Renal Cystic Disease ADPKD ARPKD Tuberous Sclerosis

Renal Cystic Disease ADPKD ARPKD Tuberous Sclerosis
Medullary Sponge Kidney Von-Hippel Lindau Disease Medullary Cystic Disease Acquired Cystic Kidney Disease Multicystic Renal Dysplasia Mark D. Purcell DO Nephrology/Internal Medicine Carolina Nephrology, PA 203 Mills Avenue Greenville, SC (864)

Case Presentation 54 y.o. Caucasian male
C.C.: “Concerned about developing cysts in kidneys. 3 of 4 of my siblings have it!” PMH: Negative PSH: Negative Meds: Rarely OTC NSAIDs Allergies: None

Case Presentation ROS: Negative Physical exam: Labs: VSS
No abnormal findings on exam Labs: Cr=1.1 Hgb=14.2 UA: Neg for protein or blood, RBC=2-4, WBC=0 Normal kidney functions Minimal findings on UA

Questions? “Do I have Cystic kidneys?”
“If not, what are my chances of developing Cystic kidneys in the future?” “If I have it, what is the treatment?” “I heard some could develop a stroke, right?” “Could my children get tested to see whether they have it?” “What are my chances of needing dialysis?” Risk of stroke with ADPKD ADPKD difficult diagnosis  no tx

Differential Diagnosis
Most common genetic = ADPKD Many ppl get simple renal cysts with age esp with decline in kidney function

Simple renal cysts The most common renal masses
Solitary, multiple and bilateral Occur most often over age 50 Often seen on screening ultrasound exam Range in size from less than 1cm to 10cm Usually do not compromise renal function Serous filled, no septation or division of the cyst (sig malig)

Simple renal cysts Usually one epithelial layer without renal elements
Differential diagnosis : rule out more serious disorders Polycystic kidney disease: family history, bilateral, gross hematuria, infection Loculated cystic disease: unilateral Malignancy: thickened irregular walls, septae, enhance with contrast, multilocular mass Rule out PKD with family history, history of chronic urine infections, and blood in the urine

Simple renal cysts Treatment: Usually none required
Pain: rare, Acetaminophen, NSAIDs short course if renal function preserved Rare if ever aspiration and surgery Infection: Rare Cysts do not usually get large enough to cause pain If they do aspirate them

Bosniak Classification
Based on morphologic and enhancement characteristics of cysts by CT scanning Used to help diagnose and manage cystic lesions in the kidney Categories from I to IV based on increasing likelihood of malignancy Just know this is a classification for malignancy - Determined by things like septation, irregular walls, and contrast enhancement on CT

Simple Cyst Clear, smooth Only on the cortex, not the medulla

Simple cyst Rarely this large

Autosomal Dominant PKD (ADPKD)
Kidneys are loaded with large cysts Hypoechoic lesions on US = cysts Family hist is impt

Autosomal Dominant PKD (ADPKD)
Sig change in tissue and interstitum

Presentation of ADPKD Usual presentations:
Screening with positive family history Flank pain, or Kidney Disease On Ultrasound or CT, large kidneys with multiple bilateral cysts are seen Cysts may also be seen in the liver, pancreas, and spleen Families with well known mutations in PKD genes Flank pain b/c larger cysts starts to impinge on other organs When they present, kidney disease is usually mild

Clinical Manifestations
HTN around 31 yo Most common EARLY clinical manifest. * As cysts get larger and more numerous get pain and hematuria Cysts rupture – hem Cysts infection – pain + hem UTI common CV  mitral valve prolapse Liver cysts is the most common extrarenal manifestation Screen for intracranial aneurism - Watch out for PKD pts with a severe headache Hernias from large kidneys pushing on the gut and ab wall

Extra-renal manifestations
Cerebral Aneurysms 4% young adults up to 10% in older patients Role of screening uncertain (MRI vs CT angiogram) High risk patients: family history, require anticoagulation, pre-op, high risk occupation, symptomatic patients Hepatic cysts (most common extra-renal manifestation) Occur later than renal cysts, increase with age Cardiac valve disease: 25-35% of patients Colonic diverticula: seen more in patients on dialysis Abdominal wall inguinal hernias High risk pts for cerebral aneurysms - Those with a fam hist of PKD and those who have had a massive stroke and died in their family

U/S and Renal Cysts J Am Soc Nephrol 13(9):2384-98, 2002
Get simple cysts as you age, so need to diff. btwn this and ADPKD J Am Soc Nephrol 13(9): , 2002

Acquired Cysts vs. ADPKD
Patients with advanced renal failure may present with acquired multiple renal cysts on ultrasonography or CT These kidneys, however, have a normal or reduced size and the renal contour is smooth Many patients have known pre-existent renal disease There is also no family history of PKD Skipped over this

ADPKD: U/S Diagnostic Criteria
For pts with known fam hist of ADPKD Not for the general population Know this

ADPKD on U/S

ADPKD on CT Note liver also has cysts (upper left pic)
Liver does well  usually not sig dysfunction (note A)

Epidemiology and Genetics
ADPKD is by far the most commonly inherited kidney disease Prevalence ranges from % Characterized by the development of multiple renal cysts Associated with extra-renal manifestations Caused by mutations identified in at least three genes (PKD1, PKD2, PKD3) N Engl J Med 329(5):332-42, 1993

Genetics Usually a dysfunction of PKD1
End stage renal disease around 50s Better prognosis with PKD2 dysfunction End stage kidney disease around 70s J Am Soc Nephrol 13(9): , 2002

Genetics PKD1 is an extremely large and complex gene (46 exons)
14 kb mRNA Polycystin 1 is over 4000 amino acids PKD1 gene is adjacent to one of the genes for tuberous sclerosis (TSC2), a different disorder that is also associated with cyst (angiomyolipoma) formation in the kidneys Angiomyolipoma – fatty very vasc tumors in kidney J Am Soc Nephrol 13(9): , 2002

Genetics PKD2 is a much smaller gene Encodes a much smaller mRNA
Polycystin 2 is a little smaller than 1000 amino acids Much better prognosis than with PKD1 J Am Soc Nephrol 13(9): , 2002

Polycystin 1 and 2 Shows integral membrane protein (didn’t stress this)

Polycystin-1 Polycystin-1 is localized in renal tubular epithelia, hepatic and pancreatic ducts, and all sites of cyst formation in ADPKD It is an integral membrane protein, found primarily in plasma membranes It is over-expressed in most but not all cysts in kidneys from patients with ADPKD A membrane protein  When overexpressed  secretes Na and Cl  allows cysts to get bigger and bigger  Eventually breaks of nephron and becomes its own entity J Am Soc Nephrol 13(9): , 2002

ADPKD pathophysiology
PKD 1 gene codes a large and complex protein (polycystin-1) Polycystin 1 acts as a receptor that binds to and activates polycystin 2 leads to rapid flux of Ca++ through cell membrane cation channels G- protein binding site is activated Normal tubular morphogenesis and growth Mutations in the polycystin gene with promote abnormal growth of cysts A second “hit” or somatic mutation of the allele inherited from the normal parent is required for cyst formation Thought to be second hit mutation

Double-hit and Cyst Formation
Second hit  triggers abnormal secretion  get isolated cysts from nephron Kidney Int 67(4): , 2005

Cyst Formation Protein-protein, cell-cell, and cell-matrix interaction defects Impaired tubulogenesis in cells derived from ADPKD cysts in vitro Abnormalities in renal cilia due to polycystin mutations contribute to renal cyst formation. Certain genetic defects in cilia formation and function are related to cyst development Secretion most impt outcome from these cysts  makes them grow J Am Soc Nephrol 13(9): , 2002

Cyst Formation Sodium concentrations vary within different cysts, generally being under 60 meq/L or over 75 meq/L It has been proposed that the high-sodium cysts might derive from the proximal tubule (particularly in cysts with a sodium concentration similar to that in the plasma) while the low-sodium cysts might derive from the distal nephron (the site at which a low urine sodium concentration is normally achieved) Skipped this

Cyst Formation Fluid secretion in the cysts may be mediated in part by the cystic fibrosis transmembrane conductance regulator (TCR) Individuals with both ADPKD and cystic fibrosis may have less severe cystic disease of the kidney and liver compared to family members with ADPKD but without cystic fibrosis Know if have CF + ADPKD = LESS SEVERE variance in the kidney

Renal Manifestations Hematuria Isosthenuria Proteinuria
Can be gross or microscopic Isosthenuria Proteinuria Nephrolithiasis Pain Cancer Anemia

Hematuria May be macroscopic Incidence 35-50%
Macroscopic hematuria associated with worse outcome Etiology: UTI Nephrolithiasis Strenuous activity RCC ?Cyst rupture Gross hematuria  cysts getting big Tends to be assoc with worse outcome Cysts can get infected Can get stones as well Watch out for getting hit in the side  can rupture them So many cysts  hard to det if one is cancerous RCC = renal cell carcinoma Worry about fever, chills, night sweats, weight loss, etc…. Am J Kidney Dis 20(2):140-3, 1992

Isosthenuria Many have a mild concentrating defect
177 adult patients with normal kidney function, all had a modest impairment in concentrating ability in response to overnight water deprivation, which worsened with age in parallel to the decline in concentrating ability of unaffected family members Kidney Int. 35(2):675-80, 1989 The concentrating defect may not be clinically evident except if a history of polydypsia or polyuria is elicited The underlying cause is not known, but disruption of tubular architecture, defect in principal cell function, or early tubulointerstitial disease are postulated factors A central cause has been excluded since vasopressin levels are elevated in this disorder Kidney Int. 68(5): , 2005 Cannot concentrate urine Cysts start to balloon up in the interstitum and the tubules If cannot reabsorb salts, cannot reabsorb water  dump lots of urine  mild concentrating defect Low specific gravity on the UA Vasopressin, ADH levels are increased in this disorder with PKD and isosthenuria - ADH goes to the collecting duct of the kidney and causes you to reabsorb more water  Would expect a pt with high ADH levels to b able to reabsorb, but because of PKD cannot do this

Proteinuria Not very common Usually <1 g/d
Parallel to renal function Nephrotic syndrome usually means superimposed GN Interstitial tubular process  no proteineuria (not GF issue) N Engl J Med 329(5):332-42, 1993

Nephrolithiasis Up to 20% of patients >50% uric acid
Rest is mostly calcium oxalate ESWL successful with small stones Risks Low urine volume low urinary citrate less often hyperuricosuria and hypercalciuria Kidney stones Most stones in gen pop = calcium oxalate but in PKD it’s uric acid usually ESWL – shock wave lithotripsy Get pts to inc urine output Am J Kidney Dis 22(4):513-9, 1993

Pain Abdominal and flank pain Infection Nephrolithiasis
Cyst rupture/hemorrhage

Renal Cell Carcinoma Mayo Clinic and Foundation, Rochester 25 patients
No male predominance was observed (12 men, 13 women) The age of presentation was earlier than that seen in the general population (45 versus 61 yr) Fever, night sweats, and weight loss were prominent at presentation Fever is a more common presenting symptom of renal cell carcinoma in ADPKD (32% vs 7%) 20% of the patients had metastatic disease at presentation Even with computed tomography and magnetic resonance, the diagnosis was difficult and often delayed WBC scan can wrongly suggest a cyst infection More often concurrently bilateral (12 versus 1 to 5%), multicentric (28 versus 6%), and sarcomatoid in type (33 versus 1 to 5%) Am Soc Nephrol 1994 Mar;4(9):1661-9 Age presentation earlier

Urinary Tract Infection
30-50% lifetime incidence Similar to general population (organisms, antibiogram, presentation and treatment) Infected cyst present with a new area of discrete tenderness (pyelonephritis is associated with diffuse flank pain) For infected cysts, fluoroquinolone orally for a minimum of 4-6 weeks Note you have to use a much longer course of Ab in a pt with PKD This is because if the cysts has not ruptured then it could take a lot longer for the Ab to get into the cysts Am J Kidney Dis 10(2):81-8, 1987 Nephrol Dial Transplant 13:2455, 1998 Am J Kidney Dis 2006; 47:e9

Autosomal Dominant PKD
Skipped

Clinical findings and course
Patients may present with hypertension, hematuria, flank pain, calculi, or urinary tract infection Hypertension may present with normal renal function. Renal function starts to decline usually by the fourth decade. (GFR decreases 4-6 mL/min/year) Gradual progression to End Stage Renal Disease Pain from cysts and enlarged kidneys is a common manifestation as disease progresses HTN earliest manifestation * test Q Most of us loose 1ml/min/yr after the age of 40

Clinical findings and course
Risk for progression to ESRD Genotype PKD1 vs PKD2 Hypertension Early onset proteinuria and hematuria Males Increasing kidney size and rate of growth Biggest risk factor for progression to end stage renal disease (CRISP trial) Left ventricular mass index Proteinuria alone Family members who progress to ESRD HTN b/c blood pressure effects kidney function within itself

Mortality National registry data: similar to other patients with end-stage renal disease and most are due to cardiac causes One report examined the cause of death in 129 pts Cardiac 36% Infection 24% Neurologic 12% (rupture ICA and bleed) Cancer 0% Pregnancy Fertility rate similar to unaffected family members Hypertensive women at increase risk of fetal loss Increase risk of ectopic pregnancy ESRD and ADPKD  cardiac failure most common cause of death J Am Soc Nephrol 5(12): , 1995

Treatment 1. Inhibit fluid secretion to slow cyst growth:
Vasopressin V2 receptor antagonists (animals) J Am Soc Nephrol 16:846, 2005 blocking sodium channels with the potassium-sparing diuretic amiloride (animals) Kidney Int 35:1379, 1989 ? Caffeine restriction (In vitro) J Am Soc Nephrol 13:2723, 2002 2. Inhibition of cell proliferation No clinical studies are available mTOR inhibitors reduces cyst formation and growth in animal models mTOR inhibitors – were used in transplantation Not good tx options If have HTN – ACES and ARBS first line

Treatment 3. Control of hypertension: renoprotection and IC bleeding
Nephrol Dial Transplant 18:2314, 2003, Journal of the Renin-Angiotensin-Aldosterone System. 7(3):139-45, 2006 4. Cyst drainage: pain control, not for renal function J Am Soc Nephrol 2(7): , 1992 5. Metabolic acidosis to prevent bone disease and muscle wasting 6. Protein restriction: no benefit 7. Transarterial embolization/ Ethanol ablation Bone disease – renal osteodystrophy 7. Rarely done

Treatment No specific treatment proven to delay progression of ADPKD
Rigorous blood pressure control may slow progression of ESRD and decrease risk of cardiovascular mortality If no contraindication, ACE-inhibitor should be first line therapy Statin therapy to reduce risk of cardiovascular disease Vasopressin receptor antagonists with some in vitro evidence Increased fluid intake, suppress ADH, inhibit cyst growth Inc fluids esp with stones Hemodialysis favored over peritoneal dialysis peritoneal dialysis – do through Abdomen

Transplantation Post-transplant erythrocytosis
Diverticulitis with perforation Symptomatic aneurysms Often require unilateral or bilateral nephrectomy Avoid recurrent urinary infections Need a place to put the graft Increased patient satisfaction No benefit to survival The list are potential risks from a kidney transplant If they get really big, may need to remove kidneys Even with transplant, can still develop renal cell carcinoma If have underlying cancer, will grow with immunosuppressants

ADPKD and ICA Screening

Screening Watch out for anxiety the pt will have if this is + and you cannot really treat them - May be wise to screen for family planning purposes

Screening The diagnosis of ADPKD is somewhat more difficult to establish when children of an affected parent are screened for the disease, both for genetic counseling and for possible early therapy Cysts as small as 1 to 1.5 cm in diameter can be detected by U/S and 0.5 cm by CT Cyst formation in ADPKD appears to begin in Utero Since there is no effective therapeutic intervention to inhibit cyst growth, some suggest not screening asymptomatic patients Says the same thing as the slide before points out

Screening Already had this slide

ADPKD, Mortality and ESRD
Clinical pres earlier, ESRD earlier, and die earlier with PKD1

Progression to ESRD, why?
Compression of adjacent normal parenchyma (?) But no one knows for sure. This is a hypothesis Histologic examination of patients with early and end-stage renal failure suggests that progressive renal failure in ADPKD correlates with the development of vascular sclerosis and interstitial fibrosis ADPKD most common inherited disease * Kidney Int 42(5): , 1992

Negative family history
Diagnosed in up to 25% of cases Milder forms of the disease may have gone undetected in previous family members 5 % may be a new mutation No definitive diagnostic imaging criteria 10 or more cysts in each kidney Know that a neg fam hist doesn’t rule out PKD

Autosomal recessive PKD
Incidence 1:10,000 – 1:40,000 Always associated with hepatic involvement Congenital hepatic fibrosis More severe cases seen on ultrasound in utero Less severe seen with enlarging kidneys after birth Patients alive after 1st month have 80% chance of survival to 15 and beyond Genetic defect on chromosome 6 – PKHD1 gene encodes protein fibrocystin Found in cortical and medullary collecting ducts Epithelial cells of bile ducts Already large kidney in utero Portal HTN by 10yo Many liver issues Most common reason die in utero – pulm issues (push on lungs and they do not fully develop)

Kidneys push on lungs  died in utero

Diagnosis and Outcomes
Diagnosis usually made by ultrasound Kidneys diffusely hyperechogenic with multiple small cysts Dilated water filled collecting ducts on MR Adults may have slowly progressive kidney dysfunction Systemic hypertension develops in 75% No good screening for the gene currently

Medullary sponge kidney
Malformation of the terminal collecting ducts in the renal pyramids Formation of small and large medullary cysts, do not involve the cortex Usually bilateral but can be unilateral Benign disease with complications of nephrolithiasis and urinary tract infections Underlying defect is not known Often discovered by incidental radiology study such as intravenous pyelogram Flank pain, hematuria, UTIs related to stones Cysts in medulla * Usually not until 4th or 5th decade of life before diagnosed with this Usually found on unreleated imaging Can get severe flank pain from a UTI with this This is not uncommon , and is very benign

Cystic dilations lead to a “brush-like” appearance on IVP. Stones may appear in clusters at the affected renal calyces Can use CAT scan for diagnosis

Prognosis Impaired urinary calcium excretion leads to stones
Long term prognosis excellent Rarely advances to End Stage Renal Disease

Tuberous sclerosis Autosomal Dominant genetic disorder 1 in 5,000-10,000 births Only one-third of cases are familial Neurocutaneous disorder involving many organ systems Clinical diagnosis made by disease findings Two separate gene mutations TSC1 chromosome 9q34, encodes hamartin protein, expressed in normal tissues TSC2 chromosome 16p13, encodes tuberin protein, participates in normal brain development The two proteins form a complex that is thought to function as a negative regulator of the cell cycle Interaction with polycystin 1 and tuberin Clinical features: Triad seizures, mental retardation, and facial angiofibromas occur in 50% of patients Rare conditions One of these disease lie closely to PKD1 gene

Tuberous sclerosis complex
Major criteria Minor criteria Autosomal dominant Renal angiomyolipoma Facial angiofibromas, forehead plaques Periungual fibromas Three or more hypomelanotic macules Shagreen patch Multiples retinal nodular hamartomas Cortical tubers, giant cell atrocytomas Cardiac rhabdomyoma lymphangioleiomyomatosis Multiple renal cysts Nonrenal hamartoma Hamartomatous rectal polyps Retinal achromic patch Cerebral white matter radial migration tracts Bone cysts Gingival fibromas Confetti skin lesions Multiple enamel pits Angiomylolipomas common  benign fatty very vascular tumors, but can cause hemorrhage if get big enough  pt could bleed to death

Facial angiofibromas

Ash leaf spot

Fibrous plaque

Angiomyolipoma Super vascular
- Biggest risk is with bleeding, not cancer

Von Hippel-Lindau Disease
Autosomal dominant syndrome 1 in 36,000 newborns Syndrome of benign and malignant tumors Presents in childhood, adolescence or adults Mean presentation age 26 VHL gene mutation Type I Type II: High risk for pheochromocytoma Worry about malignancy with renal cell carcinoma (malignant) Pheochromocytoma – pts will have extremely elevated bp, and then it can drop suddenly Can present with diphoresis, heart palpatations, etc… Think of this with someone with an angiomyolipoma

Von Hippel-Lindau disease
Renal cysts Retinal hemangiomas – Most common Clear cell carcinomas of the kidney Cerebellar and spinal hemangioblastomas Pheochromocytoma Endocrine pancreatic tumors Epididymal cystadenomas Angiomas of eye Retinal hemangiomas – Most common If have this look for cancer Causes blindness

Treatment Genetic counseling Early diagnosis of more invasive tumors
Hemangioblastoma

Medullary cystic disease
Rare autosomal dominant cystic disease 30-50 new cases in U.S. each year Renal cysts at the corticomedullary junction Small to normal size kidneys Hyperuricemia and gout Grouped with other hyperuricemic diseases Nephronophthisis/MCKD complex Cysts are closer to cortex KNOW gout assoc

Diagnosis and Treatment
Strong family history Preponderance of gout Bland urinary sediment, no protein US- may show medullary cysts Slow progressive chronic kidney disease Allopurinol for gout Transplant is best option: disease does not recur

Aquired cystic Disease
Associated with hemo/peritoneal dialysis Multiple small bilateral cysts Easily distinguished from PCKD No family history Kidneys small to normal size Incidence rises with time on dialysis Pathogenesis not completely understood Nephron loss leads to hypertrophy of normal nephrons, activates proto-oncogenes, growth factors Over time tubular hyperplasia and cyst formation Have long standing kidney disease and may be on dialysis  must differentiate this from ADPKD Usually no fam hist Can develop to renal cell carci

Dialysis associated cystic disease
Most patients assymptomatic Risk of renal cell carcinoma 4-7% over 10 years Smaller, numerous

Multicystic Renal Dysplasia
Abnormal differentiation of renal parenchyma Often unilateral, opposite kidney undergoes unilateral hyperplasia Abnormal differentiation of metanephric parenchyma One of the most common forms of congenital cystic renal diseases One of the most common causes of abdominal mass in newborns Usually nephrectomy Happens in utero Can get refulx into a good kidney, likely remove damage kidney

Polycystic liver disease
No kidney involvement Genetic testing may be required No association with aneurysms Triad of pain, jaundice, and abdominal mass found in infants Separate gene PRKCSH codes hepatocystin Skipped

Mark D. Purcell, DO e-mail: mpurcell@mykidneydoc.com
Questions Mark D. Purcell, DO

Renal Cystic Disease ADPKD ARPKD Tuberous Sclerosis

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