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Nephrology Core Curriculum: Autosomal Dominant Cystic Kidney Disease (ADPKD and others) Inherited Kidney Diseases Background • Dominant inherited polycystic diseases – ADPKD – Tuberous sclerosis – von Hippel-Lindau disease • Recessive inherited polycystic diseases – ARPKD • As would be expected with recessive, onset early in life with ESRD in youth • Always associated with congenital hepatic fibrosis Tuberous Sclerosis • Hereditary disease with hamartomas in multiple organ systems – Autosomal dominant with high penetrance, but extreme phenotypic variability Tuberous Sclerosis Clinical Features • Hamartomas – Benign tumors resulting from disordered cell migration • Skin – Facial angiofibromas (adenoma sebaceum) – Fibrous forehead plaques – Ungual fibromas – Shagreen patcheslumbosacral palpable lesions – Hypomelanotic macules- earliest and most common skin lesions, occurring in 90% of cases Tuberous Sclerosis Clinical Features • Hamartomas – Benign tumors resulting from disordered cell migration • Skin • Brain – Cortical tubers » Associated with infantile seizures and mental retardation Tuberous Sclerosis Clinical Features • Hamartomas – Benign tumors resulting from disordered cell migration • Skin • Brain – Subependymal glial nodules » Arise in the ventricles. Cause increased ICP Tuberous Sclerosis Clinical Features • Hamartomas – Other organs affected: • • • • • • • • Skin Brain Retina Heart- cardiac rhabdomyomas Kidneys Liver Lungs Bone Tuberous Sclerosis Clinical Features • Hamartomas – Benign tumors resulting from disordered cell migration • Kidneys – Present in 50% of cases – #1 lesion is angiomyolipomas » Benign lesion made of adipose tissue, smooth muscle cells, and arterial vessels » Fat content makes them easy to diagnose by CT scan » Bleeding is a risk if >4cm, esp during pregnancy – Renal cysts (unrelated to angiomyolipomas) also occur in 30% of patients Tuberous Sclerosis Diagnosis • No definitive features • Made by combination of major and minor features – Require at least two features Tuberous Sclerosis Management • No specific therapy • Consensus conference – Evaluated every 1 to 3 years with renal US, CT or MRI of the brain – One chest radiograph in adult women • Surgical resection for CNS lesions causing hydrocephalus Von Hippel-Lindau Disease • Autosomal dominant disease with high penetrance – Development of benign and malignant tumors in multiple organs • Type I - NO pheos • Type II- Pheos (runs in 7-20% of families) Von-Hippel-Lindau Disease Clinical Features • Potential Sites– Central nervous system, eyes, kidneys, adrenal glands, pancreas, and epididymis are commonly affected • Usual lesions – CNS hemangioblastomas • In the cerebellum, spinal cord and brainstem. No supratentorial lesions • Benign, but mass effects cause difficulties – Recur after surgery Von-Hippel-Lindau Disease Clinical Features • Usual lesions – Retinal hemangioblastomas • In 50% of cases • Multiple or bilateral • Red “dots” on retina that slowly enlarge • Regular ophtho eval important – Laser tx Von-Hippel-Lindau Disease Clinical Features • Usual lesions – Renal • Cysts – 50-70% of patients • Carcinoma – 77% of patients by 60 years old – Usually multiple and bilateral – #1 cause of death – Inherited form of renal cancer due to the loss of a suppressor gene Von-Hippel-Lindau Disease Clinical Features • Usual lesions – Pancreas • Cysts in 30% of patients • Likely to cause confusion with ADPKD Von-Hippel-Lindau Disease Diagnosis • Positive family history, plus a single hemangioblastoma or visceral lesion • No family history, two or more hemangioblastomas or one and a visceral lesion • Direct mutation analysis is now possible • Distinguish from ADPKD – Both with kidney cysts – ADPKD with rare panc and freq hepatic – VHL with rare hepatic and freq panc • Suspect in any patient with kidney and pancreas cysts without liver cysts Von-Hippel-Lindau Disease Management • Regular screening program – Annual physical and ophtho – Annual MRI of CNS – Annual abdominal imaging • Either US,CT,MRI – If positive family history, • Periodic metanephrines screening for pheo ADPKD Epidemiology • Prevalence approximately 1:400 to 1:1000 in people of European descent – 600,000 Americans with the disease – More than CF, muscular dystrophy, hemophilia, Down’s syndrome and sickle cell anemia– COMBINED – Frequency in NonEuropeans unknown • 4% of ESRD patients • Common in cats ADPKD Genetics • Two different mutations – ADPKD-1 – ADPKD-2– same as one, except: • Milder disease • Older age at diagnosis • Later onset of hypertension • Later onset of renal failure ADPKD Genetics • Only 1-2% of tubules affected – Two-hit hypothesis– genetic abnormality not sufficient, requires an additional insult to manifest • (argument for aggressive treatment of ADPKD patients) • Cysts begin as focal dilatations of tubular segments • Not just impermeable cul-de-sacs. They collect and store urine from more proximal nephron segments – Synthesize and transport proteins, hormones, and cytokines ADPKD Diagnosis • Ultrasound – Insert Australian ultrasound study – Age adjusted criteria • 18-29yo, at least 2 cysts • 30-59yo, at least 2 cysts in each kidney • >60yo, four cysts in each kidney – For r/o diagnosis of ADPKD in patient at risk, no age at which 100% of gene carriers have detectable cysts • US can only prove ADPKD, it cannot r/o • 2 studies in families with gene linkage analysis showed no false negatives after age 30 yo (but only two families) – Can’t just screen parents • 10% of ADPKD patients are new mutations ADPKD Genetics • Genetic tests by linkage analysis only – No direct mutation analysis – Requires at least two related family members with the disease. – Expensive ($1000s) – Only utility is for donor screening • Other reported uses include family planning decisions and prenatal diagnosis – Athena diagnostics launched a molecular test based on direct mutation analysis • Detects only 50% of PKD-1 and 75% of PKD-2 mutations • (takes 4 weeks and $2600 by credit card) ADPKD Signs and Symptoms Signs and symptoms Frequency Back pain and flank pain 60% of adults Hypertension 80% of adults Gross Hematuria 50% of adults Renal Concentrating defect All adults Palpable kidneys Potentially all adults Hepatomegaly 20-30% of women >50yo Proteinuria 18-68% of adults CRI Age dependent ADPKD Signs and Symptoms • Back pain – Chronic- Likely the result of stretching of the renal capsule by the enlarging cysts • • • • • Tylenol Physical measures- ice massage and heating packs TENS Autonomic plexus blockade Decompression of cysts – Usually laproscopic. Can drain one or hundreds of cysts – Immediate pain relief in 90%. Persistent relief at 3 years in 2560% of patients – Some bp improvement. ADPKD Signs and Symptoms • Hypertension – Occurs well before renal insufficiency • 40% by 18-24yo • 54% by 24-30yo • 65-80% > 30yo – Hypertension correlates with renal size • Mechanism clearly complex– but demonstrated to have hyperplasia of renin producing cells and increased renin levels ADPKD Signs and Symptoms • Gross hematuria – Painless or associated with dull colicky pain – 40-50% of patients experience at least one episode • In 20% of patients it is how ADPKD is discovered – Last 2-7days and cease spontaneously – Can be seen on CT with contrast- high density cyst without enhancement after administration of contrast ADPKD Signs and Symptoms • Renal concentrating defect • Palpable kidneys- exam is poor at estimating size • Palpable hepatomegaly – 20-30% of patients older than 50 • UTI – Must use lipophilic agents to treat • Cipro, Clindamycin, Emycin, and Bactrim ADPKD Manifestations Not just a renal process, it is a basement membrane abnormality that affects multiple sites Manifestation Frequency Renal Cysts 100% by 30 yo Nephromegaly 95% by 30 yo Decreased concentrating ability All adults Hypertension 65-80% of adults Extra-renal Liver cysts 75% by age 60yo Pancreatic cysts 9% after age 30yo Seminal vesicle and prostate cysts 60% and 11% at 40yo Arachnoid cysts 5-8% MVP 25% Intracranial Aneurysms 2-3% Abdominal Wall Hernia 45% with ESRD ADPKD Signs and Symptoms • Nephrolithiasis – 20-36% – Stone composition • Higher uric acid than general population--- 50% • Remainder CaOx – Due to metabolic factors and urine stasis associated with distorted renal architecture • 50% have hypocitraturia – Can use lithotripsy ADPKD Signs and Symptoms • Renal Cell Cancer – No increased risk – Presence should raise the suspicion of a misdiagnosis • Consider Von Hippel Lindau disease, esp. if familial cancers ADPKD Urinary findings • Microscopic hematuria • Pyuria • Dipstick Proteinuria 23% up to 45% 34-68% – Nephrotic range proteinuria does not occur with ADPKD alone – Only 18% with > 300mg/day proteinuria ADPKD Extra-renal manifestations • Liver cysts – The most common extrarenal manifestation – Arise from bile ducts – Occur later than renal cysts – By 60yo, 75% will have liver cysts – Women > Men • Multiple pregnancies puts at greater risk – Despite hundreds of cysts- liver function typically remains NORMAL – Can become infected- unlike renal cysts, requires drainage for clearance ADPKD Extra-renal manifestations Cystic • Other cysts – Pancreas– Ovaries – Seminal vesicles 9% of patients >30 yo No increase (12%) 60% • No signif – Prostate – Arachnoid cysts 11% 8% ADPKD • • • • Extra-renal manifestations Non-Cystic Mitral valve prolapse 25% LVH Intracranial Aneurysm Colonic divertics – Increased in ADPKD ESRD patients, but not pre-ESRD • Abdominal wall hernias, up to 45% – Not associated with renal size or volume ADPKD Berry Aneurysm • 4 large, prospective studies screening asx subjects (High res CT,MRI, or Conventional Angiography) • 5-10% of asymptomatic adults with ADPKD harbor an Intracranial aneurysm (vs. normal--???) • All aneurysms found by screening were less than 8mm • No change during a mean f/u of 2.5 years • Annual risk of rupture for cysts <10mm is 1/2000 – If >10mm or prior ruptured aneurysm 1/100-200 – Risk of elective surgery » Death 1-4% at one year » Morbidity rate of 15% at one year ADPKD Berry Aneurysm • Sawyer’s rule of 20s – – – – 1/20 chance of having an asx aneurysm (5-10%) 1/200 chance of rupture if >10mm 1/2000 chance of rupture if <10mm 20% chance of complications with surgery • 1-4% death + 15 % morbidity at one year – 20% of aneurysms multiple ADPKD Subarachnoid Hemorrhage • Familial clustering of aneurysm rupture – Occurs in the general population as well – 5% of ADPKD, but 22% if + fhx • 20-30% with have multiple aneurysms • 10% who have one aneurysm rupture will have a second rupture ADPKD Berry Aneurysm • Screening recommendations – Risk benefit ratio against routine screening of asx patients – Screen • • • • Prior rupture Positive Family history High risk occupation- Air Line Pilots etc Prior to a surgery with hemodynamic instability associated with hypertension (KI, 1994 IC aneurysms in ADPKD) • Neurologic symptoms suggestive of an aneurysm • ** Trash indication** – Patient’s who need screening for peace of mind ADPKD Berry Aneurysm • Questions to answer if you screen anyway – How often? • Does a negative screen you will never develop cysts? • At what age will you develop cysts? • Are you born with cysts and the remain stable for life, or do they enlarge? – Serial MRAs show stability for at least 30 months – No de novo aneurysms over an 8 year period – Stable for 2.5 – 5 years, otherwise no data – General recommendation are q5-10 years – Note • ADPKD patients have more CVAs than subarachnoids • ADPKD patients have more hemorrhagic strokes than subarachnoids ADPKD Pregnancy with normal renal function 235 women with 605 pregnancies • ADPKD has no impact on fertility • Rate of live birth unchanged – 77% vs. 82% of normals • Fetal complication rate- unchanged • Maternal complications INCREASED (35% vs 19%) – New or worsening hypertension – Pre-eclampsia – Edema • No impact on renal function – Except if FOUR or more pregnancies and hypertensive ADPKD ESRD • 50% at 60 years, 75% at 70 years at ESRD • Negative prognostic factors: – HTN • Reviewed 1215 subjects • Median renal survival 14 years longer if not hypertensive by age 35 years old – LVH – Male – Younger age at diagnosis• -difference of ten years to ESRD between onset <30 vs >30yo – 3+ pregnancies, UTIs (in men) – Episodes of gross hematuria, H/o hypertension in parent – If you have HTN, hematuria, and diagnosis before age 30 years old– 100% ESRD by 48 yo ADPKD Modifier Genes • ACE sub-type – 2 studies show impact, 2 don’t • Sickle cell trait – Likely accelerates ADPKD Treatment • HTN – MDRD had 200 patients with ADPKD • No protective effect over a mean 2.2 years – ? Disease already too far advanced – Progression is slowed in animal models – Use of ACE-I • No evidence that hemodynamics plays an important role in progression – Can perform unilateral nephrectomy without accelerating the disease process – Proteinuria always less than nephrotic range – However ultimate progression of disease is due to fibrosis and ACEIs selectively block – Use of amiloride • Shown to block Na entry into cysts and halt cyst enlargement in animal models ADPKD Treatment • Protein restriction – MDRD- no protective effect on moderate or severe restriction • Cyst decompression – Pain management tool. No evidence for delayed disease progression • Animal models • • • • • Protein restriction beneficial Soy protein supplementation beneficial Flaxseed beneficial Statins beneficial Alkalinization- helps in rats, but not mice – Thought is that the 2nd ammonia genesis by the kidney in order to compensate leads to tubular damage ADPKD Counseling and Screening • Newly diagnosed patients should be informed about ADPKD, it’s hereditary nature, and that children have a 50% chance of inheriting the gene • Before screening, subjects should be “informed of the consequences of diagnostic screening, particularly regarding insurability.” – My practice--Screening offers no benefit • A negative US doesn’t r/o disease • A positive US will not lead to a change in therapy, but it will make the person uninsurable and potentially unemployable • Gene linkage can be performed if potential donation is considered -remember it costs approximately $2600 Acquired Cystic Kidney Disease • Development of multiple, bilateral cysts in kidneys of patients with chronic renal disease due to causes other than cystic kidney disease – 10-20% of pre-dialysis patients – Increases with dialysis, 50% of patients on HD x 3 years with cysts – Major determinant is the duration of renal insufficiency Acquired Cystic Kidney Disease • Cysts are usually less than 0.5 cm – Occasionally reach 2-3cm • Affect both the cortex and medulla • Result of a failure to clear unknown “mytogenic and cystogenic” substances due to renal insufficiency – Lesions regress with transplantation • Concern is transition to cancer – Men 7x more than women – Some recommend screening starting at 3years with annual US – Given shortened lifespan with ESRD, others refute