Acquired Cystic Kidney Disease

1. Acquired Cystic Kidney Disease Alicia Notkin February 26, 2008

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

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

4. Features of acquired cystic kidney disease • 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 • Men and blacks are at much higher risk

5. Pathogenesis • 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 • Above suggest that cysts arise from proliferation of proximal tubular epithelial cells

6. Pathogenesis: proposed progression to adenocarcinoma (Grantham 1991)

7. Pathogenesis (cont.) • 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 • However, cyclosporine actually  ACKD by: inducing TGF-β expression, suppressing tumor surveillance, & possibly by its ischemic effects on the native kidneys

8. 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 • 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

9. Pathogenesis (cont.) • 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

10. Pathogenesis (cont.) • 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 • Adenylate cyclase stimulants  induction & growth of cysts

11. Pathogenesis (cont.) • In vitro: hydrocortisone promotes cyst formation, possibly by increasing the activity of Na+/K+-ATPase • Cysts develop in the proximal tubule • 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

12. 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) • Medium alone: no proliferation or cysts • Add cAMP agonist (results in cell proliferation & fluid secretion)  cyst formation • 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

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

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

15. Renal cell carcinoma in ESRD • Usually develops after 8-10 years of dialysis • Occurs in ~ 6% of dialysis patients • 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) • Clear cell RCC is much less common as is its associated chromosome 3p deletions • Seems to have lower metastatic potential • May not always be related to acquired cystic disease

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

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

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

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

20. Bosniak classification (Israel 2005)

21. Screening for RCC • ? Screen dialysis patients for acquired cystic kidney disease • ? 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) • 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

22. Screening for RCC • 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

23. References • 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 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. • 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. • 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. • 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. • 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. • 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 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 population. Am J Kidney Dis 2000; 35:237. • 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. • 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. • MacDougall, ML et al. Predication of carcinoma in acquired cystic disease as a function of kidney weight. J Am Soc Nephrol 1990; 1:828. • Marple, JT et al. Renal cancer complicating acquired cystic kidney disease. J Am Soc Nephrol 1994; 4:1951. • Nadasdy, T et al. Proliferative activity of cyst epithelium in human renal cystic diseases. J Am Soc Nephrol 1995; 5:1462. • Sarasin, FP et al. Screening for acquired cystic kidney disease: A decision analytic perspective. Kidney Int 1995; 48:207. • Truong, LD et al. Renal neoplasm in acquired cystic kidney disease. Am J Kidney Dis 1995; 26:1.