Cystitis and Tumors of Kidney

Question 1

Adult polycistic kidney disease

Answer 1

• Autosomal dominant

large, multicycstic kidneys, liver cysts, berry aneurysms

hematuria, flank pain, UTI, renal stones, HTN

chronic renal failure beginning at age 40-60 years

Question 2

childhood polycystic kidney

Answer 2

Autosomal recessive

enlarged, cystic kidneys at birth

hepatic fibrosis

death in infancy or childhood

Question 3

medullary sponge kidney

Answer 3

no inheritance

• medullary cysts on excretory urography
• see hematuria, UTI, recurrent renal stones
• cortical scarring is absent
• Benign

Question 4

Familial juvenile nephronophthisis

Answer 4

• autosomal recessive
• corticomedullary cysts and shrunken kidneys
• salt wasting, polyuria, growth retardation
• progressive renal failure from childhood

Question 5

adult-onset nephronophthisis

Answer 5

• Autosomal dominant
• Corticomedullary cysts, shrunken kidneys
• Salt wasting, polyuria
• Chronic renal failure adult onset

Question 6

simple cysts

Answer 6

no inheritance pattern

• single or several cysts in normal sized kidneys, translucent, lined by grap smooth membrane filled with clear fluid
• see microscopic hematuria (on occasion see hemorrhage and sudden distention/pain)
• benign (do not bulge from cortex, as might be seen in carcinoma)
• in contrast to renal tumors, renal cysts have smooth contours and are almost always avascular, and give fluid rather than solid signals on ultrasonography

Question 7

acquired renal cystic disease

Answer 7

• no inheritance (dialysis associated)
• cystic degeneration in end-stage kidney
• see hemorrhage, erythrocytosis, neoplasia, hematuria
• see calcium oxalate crystals
• 18 fold increased risk of renal cell carcinoma
• reqs. dependence upon dialysis

Question 8

multicystic renal dysplasia

Answer 8

• no inheritance
• irregular kidneys w/ cysts of various sizes
• assoc. w/ other renal abnormalities
• most cases assoc. w/ ureteropelvic obstruction, ureteral agenesis/atresia
• renal failure occurs if bilateral, if unilateral it is surgically correctable

Question 9

Genetics of ADPKD?

Answer 9

• PKD1 gene mutation: (85%) encodes membrane protein polycystin-1 which is expressed in tubular epithelial cells, esp, the distal nephron
• PKD2 gene mutation: (15%) encodes polycystin-2, an integral membrane protein expressed in all segements of renal tubules and functions as a Ca2+ permeable cation channel
• defects in mechanosensing and Ca2+ flux underlie cyst formation – PKD1/PDK2 form a complex that regulates intracellular Ca2+ in response to fluid flow
• mutation leads to loss of plycystin complex and disruption of downstream signaling events
• increase in Ca2+ stimulates proliferation and secretion from epithelial cells lining the cysts

Question 10

clinical features of ADPKD?

Answer 10

• many remain asymptomatic until later years
• hemorrhage and pain
• ecretion of blood clots → renal colic
• enlarged kidneys, hematuria, proteinuria, polyuria, HTN
• patients w/ PKD2 have older age of onset, less aggressive
• progression worse in blacks, males and people w/ HTN
• individuals also tend to have extrarenal congenital anomalies
• 40% have cysts also occur in other places (liver, spleen, pancreas, lungs, intracranial berry aneurysms)
o 4-10% die of subarachnoid hemorrhage (berry aneurysms in circle of willis)
o mitral valve prolapse
o diverticualar disease of colon
• PKD1 is most likely to develop ESRF than PKD2
• insidious onset presenting in 4th-6th decade w/ renal insufficiency (hypertension and azotemia)
• may exhibit abdominal pain due to cyst enlargement and hemorrhage → hematuria

Question 11

pathogenesis/morphology of childhood polycstic kidney disease

Answer 11

• serious complications at birth – the young usually succumb rapidly to renal failure
Pathogenesis:
• mutations in PKHD1 gene on chromosome 6: encodes fibrocystin – which may be a cell surface receptor w/ a role in CD and biliary differentiation
Morphology:
• kidneys are enlarged and have smooth external appearance
• small cysts in cortex/medulla give sponge appearance
• dilated elongated channels are present radially, at right angles to the cortical surface

Question 12

clinical features of autosomal recessive PKD?

Answer 12

• “congenital hepatic fibrosis” patients who survive develop hepatic injury characterized by bland periportal fibrosis
• hepatic disease is dominant concern in older children
• development of portal HTN and splenomegaly

Perinatal: most common – 90% of CD are cystic; minimal hepatic fibrosis, only survive a few hours

Neonatal: 60% of CD are cystic; mild hepatic fibrosis: generally survive a few months, die from renal failure

Infantile: 20% CD are cystic; hepatic fibrosis/failure, portal HTN – 90% survive but die in early childhood

Juvenile: <10% CD are cystic, hepatic fibrosis is progressive and portal HTN results in death in adolescence

Question 13

Nephronopthisis

Answer 13

• variable number of cysts in the medulla, usually concentrated at the corticomedullary junction
• cortical tubulointerstitial damage is the cause of eventual renal insuff.

present w/ polyuria and polydipsia, sometimes also sodium wasting and tubular acidosis

as a group, now considered to be the most common genetic cause of ESKD in adolescence/young adults
• should be strongly considered in children w/ otherwise unexplained chronic renal failure

Pathogenesis:
• mutations in MCKD1 and MCKD2 have been identified in causing medullary cystic disease
• mutations in NPH1/2/3 underlie juvenile form of nephronphthisis

Morphology:

kidneys are small, contracted granular surfaces, cysts in the medulla at corticomedullary junction

Question 14

non-familial congenital unilateral multicystic renal dysplasia

Answer 14

• most common congenital renal cystic disease: 1 in 4000 live births
• Caused by failure of the ureteric bud to reach renal blastema during embryologic development and stimulate formation of the renal cortex and associated development of the nephron. 90% cases have an absent ureter (agenesis) or ureteropelvic obstruction
Pathologic findings:
• Extensive multiple variably-sized cysts with intervening rather poorly-differentiated mesenchyme (often cartilage formation)
• No development of glomeruli
• Generally no increased incidence of additional or concomitant congenital abnormalities

Question 15

hydronephrosis

Answer 15

= dilation of renal pelvis and calyces assoc. w/ progressive atrophy of the kidney due to obstruction to the outflow of urine
• even w/ complete obstruction, glomerular filtration remains b/c filtrate diffuses back into renal interstitium and perirenal space
• high pressure in pelvis transmitted back through CD and into the cortex → renal atrophy, compressing renal vasculature in medulla → dinishing medullary blood flow
• obstruction also triggers interstitial inflamm. rxn → interstitial fibrosis

Question 16

clinical features of hydronephrosis?

Answer 16

• calculi lodged in ureters → renal colic
• prostatic enlargements → bladder sx
• unilateral hydronephrosis → unaffected kidney maintaining adequate renal fn.
• bilateral partial obstruction → inability to concentrate urine, polyuria and nocturia, distal tubular acidosis, salt wasting, nephritis, scarring and HTN
• complete bilateral obstruction → oliguria/anuria and death if not corrected

Question 17

urolithiasis

Answer 17

(Renal Calculi, Stones) or “nephrolithiasis”
• affects 5-10% of Americans (most just unilaterally)
• men affected more, peak onset age 20-30 y/o
• familial/hereditary predisposition
• when kidney stones enter the ureter may cause intense pain renal colic, ulceration and bleeding of ureter and obstruction of urinary flow
• major determinant to stone formation is urinary concentration of constituents and supersaturation
• urinary pH and decreased urine volume also play role in formation
• become lodged in renal calyces and pelves

Question 18

calcium oxalate sontes

Answer 18

70% (radiopaque - white)
• most common finding is hypercalciuria (some have hypercalcemia as well)
• hyperparathyroidism is uncommon cause of stone formation
• diffuse bone disease and sarcoidosis
• hyperabsorption of Ca2+ from intestine

Question 19

struvite stones

Answer 19

(Magnesium ammonium phosphate) – 20%
• formed after infections by urea-splitting bacteria
• alkaline urine causes their precipitation

Question 20

uric acid stones

Answer 20

– 5% (radioluscent - black)
• most have neither hyperuricemia nor increased urinary excretion of uric acid
• pH of urine below 5.5 may be disposing factor

Question 21

renal papillary adenoma

Answer 21

“renal cortical adenoma”
- most common of benign neoplasms
• small, discrete adenomas arising from renal tubular epithelium
• small cortical tumors w/ pale yellow-gray discrete well circumscribed nodules
• histologically don’t differ from low grade papillary renal cell carcinoma but are usually less than 3 cm (separating them from those that metastasize)

note: Adenoma is used for benign epithelial neoplasm derived from glands

• neoplasms over 1 cm now often considered low grade renal cell carcinoma

Question 22

angiomyolipoma

Answer 22

benign neoplasm of vessels, smooth mm. and fat
• angiomyolipomas are present in 25-50% of pt. w/ tuberous sclerosis – caused by loss-of-function mutation in the TSC1 or TSC2 tumor suppressor genes

Tuberous sclerosis characterized by epilepsy, mental retardation, skin abnormalities and benign tumors

may cause spontaneous hemorrhage

Question 23

oncocytoma

Answer 23

epithelial benign neoplasm made of large eosinophilic cells (5-15% of primary renal epithelial neoplasms)
• tumors are tan to mahogany brown, homogenous, and usually well encapsulated with a central scar
• arise from type A intercalated cells of renal cortical collecting ducts (imp. in acid-base hemostasis)
• present in adulthood, and can be large
• can be mistaken for renal cell carcinoma, though these rarely metastasize

Question 24

Renal cell carcinoma

Answer 24

(Adenocarcinoma of the kidney)
• most common in ages 50-70 y/o w/ males more heavily affected
• 85% of renal cancers in adults
• arises from renal tubular epithelium
• renal cell carcinoma tends to invade the renal vein, may grow as solid column of cells up the IVC → right atrium
• only adenocarcinoma that elaborates fats (they are lipid positive!)

Question 25

risk factors of renal cell carcinoma?

Answer 25

• tobacco and cigarette smoking, obesity, HTN, unopposed estrogen therapy, asbestos, petroleum and heavy metals , chronic renal failure

4% are hereditary, autosomal dominant, younger patients
o VHL tumor suppressor gene: 2/3 of people with VHL develop renal cell carcinoma
o hereditary leiomyomatosis and renal cell cancer syndrome: disease characterized by papillary carcinoma

Question 26

clinical features of renal cell carcinomas?

Answer 26

Clinical triad: costovertebral pain, palpable mass, hematuria** (seen in 50%)

• tendency to be large and metastasize before signs/sx
• generalized sx: fever, malaise, weakness and w/l
• 25% of pt. have metastasis at times of ddx: lung, bone, regional nodes, liver, adrenal and brain

mode of spread is hematogenous, not lymphatic

Question 27

clear cell carcinoma

Answer 27

AVERAGE

most common type- 70-80%
• non-papillary, clear cytoplasm (some granular cytoplasm)
• 95% are sporadic
• bright yellow-gray-white spherical mass (due to lipid accumulation)
• most tumors are well differentiated but some show nuclear atypia

VHL gene: tumor suppressor gene that encodes protein part of ubiquitin complex involved in targeting proteins for degredation: when VHL is inactive, HIF1 levels are high, even under normoxic conditions, causing inappropriate expression of genes such as VEGF and genes that stimulates growth like IGF-1

Question 28

papillary carcinoma

Answer 28

BETTER
• 10-15%
• papillary growth pattern, better prognosis
• trisomy 7; lost Y (MET proto-oncogene)
• arise from DCT, tend to be multifocal and bilateral
• typically hemorrhagic and cystic

Question 29

chromophobe carcinoma

Answer 29

BETTER
• 5% - doesn’t look like clear cell
• see pale eosinophilic cytoplasm, nuclear halos; better prognosis
• arise from type B intercalated cells of renal cortex CD

Question 30

Xp11 translocation carcinoma

Answer 30

• occurs in young patients
• translocation of Xp11.2
• cells consist of clear cytoplasm w/ papillary architecture

Question 31

Collecting Duct Carcinoma

Answer 31

Collecting duct (Bellini duct) carcinoma: WORST
• 1% - arise from collecting duct cells in medulla
• Medullary carcinoma is very similar but seen more often in sickle trait patients
• shows branching tubules lined by cuboidal cells

Question 32

Urothelial carcinoma of renal pelvis

Answer 32

Urothelial Carcinoma of the Renal Pelvis (Transitional cell)
• originate from urothelium of renal pelvis (5-10% of primary renal tumors)
• usually small when discovered due to lying w/in the renal pelvis and producing noticeable hematuria
• may block urinary outflow and lead to palpable hydronephrosis and flank pain
• 50% of patients have concomitant bladder tumors

Question 33

Willm’s Tumor

Answer 33

• most common renal tumor of childhood, 4th most common pediatric malignancy in US
• peak age is 2-5 y/o, and 95% occur before age 10
• bilateral tumors seen in 5-10%
o synchronous- tumor involving both kidneys
o metachronous: one kidney affected after the other
o bilateral tumors have median age of onset at 10 mos, - often due to patients harboring a germline mutation in one of wilms tumor predisposing genes

Question 34

WAGR syndrome

Answer 34

Wilms tumor, aniridia (absence of iris), genital anomalies, mental retardation
• carry deletion of 11p13
• WTI gene and PAX6 both located on chromosome 11
o patients with restricted PAX6 → aniridia
o patients with restricted WT1 → Wilms tumor
• mutation of WT1 gene represents the “first hit” to formation of Wilms tumor. Nonsense or frameshift mutation causes “second hit” in development of Wilms tumor

Question 35

Denys-Drash syndrome

Answer 35

• see gonadal dysgenesis (male pseudoherm) and early onset nephropathy → renal failure (due to diffuse mesangial sclerosis)
• patients have anvormalities in WT1 gene due to dominant-negative missense mutation,
• Wilm’s tumor only results when there is bi-allelic inactivation of WT1
• increased risk of development of gonadoblastomas
• WT1 encodes a DNA binding txn factor that is expressed in kidney and gonads during emryogenesis, thus the WT1 protein is critical for normal renal and gonadal development:

Question 36

Beckwith-Widemann syndrome

Answer 36

(BWS):
• see enlargement of body organs (organomegally), macroglossia, hemihypertrophy, omphalocele(infants intestines/organs stick out in bellybuttong) and abnormal large cells in adrenal cx
• a model for genomic imprinting
• WT2 gene: contains genes that are normally only expressed from one of parental alleles with imprinting of the other – development of BWS is due to imprinting patterns
o loss of imprinting of IGF-2 (usually only expressed by father) → overexpression of IGF-2
o uniparental paternal disomy: deletion of mothers allele, and duplication of txn. active paternal allele in tumor
o explains features of overgrowth in BWS, since IGF-2 is a embryonal growth factor
• Patients with BWS are at increased risk of developing hepatoblastoma, pancreatoblastoma, adrenocortical tumors, rhabdomyosarcomas
• Recent studies have also shown B-Catenin (WNT pathway signaling) gain –of –function mutations to cause Wilms tumors

Question 37

nephrogenic rests

Answer 37

• putative precursor lesion of Wilms tumors, seen in renal parenchyma adjacent to tumors
• arises in 100% of all bilateral Wilm’s tumors, and 25-40 % of unilateral tumors
• important to document presence of nephrogenic rests b/c patients are at an increased risk of developing Wilms tumors in contralateral kidney and require surveillance for many years

Question 38

morphology of Wilm’s tumor

Answer 38

• grossly presents as large, solitary, well-circumscribed mass (though 10% are bilateral)
• tumor is soft, homogenous, tan-gray, with occasional foci of hemorrhage, cyst formation and necrosis
• Microscopically see stages of nephrogenesis: see triphasic combination of blastemal, stromal and epithelial cell types
• sheets of small blue cells with few distinctive features
• 5% of tumors are anasplastic: see large, hyperchromatic pleomorphic nuclei with abnormal mitoses
o presence of anaplasia correlates to p53 mutations (keeps the cells from apoptosing) – loss of p53 explains unresponsiveness of anaplastic cells to cytotoxic chemotherapy

Question 39

clinical features of wilms tumor

Answer 39

• most children present with large abdominal mass, that may be unilateral, or extend across pelvis
• hematuria, pain in abdomen, intestinal obstruction and appearance of HTN are all common patterns
• in many children pulmonary metastases are present at time of primary dx
• Most patients with Wilms can expect to be cured
• anaplastic histology remains critical determinant for adverse prognosis
• furthermore, loss of material on chromosomes 11q and 16q, and gain of 1q = adverse prognosis
• increased relative risk of developing second primary tumors, including bone and soft tissue sarcomas, leukemia and lymphomas and breast cancers
o some are due to point mutations, while others are because of radiation administered for treatment, thus radiation needs to be used judiciously in treatment of this and other childhood cancers

Question 40

bad prognosis for wilms tumor?

Answer 40

best prognosis = diffuse anaplasia = bad!

triphasic = more favorable
anaplastic = unfavorable 

p53 mutation; 11q +16q deletion; 1q gain = bad prognosis

older children = bad prognosis

Question 41

neuroblastomas

Answer 41

• most common extracranial solid tumor of childhood
• adrenal medulla
• most occur sporadically
• younger children have better prognosis
• presents w/ large abdominal masses, fever and w/l
• older children may not be evident until it has metastasized and causes bone pain
• metastasize to liver, lungs, bones and bone marrow
• “blueberry muffin baby” - in neonates may cause multiple cutaneous metastases
• produce catecholamines, would have high concentration of VMA and HVA in blood
  <18 mos = better prognosis