Acquired Cystic Kidney Disease Alicia Notkin February 26, 2008

History First described in 1847 by John Simon in patients with subacute glomerulonephritis (Bright’s disease) First described in 1847 by John Simon in patients with subacute glomerulonephritis (Bright’s disease) Re-described in 1977 by Dunnill in a study of kidneys from autopsies performed on ESRD patients on dialysis Re-described in 1977 by Dunnill in a study of kidneys from autopsies performed on ESRD patients on dialysis Has been reported in association with all causes of renal disease (except hereditary cystic disease – b/c of the difficulty in distinguishing the two) Has been reported in association with all causes of renal disease (except hereditary cystic disease – b/c of the difficulty in distinguishing the two)

Features of acquired cystic kidney disease Multiple Multiple Bilateral Bilateral Usually < 0.5 cm Usually < 0.5 cm “Positive” u/s or CT: both kidneys w/ >/= 4 cysts “Positive” u/s or CT: both kidneys w/ >/= 4 cysts

Features of acquired cystic kidney disease No FH ADPKD, small/normal sized kidneys, smooth contour, cysts are only in the kidney No FH ADPKD, small/normal sized kidneys, smooth contour, cysts are only in the kidney Increased incidence w/ increasing time on dialysis; ~ 35-50% of dialysis patients overall Increased incidence w/ increasing time on dialysis; ~ 35-50% of dialysis patients overall Men and blacks are at much higher risk Men and blacks are at much higher risk

Pathogenesis Cyst fluid composition resembles that of plasma (thought to derive minimally from glomerular filtrate & primarily from transepithelial solute & fluid secretion) Cyst fluid composition resembles that of plasma (thought to derive minimally from glomerular filtrate & primarily from transepithelial solute & fluid secretion) A brush border is present on the luminal membrane of the cysts A brush border is present on the luminal membrane of the cysts Above suggest that cysts arise from proliferation of proximal tubular epithelial cells Above suggest that cysts arise from proliferation of proximal tubular epithelial cells

Pathogenesis: proposed progression to adenocarcinoma (Grantham 1991)

Pathogenesis (cont.) Aldosterone & hypokalemia seem to stimulate tubular cell proliferation, & adenoma resection in humans has been shown to result in cyst regression Aldosterone & hypokalemia seem to stimulate tubular cell proliferation, & adenoma resection in humans has been shown to result in cyst regression Renal transplantation may  stabilization or regression of cysts by restoring normal renal function & biochemical milieu Renal transplantation may  stabilization or regression of cysts by restoring normal renal function & biochemical milieu However, cyclosporine actually  ACKD by: inducing TGF-β expression, suppressing tumor surveillance, & possibly by its ischemic effects on the native kidneys However, cyclosporine actually  ACKD by: inducing TGF-β expression, suppressing tumor surveillance, & possibly by its ischemic effects on the native kidneys

Pathogenesis (cont.) In vivo, rats w/ normal kidneys given diphenylamine, diphenylthiazole, or nordihydroguaiacetic acid develop cysts – renal epithelium is damaged followed by focal tubule dilatation & expansion In vivo, rats w/ normal kidneys given diphenylamine, diphenylthiazole, or nordihydroguaiacetic acid develop cysts – renal epithelium is damaged followed by focal tubule dilatation & expansion The cyst formation from diphenylthiazole can be reversed by stopping the drug The cyst formation from diphenylthiazole can be reversed by stopping the drug The cyst formation from nordihydroguaiacetic acid is significantly enhanced by exposure of the animals to endotoxins or enteric microbes, suggesting the role of secondary factors in cyst development The cyst formation from nordihydroguaiacetic acid is significantly enhanced by exposure of the animals to endotoxins or enteric microbes, suggesting the role of secondary factors in cyst development

Pathogenesis (cont.) Five-sixths nephrectomy w/ azotemia provides a milieu for cyst development in remaining parenchyma Five-sixths nephrectomy w/ azotemia provides a milieu for cyst development in remaining parenchyma This cyst formation can be enhanced by feeding the animals a high protein diet This cyst formation can be enhanced by feeding the animals a high protein diet

Pathogenesis (cont.) In vitro: Normal Human Kidney (NHK) epithelial cells are a good model of cyst development in ACKD In vitro: Normal Human Kidney (NHK) epithelial cells are a good model of cyst development in ACKD Cyst formation depends on epidermal growth factor (EGF) & insulin Cyst formation depends on epidermal growth factor (EGF) & insulin Adenylate cyclase stimulants  induction & growth of cysts Adenylate cyclase stimulants  induction & growth of cysts

Pathogenesis (cont.) In vitro: hydrocortisone promotes cyst formation, possibly by increasing the activity of Na + /K + -ATPase In vitro: hydrocortisone promotes cyst formation, possibly by increasing the activity of Na + /K + -ATPase Cysts develop in the proximal tubule Cysts develop in the proximal tubule Cyst regress when hydrocortisone is removed from medium Cyst regress when hydrocortisone is removed from medium As there is no glomerular filtration occurring, fluid is accumulating only by secretion across the tubular wall As there is no glomerular filtration occurring, fluid is accumulating only by secretion across the tubular wall

Pathogenesis (cont.) The notion of renal cysts as benign tumors filled w/ fluid comes from studies of Madin-Darby Canine Kidney (MDCK) epithelial cells (which actually more accurately reflect hereditary cystic disease rather than acquired cystic disease) The notion of renal cysts as benign tumors filled w/ fluid comes from studies of Madin-Darby Canine Kidney (MDCK) epithelial cells (which actually more accurately reflect hereditary cystic disease rather than acquired cystic disease) Medium alone: no proliferation or cysts Medium alone: no proliferation or cysts Add cAMP agonist (results in cell proliferation & fluid secretion)  cyst formation Add cAMP agonist (results in cell proliferation & fluid secretion)  cyst formation Add EGF  balls of cells Add EGF  balls of cells Addition of low concentration ouabain (blocks Na + /K + - ATPase) to these cells blocks fluid secretion & therefore cyst enlargement, but does not inhibit proliferation, resulting in a dissociation of fluid transport & cell proliferation, ie. a cellular mass instead of a cyst Addition of low concentration ouabain (blocks Na + /K + - ATPase) to these cells blocks fluid secretion & therefore cyst enlargement, but does not inhibit proliferation, resulting in a dissociation of fluid transport & cell proliferation, ie. a cellular mass instead of a cyst

Complications Hematuria +/- pain (or overt hemorrhage) Hematuria +/- pain (or overt hemorrhage) Increase in number & size of cysts over time Increase in number & size of cysts over time Cyst infection Cyst infection Erythrocytosis Erythrocytosis Renal cell carcinoma: ~ ½ of the time are multiple & bilateral Renal cell carcinoma: ~ ½ of the time are multiple & bilateral

Renal cell carcinoma risk factors Smoking: ~ 2x risk Smoking: ~ 2x risk Occupational exposure to cadmium, asbestos, & trichloroethylene: ~ 1-2x risk Occupational exposure to cadmium, asbestos, & trichloroethylene: ~ 1-2x risk Obesity Obesity Acquired cystic renal disease: ~ 30x risk??? Acquired cystic renal disease: ~ 30x risk??? Analgesic abuse nephropathy Analgesic abuse nephropathy Genetic factors Genetic factors ? Hypertension, prior radiation, sickle cell disease ? Hypertension, prior radiation, sickle cell disease

Renal cell carcinoma in ESRD Usually develops after 8-10 years of dialysis Usually develops after 8-10 years of dialysis Occurs in ~ 6% of dialysis patients Occurs in ~ 6% of dialysis patients M:F ratio of ~ 7:1 M:F ratio of ~ 7:1 Larger cysts that  supranormal kidney size  increased risk of transformation (kidneys weighing > 150g are 6x more likely to contain carcinoma than smaller size kidneys) Larger cysts that  supranormal kidney size  increased risk of transformation (kidneys weighing > 150g are 6x more likely to contain carcinoma than smaller size kidneys) Clear cell RCC is much less common as is its associated chromosome 3p deletions Clear cell RCC is much less common as is its associated chromosome 3p deletions Seems to have lower metastatic potential Seems to have lower metastatic potential May not always be related to acquired cystic disease May not always be related to acquired cystic disease

Renal cancer in ACKD compared to the general population (Marple 1994)

ACKD-associated RCC Serum hepatocyte growth factor (HGF) increases as renal failure progresses Serum hepatocyte growth factor (HGF) increases as renal failure progresses HGF is also higher in patients who have been on dialysis for a longer time HGF is also higher in patients who have been on dialysis for a longer time HGF mRNA & protein, along w/ c-met protein have been shown to be upregulated in non-tumor & tumor regions in ACKD patients w/ RCC HGF mRNA & protein, along w/ c-met protein have been shown to be upregulated in non-tumor & tumor regions in ACKD patients w/ RCC

ACKD-associated RCC C-Jun is activated in atypical hyperplastic proliferative cells in ACKD & is thought to play a role in RCC carcinogenesis C-Jun is activated in atypical hyperplastic proliferative cells in ACKD & is thought to play a role in RCC carcinogenesis Bcl-2 overexpression may also have a role in tumor development Bcl-2 overexpression may also have a role in tumor development Nadasdy, in 1995, characterized the proliferative activity of cyst epithelia in ACKD (& ADPKD & ARPKD) as high, & suggested that these cysts may be RCC precursors Nadasdy, in 1995, characterized the proliferative activity of cyst epithelia in ACKD (& ADPKD & ARPKD) as high, & suggested that these cysts may be RCC precursors

Bosniak classification of renal cysts Classifies renal cysts into one of five categories based on morphology & enhancement on CT scan Classifies renal cysts into one of five categories based on morphology & enhancement on CT scan Designation helps w/ diagnosis & management of the cysts Designation helps w/ diagnosis & management of the cysts

Bosniak classification (Israel 2005)

Screening for RCC ? Screen dialysis patients for acquired cystic kidney disease ? Screen dialysis patients for acquired cystic kidney disease ? If one decides to screen, should one use contrast CT or u/s ? If one decides to screen, should one use contrast CT or u/s One recommendation: screen w/ u/s, & if positive for cysts, screen yearly w/ contrast CT (particularly if patient has very large cysts) One recommendation: screen w/ u/s, & if positive for cysts, screen yearly w/ contrast CT (particularly if patient has very large cysts) Another recommendation: only do radiographic screening if patient has new hematuria or flank pain or has been on dialysis for a long time or has large kidneys from acquired cystic kidney disease Another recommendation: only do radiographic screening if patient has new hematuria or flank pain or has been on dialysis for a long time or has large kidneys from acquired cystic kidney disease Somewhere in between? – screen patients who have been on dialysis for 3-5 years Somewhere in between? – screen patients who have been on dialysis for 3-5 years

Screening for RCC Probably want to screen on an individual basis Probably want to screen on an individual basis Similarly to screening for other malignancies, like colon or breast cancer, should probably consider comorbidities/overall life expectancy of the individual patient Similarly to screening for other malignancies, like colon or breast cancer, should probably consider comorbidities/overall life expectancy of the individual patient

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