Cystic disease of the kidney
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  • 1.  
  • 2.
    • Definition
    • Pathophysiology
    • Classification (or lack thereof)
    • Diseases
  • 3.
    • Cyst: fluid-filled sac that grows on the surface of, or within the kidney
    • Generally arise from renal tubules
  • 4.  
  • 5.  
  • 6.
    • No good classification system – 9 proposed schema over past 120 years
    • Classification initially began with structural features, but has evolved to include advances in genetics
    • Ideal scheme would take into account morphological features, pathogenesis, and therapeutic potential
  • 7.  
  • 8.
    • Genetic vs Non-genetic
    • Congenital vs Acquired
    • Isolated vs Systemic Disease
    • Malignant Potential
  • 9.  
  • 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
  • 11.
    • Prevalence 1:400 to 1:1000, but estimated ½ cases clinically silent and undiagnosed
    • Commonest defect is in PKD1 gene on chromosome 16 (85-95%), or PKD2 on chromosome 4
    • Cysts/ESRD occur later in PKD2 vs PKD1 (mean age of ESRD is 74 vs 54)
  • 12.
    • PKD1/2 encode genes for Polycystin 1/2
    • Polycystin1 involved in cell-cell interactions; activates JAK-STAT pathway, causing cell cycle arrest
    • Polycystin2 involves calcium signaling via G-proteins
    • Expressed in renal tubulular epithelium, hepatic bile ducts, and pancreatic ducts
  • 13.  
  • 14.  
  • 15. Diagnosis/Screening
    • Diagnosis generally relies on imaging (usually U/S); sometimes genetic testing is required for definitive diagnosis
    • 3 main criteria: family history, number/type of cysts, age of patient
    • Screening not recommended before age 18 (psychological)
  • 16. Family History Positive - Genotype Unknown
    • Age 15-39: 3 or more unilateral or bilateral cysts (sensitivity 82-96%, specificity 100%)
    • Age 40-59: 2 or more cysts in each kidney (sensitivity 90%, specificity 100%)
    • Age 60 or more: 4 or more cysts in each kidney (sensitivity/specificity 100%)
  • 17. Family History of PKD1
    • Genetic screening is often better
    • Age 15-30: At least two unilateral or bilateral cysts (sens 95%, spec 100%)
    • Age 30-59: At least 2 cysts in each kidney (sensitivity 97%, specificity 100%)
    • Age >60: 4 cysts in each kidney (sensitivity 97%, specificity 100%)
  • 18. Family History of PKD2
    • Genetic testing recommended
    • Same ultrasound criteria as unknown genotype
  • 19. Criteria for Exclusion of Disease (if family history positive)
    • Age <30: no criteria
    • Age 30-39: No cysts – false negative rate of 2%
    • Age >40: 0 or 1 cyst (NPV 100%)
  • 20. Alternate Imaging
    • CT and MRI are more sensitive and may pick up smaller cysts
    • No studies have examined diagnostic criteria with these modalities
    • Current opinion – if no cysts detected in kidney or liver by age 20, may exclude disease; if results inconclusive, genetic testing should be pursued
  • 21. Absence of Family History
    • What about patients who meet criteria but have no family history of disease?
    • 25% of these patients have an undiagnosed relative (can screen family); 5% represent new mutation
    • In absence of FH, there is no definitive criteria – diagnosis suspected if >10 cysts in each kidney; other cystic disease should be considered
  • 22. Genetic Testing
    • Linkage analysis: uses microsatellite DNA markers that flank the PKD genes
    • Requires at least 4 diagnosed family members; therefore useful in <1/2 of cases
  • 23. Direct DNA Analysis
    • Difficulty arises from large size of gene, multitude of “PKD-like” genes, and heterogeneity of alleles
    • 65-70% detection rates with liquid chromatography
    • 85-90% detection with direct sequencing
    • Drawback: mutation of gene does not necessarily lead to pathology
  • 24. Clinical Course
    • Symptoms may present as flank pain, hematuria, proteinuria, calculus, UTI, HTN, renal insufficiency
    • Renal function intact until 4 th decade, and declines at rate of 4-6ml/min per year (faster with PKD1, proteinuria, HTN, male)
  • 25.
    • Cerebral Aneurysm
    • 4-10% based on age; family history of aneurysm or SAH increases risk
    • Rupture occurs with larger aneurysms and with poorly controlled HTN
    • SAH presents as acute severe headache
    • CT scan might miss small bleed – lumbar puncture should be done 6-12 hrs later
  • 26.  
  • 27.
    • Role of radiological screening studies in asymptomatic patients with ADPKD is controversial
    • Rate of interventional-related morbidity/mortality is 13.7%
    • Routine screening recommended for high-risk pts (previous rupture, FH, high-risk occupation)
  • 28.
    • Procedures of choice are CTA/MRA (but beware NSF with GFR<30 {?<60})
    • Suggested screening is yearly for 3 years, and if stable, every 2-5 years afterwards
    • Unknown if warfarin increases risk of bleeding; reasonable to screen these pts
  • 29.
    • Hepatic Cysts
    • Prevalence of ~80% in pts age 15-45
    • Massive cysts occur almost exclusively in women; multiple pregnancies accelerates growth (? Estrogen)
    • Most asymptomatic; some require pain control or antibiotics
  • 30.  
  • 31.
    • Cardiac Disease
    • Valvular abnormalities in 30% (MVP, AR)
    • Coronary aneurysms not infrequent
    • Asymptomatic pericardial effusion seen in 35%, with 50% of these being moderate to severe in size
  • 32.
    • Other
    • Colonic Diverticula (abd pain may be misleading)
    • Abd wall hernia in up to 45% (consideration in PD patients)
  • 33.
    • No treatment has been proven to delay progression of disease
    • Control of HTN should be attained with ACE-I (increased RAS activity from focal ischemia due to cyst expansion)
    • Nephrectomy is sometimes necessary for transplant, recurrent UTI, RCC, chronic pain, chronic hematuria
  • 34.
    • Ideas for the future?
    • 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
    • Vasopressin receptor antagonists have shown promising results in mice/rat models (via intracellular cAMP), phase 3 trials in progress
  • 35.  
  • 36.  
  • 37. ARPKD
    • Estimated incidence 1:10,000-40,000
    • Generally diagnosed in pediatric age; cases diagnosed in adulthood have mild renal impairment but more hepatic dysfunction
    • PKHD1 gene encodes fibrocystin, a cilial protein of cortical/medullary collecting ducts and hepatic bile duct
  • 38. Features
    • Kidneys enlarge due to microcysts (<3mm)
    • Liver always has hepatic fibrosis (portal hypertension, ascites, esophageal varices)
    • Diagnostic criteria: imaging criteria plus one of following: absence of cysts in parents, sibling with disease, evidence of hepatic fibrosis
  • 39.  
  • 40. Nephronophthisis
    • Autosomal recessive, heterogenous disorder affecting proteins in cilia
    • Characteristic findings: reduced urinary concentrating ability; chronic tubulointerstitial nephritis resulting in ESRD by age of 20
    • Commonest extrarenal manifestation is retinitis pigmentosa (20%)
  • 41. Manifestations
    • Presents as polyuria/polydipsia due to impaired concentration of urine
    • Hepatic Fibrosis
    • Situs Inversus
  • 42. Diagnosis
    • -Polyuria with bland urinalysis
    • -Progressive CKD without HTN
    • -Normal Size Kidneys
    • If above 3 are present, genetic testing should be undertaken
    • If genetic test negative, biopsy can be suggestive – tubulointerstitial nephritis with thickened basement membrane
  • 43.
    • Medullary cysts in normal-sized kidneys
  • 44. Medullary Cystic Kidney Disease
    • A rare (~50 cases per year in USA) autosomal dominant disease
    • Two types, with variable clinical courses - ESRD at age 20-70
  • 45. MCKD2
    • Also called Familial Juvenile Hyperuricemia
    • Describes families with mutations in the uromodulin gene – a Tamm-Horsfall mucoprotein
  • 46.
    • Uromodulin is produced exclusively in thick ascending limb of Loop of Henle
    • It is a sticky insoluble protein which may assist with water-tight integrity
    • Mutant proteins cannot exit cell, and cause tubular atrophy/death
  • 47.
    • Hyperuricemia/Gout results from reduced urate excretion (mechanism not well understood)
    • Progressive decline in renal function secondary to tubular death
  • 48.
    • 3 criteria:
    • -Family history of renal disease in autosomal dominant pattern
    • -Family History of Gout
    • -Bland Urinary sediment without little or no proteinuria
    • Definitive Diagnosis through genetic test, which is cheaper and more specific than biopsy (IF with antibody to uromodulin shows deposition in tubules)
  • 49.
    • Gout is best controlled with allopurinol; uncertain whether this slows progression of kidney disease
  • 50. MCKD1
    • Gene within chromosome 1q21 has not been identified, so pathophysiology unknown
    • HTN and Hyperuricemia are more prevalent as renal function declines, therefore late features (contrast to MCKD2)
    • Course within families in extremely variable (ESRD ranging from age 30-75)
  • 51.
    • Biopsy reveals tubular atrophy, interstitial fibrosis, splitting of basement membrane (which is thick and irregular)
    • No specific treatment
    • Transplant is preferred therapy – disease will not recur
  • 52.
    • A congenital dysplasia in which a mass of cysts and connective tissue forms, with no identifiable renal tissue
    • Usually unilateral, with compensatory hypertrophy of remaining kidney (but may have positional or structural defect)
    • Often detected on prenatal sonography, or palpable flank mass
  • 53.  
  • 54.
    • Evaluation of contralateral kidney, including ultrasound and voiding cytourethrography to rule out vesicoureteral reflux (25%)
    • No indication for nephrectomy (no increased risk of Wilms tumor)
  • 55.
    • Characterized by malformation of terminal collecting ducts in pericalyceal region of pyramids
    • Generally clinically benign, but recurrent nephrolithiasis and UTI may lead to renal insufficiency
    • Sometimes autosomal dominant, but usually sporadic mutations
  • 56.
    • Prevalence unknown, but seen in 10-20% of patients who form calcium stones
    • Diagnosis usually incidental - made by IVP, with dilation of cystic ducts showing “brush” appearance radiating outward from calyces
    • U/S and CT less specific – show nephrocalcinosis
  • 57.  
  • 58.  
  • 59.
    • Usually asymptomatic - incidental
    • Recurrent calcium phosphate or calcium oxalate stones – concretions within cysts act as nidus for stone formation
    • UTI (secondary to stones, stasis)
    • Hematuria
  • 60.
    • Patients with stone risk factors (hypercalciuria, hyperuricosuria, hyperoxaluria, hypocitraturia) may benefit from potassium citrate
    • Initial dose 20meq/day titrated to urinary citrate level of 450mg/day
  • 61.
    • Tuberous Sclerosis
    • Autosomal dominant; 1/3 familial
    • Characterized by formation of angiomyolipomas of skin, brain, kidneys, other organs
    • 2 genes – TSC1 (hamartin) and TSC2 (tuberin)
  • 62.  
  • 63.
    • Commonest lesion is angiomyolipoma (50-70%), then benign cysts (30-50%)
    • Symptoms include flank pain, hematuria from mass effect of angiomyolipoma; cysts usually asymptomatic
    • Renin-dependent HTN from ischemia
    • Since TSC2 gene is adjacent to PKD1, some have both diseases
  • 64.
    • ESRD can occur from mass effect
    • RCC in 1-2% - U/S every 1-3 years
    • Intervention for pain, bleeding, malignancy – 1 st line is arterial embolization, second line is partial or total nephrectomy
  • 65. Treatment
    • 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
    • Transplantation should be accompanied by bilateral nephrectomy due to increased risk of RCC by immunosuppresssion
  • 66. Von-Hippel Lindau
    • Autosomal dominant syndrome with a variety of benign and malignant tumors
    • Commonest systemic lesion is hemangioblastoma of eye/brain; pheochromocytoma in 10-20%
    • Renal involvement includes multiple cysts and RCC (2/3 of pts)
  • 67.
    • RCC often multicentric and bilateral, therefore cysts are benign, but considered premalignant
    • Screening for RCC should begin in adolescence
    • No guidelines, but current opinion is annual ultrasound, plasma catecholamine, retinal exam, MRI brain and spine with gad at age 10
  • 68.
    • New tumors arise every 5 years in 30% of pts; every 10 years in 85%
    • Small lesions may be observed (<3cm), or undergo radiation ablation, cryotherapy, or partial nephrectomy
    • Transplantation feasible in setting of bilateral nephrectomy; minimal data available regarding RCC recurrence
  • 69.
    • HD and PD associated with development of multiple bilateral small cysts; usually less than 0.5cm but up to 3 cm
    • Criteria: 4 or more total cysts in both kidneys
    • Differentiated from ADPKD by lack of family history, small/normal size kidneys, smooth contoured kidneys
  • 70.
    • Incidence increases with increased time on dialysis; also occurs in children
    • Pathogenesis unknown; believed to be result of compensatory hypertrophy leading to tubular hyperplasia and cysts
    • Cysts may regress following transplant
  • 71.
    • Commonest symptoms: hematuria, lumbar pain, UTI
    • RCC has varied incidence, ~5%; malignancy develops after 8-10 years on dialysis; risk factors are male and large cysts
    • No guidelines for screening; some suggest radiological studies only for new symptoms (hematuria/flank pain), or young pts (long duration of HD)
  • 72.
    • The term is histopathological (descriptive); Can only be distinguished from tubular cystic disease by biopsy
    • A rare disease that may be seen independently; but more commonly in association with other pathology
    • Often a pediatric diagnosis
  • 73.  
  • 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