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 (Brights
  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 lt 0.5 cm
• Positive u/s or CT both kidneys w/ gt/ 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-ß 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
• MF ratio of 71
• Larger cysts that ? supranormal kidney size ?
  increased risk of transformation (kidneys
  weighing gt 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 1561345.Denton, MD et al.
  Prevalence of renal cell carcinoma in patients
  with ESRD pre-transplantation A pathologic
  analysis. Kidney Int 2002 612201.
• Farivar-Mohseni, H et al. Renal cell carcinoma
  and end stage renal disease. J Urol 2006
  1752018.
• Fick, GM et al. Hereditary and acquired cystic
  disease of the kidney. Kidney Int 1994 46951.
• Grantham, JJ. Acquired cystic kidney disease.
  Kidney Int 1991 40143.
• Hughson, MD et al. Renal cell carcinoma of
  end-stage renal disease A histopathologic and
  molecular genetic study. J Am Soc Nephrol 1996
  72461.
• 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 8468.
• Ishikawa, I et al. Ten-year prospective study on
  the development of renal cell carcinoma in
  dialysis patients. Am J Kidney Dis 1990 16452.
• Israel, GM et al. An update of the Bosniak renal
  cyst classification system. Urology 2005
  66484.
• 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 1712166.
• LeBrun, CJ et al. Life expectancy benefits of
  cancer screening in the end-stage renal disease
  population. Am J Kidney Dis 2000 35237.
• Levine, E et al. Natural history of acquired
  renal cystic disease in dialysis patients A
  prospective longitudinal CT study. Am J
  Roentgenol 1991 156501.
• Lien, YH et al. Association of cyclosporin A
  with acquired cystic kidney disease of the native
  kidneys in transplant recipients. Kidney Int
  1991 44613.
• MacDougall, ML et al. Predication of carcinoma
  in acquired cystic disease as a function of
  kidney weight. J Am Soc Nephrol 1990 1828.
• Marple, JT et al. Renal cancer complicating
  acquired cystic kidney disease. J Am Soc Nephrol
  1994 41951.
• Nadasdy, T et al. Proliferative activity of cyst
  epithelium in human renal cystic diseases. J Am
  Soc Nephrol 1995 51462.
• Sarasin, FP et al. Screening for acquired cystic
  kidney disease A decision analytic perspective.
  Kidney Int 1995 48207.
• Truong, LD et al. Renal neoplasm in acquired
  cystic kidney disease. Am J Kidney Dis 1995
  261.