Renal Cystic Diseases, Part I

Question 1

Multicystic Kidney Disease

Background

Answer 1

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.

Question 2

Multicystic Kidney Disease

Epidemiology

Answer 2

0.1%; male-to-female ratio: 1.3 to 1.9:1

Question 3

Multicystic Kidney Disease

Pathogenesis

Answer 3

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

Question 4

Multicystic Kidney Disease

Clinical Manifestations of MCDK

Answer 4

Age of onset: in utero, may present with oligohydramnios

Question 5

Multicystic Kidney Disease

Clinical Manifestations of MCDK

Answer 5

Thirty percent of patients have other CAKUT: vesicoureteral reflux in contralateral kidney, neurogenic bladder, duplicating collecting systems, ectopic kidney.

Question 6

Multicystic Kidney Disease

Clinical Manifestations of MCDK

Answer 6

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).

Question 7

Multicystic Kidney Disease

Clinical Manifestations of MCDK

Answer 7

MCDK is not associated with HTN or malignancy.

Long-term follow-up for vesicoureteral reflux, albuminuria, and kidney injury is recommended.

Question 8

Autosomal Dominant Tubulointerstitial Kidney Disease

Background

Answer 8

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).

Question 9

Autosomal Dominant Tubulointerstitial Kidney Disease

Clinical Manifestations Common to Various ADTKD

Answer 9

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.

Question 10

Autosomal Dominant Tubulointerstitial Kidney Disease

Clinical Manifestations Common to Various ADTKD

Answer 10

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.

Question 11

Autosomal Dominant Tubulointerstitial Kidney Disease

Pathogenesis of ADTKD

Answer 11

ADTKD—UMOD (a.k.a. uromodulin kidney disease, familial juvenile hyperuricemic nephropathy, medullary cystic kidney disease type 2)

Question 12

Autosomal Dominant Tubulointerstitial Kidney Disease

Pathogenesis of ADTKD

Answer 12

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.

Question 13

Autosomal Dominant Tubulointerstitial Kidney Disease

Pathogenesis of ADTKD

Answer 13

Renal insufficiency, bland urine, ESRD: early third decade of life

Early-onset hyperuricemia and gout

Question 14

Autosomal Dominant Tubulointerstitial Kidney Disease

Pathogenesis of ADTKD

Answer 14

ADTKD—MUC1 (a.k.a. Mucin-1 kidney disease, medullary cystic kidney disease type 1)

Mutation of MUC1 which encodes for Mucin-1

Question 15

Autosomal Dominant Tubulointerstitial Kidney Disease

Pathogenesis of ADTKD

Answer 15

Age to ESRD: sixth decade of life

ADTKD—REN (a.k.a. familial juvenile hyperuricemic nephropathy type 2)

Question 16

Autosomal Dominant Tubulointerstitial Kidney Disease

Pathogenesis of ADTKD

Answer 16

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.

Question 17

Autosomal Dominant Tubulointerstitial Kidney Disease

Pathogenesis of ADTKD

Answer 17

Associated with anemia, hyporenin, hypovolemia, early onset hyperuricemia, gout

Question 18

Autosomal Dominant Tubulointerstitial Kidney Disease

Pathogenesis of ADTKD

Answer 18

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

Question 19

Autosomal Recessive Tubulointerstitial Disease

Background:

Answer 19

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

Question 20

Autosomal Recessive Tubulointerstitial Disease

Pathogenesis:

Answer 20

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.

Question 21

Autosomal Recessive Tubulointerstitial Disease

Clinical Manifestations:

Answer 21

Age of onset: in utero

Growth retardation

ESRD by age 30s in general; ESRD by age 3 in NPHP2

Question 22

Autosomal Recessive Tubulointerstitial Disease

Clinical Manifestations:

Answer 22

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.

Question 23

Autosomal Recessive Tubulointerstitial Disease

Histopathology:

Answer 23

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

Question 24

Autosomal Recessive Tubulointerstitial Disease

Histopathology:

Answer 24

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.

Question 25

Autosomal Recessive Tubulointerstitial Disease

Management:

Answer 25

Blood pressure control if applicable, preferably with renin–angiotensin–aldosterone system (RAAS) inhibitors; consider salt, fluids, with or without fludrocortisone if hypotension/hypovolemia.

Question 26

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Background:

Answer 26

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

Question 27

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Pathogenesis:

Answer 27

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.

Question 28

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Pathogenesis:

Answer 28

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.

Question 29

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Clinical Manifestations:

Answer 29

Classic Vogt triad (< 30% of TSC): seizures, mental retardation, facial angiofibromas.

Question 30

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Clinical Manifestations:

Answer 30

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

Question 31

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Clinical Manifestations:

Answer 31

Lymphangioleiomyomatosis AML may occur almost exclusively in women with or without spontaneous pneumothorax.

Question 32

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Clinical Manifestations:

Answer 32

Others: brain: mental retardation, seizures, autism; skin: angiofibromas, hypomelanotic macules; lungs: interstitial disease; RCC (often bilateral and multifocal)

Question 33

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Management:

Answer 33

Management:
Annual renal ultrasound screening is recommended.

mTOR inhibitor everolimus for TSC-related renal AML.

Question 34

Autosomal-Dominant or Spontaneous Germ Line and Somatic Mutation: Tuberous Sclerosis Complex

Management:

Answer 34

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).

Question 35

TSC/PKD1 Contiguous Gene Syndrome

Answer 35

Deletion mutation involving both TSC2 and PKD1 genes resulting in severe polycystic kidney disease.

Question 36

TSC/PKD1 Contiguous Gene Syndrome

Answer 36

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)

Question 37

Von Hippel–Lindau Disease

Background

Answer 37

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

Question 38

Von Hippel–Lindau Disease

Pathogenesis:

Answer 38

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.

Question 39

Von Hippel–Lindau Disease

Pathogenesis:

Answer 39

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

Question 40

Von Hippel–Lindau Disease

Renal imaging:

Answer 40

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.

Question 41

Von Hippel–Lindau Disease

Clinical Manifestations of VHL Disease

Answer 41

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.

Question 42

Von Hippel–Lindau Disease

Management:

Answer 42

Annual blood pressure measurements, urinary studies for pheochromocytomas, MRI or CT of kidneys and CNS

Question 43

Von Hippel–Lindau Disease

Management:

Answer 43

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.

Question 44

Autosomal Recessive Polycystic Kidney Disease

Pathogenesis:

Answer 44

1. 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.

Question 45

Autosomal Recessive Polycystic Kidney Disease

Pathogenesis:

Answer 45

2. 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.

Question 46

Autosomal Recessive Polycystic Kidney Disease

Answer 46

Epidemiology

Occurs in 1 of 20,000 live births; carrier rate: 1 in 70

Question 47

Autosomal Recessive Polycystic Kidney Disease

Clinical Manifestations:

Answer 47

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.

Question 48

Autosomal Recessive Polycystic Kidney Disease

Clinical Manifestations:

Answer 48

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).

Question 49

Autosomal Recessive Polycystic Kidney Disease

Clinical Manifestations:

Answer 49

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.

Question 50

Autosomal Recessive Polycystic Kidney Disease

Clinical Manifestations:

Answer 50

Hepatobiliary complications: hepatosplenomegaly, portal HTN, ascending cholangitis, cholangiocarcinoma.

Question 51

Autosomal Recessive Polycystic Kidney Disease

Clinical Manifestations:

Answer 51

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).

Question 52

Autosomal Recessive Polycystic Kidney Disease

Management:

Answer 52

Blood pressure control with RAAS inhibitors

Maintain high index of suspicion for ascending cholangitis.

Question 53

Autosomal Recessive Polycystic Kidney Disease

Management:

Answer 53

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.