Cystic disease of the kidney


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A brief overview of cystic diseases of the kidney

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Cystic disease of the kidney

  1. 2. <ul><li>Definition </li></ul><ul><li>Pathophysiology </li></ul><ul><li>Classification (or lack thereof) </li></ul><ul><li>Diseases </li></ul>
  2. 3. <ul><li>Cyst: fluid-filled sac that grows on the surface of, or within the kidney </li></ul><ul><li>Generally arise from renal tubules </li></ul>
  3. 6. <ul><li>No good classification system – 9 proposed schema over past 120 years </li></ul><ul><li>Classification initially began with structural features, but has evolved to include advances in genetics </li></ul><ul><li>Ideal scheme would take into account morphological features, pathogenesis, and therapeutic potential </li></ul>
  4. 8. <ul><li>Genetic vs Non-genetic </li></ul><ul><li>Congenital vs Acquired </li></ul><ul><li>Isolated vs Systemic Disease </li></ul><ul><li>Malignant Potential </li></ul>
  5. 10. Disease Kidney Size Cyst Size Cyst Location Liver Nephronophthisis Small 1MM-2CM Medullary Normal Acquired Cysts Normal/Small 0.5-3CM Any Normal Medullary Sponge Normal/Enlarged MM Precalyceal Normal ARPKD Enlarged MM Any Fibrosis Multicystic Dysplastic Enlarged 1MM-10CM Any Normal ADPKD Enlarged MM-10CM Any Cysts
  6. 11. <ul><li>Prevalence 1:400 to 1:1000, but estimated ½ cases clinically silent and undiagnosed </li></ul><ul><li>Commonest defect is in PKD1 gene on chromosome 16 (85-95%), or PKD2 on chromosome 4 </li></ul><ul><li>Cysts/ESRD occur later in PKD2 vs PKD1 (mean age of ESRD is 74 vs 54) </li></ul>
  7. 12. <ul><li>PKD1/2 encode genes for Polycystin 1/2 </li></ul><ul><li>Polycystin1 involved in cell-cell interactions; activates JAK-STAT pathway, causing cell cycle arrest </li></ul><ul><li>Polycystin2 involves calcium signaling via G-proteins </li></ul><ul><li>Expressed in renal tubulular epithelium, hepatic bile ducts, and pancreatic ducts </li></ul>
  8. 15. Diagnosis/Screening <ul><li>Diagnosis generally relies on imaging (usually U/S); sometimes genetic testing is required for definitive diagnosis </li></ul><ul><li>3 main criteria: family history, number/type of cysts, age of patient </li></ul><ul><li>Screening not recommended before age 18 (psychological) </li></ul>
  9. 16. Family History Positive - Genotype Unknown <ul><li>Age 15-39: 3 or more unilateral or bilateral cysts (sensitivity 82-96%, specificity 100%) </li></ul><ul><li>Age 40-59: 2 or more cysts in each kidney (sensitivity 90%, specificity 100%) </li></ul><ul><li>Age 60 or more: 4 or more cysts in each kidney (sensitivity/specificity 100%) </li></ul>
  10. 17. Family History of PKD1 <ul><li>Genetic screening is often better </li></ul><ul><li>Age 15-30: At least two unilateral or bilateral cysts (sens 95%, spec 100%) </li></ul><ul><li>Age 30-59: At least 2 cysts in each kidney (sensitivity 97%, specificity 100%) </li></ul><ul><li>Age >60: 4 cysts in each kidney (sensitivity 97%, specificity 100%) </li></ul>
  11. 18. Family History of PKD2 <ul><li>Genetic testing recommended </li></ul><ul><li>Same ultrasound criteria as unknown genotype </li></ul>
  12. 19. Criteria for Exclusion of Disease (if family history positive) <ul><li>Age <30: no criteria </li></ul><ul><li>Age 30-39: No cysts – false negative rate of 2% </li></ul><ul><li>Age >40: 0 or 1 cyst (NPV 100%) </li></ul>
  13. 20. Alternate Imaging <ul><li>CT and MRI are more sensitive and may pick up smaller cysts </li></ul><ul><li>No studies have examined diagnostic criteria with these modalities </li></ul><ul><li>Current opinion – if no cysts detected in kidney or liver by age 20, may exclude disease; if results inconclusive, genetic testing should be pursued </li></ul>
  14. 21. Absence of Family History <ul><li>What about patients who meet criteria but have no family history of disease? </li></ul><ul><li>25% of these patients have an undiagnosed relative (can screen family); 5% represent new mutation </li></ul><ul><li>In absence of FH, there is no definitive criteria – diagnosis suspected if >10 cysts in each kidney; other cystic disease should be considered </li></ul>
  15. 22. Genetic Testing <ul><li>Linkage analysis: uses microsatellite DNA markers that flank the PKD genes </li></ul><ul><li>Requires at least 4 diagnosed family members; therefore useful in <1/2 of cases </li></ul>
  16. 23. Direct DNA Analysis <ul><li>Difficulty arises from large size of gene, multitude of “PKD-like” genes, and heterogeneity of alleles </li></ul><ul><li>65-70% detection rates with liquid chromatography </li></ul><ul><li>85-90% detection with direct sequencing </li></ul><ul><li>Drawback: mutation of gene does not necessarily lead to pathology </li></ul>
  17. 24. Clinical Course <ul><li>Symptoms may present as flank pain, hematuria, proteinuria, calculus, UTI, HTN, renal insufficiency </li></ul><ul><li>Renal function intact until 4 th decade, and declines at rate of 4-6ml/min per year (faster with PKD1, proteinuria, HTN, male) </li></ul>
  18. 25. <ul><li>Cerebral Aneurysm </li></ul><ul><li>4-10% based on age; family history of aneurysm or SAH increases risk </li></ul><ul><li>Rupture occurs with larger aneurysms and with poorly controlled HTN </li></ul><ul><li>SAH presents as acute severe headache </li></ul><ul><li>CT scan might miss small bleed – lumbar puncture should be done 6-12 hrs later </li></ul>
  19. 27. <ul><li>Role of radiological screening studies in asymptomatic patients with ADPKD is controversial </li></ul><ul><li>Rate of interventional-related morbidity/mortality is 13.7% </li></ul><ul><li>Routine screening recommended for high-risk pts (previous rupture, FH, high-risk occupation) </li></ul>
  20. 28. <ul><li>Procedures of choice are CTA/MRA (but beware NSF with GFR<30 {?<60}) </li></ul><ul><li>Suggested screening is yearly for 3 years, and if stable, every 2-5 years afterwards </li></ul><ul><li>Unknown if warfarin increases risk of bleeding; reasonable to screen these pts </li></ul>
  21. 29. <ul><li>Hepatic Cysts </li></ul><ul><li>Prevalence of ~80% in pts age 15-45 </li></ul><ul><li>Massive cysts occur almost exclusively in women; multiple pregnancies accelerates growth (? Estrogen) </li></ul><ul><li>Most asymptomatic; some require pain control or antibiotics </li></ul>
  22. 31. <ul><li>Cardiac Disease </li></ul><ul><li>Valvular abnormalities in 30% (MVP, AR) </li></ul><ul><li>Coronary aneurysms not infrequent </li></ul><ul><li>Asymptomatic pericardial effusion seen in 35%, with 50% of these being moderate to severe in size </li></ul>
  23. 32. <ul><li>Other </li></ul><ul><li>Colonic Diverticula (abd pain may be misleading) </li></ul><ul><li>Abd wall hernia in up to 45% (consideration in PD patients) </li></ul>
  24. 33. <ul><li>No treatment has been proven to delay progression of disease </li></ul><ul><li>Control of HTN should be attained with ACE-I (increased RAS activity from focal ischemia due to cyst expansion) </li></ul><ul><li>Nephrectomy is sometimes necessary for transplant, recurrent UTI, RCC, chronic pain, chronic hematuria </li></ul>
  25. 34. <ul><li>Ideas for the future? </li></ul><ul><li>MTOR inhibitors: show some benefit in limiting the increase in kidney size, but do not limit the decrease in GFR (over 2 yrs) and cause more proteinuria </li></ul><ul><li>Vasopressin receptor antagonists have shown promising results in mice/rat models (via intracellular cAMP), phase 3 trials in progress </li></ul>
  26. 37. ARPKD <ul><li>Estimated incidence 1:10,000-40,000 </li></ul><ul><li>Generally diagnosed in pediatric age; cases diagnosed in adulthood have mild renal impairment but more hepatic dysfunction </li></ul><ul><li>PKHD1 gene encodes fibrocystin, a cilial protein of cortical/medullary collecting ducts and hepatic bile duct </li></ul>
  27. 38. Features <ul><li>Kidneys enlarge due to microcysts (<3mm) </li></ul><ul><li>Liver always has hepatic fibrosis (portal hypertension, ascites, esophageal varices) </li></ul><ul><li>Diagnostic criteria: imaging criteria plus one of following: absence of cysts in parents, sibling with disease, evidence of hepatic fibrosis </li></ul>
  28. 40. Nephronophthisis <ul><li>Autosomal recessive, heterogenous disorder affecting proteins in cilia </li></ul><ul><li>Characteristic findings: reduced urinary concentrating ability; chronic tubulointerstitial nephritis resulting in ESRD by age of 20 </li></ul><ul><li>Commonest extrarenal manifestation is retinitis pigmentosa (20%) </li></ul>
  29. 41. Manifestations <ul><li>Presents as polyuria/polydipsia due to impaired concentration of urine </li></ul><ul><li>Hepatic Fibrosis </li></ul><ul><li>Situs Inversus </li></ul>
  30. 42. Diagnosis <ul><li>-Polyuria with bland urinalysis </li></ul><ul><li>-Progressive CKD without HTN </li></ul><ul><li>-Normal Size Kidneys </li></ul><ul><li>If above 3 are present, genetic testing should be undertaken </li></ul><ul><li>If genetic test negative, biopsy can be suggestive – tubulointerstitial nephritis with thickened basement membrane </li></ul>
  31. 43. <ul><li>Medullary cysts in normal-sized kidneys </li></ul>
  32. 44. Medullary Cystic Kidney Disease <ul><li>A rare (~50 cases per year in USA) autosomal dominant disease </li></ul><ul><li>Two types, with variable clinical courses - ESRD at age 20-70 </li></ul>
  33. 45. MCKD2 <ul><li>Also called Familial Juvenile Hyperuricemia </li></ul><ul><li>Describes families with mutations in the uromodulin gene – a Tamm-Horsfall mucoprotein </li></ul>
  34. 46. <ul><li>Uromodulin is produced exclusively in thick ascending limb of Loop of Henle </li></ul><ul><li>It is a sticky insoluble protein which may assist with water-tight integrity </li></ul><ul><li>Mutant proteins cannot exit cell, and cause tubular atrophy/death </li></ul>
  35. 47. <ul><li>Hyperuricemia/Gout results from reduced urate excretion (mechanism not well understood) </li></ul><ul><li>Progressive decline in renal function secondary to tubular death </li></ul>
  36. 48. <ul><li>3 criteria: </li></ul><ul><li>-Family history of renal disease in autosomal dominant pattern </li></ul><ul><li>-Family History of Gout </li></ul><ul><li>-Bland Urinary sediment without little or no proteinuria </li></ul><ul><li>Definitive Diagnosis through genetic test, which is cheaper and more specific than biopsy (IF with antibody to uromodulin shows deposition in tubules) </li></ul>
  37. 49. <ul><li>Gout is best controlled with allopurinol; uncertain whether this slows progression of kidney disease </li></ul>
  38. 50. MCKD1 <ul><li>Gene within chromosome 1q21 has not been identified, so pathophysiology unknown </li></ul><ul><li>HTN and Hyperuricemia are more prevalent as renal function declines, therefore late features (contrast to MCKD2) </li></ul><ul><li>Course within families in extremely variable (ESRD ranging from age 30-75) </li></ul>
  39. 51. <ul><li>Biopsy reveals tubular atrophy, interstitial fibrosis, splitting of basement membrane (which is thick and irregular) </li></ul><ul><li>No specific treatment </li></ul><ul><li>Transplant is preferred therapy – disease will not recur </li></ul>
  40. 52. <ul><li>A congenital dysplasia in which a mass of cysts and connective tissue forms, with no identifiable renal tissue </li></ul><ul><li>Usually unilateral, with compensatory hypertrophy of remaining kidney (but may have positional or structural defect) </li></ul><ul><li>Often detected on prenatal sonography, or palpable flank mass </li></ul>
  41. 54. <ul><li>Evaluation of contralateral kidney, including ultrasound and voiding cytourethrography to rule out vesicoureteral reflux (25%) </li></ul><ul><li>No indication for nephrectomy (no increased risk of Wilms tumor) </li></ul>
  42. 55. <ul><li>Characterized by malformation of terminal collecting ducts in pericalyceal region of pyramids </li></ul><ul><li>Generally clinically benign, but recurrent nephrolithiasis and UTI may lead to renal insufficiency </li></ul><ul><li>Sometimes autosomal dominant, but usually sporadic mutations </li></ul>
  43. 56. <ul><li>Prevalence unknown, but seen in 10-20% of patients who form calcium stones </li></ul><ul><li>Diagnosis usually incidental - made by IVP, with dilation of cystic ducts showing “brush” appearance radiating outward from calyces </li></ul><ul><li>U/S and CT less specific – show nephrocalcinosis </li></ul>
  44. 59. <ul><li>Usually asymptomatic - incidental </li></ul><ul><li>Recurrent calcium phosphate or calcium oxalate stones – concretions within cysts act as nidus for stone formation </li></ul><ul><li>UTI (secondary to stones, stasis) </li></ul><ul><li>Hematuria </li></ul>
  45. 60. <ul><li>Patients with stone risk factors (hypercalciuria, hyperuricosuria, hyperoxaluria, hypocitraturia) may benefit from potassium citrate </li></ul><ul><li>Initial dose 20meq/day titrated to urinary citrate level of 450mg/day </li></ul>
  46. 61. <ul><li>Tuberous Sclerosis </li></ul><ul><li>Autosomal dominant; 1/3 familial </li></ul><ul><li>Characterized by formation of angiomyolipomas of skin, brain, kidneys, other organs </li></ul><ul><li>2 genes – TSC1 (hamartin) and TSC2 (tuberin) </li></ul>
  47. 63. <ul><li>Commonest lesion is angiomyolipoma (50-70%), then benign cysts (30-50%) </li></ul><ul><li>Symptoms include flank pain, hematuria from mass effect of angiomyolipoma; cysts usually asymptomatic </li></ul><ul><li>Renin-dependent HTN from ischemia </li></ul><ul><li>Since TSC2 gene is adjacent to PKD1, some have both diseases </li></ul>
  48. 64. <ul><li>ESRD can occur from mass effect </li></ul><ul><li>RCC in 1-2% - U/S every 1-3 years </li></ul><ul><li>Intervention for pain, bleeding, malignancy – 1 st line is arterial embolization, second line is partial or total nephrectomy </li></ul>
  49. 65. Treatment <ul><li>Since angiomyolipoma is associated with phosphorylation by MTOR, there is limited evidence that rapamycin decreases size of mass by 50%, but returns upon discontinuation of drug </li></ul><ul><li>Transplantation should be accompanied by bilateral nephrectomy due to increased risk of RCC by immunosuppresssion </li></ul>
  50. 66. Von-Hippel Lindau <ul><li>Autosomal dominant syndrome with a variety of benign and malignant tumors </li></ul><ul><li>Commonest systemic lesion is hemangioblastoma of eye/brain; pheochromocytoma in 10-20% </li></ul><ul><li>Renal involvement includes multiple cysts and RCC (2/3 of pts) </li></ul>
  51. 67. <ul><li>RCC often multicentric and bilateral, therefore cysts are benign, but considered premalignant </li></ul><ul><li>Screening for RCC should begin in adolescence </li></ul><ul><li>No guidelines, but current opinion is annual ultrasound, plasma catecholamine, retinal exam, MRI brain and spine with gad at age 10 </li></ul>
  52. 68. <ul><li>New tumors arise every 5 years in 30% of pts; every 10 years in 85% </li></ul><ul><li>Small lesions may be observed (<3cm), or undergo radiation ablation, cryotherapy, or partial nephrectomy </li></ul><ul><li>Transplantation feasible in setting of bilateral nephrectomy; minimal data available regarding RCC recurrence </li></ul>
  53. 69. <ul><li>HD and PD associated with development of multiple bilateral small cysts; usually less than 0.5cm but up to 3 cm </li></ul><ul><li>Criteria: 4 or more total cysts in both kidneys </li></ul><ul><li>Differentiated from ADPKD by lack of family history, small/normal size kidneys, smooth contoured kidneys </li></ul>
  54. 70. <ul><li>Incidence increases with increased time on dialysis; also occurs in children </li></ul><ul><li>Pathogenesis unknown; believed to be result of compensatory hypertrophy leading to tubular hyperplasia and cysts </li></ul><ul><li>Cysts may regress following transplant </li></ul>
  55. 71. <ul><li>Commonest symptoms: hematuria, lumbar pain, UTI </li></ul><ul><li>RCC has varied incidence, ~5%; malignancy develops after 8-10 years on dialysis; risk factors are male and large cysts </li></ul><ul><li>No guidelines for screening; some suggest radiological studies only for new symptoms (hematuria/flank pain), or young pts (long duration of HD) </li></ul>
  56. 72. <ul><li>The term is histopathological (descriptive); Can only be distinguished from tubular cystic disease by biopsy </li></ul><ul><li>A rare disease that may be seen independently; but more commonly in association with other pathology </li></ul><ul><li>Often a pediatric diagnosis </li></ul>
  57. 74. Classifications of glomerulocystic kidney disease Example Familial nonsyndromic Autosomal dominant polycystic kidney disease in young infants Associated with inheritable malformation syndromes Tuberous sclerosis complex Syndromic, non-Mendelian Trisomy 9, 13, or 18 Sporadic New mutations Acquired and dysplastic kidneys Hemolytic uremic syndrome and obstructive uropathy