Acquired Cystic Kidney Disease
Alicia Notkin
February 26, 2008
History
• First described in 1847 by John Simon in
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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)
Features of acquired cystic kidney
disease
• Multiple
• Bilateral
• Usually < 0.5 cm
• “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
• Increased incidence w/ increasing time on
dialysis; ~ 35-50% of dialysis patients
overall
• Men and blacks are at much higher risk
Pathogenesis
• Cyst fluid composition resembles that of plasma
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(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
Pathogenesis: proposed
progression to adenocarcinoma
(Grantham 1991)
Pathogenesis (cont.)
• Aldosterone & hypokalemia seem to stimulate
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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
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
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
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
Pathogenesis (cont.)
• In vitro: hydrocortisone promotes cyst
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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
Pathogenesis (cont.)
• The notion of renal cysts as benign tumors filled w/ fluid
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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
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
Renal cell carcinoma risk factors
• Smoking: ~ 2x risk
• Occupational exposure to cadmium, asbestos, &
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trichloroethylene: ~ 1-2x risk
Obesity
Acquired cystic renal disease: ~ 30x risk???
Analgesic abuse nephropathy
Genetic factors
? Hypertension, prior radiation, sickle cell
disease
Renal cell carcinoma in ESRD
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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
Renal cancer in ACKD compared to
the general population (Marple
1994)
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
ACKD-associated RCC
• C-Jun is activated in atypical hyperplastic
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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
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
Bosniak classification (Israel 2005)
Screening for RCC
• ? Screen dialysis patients for acquired cystic kidney disease
• ? If one decides to screen, should one use contrast CT or
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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
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
References
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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 pretransplantation: 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
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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
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LeBrun, CJ et al. Life expectancy benefits of cancer screening in the end-stage renal disease population. Am
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Lien, YH et al. Association of cyclosporin A with acquired cystic kidney disease of the native kidneys in
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MacDougall, ML et al. Predication of carcinoma in acquired cystic disease as a function of kidney weight. J
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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
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Sarasin, FP et al. Screening for acquired cystic kidney disease: A decision analytic perspective. Kidney Int
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Truong, LD et al. Renal neoplasm in acquired cystic kidney disease. Am J Kidney Dis 1995; 26:1.