Podocyte Fig. 7.8 Cartoon of subepithelial deposits in MN. Symptoms and signs \200 Proteinuria, occasionally sub-nephrotic or asymptomatic, but ofte n heavy and associated with the nephrotic syndrome ( 7 80%). Microscopic haematuria is relatively common. \200 i BP. \200 Venous thromboembolism ( 2 up to 20% of patients with nephrotic syndrome s to membranous nephropathy will develop a D VT). MEMBRANOUS NEPHROPATHY (MN) 565 Secondary MN \200 More common worldwide than IMN. Presentation with nephrotic syndrome may not coincide with presentation of underlying disease. MN may precede the prese ntation of malignancy by many years. Development of nephrotic syndrome in a patient with a known malignancy may herald a relapse of their cancer. Infections: HBV, HCV, HIV, malaria, syphilis, leprosy, schistosomiasis. \200 Neoplasms: s olid tumors (including lung, colon, breast, kidney, stomach, oesophageal, ovarian, prostate ), lymphoma, leukemia, mesothelioma. Autoimmune disease: SLE, thyroiditis, dermatitis herpetiformis, sarcoidosis, in \202 ammat ory bowel disease, myasthenia gravis. Drugs and toxins: NSAIDs, captopril, gold, penicillamine, lithium, clopidogrel. Investigations \200 SCr, eGFR, U&E, d albumin, LFT, bone pro \201 le, i total and LDL cholesterol, d Igs common (IgG > IgA), HBV and HCV serology, ANA. uPCR or uACR (tests for non-selective proteinuria may be helpful) ( b p. 60). Urine microscopy (may show lipid bodies, hyaline or granular casts). \200 Renal biopsy. \200 Consider investigations for s causes of MN. Approaching MN Careful history and examination are essential. Focus on: \200 Drug history . \200 Risk factors for hepatitis viruses or other infections (travel, sexual history, blood transfusions, etc.). Malignancy? <10% of cases, but proportion increases with age. \200 Check for recent weight loss and a ny localizing symptoms. \200 If history and physical examination alone do not suggest an associated neoplasm, extensive investigation is unwarranted and unlikely to reveal a tumor. X Some clinicians advocate additional imaging (e.g. CT chest, abdomen, pelvis, mammography in \231\200 ) + upper and lower GI endoscopy in patients aged >50. Histology \200 Light microscopy: often normal, but, in more advanced cases, diffuse GBM thickening, with \200\230 spikes \200\231 of GBM extending around subepithelial depos its, are usually evident (best seen on silver stains). Variable degrees of ATI and tubuloin terstitial \201 brosis may also be seen \200 Immunostaining: granular IgG 9 C3 deposits within capillary wall. Presence of the IgG4 subclass may be a pointer toward s MN. \200 EM: subepithelial electron dense deposits. Foot process effacement. CHAPTER 7 Diseases of the kidney 566 Idiopathic MN: treatment Treatment General measures Symptomatic treatment of the nephrotic syndrome ( b p. 556). Treatment of secondary MN Treating the underlying condition (e.g. treatment of HBV or resec tion of tumor) may lead to remission of the MN and the nephrotic syndrome in many cases. Th ere is rarely, if ever, a role for immune suppression. Natural history and risk strati \201 cation The natural history of IMN is variable, with 2 0 \200\223 30% progressing to ESRD and about 25 \200\223 40% remitting spontaneously. It has 6 traditionally been referred to as a \200\230 disease of thirds \200\231 : 7 1/3 spo ntaneously remit, 7 1/3 continue to exhibit low-grade proteinuria with normal renal functio n, and 7 1/3 have progressive CKD, eventually leading to ESRD. Remission may be complete (<0.3g/day urinary protein, with normal serum albumin and normal renal function) or partial (<3.5g/day urinary protein and 50% reduction from peak protein e xcretion, with an improve- ment in serum albumin and stabilization of renal function). Aim to predict the course of the disease. Low risk \200 Normal renal function. \200 Age <50 . \200 \231\200 . \200 Proteinuria <4g/day or spontaneously declining proteinuria. \200 Management: Symptomatic treatment ( b p. 556). \200 Expect remission (may occur up to 2 years after d iagnosis; mean 7 15 months), but regularly reassess risk. High risk \200 Progressive renal impairment. \200 Age >50. \200 \231\202 . \200 Pr oteinuria >8g/day. \200 Persistent proteinuria >4g/day for >6 months, with no evidence of decline (despite ACE-I/ARB). Management: consider disease-modifying treatment with immune suppression, unless renal biopsy demonstrates excessive interstitial scarring ( 6 likely to be irretrievable) or kidneys are small on USS. Most clinicians will wait for 6 months to s ee if spontaneous remission occurs, but treat earlier if severe, symptomatic nephrotic synd rome, or early decline in renal function. IDIOPATHIC MN: TREATMENT 567 Immune suppression \200 Disease-modifying therapy: the aim of immunosuppression is to red uce proteinuria, spare renal function, and induce complete, or partial, remission. Achievement of either complete or partial remission, either spontaneously or after treatment, is associated with a much improved prognosis. 2 See initiation of immune suppression on b p. 540. \200 Alternating monthly steroids and alkylating agents for 6 months \200\224 the \200\230 Ponticelli regimen \200\231 : \200 Month 1: IV methylprednisolone 1g x 3, then oral methylprednisolone (0.5mg/kg/day) for the remainder of the month. Month 2: oral cyclophosphamide 2.0mg/kg/day (or chlorambucil 0.15 \200\223 0.2mg/kg/day). Month 3: repeat month 1. \200 Month 4: repeat month 2. \200 Month 5: repeat month 1. \200 Month 6: repeat month 2. For practical reasons, many clinicians adapt this to a non-cyclical regimen, giving prednis olone 1mg/kg/day PO daily (max 60 mg) (with or without 3 x pulses of IV methylprednisolone at the outset) + cyclophosphamide 1.5 \200\223 2.0mg/kg/day PO, tapering steroids against response. X Whilst this is common practice, it does not have the evidence base available fo r the cyclical regimen. Most clinicians are less familiar with chlorambucil so prefer to use cyclophosphamide. CNIs are an alternative, particularly where alkylating agents are undesirable (or have been unsuccessful). \200 Ciclosporin 3.5 \200\223 5mg/kg/day in two divided doses, with low prednisolone (0.15mg/kg/day) for at least 6 months. Tacrolimus 0.05 \200\223 0.075mg/kg/day in two divided doses may also be used. Start at lower dose, and titrate up, as tolerated. (cid:2) Watch GFR closely. CNI levels sh ould be monitored, particularly during the initial stages. If no response, stop at 6 months. In those that respond, aim to reduce to the minimum dose that maintains remission, and continue for at least 12 months. MMF may have a role (in combination with steroids), but supporting evidence is currently la cking, and there appears to be a higher risk of relapse. Rituximab (e.g. 375mg/m 2 weekly x 4 doses) has been used, with encouraging success in observational studies. Long-term follow-up is currently lacking, so relapse rates are unknown. Relapse \200 Treat with the same regimen that was successful initially, although an alkylating agent should, in general, only be used once more. CHAPTER 7 Diseases of the kidney 568 Hereditary nephropathies Alport syndrome Classically presents as a triad of: \200 Family history of progressive nephropathy. \200 Sensorineural deafness. \200 Ocular abnormalit ies. Defective basement membrane formation in the glomerulus, cochlea, and eye accounts for thes e \201 ndings. Although inheritance is varied, an X-linked inherited mutation in the COL4 A5 gene (>200 described) that encodes A 5 type IV collagen accounts for 80% of cases. This leads to af \202 icted \231\202 , with \231\200 carriers. Autosomal recessive (AR) forms account for 7 15% and auto- somal dominant (AD) for 7 5% (gene: COL4A3 / COL4A4 on chromos ome 2). Affects 7 1 in 5,000 live births. Thin membrane disease (TMD) A common AD inherited (occasionally sporadic) familial conditio n, pre- senting with microscopic haematuria, almost always with normal renal function. TMD was previously known as \200\230 benign familial haematuria \200\231 . It is present in 7 5% of post-mortem studies and is a relatively common \201 nding during the assessment of potential live kidney donors. The normal GBM is 9 350nm thick \200\224 but, in TMD, it is often less than 200nm (although other- wise structurally normal). The underlying defect probably affects type IV collagen integration into the GBM and result s in a partial failure of basement membrane function. 40% of families have mutations in COL 4A3 / COL4A4 (>20 described, usu- ally a single nucleotide substitution associated with a s ingle family). These probably represent the benign end of the spectrum of Alport syndrome. The additional TMD genetic loci have not yet been identi \201 ed. Symptoms and signs Both present with persistent microscopic haematuria. This occurs earlier in Alport \200\231 s \200\224 no haematuria by age 10 in a \231\202 makes the diagnosis unlikely. Alport \200\231 s: proteinuria (often nephrotic range) and i BP usually present by adolescence. Progressive CKD l ESRD by the 3rd to 4th decade ( 7 2% of an ESRD program) . Severity is often consistent within a family. High-tone sensorineural deafness (in the ma jority) and anterior lentico- nus (conical, rather than spherical, lens, leading to distort ed vision: 7 20%). X-linked \231\200 carriers often have microscopic haematuria alone. How ever, proteinuria and progression to ESRD by 5th decade in 7 10 \200\223 15%. The AR form is clinically similar to disease in X-linked \231\202 . The AD form is clinically very heterogeneous. TMD: often a diagnosis of exclusion. Probably accounts for 7 25% of all microscopic haematu ria presenting to a renal clinic (the majority of whom will not undergo a renal biopsy). Ma croscopic haematuria in 7 20%. Proteinuria, i BP, and renal impairment are rare. TMD has no extrarenal manifestations. HEREDITARY NEPHROPATHIES 569 Investigations See Table 7.2. \200 Documentation of inheritance may be very helpful: AD i nheritance of haematuria, with no proteinuria, CKD, or extrarenal manifestations, suggests TMD (although a con \201 rmatory biopsy in at least one family member is desirable). Urinalysis 9 microscopy, uPCR or uACR. SCr, eGFR, U&E, albumin. \200 Audiometry for subcl inical hearing de \201 cits and ophthalmic assessment. \200 Skin biopsy with negative 5 type IV collagen staining is much less invasive than a renal biopsy and may be helpful in the assessment of possible X-linked Alpo rt syndrome. Renal biopsy: Alport \200\231 s : non-speci \201 c glomerulosclerosis and tubulointerstitial scarring o n LM (esp. if i SCr). A thin GBM on EM, with a characteristic \200\230 basket weave \200 \231 pattern, is characteristic. TMD: normal light microscopy. EM demonstrates reduction in GBM thickness. Staining of the GBM for the A chain of type IV collagen is instructive. In X-linked and AR Alport syndrome, the A 3, A 4, and A 5 chains are absent (w ith a mosaic pattern of expression in \231\200 carriers); in AD Alport syndrome, the A 4 a nd A 5 chains are absent, whereas, in TMN, normal A chain distribution is preserved. \200 Genetic testing for COL4A3 / A4 / A5 mutations is available, but the large number of mutat ions means it is not always straightforward. However, it may be useful for prenatal diagnos is in previously characterized families. Management \200 Patients with uncomplicated TMD can be reassured but should be followed u p at annual intervals (urinalysis 9 uPCR, BP, and eGFR). \200 No speci \201 c treatment for Alport syndrome. As with all progressive nephropathies, good control of BP, use of ACE-I/ARB, and proteinuria reduction should be co nsidered early; this includes \231\200 carriers. \200 Family members should be screened for haematuria and i BP. \200 Offer genetic counseling. Transplantation and Alport syndrome In <5%, transplanted Alport patients may develop de nov o anti-GBM anti- bodies that cause an RPGN; i.e. donor 5 type IV collagen is recognized as non-self. It is not a contraindication to transplantation. CHAPTER 7 Diseases of the kidney 570 Table 7.2 TMD or Alport syndrome TMD Alport Haematuria + to +++ 9 \200\223 9 \200\223 ++ Proteinuria +++ (>3g/day) i BP +++ Renal dysfunction +++ Deafness/lenticonus ++ History of ESRD \200\223 + Father-to-son transmission + \200\223 (if x-linked) Nail-patella syndrome A rare ( 7 20 pmp) autosomal dominant condition that has renal involv e- ment in 7 50% cases. It is caused by mutation of the LMX1B gene found on chromo- some 9q34. This codes for a tra nscription factor critical to other genes involved in the maintenance of GBM structure and function, including COL4A3 and COL4A4 . Renal disease Usually presents in adolescence: microscopic haematuria, proteinuria, i BP, a nd CKD. ESRD in <10%, usually in middle age. Other features Absent or hypoplastic patellae ( 7 70%), often leading to secondary osteoarthritis. Hypoplasia of the radial head and dist al humerus leads to a limited range of forearm movement. 80% develop iliac horns (symmetric al osseous processes arising from the iliac wings), which are asymptomatic but visible on X -ray. Bilateral, symmetrical nail abnormalities are present (from birth) in the majority, a ffecting both \201 ngers and toes, but commonly the thumb and index \201 nger. Nails ma y be absent, dysplastic, misshapen, ridged, or discolored. Histology Light microscopy can resemble FSGS. Immunostaining may show IgM and C3 in sclerot ic areas. EM is diagnostic, demonstrating irregular basement membrane thickening with areas of rarefaction, giv- ing rise to a \200\230 moth-eaten \200\231 appearance. Foot process effacement will also be present. Management As for all progressive proteinuric nephropathies. No spe- ci \201 c treatment i s available. Offer genetic counseling. HEREDITARY NEPHROPATHIES 571 CHAPTER 7 Diseases of the kidney 572 Miscellaneous mesangioproliferative glomerulonephritides Introduction These uncommon lesion s, sometimes referred to collectively as \200\230 mesan- gial proliferative GN \200\231 r emain partially characterized. They are increasingly viewed as part of the spectrum of mini mal change or FSGS and usually present with proteinuria (often nephrotic range), microscopi c haematuria i SCr. They are all characterized, in part, by focal or diffuse mesangial p roliferation, which might be a relatively non-speci \201 c glomerular response to injury, although consensus on the speci \201 c histological criteria required for diagnosis are la cking. They are often a diagnosis of exclusion. They tend to be poorly steroid-responsive and associated with a poor renal prognosis. Cytot oxic therapy has been tried, with variable degrees of success. C1q nephropathy A mesangial proliferative GN, originally recognized for its close histologi - cal resemblance to lupus nephritis, in the absence of any serological or clinical criteri a for the diagnosis of SLE. Histology shows a characteristic heavy deposition of C1q-contai ning deposits in the mesangium and else- where, with varying degrees of mesangial hypercell ularity and \200\230 wire loop \200\231 capillary wall thickening. There are two dominant clinical and pathologi- cal phenotypes: (i) a minimal change or FSGS-like lesion, which ty pically presents as steroid-unresponsive nephrotic syndrome; (ii) an immune complex-mediate d glomerulonephritis, associated with several different types of glomerular lesion, typical ly presenting as CKD. C1q nephropathy is now generally considered as an FSGS variant. IgM nephropathy Is a similar lesion, again characterized by mesangial hypercellularity on l ight microscopy, with diffuse granular mesangial IgM and C3 deposition on immunostaining. I gM may also be non-speci \201 cally deposited in areas of sclerosis in many glomerular dis eases, but here it is seen in the mesangium of non-sclerotic glomeruli. EM reveals generali zed foot process efface- ment. It is still debated whether it represents a distinct disease entity or a variant of minimal change disease or FSGS. The most important clinical distinc tion is that it is poorly steroid-responsive and 6 associated with a poorer prognosis. Pres ents with proteinuria, often heavy, 9 microscopic haematuria. Idiopathic mesangial proliferative GN Essentially, a diagnosis of exclusion. There is mesan gial proliferation on biopsy but no immune complex deposition on immunostaining. MESANGIOPROLIFERATIVE GLOMERULONEPHRITIDES 573 CHAPTER 7 Diseases of the kidney 574 Thrombotic microangiopathies Introduction Thrombotic microangiopathy (TMA) is a histologic description encom- passing several rare, but related, disorders, characterized clinically b y a triad of haemolysis, consumptive thrombocytopenia, and tissue ischaemia (caused by plat elet aggregation and thrombotic occlusion of small vessels) (see Table 7.3). The two classical clinical presentations involving TMA are thrombotic thrombocytopenic purp ura (TTP) ( b p. 576) and the haemolytic uraemic syndrome (HUS) ( b p. 578) (see Table 7.3) . These conditions affect both adults and children and carry a very poor prognosis if left undiagnosed and untreated. 2 Suspect in the context of otherwise unexplained thrombocytopenia and microangiopathic hae molytic anemia (MAHA). HUS vs TTP? These two conditions are increasingly considered as different presen- tations o f the same underlying pathophysiological process (with the exception of diarrhea associated (D+) HUS, particularly in childhood (see b p. 578). \200 TTP \200\224 predominantly neu rological 9 AKI (minimal). \200 HUS \200\224 AKI generally dominates the clinical pictur e. Neurological involvement minimal/absent. In view of this, they are now often referred to as \200\230 TTP-HUS \200\231 , with less weight being given to differentiating between the two. Clinical assessment \200 Take a careful history for a diarrhoeal illness. Examine for pet echiae, purpura, signs of systemic sclerosis, splenomegaly. Check BP and fundi. Urinalysis for haematuria, proteinuria, and bilirubinuria (haemolysis). \200 FBC ( d Hb, dd Plt), \201 lm for red cell fragments (MAHA), clotting, D-dimers/FDP, G&S, d haptoglobi ns, Coombs \200\231 test (negative). ii LDH, i B -HCG., U&E, LFT ( i bilirubin), urate. \200 Blood and stool cultures. \200 ANA, dsDNA, complement, antiphospholipid antibodies ( b p. 40). \200 ADAMTS13 activity (s ee p. 576). \200 Consider renal biopsy only once (and if) platelet count normalizes. Histology All TMAs share similar renal histology. Fibrin thrombi are present in the glomeru lar capillaries, with resultant ischaemia. Fluorescence for Ig and complement negative. EM shows capillary thrombi, \201 brin deposition, and endothelial injury and swelling. THROMBOTIC MICROANGIOPATHIES 575 Table 7.3 Causes of TMA Primary TTP-HUS Secondary TTP-HUS Hereditary ( \200\230 atypical \200\231 ) Idiopathic/autoimmune \200\230 Typical \200\231 HUS secondary to Shiga toxin Malignant hypertension Autoimmune/ vascular: \200 SLE \200 Systemic sclerosis \200 Rheumatoid arthritis \200 Systemic vasculitis \200 Antiphospholipid syndrome \200 PNH Drugs: \200 Hypersensitivity react ion (e.g. quinine, ticlopidine, clopidogrel) Dose-related (e.g. ciclosporin, chemotherapy) Pregnancy/post-partum HIV Metastatic malignancy DIC Allogeneic haematopoietic cell transplantation Broad categories of TMAs are shown. These differ in target population and pattern of organ involvement. Clinical and laboratory \201 ndings often overlap, and diagnostic uncertaint y is not uncommon. CHAPTER 7 Diseases of the kidney 576 Thrombotic thrombocytopenic purpura (TTP) Pathogenesis von Willebrand factor is released fr om endothelial cells as a large polymer and cleaved to form the mature polypeptide that act s as a matrix for hae- mostasis. The protease responsible for this cleavage is the zinc met allopro- teinase ADAMTS13. If vWF-cleaving protein activity is impaired (either an IgG auto antibody directed against the protease or an inherited mutation of the gene encoding ADAMTS 13), then abnormally large vWF multimers enter the circulation where they bind and activate platelets. This leads to spontaneous platelet aggregation, platelet-rich (though \201 br in-poor) throm- bus formation and a systemic microangiopathy, with widespread deposition of platelet-vWF complexes (e.g. brain/ kidney /mesenteric vessels). Interestingly, ADAMTS13 knockout mice do not develop a TMA, sug- gesting a \200\230 second hit \200\231 (e.g. an in \202 ammatory or a prothrombotic stimulus) is required to initi ate the disease. Causes \200 Hereditary: rare, congenital mutations of the ADAMTS13 gene (e.g. Upshaw \200\223 Schulman syndrome) Autoimmune: 40 \200\223 70% of all TTP. Autoimmune inhibition of ADAMTS13. IgG autoantibodies against ADAMTS13 have also been demonstrated in drug-related T TP (e.g. ticlopidine, clopidogrel). Clinical features Classic pentad: \200 Fever. \200 Microangiopathic haemolytic anemia. \200 Thrombocytopenic purpura. \200 CNS involvement (confusion, \201 ts, or other neu rological abnormality). \200 Renal involvement (AKI). i BP is more common with HUS than TTP. (cid:2) Note: patients with profound ADAMTS13 de \201 ciency can present with bloody diarrhea (non-infectious), presumably secondary to gut ischaemia. Investigations (see also b p. 574) For disease monitoring: dd Plt, blood \201 lm for red cell fragments, ii LDH, d haptoglobins. Low ADAMTS13 activity (<5% normal) in th e correct clini- cal context is diagnostic (however, the result of this specialist investig ation may not be available to inform management decisions). Management Treatment aims to restore the ability to cleave vWF. THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) 577 Plasma exchange (PEX) Allows large-volume plasma infusion as well as removal of vWF-cleavin g protein inhibitor, esp. if AKI with oligo-anuria (where plasma infusion without exchange may cause volume overload). \200 Initiate ASAP, and continue daily until 2 days after rem ission (Plt count and LDH normalize). Usually 7 \200\223 16 days. Exchange one plasma volume/day ( b p. 950). \200 May require hydrocortisone 100 mg + chlo rphenamine 10 mg IVI to prevent allergic reactions to large volumes of plasma. Fresh frozen plasma (ideally platelet-poor) or cryosupernatant infusion. As 25 \200\223 30 mL/kg/day until improvement. 2 But only if passing urine: beware volume overload. This is i nferior to PEX but is ef \201 cacious if PEX is not available. Rituximab may have a role in more severe disease (particularly with severe neurologic invol vement), non-responders to PEX, and if disease worsens despite treatment. Rituximab 375mg/m 2 weekly x 4 (given in addition to steroids and PEX) appears to be safe and effective and reduce relapses. Other avoid platelet transfusion unless life-threatening bleeding ( \200\230fuels the \201 re \200\231). No role for aspirin or anticoagulants. For severe disease, consider add- on prednisolone 1mg/kg/day or IV immunoglobulin, in addition to rituximab. Prognosis Mortality remains 7 10 \200\223 20%. Prompt recognition and treatment will reduc e this. A third will relapse. Renal survival is good, with dialysis-requiring AKI unusual i n TTP (more common in HUS). CHAPTER 7 Diseases of the kidney 578 Haemolytic uraemic syndrome (HUS) Introduction HUS is a renal-limited TMA, with widespread complications. There are three forms: (i) typical, (ii) atypical, and (iii) autoimmune. All present with AKI, thrombocytopenia, and MAHA. Typical (80 \200\22390%) Associated with diarrhea ( D+ ). Peak incidence in summer. Usually affects children <5 years. Occurs after food poisoning (e sp. undercooked meat, unpasteurized milk). Pathogenic bacteria produce a Shiga-like exotoxi n that is able to translocate, perhaps via neutrophils, across in \202 amed colonic mucosa into blood. It then binds glomerular epithelial cells with high af \201 nity causing the release of pro- thrombotic factors and ultra-large vWF multimers. Atypical (10 \200\22315%) Not associated with diarrhea ( D \200\223 ). Factor H de \201 ciency (a complement regulatory protein) causes relapsing or familial HUS . De \201 ciencies in other factors, e.g. C3, B, I, and CD46 (membrane cofactor protein), cause a similar syndrome. Drugs and non-diarrhoeal infections can cause an HUS-like syndrome. These are generally ass ociated with no (or only minor) reduction in ADAMTS13, suggesting a different pathophysiolo gy to TTP. Autoimmune \200\224 DEAP-HUS (de \201 ciency of complement factor H-related (CFHR) plasma proteins and autoantibody-positive HUS) is a novel subtype, affecting children. It is due to a combination of acquired and genetic factors and has a favorable response to treatment. Several hypotheses have been proposed for the pathophysiological basis of HUS-TTP in contex t of a normal ADAMTS13. These include endothe- lial injury ( l loss of, or de \201 cient, VEGF leads to TMA) and increased plasminogen activator inhibitor. Infections associated with D+ HUS \200 E. coli O157:H7 subtype (70% of D+ HUS in develope d countries). \200 Shigella dysenteriae serotype 1. \200 Salmonella , Campylobacter, or Yersinia. Associations of D \200\223 HUS \200 Inherited HUS. \200 Drugs: quinine, ciclosporin, ta crolimus, sirolimus, cipro \202 oxacin, the contraceptive pill, heparin, chemotherapy. \200 Infections, e.g. S. pneumoniae or rickett sial. HAEMOLYTIC URAEMIC SYNDROME (HUS) 579 Clinical features \200 Triad of microangiopathic haemolytic anemia, thrombocytopenia, and renal injury. Watery or bloody diarrhea. \200 Fever, i BP, AKI, and volume overload. \200 May progres s to multiorgan failure, with pancreatitis and a cardiomyopathy. Investigations (see b p. 576) \200 i WCC common. \200 Fresh stool for culture. \200 D isease monitoring: dd Plt, red cell fragments on \201 lm, ii LDH. Management \200 2 If in doubt, treat as TTP until diagnosis con \201 rmed. \200 For D+ HUS, management is supportive alone (including RRT if required). No role for anticoagulation. Antibiotics may paradoxically increase Shiga toxin release and should be avoided. PEX or plasma infusion do not improve outcome (as, unlike TTP, there is no underlying replaceable causative factor). Eculizumab is a monoclonal antibody that blocks complement activity by cleavage of C5 ( b p . 391). There is great interest in its use in atypical HUS and for the prevention of relaps e post-transplantation ( b p. 420). Prognosis Poor prognostic factors: i age, high WCC, D \200\223 HUS, S. pneumoniae or Shige lla infection, complete anuria. CHAPTER 7 Diseases of the kidney 580 Acute tubulointerstitial nephritis Introduction Acute (tubulo-)interstitial nephritis (AIN) is a common parenchymal cause of AKI. Peak incidence in middle age but can affect all ages . \231\202 = \231\200 . 70 \200\223 90% of cases are drug-induced, although the spectrum of causative agents has changed. AIN is characterized by an in \202 ammatory cell in \201 ltrate in the renal inter- stiti um. This is occasionally associated with a systemic delayed-type hyper- sensitivity reactio n (fever, arthritis, rash). Recurrent disease is common on repeat drug exposure. Common causes of AIN \200 Drugs: NSAIDs (including COX-2 inhibitors). \200 Penicillins (classically meticillin), cephalosp orins, rifampicin, and sulfonamides. Consider any antibiotic as a potential cause. Proton pump inhibitors. \200 Diuretics. \200 Allopurinol. \200 Antiretrovirals. Infections: Tuberculosis, legionellosis, and leptospirosis. Autoimmune disease: Sarcoidosis. \200 Sj gren \200\231s syndrome. \200 TINU (see b p. 581). Symptoms and signs Often asymptomatic until AKI supervenes. The classical presentation of f ever, arthralgia, rash, and AKI is rare ( 7 10%). Flank pain (renal swelling l capsular str etch) is uncommon. Causative drugs may have been started 3 \200\223 21 days previously, although delayed AIN, occurring up to 18 months after starting a drug, has been described. There may be clinical evidence of an associated systemic condition, such as Sj gren \200\231 s syndrome or sarcoidosis. Investigations \200 Urine dipstick may be bland or have modest proteinuria (uPCR usually <100mmol/mg or <1g/day). Microscopic haematuria is rare, and its presence may point toward a glomerular lesion. Urine microscopy may reveal eosinophiluria and white cell casts. EMU f or AFB in high-risk patients. U&E, bone pro \201 le ( ? i Ca 2+ \200\224esp. in sarcoidosis), LFT, FBC + differentials (eosinophilia may be present), i ESR. Consider ANA, anti-Ro, and anti-La (? S j gren \200\231 s syndrome). USS shows normal-sized (or slightly enlarged) kidneys. \200 CXR and serum ACE (? sarcoid) . \200 Renal biopsy: usually necessary to con \201 rm diagnosis. ACUTE TUBULOINTERSTITIAL NEPHRITIS 581 Histology Intense interstitial in \202 ammatory cell in \201 ltrate, consisting of lympho cytes and monocytes ( 9 eosinophils). Giant cells and granulomata may point to TB or sarcoi dosis. The presence of interstitial \201 brosis imparts a worse prognosis, as in all form s of renal injury. Glomeruli are normal. Management \200 Depends, to an extent, on the underlying cause or precipitant. \200 Tre atment of sarcoidosis ( b p. 670) are outlined elsewhere. \200 3 Stop offending drug(s). \200 X Corticosteroids: Widely used, although there is no good evidence to support this practice. May hasten recove ry but do not appear to in \202 uence overall prognosis. A reasonable approach: Dialysis-dependent: treat with corticosteroids. \200 Dialysis-independent: observe for up to 14 days following drug withdrawal; if improvement, continue expectant management; if no improvement, treat with co rticosteroids. Information from a renal biopsy may also inform decision- making; e.g. acute in \202 ammat ion with interstitial oedema may favor steroid treatment, whilst established \201 brosis would not. Treatment with prednisolone 1mg/kg/day PO, tapering slowly against response for a 3 \200\223 6 month course ( b p. 540). For drug-related AIN: Outcomes: 40% will be left with CKD, and 10% will progress to ESRD. Final GFR does not correlate with the maximal value during the early acute phase. Of those with milder disease, the majority will return to baseline renal function. Even those requiring renal replacement therapy for AKI usually regain independent renal function. Mort ality rate <5%. Tubulointerstitial nephritis and uveitis syndrome (TINU) Uncommon. Unlike AIN, affects pred ominantly younger \231\200 . Presents as anterior uveitis (often bilateral) and AIN (which may be separated in time). Additional features include weight loss, d Hb, i ESR, and deran ged LFT. Pathophysiology is poorly understood, although IgG antibodies against modi \201 e d C-reactive protein, (mCRP) may be rel- evant. Differential diagnosis: autoimmune disease (esp. Sj gren \200\231 s) and sarcoidosis. Ophthalmology input should be sought urgently. Treat the renal lesion with 1mg/kg/day predn isolone, tapering slowly against resolution for 3 \200\223 6 months. Relapse is common, an d complete steroid withdrawal may not be possible. CHAPTER 7 Diseases of the kidney 582 Chronic tubulointerstitial disease Introduction Chronic tubulointerstitial disease encompas ses a variety of disorders that share similar histological appearances on kidney biopsy. Th e tubulointer- stitial compartment is extensively \201 brosed, often with a lymphocytic i n \201 l- trate in scarred areas. Tubules are often dilated and atrophic. Glomeruli are la rgely spared (although glomerular obsolescence may be seen as a result of nephron dropout). 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.