lindau Disease
Pathogenesis:
Autosomal mutation occurs in 80% of cases and sporadic in 20%.
Diagnosis may be made with:
One tumor if positive family history, two tumors if no family history, or genetic analysis
Von Hippel–Lindau Disease
Renal imaging:
Normal kidney size with cysts in >50% of cases. Cysts typically present in small number and small size. While not all renal tumors are preceeded by cysts, all renal cysts must be considered preneoplastic.
Von Hippel–Lindau Disease
Clinical Manifestations of VHL Disease
Onset of disease between 20 and 30s, >90% by age 65
Retinal or CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytomas (plasma norepinephrine), pancreatic islet tumors, endolymphatic sac tumors, renal and pancreatic cysts, epididymal or broad ligament cystadenomas.
RCCs in VHL tend to be slower growing than those seen in sporadic cases.
Von Hippel–Lindau Disease
Management:
Annual blood pressure measurements, urinary studies for pheochromocytomas, MRI or CT of kidneys and CNS
Von Hippel–Lindau Disease
Management:
Renal-sparing surgery is appropriate for RCC < 3 cm in size due to the life-long risk for the development of new lesions at different sites. Radioablative therapy is an option for multicentric lesions. Medical therapies with promising results include VEGF tyrosine kinase inhibitors (sunitinib) and mTOR inhibitor rapamycin.
Autosomal Recessive Polycystic Kidney Disease
Pathogenesis:
- Mutations of the polycystic kidney and hepatic disease 1 gene (PKHD1) gene encoding fibrocystin/polyductin (FCP), a transmembrane protein found in mitotic spindle, microtubules, and apical primary cilia in biliary and renal tubular epithelia. FCP interacts with polycystin 2 and is thought to play a central role in microtubule formation and function and epithelial proliferation and secretion of renal tubules and biliary ducts.
Autosomal Recessive Polycystic Kidney Disease
Pathogenesis:
- Mutations of FCP lead to abnormal dilation of collecting ducts and abnormal remodeling of the biliary system, resulting in renal cystic disease and progressive portal fibrosis respectively. This condition is also known as “congenital hepatic fibrosis.”
Genetic testing is available.
Autosomal Recessive Polycystic Kidney Disease
Epidemiology
Occurs in 1 of 20,000 live births; carrier rate: 1 in 70
Autosomal Recessive Polycystic Kidney Disease
Clinical Manifestations:
Majority of patients present in utero or at birth.
In utero presentation includes enlarged echogenic kidneys with poor kidney function, thus oligohydramnios. The latter may lead to abnormal fetal development with Potter phenotype consisting of pulmonary hypoplasia, characteristic facies, and spine and limb deformities.
Autosomal Recessive Polycystic Kidney Disease
Clinical Manifestations:
Perinatal mortality is estimated to be 25%.
ESRD is reached in >60% by age 10.
Findings of echogenic or cystic kidneys and congenital hepatic fibrosis in childhood is specific for autosomal-recessive polycystic kidney disease (ARPKD).
Autosomal Recessive Polycystic Kidney Disease
Clinical Manifestations:
Ultrasound: radially arrayed dilated collecting ducts spanning from cortex to medulla. ARPKD cysts are not discrete sacs as seen in ADPKD, TSC, and VHL disease;
CT: striated nephrogram due to stasis of contrast media in dilated tubules.
Autosomal Recessive Polycystic Kidney Disease
Clinical Manifestations:
Hepatobiliary complications: hepatosplenomegaly, portal HTN, ascending cholangitis, cholangiocarcinoma.
Autosomal Recessive Polycystic Kidney Disease
Clinical Manifestations:
Patients may present with combined severe kidney and liver disease, or mild disease of one organ and severe disease of the other, mild disease of both organs, or isolated hepatic fibrosis and nonobstructive dilation of intrahepatic bile ducts (Caroli disease).
Autosomal Recessive Polycystic Kidney Disease
Management:
Blood pressure control with RAAS inhibitors
Maintain high index of suspicion for ascending cholangitis.
Autosomal Recessive Polycystic Kidney Disease
Management:
Kidney transplantation is preferred in ESRD. Combined kidney liver transplantation should be considered in case of extensive portal HTN. Parental organ donation is generally possible if normal imaging studies of kidneys and liver due to recessive nature of disease.
