Acquired Cystic Kidney Disease Alicia Notkin February 26, 2008

Acquired Cystic Kidney Acquired Cystic Kidney DiseaseDisease

Alicia NotkinAlicia Notkin

February 26, 2008February 26, 2008

HistoryHistory

• First described in 1847 by John Simon in First described in 1847 by John Simon in patients with subacute glomerulonephritis patients with subacute glomerulonephritis (Bright’s disease)(Bright’s disease)

• Re-described in 1977 by Dunnill in a study of Re-described in 1977 by Dunnill in a study of kidneys from autopsies performed on ESRD kidneys from autopsies performed on ESRD patients on dialysispatients on dialysis

• Has been reported in association with all Has been reported in association with all causes of renal disease (except hereditary causes of renal disease (except hereditary cystic disease – b/c of the difficulty in cystic disease – b/c of the difficulty in distinguishing the two)distinguishing the two)

Features of acquired cystic Features of acquired cystic kidney diseasekidney disease

• MultipleMultiple

• BilateralBilateral

• Usually < 0.5 cmUsually < 0.5 cm

• ““Positive” u/s or CT: both kidneys w/ Positive” u/s or CT: both kidneys w/ >/= 4 cysts>/= 4 cysts

Features of acquired cystic Features of acquired cystic kidney diseasekidney disease

• No FH ADPKD, small/normal sized No FH ADPKD, small/normal sized kidneys, smooth contour, cysts are kidneys, smooth contour, cysts are only in the kidneyonly in the kidney

• Increased incidence w/ increasing Increased incidence w/ increasing time on dialysis; ~ 35-50% of dialysis time on dialysis; ~ 35-50% of dialysis patients overallpatients overall

• Men and blacks are at much higher Men and blacks are at much higher riskrisk

PathogenesisPathogenesis

• Cyst fluid composition resembles that of Cyst fluid composition resembles that of plasma (thought to derive minimally from plasma (thought to derive minimally from glomerular filtrate & primarily from glomerular filtrate & primarily from transepithelial solute & fluid secretion)transepithelial solute & fluid secretion)

• A brush border is present on the luminal A brush border is present on the luminal membrane of the cystsmembrane of the cysts

• Above suggest that cysts arise from Above suggest that cysts arise from proliferation of proximal tubular epithelial proliferation of proximal tubular epithelial cellscells

Pathogenesis: proposed Pathogenesis: proposed progression to progression to

adenocarcinoma (Grantham adenocarcinoma (Grantham 1991)1991)

Pathogenesis (cont.)Pathogenesis (cont.)

• Aldosterone & hypokalemia seem to Aldosterone & hypokalemia seem to stimulate tubular cell proliferation, & stimulate tubular cell proliferation, & adenoma resection in humans has been adenoma resection in humans has been shown to result in cyst regression shown to result in cyst regression

• Renal transplantation may Renal transplantation may stabilization or stabilization or regression of cysts by restoring normal regression of cysts by restoring normal renal function & biochemical milieurenal function & biochemical milieu

• However, cyclosporine actually However, cyclosporine actually ACKD by: ACKD by: inducing TGF-inducing TGF-ββ expression, suppressing expression, suppressing tumor surveillance, & possibly by its tumor surveillance, & possibly by its ischemic effects on the native kidneysischemic effects on the native kidneys


• In vivo, rats w/ normal kidneys given In vivo, rats w/ normal kidneys given diphenylamine, diphenylthiazole, or diphenylamine, diphenylthiazole, or nordihydroguaiacetic acid develop cysts – renal nordihydroguaiacetic acid develop cysts – renal epithelium is damaged followed by focal tubule epithelium is damaged followed by focal tubule dilatation & expansiondilatation & expansion

• The cyst formation from diphenylthiazole can be The cyst formation from diphenylthiazole can be reversed by stopping the drugreversed by stopping the drug

• The cyst formation from nordihydroguaiacetic The cyst formation from nordihydroguaiacetic acid is significantly enhanced by exposure of the acid is significantly enhanced by exposure of the animals to endotoxins or enteric microbes, animals to endotoxins or enteric microbes, suggesting the role of secondary factors in cyst suggesting the role of secondary factors in cyst developmentdevelopment


• Five-sixths nephrectomy w/ azotemia Five-sixths nephrectomy w/ azotemia provides a milieu for cyst provides a milieu for cyst development in remaining development in remaining parenchymaparenchyma

• This cyst formation can be enhanced This cyst formation can be enhanced by feeding the animals a high protein by feeding the animals a high protein dietdiet


• In vitro: Normal Human Kidney (NHK) In vitro: Normal Human Kidney (NHK) epithelial cells are a good model of epithelial cells are a good model of cyst development in ACKDcyst development in ACKD

• Cyst formation depends on epidermal Cyst formation depends on epidermal growth factor (EGF) & insulin growth factor (EGF) & insulin

• Adenylate cyclase stimulants Adenylate cyclase stimulants induction & growth of cystsinduction & growth of cysts


• In vitro: hydrocortisone promotes cyst In vitro: hydrocortisone promotes cyst formation, possibly by increasing the formation, possibly by increasing the activity of Naactivity of Na++/K/K++-ATPase-ATPase

• Cysts develop in the proximal tubuleCysts develop in the proximal tubule• Cyst regress when hydrocortisone is Cyst regress when hydrocortisone is

removed from mediumremoved from medium• As there is no glomerular filtration As there is no glomerular filtration

occurring, fluid is accumulating only by occurring, fluid is accumulating only by secretion across the tubular wallsecretion across the tubular wall


• The notion of renal cysts as benign tumors filled w/ The notion of renal cysts as benign tumors filled w/ fluid comes from studies of Madin-Darby Canine fluid comes from studies of Madin-Darby Canine Kidney (MDCK) epithelial cells (which actually more Kidney (MDCK) epithelial cells (which actually more accurately reflect hereditary cystic disease rather accurately reflect hereditary cystic disease rather than acquired cystic disease)than acquired cystic disease)

• Medium alone: no proliferation or cystsMedium alone: no proliferation or cysts• Add cAMP agonist (results in cell proliferation & fluid Add cAMP agonist (results in cell proliferation & fluid

secretion) secretion) cyst formation cyst formation• Add EGF Add EGF balls of cells balls of cells• Addition of low concentration ouabain (blocks NaAddition of low concentration ouabain (blocks Na++/K/K++--

ATPase) to these cells blocks fluid secretion & ATPase) to these cells blocks fluid secretion & therefore cyst enlargement, but does not inhibit therefore cyst enlargement, but does not inhibit proliferation, resulting in a dissociation of fluid proliferation, resulting in a dissociation of fluid transport & cell proliferation, ie. a cellular mass transport & cell proliferation, ie. a cellular mass instead of a cystinstead of a cyst

ComplicationsComplications

• Hematuria +/- pain (or overt Hematuria +/- pain (or overt hemorrhage)hemorrhage)

• Increase in number & size of cysts Increase in number & size of cysts over timeover time

• Cyst infectionCyst infection

• ErythrocytosisErythrocytosis

• Renal cell carcinoma: ~ ½ of the time Renal cell carcinoma: ~ ½ of the time are multiple & bilateralare multiple & bilateral

Renal cell carcinoma risk Renal cell carcinoma risk factorsfactors• Smoking: ~ 2x riskSmoking: ~ 2x risk• Occupational exposure to cadmium, Occupational exposure to cadmium,

asbestos, & trichloroethylene: ~ 1-2x riskasbestos, & trichloroethylene: ~ 1-2x risk• ObesityObesity• Acquired cystic renal disease: ~ 30x risk???Acquired cystic renal disease: ~ 30x risk???• Analgesic abuse nephropathyAnalgesic abuse nephropathy• Genetic factorsGenetic factors• ? Hypertension, prior radiation, sickle cell ? Hypertension, prior radiation, sickle cell

diseasedisease

Renal cell carcinoma in Renal cell carcinoma in ESRDESRD• Usually develops after 8-10 years of dialysisUsually develops after 8-10 years of dialysis• Occurs in ~ 6% of dialysis patientsOccurs in ~ 6% of dialysis patients• M:F ratio of ~ 7:1M:F ratio of ~ 7:1• Larger cysts that Larger cysts that supranormal kidney size supranormal kidney size

increased risk of transformation (kidneys increased risk of transformation (kidneys weighing > 150g are 6x more likely to contain weighing > 150g are 6x more likely to contain carcinoma than smaller size kidneys)carcinoma than smaller size kidneys)

• Clear cell RCC is much less common as is its Clear cell RCC is much less common as is its associated chromosome 3p deletionsassociated chromosome 3p deletions

• Seems to have lower metastatic potentialSeems to have lower metastatic potential• May not always be related to acquired cystic May not always be related to acquired cystic

diseasedisease

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

ACKD-associated RCCACKD-associated RCC

• Serum hepatocyte growth factor (HGF) Serum hepatocyte growth factor (HGF) increases as renal failure progressesincreases as renal failure progresses

• HGF is also higher in patients who have HGF is also higher in patients who have been on dialysis for a longer timebeen on dialysis for a longer time

• HGF mRNA & protein, along w/ c-met HGF mRNA & protein, along w/ c-met protein have been shown to be protein have been shown to be upregulated in non-tumor & tumor upregulated in non-tumor & tumor regions in ACKD patients w/ RCCregions in ACKD patients w/ RCC

ACKD-associated RCCACKD-associated RCC

• C-Jun is activated in atypical hyperplastic C-Jun is activated in atypical hyperplastic proliferative cells in ACKD & is thought to proliferative cells in ACKD & is thought to play a role in RCC carcinogenesisplay a role in RCC carcinogenesis

• Bcl-2 overexpression may also have a role in Bcl-2 overexpression may also have a role in tumor developmenttumor development

• Nadasdy, in 1995, characterized the Nadasdy, in 1995, characterized the proliferative activity of cyst epithelia in ACKD proliferative activity of cyst epithelia in ACKD (& ADPKD & ARPKD) as high, & suggested (& ADPKD & ARPKD) as high, & suggested that these cysts may be RCC precursorsthat these cysts may be RCC precursors

Bosniak classification of renal Bosniak classification of renal cystscysts

• Classifies renal cysts into one of five Classifies renal cysts into one of five categories based on morphology & categories based on morphology & enhancement on CT scanenhancement on CT scan

• Designation helps w/ diagnosis & Designation helps w/ diagnosis & management of the cystsmanagement of the cysts

Bosniak classification (Israel Bosniak classification (Israel 2005)2005)

Screening for RCCScreening for RCC

• ? Screen dialysis patients for acquired cystic kidney ? Screen dialysis patients for acquired cystic kidney diseasedisease

• ? If one decides to screen, should one use contrast ? If one decides to screen, should one use contrast CT or u/sCT or u/s

• One recommendation: screen w/ u/s, & if positive for One recommendation: screen w/ u/s, & if positive for cysts, screen yearly w/ contrast CT (particularly if cysts, screen yearly w/ contrast CT (particularly if patient has very large cysts)patient has very large cysts)

• Another recommendation: only do radiographic Another recommendation: only do radiographic screening if patient has new hematuria or flank pain screening if patient has new hematuria or flank pain or has been on dialysis for a long time or has large or has been on dialysis for a long time or has large kidneys from acquired cystic kidney diseasekidneys from acquired cystic kidney disease

• Somewhere in between? – screen patients who have Somewhere in between? – screen patients who have been on dialysis for 3-5 yearsbeen on dialysis for 3-5 years

Screening for RCCScreening for RCC

• Probably want to screen on an Probably want to screen on an individual basisindividual basis

• Similarly to screening for other Similarly to screening for other malignancies, like colon or breast malignancies, like colon or breast cancer, should probably consider cancer, should probably consider comorbidities/overall life expectancy comorbidities/overall life expectancy of the individual patientof the individual patient

ReferencesReferences• Chertow, GM et al. Cost-effectiveness of cancer screening in end-stage renal disease. Arch Intern Chertow, GM et al. Cost-effectiveness of cancer screening in end-stage renal disease. Arch Intern

Med 1996; 156:1345.Denton, MD et al. Prevalence of renal cell carcinoma in patients with ESRD Med 1996; 156:1345.Denton, MD et al. Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: A pathologic analysis. Kidney Int 2002; 61:2201.pre-transplantation: A pathologic analysis. Kidney Int 2002; 61:2201.

• Farivar-Mohseni, H et al. Renal cell carcinoma and end stage renal disease. J Urol 2006; 175:2018.Farivar-Mohseni, H et al. Renal cell carcinoma and end stage renal disease. J Urol 2006; 175:2018.• Fick, GM et al. Hereditary and acquired cystic disease of the kidney. Kidney Int 1994; 46:951.Fick, GM et al. Hereditary and acquired cystic disease of the kidney. Kidney Int 1994; 46:951.• Grantham, JJ. Acquired cystic kidney disease. Kidney Int 1991; 40:143.Grantham, JJ. Acquired cystic kidney disease. Kidney Int 1991; 40:143.• Hughson, MD et al. Renal cell carcinoma of end-stage renal disease: A histopathologic and Hughson, MD et al. Renal cell carcinoma of end-stage renal disease: A histopathologic and

molecular genetic study. J Am Soc Nephrol 1996; 7:2461.molecular genetic study. J Am Soc Nephrol 1996; 7:2461.• Ishikawa, I et al. Renal cell carcinoma detected by screening shows better patient survival than Ishikawa, I et al. Renal cell carcinoma detected by screening shows better patient survival than

that detected following symptoms in dialysis patients. Ther Apher Dial 2004; 8:468.that detected following symptoms in dialysis patients. Ther Apher Dial 2004; 8:468.• Ishikawa, I et al. Ten-year prospective study on the development of renal cell carcinoma in dialysis Ishikawa, I et al. Ten-year prospective study on the development of renal cell carcinoma in dialysis

patients. Am J Kidney Dis 1990; 16:452.patients. Am J Kidney Dis 1990; 16:452.• Israel, GM et al. An update of the Bosniak renal cyst classification system. Urology 2005; 66:484.Israel, GM et al. An update of the Bosniak renal cyst classification system. Urology 2005; 66:484.• Konda, R et al. Expression of hepatocyte growth factor and its receptor C-met in acquired renal Konda, R et al. Expression of hepatocyte growth factor and its receptor C-met in acquired renal

cystic disease associated with renal cell carcinoma. J Urol 2004; 171:2166.cystic disease associated with renal cell carcinoma. J Urol 2004; 171:2166.• LeBrun, CJ et al. Life expectancy benefits of cancer screening in the end-stage renal disease LeBrun, CJ et al. Life expectancy benefits of cancer screening in the end-stage renal disease

population. Am J Kidney Dis 2000; 35:237.population. Am J Kidney Dis 2000; 35:237.• Levine, E et al. Natural history of acquired renal cystic disease in dialysis patients: A prospective Levine, E et al. Natural history of acquired renal cystic disease in dialysis patients: A prospective

longitudinal CT study. Am J Roentgenol 1991; 156:501.longitudinal CT study. Am J Roentgenol 1991; 156:501.• Lien, YH et al. Association of cyclosporin A with acquired cystic kidney disease of the native Lien, YH et al. Association of cyclosporin A with acquired cystic kidney disease of the native

kidneys in transplant recipients. Kidney Int 1991; 44:613.kidneys in transplant recipients. Kidney Int 1991; 44:613.• MacDougall, ML et al. Predication of carcinoma in acquired cystic disease as a function of kidney MacDougall, ML et al. Predication of carcinoma in acquired cystic disease as a function of kidney

weight. J Am Soc Nephrol 1990; 1:828.weight. J Am Soc Nephrol 1990; 1:828.• Marple, JT et al. Renal cancer complicating acquired cystic kidney disease. J Am Soc Nephrol Marple, JT et al. Renal cancer complicating acquired cystic kidney disease. J Am Soc Nephrol

1994; 4:1951.1994; 4:1951.• Nadasdy, T et al. Proliferative activity of cyst epithelium in human renal cystic diseases. J Am Soc Nadasdy, T et al. Proliferative activity of cyst epithelium in human renal cystic diseases. J Am Soc

Nephrol 1995; 5:1462.Nephrol 1995; 5:1462.• Sarasin, FP et al. Screening for acquired cystic kidney disease: A decision analytic perspective. Sarasin, FP et al. Screening for acquired cystic kidney disease: A decision analytic perspective.

Kidney Int 1995; 48:207.Kidney Int 1995; 48:207.• Truong, LD et al. Renal neoplasm in acquired cystic kidney disease. Am J Kidney Dis 1995; 26:1.Truong, LD et al. Renal neoplasm in acquired cystic kidney disease. Am J Kidney Dis 1995; 26:1.

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Acquired Cystic Kidney Disease Alicia Notkin February 26, 2008