1. Adult polycystic kidney disease -Autosomal dominant-Large multicystic kidneys, LIVER CYSTS, berry aneurysms

Clinic: Hematuria, flank pain, urinary tract infection, renal stones, hypertension

Outcome: Chronic renal failure beginning at age 40-60

2. Childhood polycystic kidney disease -Autosomal recessive-enlarged, cystic kidneys at birth

Clinic: hepatic fibrosis

outcome: variable, death in infancy or childhood

3. Medullary sponge kidney -no inheritance-medullary cysts on excretory urography

Clinic: hematuria, UTI, recurrent renal stones

outcome: Benign

4. Familial juvenile nephronophthisis -autosomal recessive -corticomedullary cysts, SHRUNKEN kidneys

Clinic: salt wasting, polyuria, growth retardation, anemia, tubular acidosis

outcome: progressive renal failure beginning in *childhood

5. Adult-onset medullary cystic disease -autosomal dominant -corticomedullary cysts, SHRUNKEN kidneys

clinic: salt wasting, polyuria

outcome: chronic renal failure beginning in *adulthood

6. Simple cysts -None-single or multiple cysts in normal-sized kidneys

clinic: microscopic hematuria

outcome: BENIGN

7. ACQUIRED renal cystic disease -None-cystic degeneration in end stage kidney disease

-clinic: hemorrhage, erythrocytosis, neoplasia

outcome: dependence on dialysis

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8. Autosomaldominantpolycystic kidneydisease

-universally bilateral-1 in 400 to 1,000-5-10% of chronic renal failure

GENES:-in one of two genes:

1) PKD1 - 85% - encodes POLYCYSTIN 1, a large protein that localizes to tubular epithelial cellsand has domainsthat are usually involved in cell-cell and cell-matrix interactions

2) PKD2 - 15% - POLYCYSTIN 2 - a cation channel - mutations disrupt the regulation of intracellular calcium -less severe

Current hypothesis: Polycystin 1 and 2 are both localized to the PRIMARY CILIUM and potentially form a complexthat regulated intracellular calcium in response to fluid flow. mutated proteins --> affect intracellular secondmessengers and influence proliferation, apoptosis, ECM interactions and secretory function --> progressiveformation of tubular cysts

Morphology:-massively enlarged kidneys; cysts up to 3 to 4 cm in diameter-cysts arise anywhere along the nephron and compress adjacent parenchyma-late disease - interstitial inflammation and fibrosis

Clinic:-progression is accentuated in the presence of HYPERTENSION

-~40% of patients have scattered biliary cysts (polycystic liver disease)-mitral valve prolapse in 20-25%- ~40% die of hypertensive or coronary heart disease; 25% of infections; 15% from ruptured BERRY ANEURYSMSin the circle of Willis or hypertensive brain hemorrhage

9. Autosomalrecessive(childhood)polycystic kidneydisease

**perinatal through juvenile and presence of associated HEPATIC LESIONS

gene: PKHD1 - encoding FIBROCYSTIN - a large transmembrane protein that localizes to the primary cilium oftubular epithelial cells

$$ kidneys are enlarged by multiple, cylindrically dilated collecting ducts oriented at right angles to the cortex

10. Medullary spongekidney

-presents in ADULTS-multiple cystic dilations in the medullary collecting ducts-can predispose to renal calculi

11. Nephronophthisis and adult-onset medullary cystic disease

-small medullary cysts typically concentrated at the corticomedullary junction

4 Variants:

1) Sporadic, nonfamilial (20%)

2) Familial juvenile nephronophthisis (50%); autosomal recessive

3) Renal-retinal dysplasia (15%); autosomal recessive ----------4) Adult onset medullary cystic disease (15%); autosomal dominant

*renal failure over 5-10 years

Patho:-7 gene loci-NPH1, NPH2, NPH3 - underlie the JUVENILE form of nephronophthisis; the gene products ofNPH1 and NPH3 are called NEPHROCYSTINS and are associated with PRIMARY CILIA-NPH2 = INVERSIN - mediates right-left embryologic patterning

**initial injury to the distal tubules with basement membrane disruption --> chronic progressiveTUBULAR ATROPHY and INTERSTITIAL FIBROSIS

12. Acquired (Dialysis-Associated)Cystic Disease

-end stage kidney patients develop multiple cortical and medullary cysts due to obstruction fromcalculi and/or interstitial fibrosis

$$ cysts often contain CALCIUM OXALATE crystals and are commonly lined by atypical,hyperplastic epithelium that can undergo malignant transformation $$

13. Simple Cysts -Single or multiple cysts of the cortex (rarely medulla) are lined by low cuboidal epithelium and canrange from 1-10 cm in size*COMMON LESIONS-smooth walls and are filled with clear serous fluid; occasionally, hemorrhage can cause flankpain, and calcification with irregular contours can mimic renal carcinoma

14. Urinary TractObstruction (obstructiveuropathy)

-obstruction --> increases susceptibility to infection and stone formation, and unrelieved obstructionalmost always leads to permanent renal atrophy

* HYDRONEPHROSIS (Nephrosis refers to a non-inflammatory nephropathy) - is the term for pelvis andcalyceal dilation associated with progressive renal atrophy of the kidney following outflow obstruction *Causes include:-congenital anomalies -urinary calculi-prostatic hypertrophy-tumors of prostate, bladder, cervix, or uterus-inflammation-sloughed papillae or blood clots-normal pregnancy-uterine prolapse and cystocele-functional disorders (neurogenic bladder)

Morphology:-when obstruction is sudden and complete, GFR reduction --> relatively modest pelvis and calyceal dilationw/ only mild parenchymal atrophy-when the obstruction is SUBTOTAL or INTERMITTENT, GFR is not suppressed, and progressive dilationensues. *Obstruction also triggers interstitial inflammation and fibrosis

Clinical:-early symptoms - underlying obstruction-unilateral obstruction can remain silent for long periods because the unaffected kidney can usuallycompensate - in BILATERAL PARTIAL obstruction manifestations include polyuria, distal tubular acidosis, saltwasting, renal calculi, tubulointerstitial nephritis, atrophy, and hypertension

$$ COMPLETE bilateral obstruction --> oliguria or anuria-relief of such blockade is accompanied by a brisk post obstructive diuresis

15. Urolithiasis(Renal Calculi,Stones)

*Calculi - can arise at any level in the urinary tract (most form in the kidney)-peak incidence of urolithiasis is 20-30

Path:-Increased [ ]'s of stone constituents, changes in urinary pH, decreased urine volume, and bacteria all play a role instone formation*LOSS OF INHIBITORS of crystal formation (e.g. citrate, pyrophosphate, glycosaminoglycans, osteopontin, and aglycoprotein called NEPHROCALCIN) can also contribute)

* 4 types of calculi-all contain an organic matrix of MUCOPROTEIN

1) 70% - CALCIUM-CONTAINING stones composed of calcium oxalate and/or calcium phosphate-usually associated with hypercalcemia or hypercalciuria

2) 15-20% - TRIPLE PHOSPHATE or STRUVITE stones composed of magnesium ammonium phosphate -struvite stones precipitate in alkaline urine generated by bacterial infections that convert urea to ammonia (e.g.Proteus). -Staghorn calculi - occupying large parts of the renal pelvis - are struvite stones usually associated with infections

3) 5-10% are URIC ACID STONES; more than half of such patients are NEITHER hyperuricemic norhyperuricosuric; instead they make exceptionally acidic urine (i.e. pH less than 5.5) that causes uric acid toprecipitate

4) b/w 1-2% of calculi are composed of CYSTEINE, and are caused by genetic defects in renal amino acidresorption

Clinical:-obstruction, ulceration, bleeding, and pain (renal colic) -also predispose to renal infection

16. Renal PapillaryAdenomas

-common-small, yellow cortical tumors-most consist of vacuolated epithelial cells forming tubules and complex branching papillary structures-histologically indistinguishable from low-grade papillary renal cell carcinomas, and they share some of theircytogenetic features*3 cm is the size cut-off separating those that metastasize from those that rarely do*

17. Angiomyolipoma -hamartomatous (A hamartoma[2] is a benign,[3] focal malformation that resembles a neoplasm in the tissue of itsorigin. This is not a malignant tumor, and it grows at the same rate as the surrounding tissues. It is composed oftissue elements normally found at that site, but which are growing in a disorganized mass.) lesion composedvessels, smooth muscle, and fat-these are present in 25-50% of patients with tuberous sclerosis-they are clinically significant primarily for their susceptibility to spontaneously hemorrhage

18. Oncocytoma -epithelial tumor composed of eosinophilic cells arising from collecting duct intercalated cells**cells are packed with mitochondria-common: 5-15% of resected neoplasms-can be large

19. Renal cellcarcinoma(Adencarcinomaof the kidney)

-3% of all visceral cancers-85% of renal cancers of adults-50-70 years-2:1 male prependerance

*TOBACCO

-mostly sporadic -4% are autosomal dominant familial variants

20. von Hippel-Lindau (VHL)syndrome

-50-70% of patients with certain VHL mutations develop renal cysts, as well as bilateral, frequentlymulticentric renal cell carcinomas

21. Hereditary papillarycarcinoma

-ascribed to mutations in the MET proto-oncogene -autosomal dominant entity manifesting with multiple bilateral papillary tumors

22. Classification of Renal CellCarcinoma

1) CLEAR CELL (non-papillary) carcinoma (70-80%) most common type-95% are sporadic-98% loss of sequences on chromosome 3p at a locus that harbors VHL

$$ VHL is a TUMOR SUPPRESSOR GENE that encodes part of a ubiquitin ligase complex involved intargeting proteins for degradation--> when VHL is mutated, HIF-1 factor levels remain high --> increases angiogenic factors -->tumorigenesis

2) Papillary carcinoma - 10-15% of renal cell cancers - occurs in both familial and sporadic forms-familial - associated with mutations of the MET proto-oncogene that serves as a TYROSINE KINASEreceptor for HEPATOCYTE GROWTH FACTOR

3) Chromophobe renal carcinoma-5% of renal cell caners-derive from collecting duct intercalated cells-although they exhibit multiple chromosome losses and extreme hypodiploidy, they have an EXCELLENTPROGNOSIS

4) Collecting Duct (Bellini duct) carcinoma-1% of renal cancers-arises from medullary collecting duct cells

23. Morph of Clear CellCarcinomas

-usually solitary, large spherical bright yellow-gray masses that distort the renal outline-exhibit large areas of ischemic opaque, gray-white necrosis, foci of hemorrhagic discoloration, andareas of softening-tumors can bulge into the calyces and pelvis and invade the renal vein to grow as a solid column of cellswithin this vessel

-HISTO: can be solid, trabecular or tubular growths; abundant clear cytoplasm; delicate arborizingvasculature

24. Morph Papillarycarcinoma

-can be multifocal and bilateral-hemorrhagic and cystic-cuboidal cells arranged in papillary formations, often with interstitial foam cells and psammoma bodies

25. Chromophobe renalcarcinoma

-composed of pale, eosinophilic cells with perinuclear halos arranged in sheets around blood vessels