Chronic tubulointerstitial nephritis exists as a distinct diagnosis (drug-induced AIN of an y cause may progress if exposure is not limited or the underlying condition is not treated) but chronic tubulointerstitial injury is a feature of progressive CKD of any cause, includ ing glomerulo- nephritis ( b p. 200). Causes \200 Drugs (NSAIDs). \200 Re \202 ux nephropathy ( b p. 712). \200 Sarcoidosi s. \200 TB. \200 Autoimmune diseases (Sj gren \200\231 s syndrome). \200 Metaboli c causes, e.g. chronic d K + (e.g. in anorexia nervosa). \200 Heavy metals (see b p. 583) . \200 Balkan endemic and Chinese herbal nephropathies. Clinical features \200 Impaired urinary concentration (nocturia, polyuria). \200 Often normal BP (due to relative salt-losing state). \200 LMW tubular proteinuria (e.g. B 2 mic roglobulin). \200 Glycosuria (impaired tubular handling) 9 renal tubular acidosis. \200 CKD. \200 Small, symmetrical kidneys on USS (exception: re \202 ux nephropathy where asymmetry is common). Investigations MSU for M,C+S, EMU for AFB, uPCR or uACR (proteinuria often <1g/day), U&E, b one pro \201 le (? i Ca 2+ ), serum ACE, ANA, anti-Ro/La, USS kidneys. Lithium-induced nephropathy (See b p. 904.) Balkan endemic nephropathy (BEN) Affects men and women >30 years old inhabiting lands drain ed by the Danube River. Characterized by tubulointerstitial atrophy and scarring. Cause rem ains unknown. Patients are usually normotensive, with a urinary concentrating defect (polyu ria), and may have LMW tubular proteinuria (<1g/day) and glycosuria. USS shows small, symme trical kidneys. There is an increased incidence of transitional cell carcinoma of the entir e urinary tract; new haematuria should be fully investigated, and urine cytology is recomme nded at least annually. CHRONIC TUBULOINTERSTITIAL DISEASE 583 Chinese herb nephropathy (b p. 901) A histological disorder similar to BEN, with tubulointe rstitial scarring and glomerular sparing as the principal features. Appears to be due to ar is- tolochic acid, an ingredient in many Chinese herbal preparations (notably as a slimming agent). Clinical presentation and histology are so similar to BEN that a similar etiology has been suggested, although this remains to be proven. The incidence of urothelial maligna ncies is very high, and sur- veillance is mandatory. In those considered for transplantatio n after ESRD, bilateral native nephrouretectomy is often recommended to reduce the risk of malignant disease following immunosuppression. Lead nephropathy Exposure to lead, including occupational, may cause chronic poisoning, wit h progressive tubulointerstitial nephritis. Tubular injury results in decreased urate excre tion with hyperuricaemia and gout. At-risk indi- viduals with unexplained CKD, associated w ith high serum urate con- centrations, should be assessed for total lead burden by either b one X-ray \202 uorescence or an EDTA lead chelation test. Treatment includes long-term le ad depletion with EDTA or DMSA. Lead has also been shown to be a risk factor for progression of CKD of other causes. Cadmium exposure causes a similar nephropathy. Salt-losing nephropathy \200 Refers to inappropriate renal losses of sodium (and thus) wa ter. \200 It generally occurs in the context of chronic tubulointerstitial disorders. Losses rarely exceed 100mmol Na + (2 \200\223 3L/day), as increased delivery of Na + to th e macula densa causes protective afferent arteriolar vasoconstriction with d GFR (so-called \200\230 tubulo-glomerular feedback \200\231). However, hypovolaemia and hyponatraemia can be clinically signi \201 cant, if untreated. Management: appropriate \202 uid and salt intake. Dietary input may suf \201 ce for the latter. If not, salt supplementation. CHAPTER 7 Diseases of the kidney 584 Analgesic nephropathy Introduction Analgesic nephropathy (AN) was \201 rst described afte r chronic phenacetin use (a pro-drug of paracetamol). Fortunately, it has declined in preva lence over the last 3 decades from 7 3% to 7 0.2%. The use of c ombination analgesic preparations now accounts for most cases (e.g. paracetamo l + codeine, or paracetamol + aspirin). Aspirin alone will not usually cause AN, although p aracetamol, if used in suf \201 cient quantities, might (>2kg cumulatively; equivalent to about 8 years of daily full-dose ingestion). Renal injury begins with ischaemic changes in the medulla, progress- ing to tubulointerstit ial scarring, glomerulosclerosis, and papillary necrosis ( b p. 585). (See Fig. 7.9 ) Analgesic nephropathy is also associated with accelerated atherosclero- sis, although the mechanism is unclear. Fig. 7.9 Irregular, ragged renal outline, characteristic of analgesic nephropathy. Reproduc ed with permission from Davison AMA, Cameron JS, Grunfeld J-P, et al . (2005) Oxford Textbo ok of Clinical Nephrology . Oxford University Press, Oxford. Symptoms and signs A history of analgesic use may be dif \201 cult to elicit: suspect if c hronic pain syndromes, such as headaches or backache. Dyspepsia is common. Nocturia and pol yuria (loss of concentrating ability), episodic colicky \202 ank pain, and frank haematur ia due to papillary necrosis (sloughed papillae) may occasionally be evident in the urine. i BP, as CKD develops. Investigations Urine dipstick often bland or modest proteinuria only. Sterile pyuria on uri ne microscopy. d Hb, i SCr, and d eGFR. Classical IVU appearances historically (small kidne ys with clubbed calyces), but CT is now preferred. ANALGESIC NEPHROPATHY 585 Management Stop all analgesics. This is often extremely dif \201 cult, but reducing the an al- gesic burden slows disease progression (those who continue have a 6-fold risk of reachi ng dialysis or death in an observational study of 78 patients). 1 The input of a specialist pain management team is highly desirable. 2 Surveillance for urothelial malignancies (transitional cell carcinoma occurs in up to 10% of con \201 rmed cases of analgesic nephropathy). May be multiple, in unusual sites, or e ven bilateral. New haematuria merits full urological investigation. Annual urine cytology i s a useful screening tool. Papillary necrosis The end result of chronic medullary hypoxia: vulnerable papillae suffer a further (acute) ischaemic injury, undergo necrosis, and are shed into the renal pelvis. Clinical presentation \200 May be asymptomatic. \200 Colicky \202 ank pain (as the pa pilla traverses the ureter). \200 Visible passage of a papilla (or part thereof). \200 Frank haematuria. \200 Unilateral ureteric obstruction. CT may show calci \201 ed papillae and an irregular renal contour. Historically, IVU showe d contrast tracking into eroded papillae and ring shadows around detached papillae 9 calci \201 cation. Causes of papillary necrosis \200 Analgesic nephropathy. \200 Diabetes me llitus. \200 Post-obstructive uropathy. \200 Sickle cell nephropathy. \200 Tuberculos is. \200 Severe acute pyelonephritis. Reference 1. Mackinnon B, Boulton-Jones M, McLaughlin K (2003). Analgesic-associated nephro pathy in the West of Scotland: a 12-year observational study. Nephrology Dialysis Transplan tation , 18, 1800 \200\2235. CHAPTER 7 Diseases of the kidney 586 Renovascular disease Introduction Renovascular disease (RVD) refers to diseases of the larg e, medium-sized, and small renal vessels (excluding vasculitis). Atherosclerotic renal arte ry stenosis (ARAS) and \201 bromuscular dysplasia (FMD) predominantly affect the larger v essels. The umbrella term \200\230 ischaemic nephropathy \200\231 is used to describe vas culopathy involving small intrarenal vessels. ARAS and ischaemic nephropathy Increasing incidence with i age ( 9 7% in people aged >65) a nd in those known to have atherosclerotic disease elsewhere ( 9 50% if known PVD). However, anatomic ARAS may be haemodynamically unimportant and is associated with i BP in only 50% of cases. Generally, any stenosis >70% tends to be functionally signi \201 cant, as is bil ateral ARAS or disease in an artery to a single functioning kidney. Patients with ARAS or i schaemic nephropathy have a substantial excess risk for CV death (MI and stroke). ARAS shou ld be suspected in older patients with clinically evident peripheral, coronary, or cerebrov ascular atherosclerotic disease, or those with known risk factors (dyslipidaemia, smoking, diabetes, i BP). Clinical presentation \200 i BP \200\224 often resistant to treatment (i.e. >140/90mmHg on three drugs). Renal dysfunction. \200 i SCr or d eGFR of up to 20% with ACE-I or ARB. \200 Fluid rete ntion, often diuretic-resistant. Pathophysiology Atherosclerotic plaque involves the ostium or proximal 2cm of the renal art ery, often extending from the aorta. Renal disease is caused by a fall in perfusion, result ing in sympathetic overactivity and renin release. This leads to overproduction of A2 ( l v asoconstriction) and aldosterone release ( l salt and water retention). The pro- \201 brotic actions of these factors, in combination with hypoxia, drive a comple x cellular activity termed epithelial-mesenchymal transi- tion (EMT). An essential process developmentally; EMT involves loss of epithelial cell apico \200\223 basal polarity and ce ll \200\223 cell adhesion characteristics. Cells become motile and acquire a \201 brobla st phenotype. EMT underpins progressive renal \201 brosis and scarring, with loss of func tioning tubules ( l CKD clinically). Symptoms and signs \200 Evidence of central or peripheral vascular disease is perhaps the most important clinical \201 nding. i BP, peripheral oedema, pulmonary congestion, abdominal bruits (low predictive value in isolation), palpable AAA. Generally, bland urine on dipstick or low-grade proteinuria only (e.g.<1g/day). This can be a helpful clinical clue, although the development of s FSGS may lead to higher levels. RENOVASCULAR DISEASE 587 Flash pulmonary oedema refers to sudden, often episodic, pulmonary oedema, with i BP and without any precipitating cardiac event (or in the context of relativ ely normal LV function). It is caused by exaggerated activity of the RAAS ( l acute salt an d water retention and volume overload). Probably overdiagnosed: thorough cardiac assessment is mandatory. Loin pain, a sudden decline in renal function, and new haematuria may indicate renal infarction. Investigations (See Fig. 7.10) \200 SCr, eGFR, U&E (? d K + due to i aldosterone), lipids . Plasma renin will be high, but this is therapeutically unhelpful. Urine dipstick, uPCR or uACR. \200 Evidence of vascular disease elsewhere, e.g. ECG. \200 Potential imaging includes: USS kidneys for renal size and symmetry. A difference of >1.5cm in renal length is suspicious. CT angiography is increasingly sensitive for ostial lesions. \200 MRA. However, gadoliniu m-enhanced MRA is relatively contraindicated in individuals with a GFR <30mL/min ( b p. 51). MR also tends to overestima te the extent of a stenosis. Newer MRI software is enabling non-gadolinium MRA scanning. Duplex USS with Doppler examination. Resistive index (RI) is a surrogate for impeded \202 ow. Only useful in experienced hands. Captopril isotope scintigraphy. With captopril, affected kidneys may show a 30% decline in GFR using DTPA or MAG-3 ( b p. 54). \200 Formal angiography. Remain s the gold standard for diagnosis and allows endovascular intervention. High index of suspicion CT or MR angiography Choice of test based on local radiolgy expertise RAS proven Test equivocal RAS excluded Consider angiogram ((cid:2) stent?) Alternative imaging Stop Fig. 7.10 A suggested algorithm for the investigation of suspected ARVD. CHAPTER 7 Diseases of the kidney 588 Management of ARAS General management ARVD is associated with a 16% PA mortality risk, pred ominantly attribut- able to associated CVD. Modi \201 cation of CVD risk factors is 6 a pr imary objective: stop smoking, exercise, healthy diet, statins. Consider aspirin 75mg od. Control BP Aim for <130/85mmHg, using non-ACE-I/ARB drugs, for example: \200 Calcium chan nel blocker or B -blocker. \200 Early use of loop diuretics titrated vs response (e.g. fu rosemide 40 \200\223 160mg daily) can be effective, as i BP is driven by salt and water overload. Further management The primary goal is to prevent loss of renal function. Two treatment opt ions exist, conservative or interventional. Selection can be dif \201 cult. Interventional management \200 Includes percutaneous transluminal renal angioplasty (PTRA ) 9 stenting and surgical revascularization. PTRA alone is associated with a high incidence of restenosis \200\224 stenting is 6 widely advocated. However, the ASTRAL trial ( b p. 589) has suggested only a limited role for interventional management. The selection of candidates who may bene \201 t from intervention is dif \201 cult and without a robust evidence base. However, many clinicians would consider such a strategy in the following situations: \200 Bilateral critical ARAS or critical ARA S to a single functioning kidney. ARAS that is known to be of recent onset. \200 Refractory i BP and volume overload. \200 Flash pulmonary oedema ( b p. 587). \200 Rapidly deteriorating renal function. Other factors to consider if an interventional approach is considered: The stenosis should be high grade (>70%). \200 The kidney(s) should be >7.5cm in length, implying meaningful nephron mass and 6 potentially salvageable renal function. \200 The a bsence of scars on 99m Tc-DMSA isotope scintigraphy may usefully predict recoverable renal function. The presence of heavy proteinuria may imply hyper \201 ltration injury and s FSGS in a scarred kidney ( b p. 562). The risk of cholesterol emboli, arterial dissection (with potential limb injury), and contr ast-induced AKI ( b p. 148) should be weighed against potential bene \201 ts. Surgical revascularization is usually reserved for those undergoing simul- taneous aortic surgery. MANAGEMENT OF ARAS 589 Conservative management \200 Given the pathophysiological importance of A2, a trial of AC E-I/ARB is often warranted under close supervision. ACE-I/ARB will reduce CV risk and may r etard progression of CKD. They will also block A2-mediated vasoconstriction and \201 bros is. 2 However, they will also drop renal perfusion pressure and may precipitate AKI. \200 (cid:2) Patients must be adequately hydrated (check for postural drop). \200 Start with low dose, and measure SCr regularly, e.g. alternate days. \200 Increase dose, according t o BP, if no deterioration in renal function ( i SCr or d eGFR >20% from baseline). Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial ASTRAL is the largest tria l, to date, of PTRA + stenting + medical therapy vs medical therapy alone; 806 patients wer e randomized in an unblinded fashion. Primary endpoint Slope of the reciprocal creatinine plot. Secondary endpoints Time to renal and major adverse cardiovascular events (MACE), BP, and m ortality. Results A borderline signi \201 cant difference (p = 0.06) in the slope of the reciprocal creatinine plot between the two groups. However, this trans- lated into a clinically meanin gless 1.6 mol/L (0.02mg/dL) difference in SCr between the intervention and medical thera py groups. No signi \201 - cant improvements in BP or reductions in renal adverse events, MACE, or mortality were seen. Conclusion Revascularization offered no bene \201 t over medical therapy in the management of ARAS but was associated with an increased risk of morbidity (two procedural related dea ths and three limb amputations). Caveat There is a consensus view (non-evidence-based) that individu- als with \202 ash pu lmonary oedema, high-grade bilateral stenosis (or a high-grade stenosis affecting a single functioning kidney), or those pre- senting with AKI should be offered intervention. Such sc enarios were probably underrepresented in the ASTRAL cohort. ASTRAL Investigators (2009). R evascularization versus medical therapy for renal-artery stenosis. New England Journal of M edicine , 361 , 1953 \200\223 62. CHAPTER 7 Diseases of the kidney 590 Other renovascular diseases Fibromuscular dysplasia (FMD) Affects asymptomatic young women (15 \200\223 50 years), often with i BP. Renal function is generally normal. Much less com mon than ARAS. True prevalence in both normotensive and hypertensive populations unknown. C haracterized by arterial \201 broplasia that may affect many vascular beds (intracranial, carotid, coronary, and limb). Pathogenesis unknown. A genetic predisposition operates in s ome (with autosomal dominant inheritance). Often involves both renal arteries, classically affecting the mid-distal renal portion of the vessel (rather than the ostium in ARAS). Angiography shows a \200\230 string of beads \200\231 appearance with normal-caliber vess els on either side (see Fig. 7.11). i BP of FMD may be cured (with- drawal of all drugs) or improved by angioplasty, particularly in woman <50 years with i BP of <8 years \200\231 d uration and with few stenoses in other arterial beds. Renal vein thrombosis (RVT) RVT is usually found in association with the nephrotic syndrome (particu- larly membranous nephropathy, b p. 564) when it may be uni- or bilat- eral. It i s very rare without some form of concomitant hypercoagulable state. It may be seen in assoc iation with tumors, esp. renal cell carcinoma, where there is invasion and distortion of th e renal vein. May present as: pulmonary emboli, renal infarction (loin pain, haematu- ria, i SCr, i AST, and i LDH). Contrast-enhanced CT angiography/venography or Doppler USS (operator-dependent) of the rena l veins should be diagnostic. Proven RVT should be treated with anticoagulation. Cholesterol emboli May cause partial occlusion of the small renal vessels, with downstream ischaemia. Showers of emboli may present suddenly as AKI or, more com- monly, as a gradual decline in renal function. Characteristically occurs in elderly patients known to have exte nsive atherosclerosis who undergo endovascular intervention (particularly aortic). It is an important differen- tial diagnosis of contrast-induced AKI ( b p. 148). Anticoagulation (a nd thrombolysis) are also risk factors. Patients may also develop embolic infarcts in other end-arterial ter- ritories, including d igits, retina, GI tract, and skin ( l livedo reticularis). The urine is usually bland (alth ough proteinuria may occur over time). Eosinophilia, eosinophiluria, and d C3/C4 may be pre sent. Renal biopsy shows characteristic intravascular clefts where cholesterol emboli were present before tissue preparation. No speci \201 c therapy is helpful, although aggressive CV risk factor management, including BP and cholesterol, may improve patient survival. Ren al prognosis is often poor. OTHER RENOVASCULAR DISEASES 591 Fig. 7.11 Digital subtraction angiogram demonstrating \200\230 beaded \200\231 appearance of the renal artery in FMD. CHAPTER 7 Diseases of the kidney 592 Autosomal dominant polycystic kidney disease (ADPKD) Introduction ADPKD is the most common inherited kidney disease, affecting 7 1:800 live births. It is responsible for 5 \200\223 10% patients in an ESRD program. Inheritance ADPKD is inherited in an autosomal dominant manner. Mutations in the genes PKD- 1 (located on chromosome 16) and PKD-2 (chromosome 4) result in defective synthesis of the proteins polycystin-1 and -2, respec- tively. Both polycystin-1 and -2 are ubiquitously exp ressed by epithelial cells throughout the body. PKD-1 mutations are seven times more com- m on than PKD-2 and associated with more aggressive disease (onset of ESRD, on average, 15 ye ars earlier). Pathophysiology Polycystin-1 is a membrane receptor signaling protein that co-localizes wit h polycystin-2 (a calcium-permeable channel) within the cilia of renal collecting duct epit helial cells. This polycystin complex acts as an extra- cellular mechanosensor (luminal \202 ow disturbs the cilia and triggers the apparatus) that assists in the regulation of ce ll proliferation, adhesion, dif- ferentiation, and maturation ( l all ultimately maintain t ubular integrity and caliber). Failure of normal polycystin complex formation results in dy sregulated cell turnover and uncontrolled cell proliferation in response to growth factors. Proliferating tubular cells form tubular cysts that close off the associated nephron and e xpand in size over time. It is estimated that <1% of nephrons undergo such cystic transforma- tion. However, local t issue ischaemia and pro- \201 brotic cytokine release drive a process of EMT ( b p. 586), resulting in scarring and ultimately progressive CKD. Clinical presentation Patients may present with a family history of ADPKD. A careful histor y for renal disease, i BP, stroke (intracranial hemorrhage), or premature death may pinpoin t carriers of the gene mutation. Inheritance is autosomal dominant, so 50% of offspring sho uld be affected. 2 Importantly, 25 \200\223 40% of new patients will have no family history. Patients being investigated for ADPKD should be given information about the disorder before and after testing. Clinical features include: \200 Flank or loin pain arising from large cysts. Acute pain m ay suggest cyst rupture or bleeding. Dipstick-positive haematuria 9 episodic frank haematuria. \200 i BP. \200 Nocturia and polyuria (loss of urinary concentrating ability). \200 Low-grade proteinuria may be prese nt (usually <1g/day). \200 If presenting late, uraemic symptoms ( b p. 212). AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) 593 Investigations USS remains the investigation of choice. As ADPKD is an evolving disease, th e timing of the scan is important. In otherwise asymptomatic at-risk indi- viduals, USS sho uld be performed after age 20 to improve negative pre- dictive value. For con \201 rmation of diagnosis, the Ravine criteria are useful (see Table 7.4). Table 7.4 Ravine criteria Age +ve family history \200\223 ve family history <30 years 2 cysts in either kidney 5 cysts in either kidney 30 \200\223 60 years 4 cysts in either kidney 5 cysts in either kidney >60 years 8 cysts in either kidney 8 cysts in either kidney 2 Valid for PKD-1 mutation alone. PKD-2 mutations present later, so these criteria tend to give false negative results. Other radiological features Increased renal size is common (often >20cm in length). Cysts i n other organs (liver, pancreas, spleen) may also be present and helpful to differ- entiate ADPKD from multiple simple cysts. (See Fig. 7.12 ) Genetic testing Is available through specialist centers but is not currently widely used. I t has accuracy rate >95% for ADPKD1 and ADPKD2. An important indica- tion would be a young adult with a negative USS who is under considera- tion as a potential kidney donor. Fig. 7.12 Contrast-enhanced CT scan of a patient demonstrating the number, size, and locati on of the cysts in the anterior portion of the left kidney and the posterior aspect of the right kidney. Reproduced with permission from Watson ML, Torres VE (eds) (1996) Polycystic Kidney Disease , p. 214. Oxford: Oxford University Press. CHAPTER 7 Diseases of the kidney 594 ADPKD: complications and treatment Hypertension i BP may be the \201 rst presentation of ADPKD, affecting 7 60% of those with normal renal function. It is thought to be s to increa sed renin genera- tion in ischaemic renal tissue compressed by expanding cysts. Meticulous BP control (aiming for target BP <130/80mmHg) is important to protect an often young cohort of patients from progressive end-organ damage. Although proteinuria is not a dominant feat ure of the disease, ACE-I/ARB are still favored as \201 rst-line therapy, with escalation to other agents, as necessary ( b p. 204). CKD Although many patients with ADPKD will never reach ESRD, progressive CKD is nonetheless common. Males diagnosed at a younger age, early i BP, large kidneys, black race, and the P KD-1 mutation have a worse renal prognosis. At ESRD, ADPKD patients enjoy better survival following dialysis and transplantation than t he non-ADPKD ESRD population, re \202 ecting a younger age and lower burden of CV disease in this group. Cyst hemorrhage Presents with unilateral \202 ank pain of abrupt onset 9 haematuria (if t he cyst communicates with the urinary space) (see Table 7.5). Management is conservative, w ith hydration and analgesia. Individuals with a history of repeated cyst hemorrhage have an earlier onset of ESRD. Recurrent hemorrhage may sometimes necessitate nephrectomy (either bilateral or unilateral). Cyst infection Flank pain, fever, and systemic upset (see Table 7.5 ). Culture blood and ur ine, and give a prolonged course of antimicrobials (according to sensi- tivities, but cipro \202 oxacin and co-trimoxazole have good cyst penetration). CT, 99m Tc-cipro \202 oxacin , and PET scanning may demonstrate infected cysts if there is doubt regarding the source of infection. Recurrent cyst infection may sometimes necessitate nephrectomy (either bilatera l or unilateral). Nephrolithiasis 20% of ADPKD patients have associated renal stones, usually uric acid or ca lcium oxalate. Diagnosis is best made with CT scanning ( b p. 716). Intracranial aneurysms (ICAs) 4 \200\223 10% of ADPKD patients have ICAs. Speci \201 c mu tations appear to pre- dispose to aneurysm formation, so certain family pedigrees may have a positive history. Such families merit screening with MRA. Symptomatic ICAs or those >10mm diameter need surgical intervention, but the opti- mal management of asymptomatic ICAs of <10mm is less certain. Rupture presents as subarachnoid hemorrhage, most commonly in patien ts age <50 years with poor BP control (50% mortality or severe disability). ADPKD: COMPLICATIONS AND TREATMENT 595 Table 7.5 ADPKD: hemorrhage, infection, or stone? Hemorrhage 9 9 ++ Infection Stone 9 \200\223 Fever ++ Leucocytosis ++ Frank haematuria \200\223 + Renal colic _ \200\223 + +ve blood cultures _ + \200\223 Extrarenal cysts Hepatic, splenic, pancreatic, mesenteric, and in the seminal vesicles. Occ ur in 10 \200\223 40% (most commonly multiparous women). Liver cysts rarely inter- fere wi th synthetic liver function but can cause biliary obstruction. Large cysts may cause epigas tric fullness and abdominal discomfort. Needle puncture or surgical de-roo \201 ng may be possible. Other manifestations Mitral valve prolapse and aortic regurgitation, diverticular disease, and hernias are more common in patients with ADPKD. Clinical trials and potential future treatments \200 A better understanding of the pathog enesis of ADPKD has offered hope for future therapies that might ameliorate cyst developmen t. \200 As cyst formation begins in utero , such interventions would require ADPKD diagnosis and treatment from an earlier age. Experimental therapies have shown promise in both animal models and human pilot studies. These include: \200 Vasopressin receptor antagonists to d cyst f ormation (via d cAMP). mTOR inhibition (or paclitaxel) to reduce cell proliferation. \200 Antagonism of epiderma l growth factor. \200 Long acting somatostatin analogs. However, it can be dif \201 cult to select appropriate outcome measures in clinical trials that aim to assess such therapies \200\224 given the length of time it takes to develop C KD and eventual ESRD (if at all), a very long follow-up period is required. Two clinical trials involving mTOR inhibition have failed to show a bene \201 cial effect on GFR (although one did demonstrate a reduction in cyst growth with everolimus). The CRISP study demonstrated that a combination of kidney and total cyst volume, as determi ned by MRI, is negatively associated with GFR. Many trials now use such volumetric assessme nts as outcome measures. It is hoped that risk strati \201 cation for progressive CKD may identify a subpopulation of patients who will bene \201 t the most from interventions to retard cyst growth (and 6 be the ideal participants in future clinical trials). CHAPTER 7 Diseases of the kidney 596 One such risk factor for progressive CKD is increased 24h urine osmolality. Animal studies have suggested that ADH may have a role in cyst growth, so V2 receptor blockade could be of therapeutic bene \201 t. This is the subject of ongoing clinical trials; e.g. the vasopre ssin V2 antagonist tolvaptan has been shown to slow progression of ADPKD in a 3-year, multi -center, blinded study of 71500 patients, halving the rate of kidney volume expansion and s lowing GFR reduction by 30%. However, safety concerns (particularly regarding liver toxicit y) mean it is not yet approved for this indication. A recent 3-year study suggested that the somatostatin analog called octreotide long-acting release (LAR), delivered as a monthly IM injection,might redu ce kidney and cyst volume and slow CKD progression2. SE: common (including cholecystitis). Reference 2. Caroli A, Perico N, Perna A, et al, for the ALADIN study group. Lancet . Aug 2 0 2013. ADPKD: COMPLICATIONS AND TREATMENT 597 CHAPTER 7 Diseases of the kidney 598 Other cystic kidney diseases Simple cysts (see b p. 742) Solitary or multiple renal cysts a re common in the elderly: 50% of those aged 50 years or more have one or more such cysts. S o-called \200\230 simple \200\231 cysts are usually asymptomatic and are found on imaging the urinary tract for other reasons. Simple cysts have no further signi \201 cance \200 \224 complex (echoic) cysts need detailed evaluation by CT scanning to exclude malig- nancy (see b p. 742 \200\2233). Acquired cystic disease Acquired cysts refer to cysts arising in the context of advanced CK D and widespread tubulointerstitial scarring. They can be multiple and bilateral and may be confused with ADPKD. Unlike ADPKD, acquired cysts occur in scarred and thus small kidneys, and are rarely >2 \200\223 3cm in size (most are 5mm). Age at presentation, family his tory, presence of i BP, and site of the cysts on imaging can help discriminate the various cystic renal diseases (see Table 7.6). Table 7.6 Classi \201 cation of cystic kidney diseases Age Family history CKD 9 + BP Site ADPKD Any ++ 9 _ + Cortex Juvenile PKD <10 + 9 _ Cortex Simple cysts >65 _ Cortex Medullary sponge kidneys Any _ _ Medulla Medullary cystic kidneys 20 \200\223 30 ++ ++ \200\223 Medulla Nephronophthisis <15 + ++ \200\223 Medulla Autosomal recessive polycystic kidney disease (ARPKD) Caused by a rare mutation of the PKHD 1 gene (located on chromosome 6) encoding polyductin. It is a disease of infancy and childh ood, present- ing with polycystic kidneys, progressive CKD, congenital hepatic \201 brosi s, and portal hypertension. It is much less common than ADPKD (estimated prevalence 1:20,00 0 live births). Juvenile nephronophthisis A recessively inherited condition ( 7 1 in 50,000), characterized by cystic change and tubulointerstitial \201 brosis, presenting in early childhood (age >1 year) and leading to ESRD in adolescence. Mutations in at least \201 ve NPHP loci have been described, most commonly NPHP1 (associated with earlier onset). Imaging characteristi cally reveals echo-bright kidneys with a few corticomedullary cysts. Clinical features: pol ydipsia and polyuria but often presents as ESRD. Unlike medullary cystic kidney disease, ex trarenal OTHER CYSTIC KIDNEY DISEASES 599 manifestations, including oculomotor apraxia, hypoplasia of cerebellar vermis (Joubert \200\231 s syndrome), developmental delay, bone abnormalities (cone-shaped epiphyses), situ s invertus, and hepatic and portal \201 brosis) also occur. May also be associated with r etinitis pigmentosa in the Senior \200\223 L ken syndrome. Medullary sponge kidney A common, benign condition characterized by diffuse medullary cyst for- mation. It is a developmental, rather than a genetic, anomaly. Clinically, there is no family history, and patients are usually identi \201 ed either inci- dentally or when inv estigated for UTI or stones (see Table 7.7). Impaired calcium handling in the collecting du cts predisposes to formation of calcium-containing stones (often in cysts). Consider the di agnosis in young patients presenting with calcium stones. Haematuria (microscopic or gross) and recurrent UTIs may also complicate the disorder. Diagnosis is made on imaging; traditi onally IVU (typical \200\230 calyceal brush \200\231 ), now CT. Renal impairment is very rare, and management should be directed at infection and prevention of stone formation. Medullary cystic kidney disease Autosomal dominant inheritance, presenting in early adultho od with pro- gressive renal impairment. The affected genes MCKD-1 and \200\223 2 encode ke y signaling proteins in the renal cilia. Small cysts (1 \200\223 10mm) form at the cortico medullary junction, with associated tubulointerstitial in \202 ammation and scarring (glom eruli are unaffected). Affected individuals have a positive family history and present with nocturia, polydipsia, and polyuria (impaired concentrating ability). Urine dipstick is usu ally bland and BP often normal (there may be relative salt loss) (see Table 7.7). Investiga tion shows small to normal-sized kidneys on USS. CT may demonstrate the cystic change. Impa ired urate excretion and hyperuricaemia ( 9 gout) may occur. Renal function usually decline s to ESRD by age 60. No speci \201 c therapy available. Correction of salt and water deple tion may be necessary. Table 7.7 Sponge or cystic kidney disease? Medullary sponge kidney Medullary cystic kidney disease Age Any 20 \200\223 30 years CKD and ESRD \200\223 ++ (ESRD age <60) Salt-losing state \200\223 ++ Calcium stones ++ \200\223 UTI + \200\223 +ve family history \200\223 + CHAPTER 7 Diseases of the kidney 600 Tuberous sclerosis A multisystem disease associated with the growth of hamartomatous lesion s in multiple organs. Caused by mutations in the TSC1 (9q34) and TCS2 (16p13) tumor suppres sor genes. TSC2 (more common) lies adja- cent to PKD-1 , suggesting a role for PKD-1 in the development of cystic disease in some patients with tuberous sclerosis. Predominantly a ne uro- logical (presenting with epilepsy and developmental delay) and skin (e.g. facial angio \201 broma, shagreen patches, ungula \201 bromata) disease, but there are a number of c haracteristic renal features. \200 Angiomyolipomata: these benign hamartomas are present in 7 80% from early childhood. They can be a cause of signi \201 cant bleeding (requiring embolization) and ocassionally obstruction. Cystic disease: 7 20% patients have simple cysts, while 7 5% have polycystic disease that may be associated with progression to ESRD. Renal cell carcinoma: <1%. Suspect if angiomyolipoma changes appearance during surveillance. Management: Monitor BP, SCr, and eGFR (particularly if polycystic disease). \200 Renal USS annually 9 CT, as necessary. Angiomyolipomata have a characteristically high fat content. Refer to a specialist unit. Bardet \200\223Biedl syndrome AR inheritance ( 7 1 in 140,000) but genetically heterogeneou s, with muta- tions in at least 12 BBS loci described. Presents in childhood with short sta ture, weight gain, polydactyly, progressive visual loss, hypogonadism, i BP, CKD, and genit al abnormalities in \231\200 . Diabetes mellitus may occur later. Renal abnormalities in > 90%: fetal lobulation, calyceal cysts and club- bing, cystic dysplasia, and VUR. Progressiv e CKD in a minority. Lawrence Moon is similar, with additional spinocerebellar degeneration Other syndromes For renal disease associated with other syndromes, see Table 7.8. OTHER CYSTIC KIDNEY DISEASES 601 Table 7.8 Renal disease associated with syndromes Associations and renal anomalies Renal anomaly Clinical \201 ndings VATER and VACTERL 40% unilateral agenesis, others varied Vertebral defects, anal atresia, tracheoesophageal \201 stula with oesophageal atresia, a nd radial dysplasia (VATER) with cardiac malformations and limb anomalies (VACTERL) CHARGE Dysplasia Coloboma, heart defects, atresia (choanal), retarded growth and development, genital and ea r anomalies COACH Cystic dysplasia Cerebellar vermis hypo/aplasia, oligophrenia, ataxia, coloboma, and hepatic \201 brosis Chromosomal abnormalities Trisomies and deletions Variable and common Variable Turner and Noonan Variable structural anomalies Short stature, webbed neck, heart defects Supravalvular aortic stenosis, multiple peripheral pulmonary arterial stenosis, el \201 n face, mental and statural de \201 ciency, characteristic dental malformation Infantile hypercalcaemia with nephrocalcinosis, renal agenesis, pelvic kidney, renal artery stenosis, hypertension Williams (microdeletion chromosome 7) Varied Hypocalcemia arising from parathyroid hypoplasia, thymic hypoplasia, and out \202 ow tract defects of the heart DiGeorge (microdeletion chromosome 22) Single gene defects Meckel \200\223Gruber (AR) Cystic dysplasia Encephalocele, hepatic ductal dysplasia and cysts and polydactyly Cystic dysplasia Severely constricted thoracic cage and respiratory insuf \201 ciency, cysts in the liver a nd pancreas, retinal degeneration, short limbs, abnormal pelvis Jeune (asphyxiating thoracic dystrophy) (AR) Joubert (AR) Cystic dysplasia Cerebellar vermis hypoplasia, dysregulation of breathing pattern and eye movement, developm ental delay, retinal dystrophy Senior \200\223L ken (AR) Renal dysplasia or nephronophthisis Mutations in genes causing nephronophthisis may also cause retinitis pigmentosa or retinal aplasia, consistent with Leber amaurosis. (Continued) CHAPTER 7 Diseases of the kidney 602 Table 7.8 (Continued) Associations and renal anomalies Renal anomaly Clinical \201 ndings Bardet \200\223Biedl (AR) Abnormal calyces (on Retinal dystrophy, polydactyly, mental retardation and obesity IVP), renal dysplasia Lawrence \200\223Moon (AR) Renal dysplasia Similar to Bardet \200\223Biedl, with spino- cerebellar degeneration Ear pits, hearing loss, branchial cysts Branchio-oto- renal (AD) History of Potter \200\231s syn- drome, agenesis, and dysplasia Nail \200\223patella (AD) Congenital NS or glomerulonephritis Dysplasia of the nails and absent or hypoplastic patellae Neuro \201 - bromatosis (AD) Arterial stenosis and hypertension Neuro \201 bromas, pigmented patches Renal cysts or hypoplasia Overexpression causes renal cysts and tumors; underexpression causes renal hypoplasia. Colo boma Renal coloboma syndrome (PAX2 mutations) (see, Online Mendelian Inheritance in Man (OMIM), M www.ncbi.nlm.nih.gov). 603 Chapter 8 The kidney in systemic disease Polyarteritis nodosa 652 Churg \200\223 Strauss syndrome 654 Anti-GBM (Goodpasture \200 \231 s) Diabetic nephropathy 604 Diabetic nephropathy: progression 606 Diabetic nephropathy: pathol ogy 608 Diabetic nephropathy: disease 656 Lupus nephritis 658 Lupus nephritis: initial treatment 660 Lupus nephritis: further treatme nt 662 prevention, screening, and assessment 610 Diabetic nephropathy: management 612 Diabetic nep hropathy: management 2 616 Antiphospholipid syndrome (APS) 664 Systemic sclerosis 666 Rheumatoid arthritis 668 Sarcoidosis 670 Fabry \200\231 s disease 6 72 HIV and renal disease 674 HIV and renal disease: Other diabetes-related urinary tract disorders 618 Plasma cell dyscrasias 620 Myeloma: cast nephropathy 622 Monoclonal Ig deposition HIVAN 676 disease 626 HIV and renal disease: other