CHAPTER 15.2 Polycystic kidney disease in children 589 Further reading Bingham C, Bulman MP, Ellard S, et al. Mutations in the hepato- cyte nuclea r factor-1 gene are associated with familial hypoplas- tic glomerulocystic kidney disease . Am J Hum Genet 2001; 68: 219 \200\223224. Treatment Hypertension This is a common feature occurring in 33 \200\22347% of patients. Ac tivation of the renin angiotensin-aldosterone system has been documented and increased left ventricular mass has been documented in children. ACEIs and angiotensin receptor blockers (ARBs) are recommended. Fick-Brosnahan GM, Tran ZV, Johnson AM, et al. Progression of autosomal dominant polycystic kidney disease in children. Kidney Int 2001; 59: 1654 \200\2231662. Follow-up The frequency of follow-up will depend on the degree of renal impairment but shou ld occur in specialist pediatric and adult renal units. Guay-Woodford LM, Desmond RA. Autosomal recessive polycystic kidney disease: the clinical e xperience of North America. Pediatrics 2003; 111: 1072 \200\2231080. Lonergan GJ, Rice RR, Suarez ES. Autosomal recessive polycystic kidney disease: radiologic \200\223pathologic correlation. RadioGraphics 2000; 20: 837 \200\223855. Prognosis Prognosis is good if onset is in childhood, but poor if onset is within the \201 rst year of life. Peral B, Ong ACM, San Millan JL, et al. A stable nonsense mutation associated with a case o f infantile autosomal dominant polycystic kidney disease. Hum Mol Genet 1996; 5: 539 \200 \223542. Future prospects Potential drug treatments, including vasopressin type 2 (V2) receptor anta gonists, sirolimus and everolimus, are currently being tested in adult patients. Sweeney WE, Avner ED. Molecular and cellular pathophysiologyof autosomal recessive polycyst ic kidney disease (ARPKD). Cell Tissue Res 2006; 326: 671 \200\223685. Zerres K, Rudnik-Sch neborn S, Deger F. Childhood onset auto- somal dominant polycystic ki dney disease in sibs: clinical picture and recurrence risk. J Med Genet 1993; 30: 583 \200 \223588. Glomerulocystic kidney disease Glomerulocystic kidney disease (GCKD) is characterized by bi lateral cortical cysts from dilatation of Bowman \200\231s cap- sule and the proximal convo luted tubule. Glomerulocystic kidneys can be divided into three major categories: 1. GCKD c omprising both sporadic and nonsyndromal Zerres K, Rudnik-Sch neborn S, Steinkamm C, et al. Autosomal recessive polycystic kidney d isease. J Mol Med 1998; 76: 303 \200\223309. Internet resources The Polycystic Kidney Disease Charity: inherited forms. http://www.pkdcharity.co.uk/ National Kidney Federation: 2. Glomerulocystic kidneys as a feature of malformation syndromes (e.g. orofacial \200\223d igital syndrome type 1): cysts are variably expressed. http://www.kidney.org.uk/medical-info/kidney- disease/pckd.html NIH (NIDDK) Information Cle aring House: 3. Glomerular cysts in dysplastic kidneys: dysplastic fea- tures predominate. http://kidney.niddk.nih.gov/kudiseases/pubs/ polycystic/ Polycystic Kidney Disease Foundati on: A rare familial form of GCKD associated with hypoplastic kidneys has been documented. This autosomal dominant form is associated with maturity onset diabetes of the young (MODY) and is caused by mutations in hepatocyte nuclear factor (HNF)-1 . Dilatation of glomeruli is a lso seen in ADPKD and other multisystem diseases, e.g. tuberous sclerosis and Von Hippel \200\223Lindau disease. Glomerular cysts tend to be small and are located pre- dominantly i n the subcapsular region although the entire cortex can be involved. High resolution USS, C T or MRI is needed for the diagnosis. The clinical course is variable and the natural histo ry is not well documented. Infants and children present with bilater- ally enlarged kidneys with variable renal function. Adult patients may be asymptomatic or present with progressi ve renal failure. Early progression to renal failure with need for renal replacement therap y may occur. http://www.pkdcure.org See also Autosomal dominant polycystic kidney disease, p. 590 Nephronophthisis, p. 600 Tube rose sclerosis and von Hippel \200\223Lindau disease, p. 598 Rare syndromes with renal invo lvement, p. 640 Medullary sponge kidney, p. XXX Chronic kidney disease in children, p. 462 C.L. CHOW AND A.C.M. ONG 590 Autosomal dominant polycystic kidney disease Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common geneti c cause of renal failure and accounts for 10% of patients on dialysis. Unlike other causes of chronic kidney disease, ADPKD is character- ized by progressive kidney enlargement. It i s also a sys- temic disorder characterized by cyst formation in other organs such as the li ver and the pancreas as well as noncystic complications such as arterial aneurysm formation . Female PKD2 patients have delayed ESRD compared to males. There is considerable intrafamili al phenotypic variability indicating the major modifying effects of nonallelic and environm ental factors on the phenotype compared to allelic factors. True genetic anticipation does not occur. Clinical features As most patients are asymptomatic, the commonest modes of presentation ar e with asymptomatic hypertension, inci- dental USS \201 ndings or a positive family histo ry. Epidemiology ADPKD has a prevalence of 1:400 to 1:1000 live births. The disease is usually evident by the 3rd and 4th decades of life but can present at any age. Features at presentation Flank, back and/or abdominal pain (60%). Urinary tract infection. Renal stones (20 \200\22330%). Hematuria (gross 30 \200\22350%, microscopic 25%). Hypertens ion (60%). Intracerebral aneurysm or bleed (6 \200\22316%). Symptoms of renal failure (usua lly in the 4th \200\2236th decade of life): \200 \200 \200 Genetics The inheritance pattern is autosomal dominant with 100% disease penetrance. Each o ffspring has therefore a 50% chance of inheriting the disease. There is a high rate of new mutation. Mutations in either of two genes can lead to ADPKD: \200 PKD1 (chromosome 16p13.3) accounts for 85 \200\22390% of cases. PKD1 encodes for the polycy stin-1 protein; PKD2 (chromosome 4q21) accounts for 10 \200\22315% of cases. PKD2 encodes f or the polycystin-2 protein. lethargy; poor appetite; \202 uid overload. Family history of: \200 \200 A small number of families unlinked to either gene could signify the potential existence of a third gene ( \200\230PKD3 \200\231). Polycystin-1 and polycystin-2 are integral membrane proteins. Polycystin-1 is likely to act as a receptor and is found in primary cilium, foca l adhesions, desmosomes, and adher- ens junctions. Polycystin-2 is a nonselective cation ch annel which is highly permeable to calcium ions and is found in the endoplasmic reticulum, centrosome and primary cilium. Both proteins are widely expressed in multiple tissues and c ell types including epithelial cells, vascular smooth muscle cells and cardiac myocytes. Th ey are thought to form a functional complex regulating key aspects of cellular behav- ior i ncluding proliferation, apoptosis, cell adhesion, mor- phogenesis and net transepithelial f luid secretion via multiple signal transduction pathways. Cysts form in <1% of nephrons alt hough all cells carry the germline mutation. This observation has led to the two-hit model of cystogenesis which proposes that a second muta- tion (second hit or somatic mutation) is required for cyst formation. Environmental factors and modifying genes may in \202 uence the rate of second hits (Fig. 15.3.1). A different mechanism underlying cystogenesis is the hap- loinsuf \201 ciency model where reduced expression of the normal allele below a thre shold level may predispose cells to genetic/environmental triggers for cyst formation. ADPKD; cerebrovascular accident/intracranial bleed. Cardiovascular (important for risk mana gement). Examination Proteinuria >300 mg/day (18%). Nephrotic range proteinuria is uncommon. Palpabl e, bilateral \202 ank masses from enlarged kidneys. Nodular hepatomegaly. Enlarged pancre as from pancreatic cysts. Cardiac valve defects: aortic regurgitation, mitral valve pro- la pse, tricuspid regurgitation. Hernia \200\223inguinal and umbilical. Differential diagnosis of renal cysts Renal cysts are not unique to ADPKD. Other poten- tia l causes of renal cysts are listed in Table 15.3.1. The diagnosis of ADPKD can usually be m ade based on family history, extrarenal manifestations and radiological appearances. Simple cysts These become more common with age: 1.7% of 30 \200\22349-year-olds; 22.1% of >70-year-olds. \200 They are usually unilocular and are located in the cortex. The kidneys are not normally enl arged and extrarenal manifestations should be absent. Genotype/phenotype correlations PKD1 and PKD2 gene mutations result in a similar clinical p henotype but PKD2 patients have a more favorable course and slower progression to ESRD (mea n age of onset 54.3 years PKD1; 74 years in PKD2). Medullary sponge kidney This involves cystic dilatation of the medullary collecting ducts r esulting in cysts con \201 ned to the medulla with a typical appearance on excretory urogr am. CHAPTER 15.3 Autosomal dominant polycystic kidney disease 591 Locus-specific Allele-specific Genotype Somatic mutations Gender Environmental Factors Modifying genes Phenotype Fig. 15.3.1 Factors that could determine the severity of the cystic phenotype in an individ ual inheriting a germline PKD1 or PKD2 mutation. Table 15.3.1 Renal cystic diseases Von Hippel \200\223Lindau disease This is characterized by multiple tumors in the cerebellu m, spinal cord, retina, adrenal glands (pheochromocytoma), pancreas and kidney. There is a high risk of renal cell carcinoma. Genetic Autosomal-dominant \200 Autosomal-dominant polycystic kidney disease \200 Tuberous scle rosis \200 Von Hippel \200\223Lindau disease \200 Medullary cystic disease Autosomal re cessive \200 Autosomal-recessive polycystic kidney disease \200 Juvenile-onset nephrono phthisis \200 Other rare syndromes associated with multiple Acquired cystic disease Patients with a long duration of renal impairment or dialy- sis can develop acquired renal cysts. They tend to have shrunken kidneys and a negative family his tory. Autosomal recessive polycystic kidney disease ARPKD can be distinguished from ADPKD by the inherit- ance pattern, earlier age of onset (infancy or childhood) and the obligate presenc e of liver disease (congenital hepatic \201 brosis or Caroli \200\231s disease). malformations X-linked \200 Orofaciodigital syndrome type 1 Chromosomal disorders \200 Trisomy 21 \200 Trisomy 13 \200 Trisomy 18 \200 Trisomy C Investigations The diagnosis is based on family history and imaging. Renal USS is the most commonly used modality. Where the fam- ily history is unknown or negative, the diagnosis is sup- ported by the presence of bilaterally enlarged cystic kidneys, hepatic cysts, and the absence of extrarenal mani- festations that suggest a different renal cystic disease. Nongenetic Acquired \200 Simple cysts \200 Acquired renal cystic disease \200 Hypokal emia-related cysts Developmental \200 Medullary sponge kidney \200 Multicystic dysplast ic kidneys \200 Pyelocalyceal cysts Laboratory studies Serum chemistry pro \201 le, calcium and phosphate: for stag- ing of re nal function and CKD management. Full blood count: patients tend to have preserved hemo- gl obin levels due to preserved erythropoetin secretion. Urinalysis and culture. Microscopic h ematuria is present in 25%, and overt proteinuria in 18%. Nephrotic range proteinuria is ra re and should prompt further investigation for concomitant glomerulonephritis. Sterile pyur ia is common. Multicystic dysplastic kidneys or congenital multicystic kidneys This is a unilateral and c ystic kidney that has no excretory function. Genetic testing This can be performed by DNA linkage studies and sequence analysis. Linkage studies require at least two affected and one unaf- fected relative for a diagnosis to be made. Mutation analysis can be done by denaturing high perform- ance liquid chromatography (DHPLC) or direct sequencing. Tuberous sclerosis complex This should be suspected if cysts and solid masses (angi- omyoli pomas) coexist on renal scans. They also have skin lesions in the form of facial and periun gual \201 bromas and CNS involvement. C.L. CHOW AND A.C.M. ONG 592 However, the pathogenicity of unclassi \201 ed variants (mis- sense mutations vs neutral p olymorphisms), which can be seen in up to 40% of cases for PKD1, can be dif \201 cult to p rove in the absence of a valid functional assay. Imaging studies Ultrasound This is the most widely used diagnostic technique for ADPKD. Ult rasound is also useful for detecting liver or pancreatic cysts (Fig. 15.3.2). Diagnostic cr iteria: \200 at least two cysts in one kidney or one cyst in each kid- ney in at-risk patients aged <30 years; at least two cysts in each kidney in at-risk patients aged 30 \200\22359 years; at l east four cysts in each kidney for at-risk patients aged \211 60 years. Fig. 15.3.2 Ultrasound scan showing multiple cysts of varying sizes within a kidney. This criterion has a sensitivity of 97 \200\223100% in PKD1 patients \211 30 years old but may have a higher false negative rate in younger PKD2 patients. In patients under 30 years of age, false-negative rates are quoted as 23% in PKD2 and 5% in PKD1. CT and MRI These are not routinely used for diagnostic purposes but can be helpful in ident ifying cyst hemorrhage, differentiat- ing renal cell carcinoma from simple cysts, and inves tigating renal stones (Fig. 15.3.3). MRI is able to detect renal volume changes with greate r sensitivity and accuracy than USS. Change in kidney volume by sequential MRI has been fou nd to correlate inversely with GFR in the Consortium of Radiologic Imaging Studies of Polyc ystic Kidney Disease (CRISP) study of ADPKD. MRI can provide a growth rate \200\230signatu re \200\231 for individual patients and is likely to become widely adopted as the gold stan dard for estimating disease progression. Fig. 15.3.3 CT scan showing bilateral enlarged polycystic kidneys. Magnetic resonance angiography This is the preferred imaging technique for diagnosing intra c- erebral aneurysms (ICA). Screening is recom mended where there is family history of ICA, if symptoms of ICA are described, when the patient has a high risk job, or when the patien t has had a previous ICA. Presymptomatic screening of ADPKD patients is not otherwise recom mended. intracystic hemorrhage; urinary tract obstruction from stone or blood clot. \200 Chronic pain can be due to pressure, stretching of the renal capsule or structural distorti on. Other imaging Barium enema for the investigation of symptoms sugges- tive of colonic divert icular disease. Echocardiography only if valvular abnormalities are sus- pected on clinical grounds. Nonrenal This may be due to diverticulitis, liver and pancreatic enlargement, or infection. Treatment of the underlying cause and simple analgesia is necessary. NSAIDs should be avoi ded due to their potential impact on renal function. Support, reassurance and counseling ar e important in the management of pain. Lifestyle modi \201 cation and avoidance of aggrava ting activi- ties can be useful. Patients may require specialist pain clinic involvement, a nd surgical management (cyst decompression, renal denerva- tion or nephrectomy) may be nece ssary. Treatment There is no cure for ADPKD. Treatment is aimed at: \200 \200 \200 slowing the progression of renal failure; managing disease complications; managing the cons equences of CKD. Pain This is a common symptom and has several possible causes: Renal Acute pain can be due to: Hypertension This is a very common early symptom (60% of patients with normal renal functio n) and is important in the context of cardiovascular risk. \200 infection; stones; CHAPTER 15.3 Autosomal dominant polycystic kidney disease 593 Stone disease should be considered if acute pain, an acute deterioration in renal function, and hematuria are present. The higher frequency of stone formation in ADPKD could relate t o abnormalities in citrate and magnesium excretion or to prolonged urinary stasis. Diagnosi s by USS is often dif \201 cult due to the presence of large cysts; therefore, an IV pyelo gram or CT scan is preferred. Renal stones normally resolve with conservative measures incl uding hydration, treatment of infection, and analgesia. More complicated cases should be re ferred for extracor- poreal shock wave lithotripsy and/or percutaneous nephr- ostolithotomy . Activation of the renin \200\223angiotensin \200\223aldosterone and sym- pathetic nervous s ystems, and endothelin and vasopressin release have been described. The aim is to achieve a blood pressure of <130/80 mmHg. Cardiovascular risk factor reduction, e.g. smoking cessati on and hyperlipidemia, is important. There is no speci \201 c evidence that any particular antihyper- tensive drug is more effective in ADPKD. A trial currently in progress (HALT-PK D) is investigating whether the use of ACEIs or ARBs in CKD stage 1 \200\2233 confers addit ional bene \201 t. Infection The most common cause of pyrexia is urinary tract infec- tion which can originate from any part of the urinary tract. Urine cultures may be consistently negative in cyst in fection. Ureteric obstruction from stone or clot with associated infection should be exclud ed. Infection can also be extrarenal in origin, i.e. diverticulitis, pancreatic or liver cy st infection. Patients will require prompt antibiotic treatment that is adjusted according to renal function and culture results. Cyst infection requires treatment with antibiotics t hat pen- etrate the cyst. The most commonly used are cipro \202 oxacin, trimethoprim and c lindamycin. A prolonged course of anti- biotics may be required. Surgical intervention is r arely required. Patients may occa- sionally require drainage of a perinephric abscess or la rge infected cyst. Nephrectomy is only required in severe uncontrolled infections. If there is evidence of recurrent infection, it would be pru- dent to start long-term prophylactic antibiotics. If urinary tract instrumentation is ever required, antibiotic prophylaxis shou ld be given. Massive polycystic kidneys and large renal cysts Massive cysts can cause abdominal discomfo rt or pain. Cyst reduction can be achieved using: \200 \200 \200 alcohol sclerosis; percutaneous drainage; laparoscopic deroo \201 ng. Laparoscopic renal denervation can be considered in rare cases of uncontrolled pain. Infect ed cysts resistant to conventional antibiotic therapy may require surgical drainage under U SS guidance. Nephrectomy is indicated for massive kidneys as a prelude to transplantation ( occupying surgical space), and for severe resistant recurrent infection, severe pain or mal ignancy. Cancer There is no evidence for an increased risk of renal cell car- cinoma in the ADPKD po pulation. However, if renal cancer is present it is more likely to be bilateral, multicentr ic and sarcomatous. Hematuria and \202 ank pain with anorexia and weight loss should prom pt further investigation. CT and MRI are required but can prove dif \201 cult to interpret due to the highly altered kidney architecture. Comparison with previous scans (if availabl e) may prove useful. Cyst hemorrhage and hematuria Gross hematuria occurs in 30 \200\22350% of patients. The inc idence increases as kidney size increases. It usually occurs spontaneously but may be relat ed to: \200 \200 \200 \200 \200 Liver cysts Hepatic cysts are the commonest extrarenal manifestation. Their prevalence incr eases with age: \200 \200 physical activity; trauma; stones; infection; tumor formation. 20% in the 3rd decade; 75% in the 7th decade Hepatomegaly can be massive. They occur more frequently and are more severe in females, cor relating with estrogen exposure (e.g. pregnancy, contra- ceptive pill). Liver cysts origina te from bile ductules or peribiliary glands. They are usually asymptomatic and do not lead to hepatic failure. Pain from compression, feelings of satiety, cystic hemor- rhage and inf ection are the commonest symptoms. Rarely, massive polycystic liver disease can result in p ortal hyper- tension (i.e. ascites, esophageal varices). Cyst infection will require treatm ent with antibiotics that have good cyst penetration and are tailored to renal func- tion a nd microbiological sensitivities. A prolonged course of antibiotics is often required. If t he infection does not Conservative management with bed rest, hydration and analgesia is the mainstay of therapy a s it is normally self- limiting and resolves within days. Further investigation to exclude malignancy may be con- sidered if episodes are frequent or prolonged, occur in older patien ts (aged >50 years), or are associated with other systemic symptoms. Rarely, hemodynamicall y significant bleeding requiring hospital admission, transfusion and CT angiography can occur. Persistent hemorrhage may require segmental arterial embolization or nephrectomy. Nephrolithiasis This occurs in 20 \200\22330% of patients. Stones are commonly composed of calcium oxalate and uric acid. C.L. CHOW AND A.C.M. ONG 594 Risk factors for a poor outcome following intervention are: \200 \200 \200 \200 \200 settle, patients may require cyst drainage or, in rare cases, hepatectomy. If the patient d evelops problems with satiety that impact on their nutritional status, or has severe discom fort, a sur- gical debulking procedure can be considered. The options include: \200 \200 \200 \200 age >50 years; large aneurysm; posterior circulation location; previous history of ischemic cerebrovascular disease; aneurysmal symptoms. cyst deroo \201 ng or fenestration; cyst drainage and sclerosis; transcatheter hepatic art erial embolization (TAE); partial hepatectomy. Conservative management is recommended for aneurysms <7 mm in size in the anterior circulat ion. Larger aneurysms are treated by coil embolization or sur- gical clipping. If an aneury sm <7 mm is detected, follow-up surveillance scans will be required at 6 \200\22312-monthly intervals with increasing duration between scans should the aneurysm be stable. Control of hypertension and hyperlipidemia and cessation of smoking are advised. The risk of a new an eurysm developing after an initial neg- ative study is 2.6% at 10 years in patients with a positive family history of ICA. Therefore a repeat scan may be deferred for 3 \200\2235 ye ars unless there are other clinical indi- cations. A massive polycystic liver can rarely cause hepatic venous out \202 ow obstruction resulti ng in ascites and portal hyper- tension. If portal hypertension is severe or the polycystic liver is very large with nonresectable areas, liver transplan- tation may be necessary. Intracerebral aneurysms Intracerebral aneurysms (ICAs) occur in: \200 \200 6% of ADPKD patients with no family history of ICA; 16% of ADPKD patients with a family his tory of ICA. There is a combined 35 \200\22355% risk of severe morbidity and mortality foll owing aneurysm rupture. The median age of ICA rupture among ADPKD patients is less than tha t in the general population (39 vs 51 years). Kidney function and blood pressure are usuall y normal in most patients. Acute rupture results in subarachnoid hemorrhage (SAH) that is c haracterized by sudden intense occipital headache. 20 \200\22350% of patients have symptoms of headache for up to a week before the acute bleed. Other features include: \200 \200 \200 \200 \200 Chronic kidney disease and renal replacement therapy Patients with renal failure will requi re more frequent monitoring. Management of CKD and its complications (e.g. bone min- eral m etabolism, \202 uid balance, acid \200\223base balance, electro- lyte abnormalities) shou ld be started. By the age of 60 years, 50% of patients will require renal replacement ther apy. Both peritoneal dialysis and hemodialysis can be used in ADPKD patients. If massive or ganomegaly is present, peritoneal dialysis may not be feasible without prior nephrectomy. T ransplantation is the treatment of choice. There is no difference in patient or graft survi val in ADPKD patients compared with other ESRD populations. Pretransplant nephrectomy may b e considered if there are space limitations. focal neurological de \201 cit; nausea and vomiting; photophobia; seizures; an altered con scious level. However, the most common neurological event in ADPKD is hypertensive hemorrhage or ischemic stroke. CT scanning ( lumbar puncture) should be performed if there is clinical suspicio n. Patients with a confirmed bleed need to be referred urgently for neurosurgical assessmen t. The International Subarachnoid Aneurysm Trial (ISAT) of ruptured aneurysms showed that i n aneurysms suitable for coiling or clipping, endovascular coiling reduced the absolute ris k of death and dependency at 1 year by 7.4% compared to clipping. Successful obliteration b y endovas- cular repair is quoted as 66% compared to 82% for open surgery. The Internationa l Study of Unruptured Intracranial Aneurysms (ISUIA) showed that the likelihood of rupture of an aneurysm of <7 mm in diameter is 0.1% per year in patients with no history of SAH. Th e decision to treat will have to be balanced against the likely complications of surgery. T otal mortality and morbidity rates for open surgical repair are 12.6% in patients with no h istory of SAH and 10.1% in patients with previous SAH. Other extrarenal manifestations Pancreatic cysts These occur in 9% of patients aged >20 yea rs. This is not related to pancreatic dysfunction and no treat- ment is required. Cardiac Valvular abnormalities do not generally require valve replacement but, if present, antibiotic prophylaxis should be instituted for invasive procedures. Diverticulitis This has been found mainly in ADPKD patients on dialysis. It tends to be asy mptomatic and its clinical signi \201 cance is unclear. Other cystic phenomena Isolated cysts have been reported in the thyroid, spleen, arachnoid membranes and seminal vesicles of ADPKD patients. These changes are usually asymptomatic an d do not require speci \201 c treatment. CHAPTER 15.3 Autosomal dominant polycystic kidney disease 595 Follow-up Patients are best followed up through a specialist renal or genetics clinic. Gene tic counseling should be made available to all at-risk family members. The management of CK D and its complications should be undertaken according to accepted guidelines for CKD. In f uture, the development of effective early treatment could validate mutation testing in pres ymptomatic individuals. They will need to inform their general practitioner of their risk of having ADPKD and devel oping CKD. Pregnancy Preconception counseling and referral to a specialist renal/ obstetric service sh ould be undertaken. Prenatal diagnosis by chorionic villous sampling (CVS) can be done at t he 9th week of pregnancy. This is not performed routinely due to the high intrafamilial phe no- typic variability. Prenatal screening may be considered in families with one severely a ffected child (early-onset PKD) who have a 45% recurrence risk for subsequent pregnancies. The risk of renal function deterioration and ADPKD- related complications in pregnancy is h igher with: \200 \200 \200 Prognosis Patients are usually asymptomatic until the middle decades but 2 \200\2235% of pa tients present in childhood with signi \201 cant morbidity. By the age of 60 years, 50% o f patients with ADPKD will require renal replacement therapy. Commonly, renal function rema ins normal for decades despite progressive enlargement of kidneys. End-stage renal disease is not inevitable for all patients. Poor prognostic indicators for renal survival are: \200 \200 \200 \200 \200 \200 \200 moderate \200\223severe renal impairment; proteinuria; hypertension. Hypertensive complications including new and worsening hypertension have been reported in 2 5% of patients. Pre-eclampsia occurs in 11% of patients. Pregnant ADPKD patients require cl ose monitoring for infection and hypertension to enable treatment to be started promptly. L iver cysts are likely to enlarge in the context of increased estrogen exposure. male gender; Black race; hematuria before age 30 years; multiple pregnancies; hypertension before age 35 years; proteinuria; PKD1 mutation. Future prospects As our understanding of ADPKD pathophysiology grows, promising candidate d rugs are being developed to treat this disease. Several of these are undergoing clinical tr ials: Vasopressin type 2 (V2) receptor antagonists have been found to inhibit cyst developm ent in animal models. A phase III clinical trial on such a compound (tolvaptan) started in 2007. Octreotide, a somatostatin analog, has been shown to retard the progression of hepati c and renal cyst growth in rat models. It has also been shown to inhibit renal growth in a few patients. Sirolimus slows progression of cyst expansion in rodent models. Phase II clin ical trials of sirolimus and everolimus have commenced. Inhibitors of the protein kinases E rb-B1, MEK and CDK also have potential value in treating ADPKD. ADPKD patients do not have a higher risk of mortality compared with other patients with ESR D. The main cause of mortality is cardiovascular disease (in 36% of cases). Family screening Patients should be advised to inform all at-risk blood rela- tives of the diagnosis and the need for screening. The autosomal dominant inheritance pattern should be explained with advice on methods of presymptomatic diagnosis including the possibility of p renatal diagnosis. Each at-risk individual should be informed of the conse- quences of diag nostic screening. The bene \201 ts and risks of establishing the diagnosis, includ- ing th e possibility of false-negative USS tests in younger patients, should be discussed. Pros for diagnosis Allows early management of complications, particularly hypertension. All ows for family planning. Absence of ADPKD reassures the patient. Further reading Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med 2006; 354: 2122 \200\2232130. Molyneux AJ, Kerr RSC, Yu LM, e t al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus end ovascu- lar coiling in 2143 patients with ruptured intracranial aneurysms: a randomized com parison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm o cclusion. Lancet 2005; 366: 809 \200\223817. Cons for diagnosis Psychological consequences as no speci \201 c treatment or cure is avai lable at present. Insurance and employment issues. If a family member opts not to have scre ening, they should be advised to have yearly checks of: \200 \200 \200 Ong ACM, Harris PC. Molecular pathogenesis of ADPKD: the polycystin complex gets complex. K idney Int 2004; 67: 1234 \200\223 1247. Ravine D, Gibson RN, Walker RG, et al. Evaluatation of ultrasono- graphic diagnostic criter ia for autosomal dominant polycystic kidney disease 1. Lancet 1994; 343: 824 \200\223827. renal function; blood pressure; urinalysis. Rossetti S, Harris PC. Genotype \200\223phenotype correlations in auto- somal dominant and autosomal recessive polycystic kidney dis- ease. J Am Soc Nephrol 2007; 18: 1374 \200\22313 80. C.L. CHOW AND A.C.M. ONG 596 National Kidney Federation: Schrier RW, Belz MM, Johnson AM, et al. Repeat imaging of intracra- nial aneurysms in patie nts with autosomal dominant polycystic kidney disease with initially negative studies: a pr ospective ten year follow up. J Am Soc Nephrol 2004; 15: 1023 \200\2231028. http://www.kidney.org.uk/medical-info/kidney- disease/pckd.html NIH (NIDDK) Information Cle aring House: Takei R, Ubara Y, Hoshino J, et al. Percutaneous transcatheter hepatic artery embolization for liver cysts in autosomal dominant polycystic kidney disease. Am J Kidney Dis 2007; 49: 744 \200\223752. http://kidney.niddk.nih.gov/kudiseases/pubs/ polycystic/ Polycystic Kidney Disease Foundati on: Torres VE, Harris PC. Mechanisms of disease: autosomal dominant and recessive polycystic ki dney diseases. Nature Nat Clin Prac Nephrol 2006; 2: 40 \200\22354. http://www.pkdcure.org Walz G. Therapeutic approaches in autosomal dominant polycystic kidney disease (ADPKD): is there light at the end of the tunnel? Nephrol Dial Transplant 2006; 21: 1752 \200\2231757. See also Polycystic kidney disease in children, p. 586 Tuberose sclerosis and von Hippel \200\223Lindau disease, p. 598 Medullary sponge kidney, p. 664 Nephronophthisis, p. 600 Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracra- nial aneurysms: natural history, clinical outcome, and risks of sur- gical and endovascular treatment. Lancet 2003; 362: 103 \200\223110. Internet resources The Polycystic Kidney Disease Charity: http://www.pkdcharity.co.uk/ This page intentionally left blank H. MORGAN 598 Tuberous sclerosis Introduction Tuberous sclerosis complex (TSC) is a multisystem disease associated with the growth of hamartomatous lesions in multiple organs. A de \201 nitive clinical diagnosis re quires the presence of two major criteria or one major and two minor criteria: Renal involvement Renal involvement occurs in 60% of patients: \200 renal angiomyolipoma (AML)(70 \200\22380%); \200 renal cysts (30 \200\22345%); \200 renal cell carcinoma (4% ). There is a clear genotype/phenotype correlation with TSC2 mutations having a more severe re nal phenotype: \200 \200 Major criteria \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 TSC2 60% AML vs TSC1 22% AML; TSC2 31% renal cysts vs TSC1 15% renal cysts. Cardiac rhabdomyoma. Cerebral cortical tuber. Hypomelanotic macule. Retinal hamartoma. Faci al angio \201 broma. Shagreen patch. Subependymal nodule. Subependymal giant-cell tumor. R enal angiomyolipoma. Ungual \201 broma. Lymphangiomyomatosis. With more numerous and bilateral lesions of both types with TSC2 mutations. Angiomyolipoma These are benign tumors composed of abnormal blood vessels, immature smooth muscle cells and fat cells. They commonly appear by 7 years of age. They may present with f rank hematuria (uncommon occurring in 4 \200\2239%). Life-threatening hemorrhage may occur. Like sporadic cases, AML in TSC are more common and more numerous in females. The presence of multiple AML is a reliable indicator of TSC. They are more likely than not to grow in s ize. They become more vascular as they increase in size. AML >4 cm are at increased risk of hemorrhage, 50% will bleed vs 5% <4 cm. AML are unlikely to develop in an individual who has not developed them by early adulthood. It is unlikely that TSC-related AML progress to carcinoma. Minor criteria \200 \200 \200 \200 \200 \200 \200 \200 Multiple renal cysts. Multiple pits in dental enamel. Hamartomatous rectal polyps. Bone cys ts. Cerebral white-matter radial migration lines. Gingival \201 bromas. Retinal achromic patch. \200\230Confetti \200\231 skin lesions. Epidemiology Incidence: 1 in 6000 to 10 000 live births. Prevalence: 1 in 23 000 from 15 to 45 years Renal cysts Cysts commonly appear by age 9 years. They are often single or small and multip le. A contiguous deletion of TSC2 and autosomal dominant polycystic kid- ney disease (PKD1) on chromosome 16 leads to early- onset polycystic kidney disease. These cysts are numerous and large. Cysts are more often associated with hypertension and renal impairment than AML but the majority are asymptomatic. TSC should always be included in the differential diagn osis of cystic kidney disease. 1 in 97 000 age >45 years. Genetics Autosomal dominant disorder resulting from inactivating mutations in two genes: \200 \200 TSC1 : chromosome 9q34, encoding hamartin; TSC2 : chromosome 16p13, encoding tuberin. More than 200 mutations have been identi \201 ed. \200 26% of patients have mutations in TSC1 ; \200 55% of patients have mutations in TSC2; \200 20% of patients have no identi \201 ed mutation. Renal cell carcinoma The mean age of occurrence is 28 years compared with 53 years in the g eneral population. There are variable histological subtypes; clear cell, papillary, chromop hobe and oncocytomas are reported. A germline (inherited) mutation inactivates one allele and a somatic mutation or loss of he terozygosity inactivates the remaining allele. New mutations (sporadic cases) account for 6 5% of patients. TSC1 and TSC2 proteins function as tumor suppressors; they form heterodimer s that integrate growth factors, nutrients and the cell cycle via the mammalian target of r apamycin (mTOR). Mutations lead to increased activity of mTOR which has a central role in t he control of cell growth and proliferation. Chronic kidney disease Renal impairment is an uncommon initial presentation of TSC (<1%). C KD may occur as a consequence of renal compression by AML, treatment of AML or glomeruloscl erosis but most commonly due to the polycystic phenotype. Overall 1% of patients will devel op ESRD with a mean age of onset of 36 years. The TSC2 polycystic phenotype is more likely to be symp- tomatic and lead to CKD. Clinical features Most patients are identi \201 ed due to central nervous system (CNS) dis ease (epilepsy or learning dif \201 culties) and skin lesions. Renal manifestations are of ten identi \201 ed during screening. CHAPTER 15.4 Tuberous sclerosis 599 Investigations Renal angiomyolipoma AML need to be 0.4 \200\2230.5 cm in diameter to be rel iably detected on USS. They are seen as hyperechoic lesions, equal to renal sinus fat. Fat is an important identifying feature of AML. On CT scan there should be attenuation equal to that of subcutaneous fat and no enhancement with contrast. MRI scans show high signal on T 1-weighted images. Diagnostic dif \201 culty can arise due to fat-poor AML that resemble c arcinoma on imaging. In cases of diagnostic doubt, surgical exploration should be considere d, not percutaneous biopsy. There is a signi \201 cant risk of bleeding from vascular AML and seeding of malig- nant tumors. Indeterminate AML on imaging studies often have indeter- minate pathology and may be mistakenly diagnosed as malignant lesions. In female patients aged >16 years AML are associated with pulmonary lymphangiomyomatosis. Due to the signi \201 cant morbidity, lung function and chest imaging should be undertaken. Renal transplantation There is no signi \201 cant increased risk of malignancy. In the lim ited number of reported patients followed long term, no malignancy occurred. The native kid neys do not need to be removed before transplant. There is no evidence that neurological fe atures worsen after renal transplantation. Follow-up Baseline renal USS should be performed in all patients before 5 years. If normal it should be repeated every 2 \200\2233 years. If abnormal it should be repeated every 12 m onths. If suspicious of carcinoma, MRI or CT is required and this should be repeated after 6 months. Prognosis Overall life expectancy is normal. Renal manifestations are the second most commo n cause of death after complica- tions of CNS disease. Progression of AML and cysts is dif \201 cult to predict but lesions become more numerous with age. Renal lesions may develop in adulthood after normal imag- ing in childhood (3% of cases with renal involvement). Morb idity from renal involvement is low, <10% require intervention.