HISTOLOGY OF GLOMERULAR DISEASE 535 Table 7.1 (Continued) Term Haematoxylin and eosin (H&E) De \201 nition Routine histological technique which stains cytoplasm pink and nuclei blue. Allows inspection of all renal structures but is poor at distinguishing deposits or visual izing the basement membrane. Periodic acid-Schiff (PAS) Routine histological technique which clearly delineates basement membranes and allows visua lization of cellular components. Silver Silver stains highlight connective tissue structures such as reticulin, basement membrane, and collagen, which appears black. Very useful for assessment of glomerular capillary basem ent membrane architecture such as \200\230spike formation \200\231 (see \200\230Spikes \200\231 earlier in table). Congo red Stain used for the detection of amyloid, which appears red with \200\230apple green \200 \231 birefringence using polarized light examination. Martius scarlet blue (MSB) Stain which highlights \201 brin deposits as red, collagen in blue, and erythrocytes in y ellow. Toluidine blue Stain used primarily to visualize \200\230thin sections \200\231 prior to electron microsc opic examination. Glomerulonephritis In \202 ammation of the glomerulus. Tubulointerstitial nephritis In \202 ammation of the tubules and interstitium. Electron dense deposits Dark lesions identi \201 able on electron microscopic examination, usually corresponding t o sites of immunoglobulin or complement deposition. Immunohistochemistry (IHC) Technique for detecting and localizing speci \201 c antigens in tissue sections using a de tection system visible on routine light microscopy, e.g. immunoperoxidase. Immuno \202 uorescence (IF) Technique for detecting and localizing speci \201 c antigens in tissue sections using a de tection system visible on \202 uorescence microscopy. Sometimes more sensitive than IHC b ut requires fresh tissue and is not stable. Thin basement membrane (thin BM) disease Age 9 \200\22368 years: thin GBM: 262 \200\223330nm; normal: 331 \200\223547nm. \200\230Basket weave \200\231 GBM The disordered replication of lamina densa of the GBM in Alport s nephropathy. Modi \201 ed from Taylor CM, Chapman S (1989). Renal biopsy. In Handbook of renal investig ations in children, pp.160 \200\22371. Taylor CM, Chapman S (eds). Wright, London. CHAPTER 7 Diseases of the kidney 536 Acute nephritic syndrome Introduction The clinical syndrome associated with underlying glom erulonephritis ( b p. 71). Presents (often rapidly) as: \200 Haematuria and proteinuria. \200 Impaired renal function. \200 Oliguria with signs of salt and water retention. It is a spectrum of disease with a variety of aetiologies but with a common site of primary injury: the glomerulus. Onset may be insidious, with urinary abnormalities alone, or fulmi nant, with a rapidly progressive crescentic GN, AKI, and other organ involvement or failure ( b p. 71). Causes \200 IgA nephropathy and Henoch \200\223 Sch nlein purpura. \200 Lupus nephritis. \200 Post-infectious GN. \200 Anti-GBM disease. \200 ANCA-associat ed vasculitis. \200 Mesangiocapillary GN (MCGN). Mechanisms of glomerular injury The injury leading to most GN is immunologically mediated, with loss of tolerance to autoantigens, provoking both the cellular and humoral arms of the immune system. These antigens may be native to the glomerulus itself (occurring normally w ithin the tuft, e.g. the GBM in anti-GBM dis- ease) or circulating antigens/antigen-antibod y complexes that become trapped in glomerular structures. Antibody to antigen binding may then \201 x and activate complement (forming immune compl exes, ICs) or recruit in \202 ammatory cells (see Fig. 7.3). The nature of the injury will depend on the site of the IC (e.g. IgA-containing mesangial complexes activate mesangial c ells to cause IgA nephropathy). Local complement activation and cell recruitment (neutrophi ls, macrophages) generate oxidant species, proteases, in \202 am- matory cytokines, growth factors, vasoactive factors, and procoagulants. Damage to, and activation of, surrounding cells and matrix then lead to the changes evident on histological examination and the clini cal syn- drome of haematuria, proteinuria, and impairment of glomerular \201 ltra- tion. The number of ICs formed and the host response to them will determine the extent of the inj ury. Cellular immunity may also contribute to structural glomerular dam- age \200\224 this is e specially true of pauci-immune GN (e.g. the GN associated with ANCA-positive vasculitis) wh ere ICs play no pathological role. Resolution of in \202 ammation might return an in \202 amed glomerulus to normal or, if t he healing phase is poorly regulated, may result in cellular dropout, scarring, glomerulosc lerosis, and CKD. ACUTE NEPHRITIC SYNDROME 537 Antibody Antigen (endogenous or exogenous) Circulating or planted immune complexes GBM Capillary lumen Mesangium Podocyte Podocyte foot processes GBM Inflammatory cells causing local injury Complement Destruction of part or all of a glomerular lesion leads to renal failure Capillary rupture leads to haematuria and crescent formation Injury to the glomerular sieve leads to proteinuria Podocyte Fig. 7.3 An example of an immune complex-mediated GN. CHAPTER 7 Diseases of the kidney 538 Nephritis: management overview Investigations \200 Dipstick urine for haematuria, protein uria. \200 Urine microscopy for red morphology 9 casts ( b p. 22). \200 Amount of prote inuria variable (often <1g/day, i.e. uACR <70mg/mmol and uPCR <100mg/mmol, but may be nephrotic range). SCr, eGFR, U&E, FBC, bone pro \201 le, LFT. \200 Acute phase markers (CRP, ESR). \200 Immunological and serological ( \200\230 nephritic \200\231 ) screen ( b p. 40). \200 U SS kidneys. \200 Renal biopsy ( b p. 80). Salt and water restriction 2 It is vital to correctly assess volume status. \200 Fluid ov erload 9 pulmonary oedema often complicates oliguric GN. If present: \200 Limit salt intake <80mmol/day (<5g/day). \200 Set oral intake at 500 \200\223 1,000mL/day (adjusted according to volume status and UO). Diuretics may promote a natriuresis and provide symptomatic relief: use loop diuretic, e.g. furosemide 40 \200\223 160mg/day PO or IV, titrated agains t response and renal function. Less commonly, dehydration may be present, in which case increased oral intake or rehydration with IVI 0.9% NaCl may be needed. Review volume status and monitor weight daily, and chart input and output to plan following day \200\231 s \202 uid balance. Indwelling catheter only rarely required. Control BP \200 i BP is usually volume-related and may be signi \201 cant. Aim for targe t BP of \211 130/80mmHg. \200 Suggested treatment: Diuretic (as described in salt and water restriction). \200 Stepwise add-on therapy, usin g B -blockers 9 calcium channel blockers. ACE-I or ARB: titrate up from low dose with daily increments. ACE-I or ARB offer theoretica l advantages in the control of i BP secondary to renal disease due to their anti \201 brot ic and anti-proteinuric effects. However, their use in GN-associated with AKI may precipita te a further decline in renal function. (cid:2) Careful monitoring is essential. Other supportive measures \200 2 Prompt treatment of infection. \200 Adequate nutrition . \200 Management of the complications that may be associated with a systemic disease causing GN (e.g. lupus, vasculitis). Renal replacement therapy, according to standard indications ( b p. 172). NEPHRITIS: MANAGEMENT OVERVIEW 539 Speci \201 c therapies: immunosuppression Almost always tailored to a histological diagnos is (so a renal biopsy is often indicated as soon as is possible). See Nephritis: overview o f immune suppression ( b p. 540) and under each particular diagnosis. KDIGO clinical practice for glomerulonephritis This important guideline, \201 rst publish ed in 2011, aims to help clinicians caring for patients with GN understand the evidence (or lack of) that underpins current clinical practice in this area. The recommendations contai ned within it are based on a comprehensive review of relevant literature across many kidney diseases. The strength of all the evidence presented is graded, current shortcomings are a cknowledged and pro- posals for future research are offered. (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephr itis. KI, Suppl. 2012; 2: 139 \200\223274. Kidney Disease: Improving Global Outcomes Available online at M http://www.kdigo.org CHAPTER 7 Diseases of the kidney 540 Nephritis: overview of immune suppression Introduction (cid:2) Treatment of glomerulonephri tis often involves toxic therapies in the short term to improve long-term renal and patient outcomes. The initial goal is to achieve remission before altering therapy to maintain rem ission . When considering and commencing therapy, the dictum of \200\230 \201 rst do no harm \200\231 always applies. These are potentially dangerous drugs \200\224 does the risk:bene \201 t assessment justify their use? Preventing drug toxicity Corticosteroids \200 Issue patients with a steroid card, and cou nsel regarding the risks of abrupt steroid withdrawal as well as the potential need to incr ease dose with stressors (such as intercurrent illness or anesthesia). Check blood glucose at start of therapy. (cid:2) Warn diabetic patients and those with impaired glucose tolerance to monitor blood s ugars closely whilst on corticosteroid therapy and to inform their diabetic team. Prophylaxis against gastric irritation: proton pump inhibitor or H 2 receptor antagonist by convention ( X although evidence poor). \200 Steroid-induced bone demineralization is an early event (within \201 rst few months of treatment). \200 Consider bisphosphonate (e.g. risedronate 35mg weekly or a lendronic acid 70mg weekly) in those at risk (or if >5mg prednisolone/day for >3 months). ( cid:2) Many bisphosphonates require a dose reduction in renal impairment. Calcium (1,500mg/day) and vitamin D 3 (800 IU/day) preparations are a less effective alternative. Consider baseline and interval DEXA if long-term steroids. Treat steroid-exacerbated hyperlipidaemia with a statin. Tapering steroids Prednisolone is the most widely used oral corticosteroid. Its use in rena l disease is usually for >3 weeks and it will therefore often require slow tapering to allo w recovery of a suppressed hypothalamic \200\223 pituitary axis. A potential regimen from 20mg/daily prednisolone might be: \200 Reduce by 5mg every fortn ight until on 5mg/day. \200 Reduce to 5mg, alternating with 2.5mg daily for 2 weeks. \200 Reduce to 2.5mg daily for 2 weeks. \200 Reduce to 2.5mg alternate days for 2 weeks. \200 Stop. Advise re potential Addisonian symptoms, and warn to seek medical help if unwell. NEPHRITIS: OVERVIEW OF IMMUNE SUPPRESSION 541 Others, e.g. alkylating agents (cyclophosphamide, chlorambucil) \200 (cid:2) Monitor toxi city: FBC, U&E, and LFT weekly to fortnightly at induction of therapy (see b p. 542). Offer prophylaxis against PCP for duration of cyclophosphamide therapy (e.g. co-trimoxazole 480mg bd PO or nebulized pentamidine if allergic). In those at high risk for tuberculosis (e.g. previous TB, recent exposure, patients from endemic areas), consider primary prophylaxis with isoniazid + pyrid oxine ( X evidence poor). Recommend in \202 uenza and pneumococcal vaccines. Live vaccines should be avoided for the duration of treatment. Commonly used drugs \200 Induction (I) brings about disease remission. \200 Maintenance (M) maintains remission. Prednisolone (I, M) \200 To induce remission, either as high dose PO (1mg/kg/day) or as \200\230 pulsed \200\231 IV (0.5 \200\223 1g/day for 3 days). Corticosteroids are also used at lower dose for maintenance. \200 Potent anti-in \202 am matory action, modulating both B and T cell-mediated immunity. Also inhibit the effector function of both monocytes and neutrophils through regu lation of cytokine-driven responses. \200 SE: insomnia, weight gain, i BP, impaired gluco se tolerance, dyslipidaemia, mood disturbance, poor wound healing, osteoporosis. Cyclophosphamide (I) \200 Either orally (e.g. 1.5mg/kg) or as periodic (monthly) IV pulse s. \200 A cytotoxic alkylating agent that binds to purine bases and impairs cellular DNA replication ( l d cell turnover and cell death), with consequent restriction of lymphocyte proliferation. SE: Leucopenia (see b p. 542) and i risk of infection, esp. Herpes zoster . \200 Gonadal toxi city. Discuss loss of fertility prior to starting treatment \200\224 in \231\200 , measur e LH/FSH before therapy. Limit cumulative exposure as much as possible (>15 \200\223 20g c auses infertility in 7 50% of those aged >30. The risk is lower in younger patients). Consi der GnRH analogs in \231\200 (see b p. 542). Egg preservation may be possible, but the pac e of disease (and 6 need for swift intervention) often renders this impractical. Discuss sp erm banking in \231\202 . Haemorrhagic cystitis l longer-term risk of bladder cancer. (cid:2) Use mesna if giving IVI (see b Using IVI cyclophosphamide (CYC), p. 542); low thres hold for investigating haematuria in those previously exposed (mesna binds to the cyclophos phamide metabolite acrolein that is the cause of urothelial toxicity). X Oral cyclophosphamide (CYC) is potentially more toxic to ovaries and bladder than IVI bec ause cumulative doses are usually higher. Nausea and vomiting, esp. if given IVI. \200 Teratogenic; contraindicated in pregnancy (a lthough not associated with birth defects in \231\200 who receive it prior to pregnancy). SIADH. CHAPTER 7 Diseases of the kidney 542 Using IVI cyclophosphamide (CYC) \200 Body surface area is calculated as \210\232 (heigh t (cm) x wt (kg)/3,600). \200 Counsel re side effects and potential risks. \200 Protect the bladder from haemorrhagic cystitis: vigorous oral \202 uids, with 1L 0.9% NaCl over 4h post-therapy. Oral mesna at \200\223 2, +2, and +6h as (0.2 x cyclophosphamide dose in mg) per dose. \200 Antiemetics, e.g. granisetron 1mg (can repeat at +12h) + dexamethasone 10mg PO at \200\223 2h. Monitoring for CYC-induced neutropenia \200 Check WCC weekly for the \201 rst month, ev ery 2 weeks for the second and third, and monthly thereafter. If WCC <4 x 10 9 /L, then discontinue temporarily. Restart with a 25% dose reduction when WCC has recovered, and resume weekly monitoring. If the WCC is falling rapidly, e.g. by >2 x 10 9 /L between tests, reduce the dose by 25% pre-emptively. If WCC <1 x 10 9 /L or WCC <4 x 10 9 /L persists for >2 weeks, then restart at low dose (e. g. 25 \200\223 50mg/day) only after WCC recovers. \200 For IV CYC, check WCC the day of the proposed pulse. If <4 x 10 9 /L, postpone until >4 x 10 9 /L, and reduce dose by 25%. Check WCC 14 days after each pulse; if WCC nadir: 2 \200\223 3 x 10 9 /L, reduce the dose of the next pulse by 20%. \200 1 \200\223 2 x 1 0 9 /L, reduce by 40%. Protecting against gonadal cyclophosphamide toxicity Glomerular disease, particularly SLE, often affects \231\200 of childbearing age. Cyclophosphamide (CYC) treatment is associated with a signi \201 cant risk of premature ovarian failure (POF). This may play an importan t role in the choice of induction therapy but must be balanced against the risks of potenti al undertreatment. When given continuously, GnRH analogs induce reduced ovarian blood \202 ow and limit ovar ian exposure to CYC. In small observational studies, the administration of GnRH analogs dur ing treatment with CYC for lupus nephritis demonstrably preserves ovarian function. An exam ple regimen is depot leuprolide acetate, ideally administered at least 10 days prior to the commencement of CYC. NEPHRITIS: OVERVIEW OF IMMUNE SUPPRESSION 543 Calcineurin inhibitors (I, M) \200 Ciclosporin and tacrolimus ( b p. 386). \200 Limit I L-2-driven nuclear transduction, and thus T cell activation. \200 (cid:2) Nephrotoxic: mo nitor GFR throughout use. \200 Given orally (although IVI available). \200 SE (ciclospo rin (C) and tacrolimus (T)): Infection (T + C), i BP (C), tremor, hirsutism (C), gum hypertrophy, dyslipidaemia, impaired glucose tolerance (T > C), gout (C), nephrotoxicity (T + C), microa ngiopathy (T + C), amongst others. Azathioprine (M) \200 Antiproliferative pro-drug metabolized to 6-mercaptopurine. \200 Restricts lymphocyte proliferation through the inhibition of folate-dependent DNA synthesis. (cid:2) Interaction with allopurinol may precipitate profound leucopenia. \200 Given oral ly, usually as a single daily dose. \200 SE: infection, myelosuppression, hepatotoxicity (check WCC, LFT 14 \200\223 21d after starting). Long-term risk of skin cancers. Mycophenolate mofetil (I, M) \200 Antiproliferative agent that inhibits lymphocyte expans ion and antibody production. It can also promote T cell apoptosis and affect cell:cell inte ractions. Given orally in divided doses (IVI available). \200 SE: infection, myelosuppression, GI t oxicity (diarrhea is not uncommon \200\224 divide dose qds, rather than bd, or reduce dose). Teratogenic. Rituximab (I, possibly M) \200 A chimeric anti-CD20 monoclonal antibody against B cell su rface marker that induces B cell lysis. Given IVI. Results in widespread B cell and antibody depl etion over time. SE: cytokine release type syndrome during infusion, infection \200\224 particularly serious viral infections, including CMV and JC virus (the latter the cause of progressive multifocal leucoencephalopathy). Others: fever, headache, nausea, abdominal pai n, hepatitis, bronchospasm, hypogammaglobulinaemia. Serious neutropenia is uncommon. Circulating B cell counts may be helpful to guide dosing. CHAPTER 7 Diseases of the kidney 544 IgA nephropathy Introduction The most common primary glomerulonephritis in the world, affec ting an estimated 1.5% of the population. Often presents with haematuria in the 2nd and 3rd decades. Usually idiopathic, but IgAN is also found in association with Henoch \200\223 Sch nlei n purpura ( b p. 650), alcoholic cirrhosis, GI disorders (coeliac disease, in \202 ammator y bowel disease), and skin and joint disorders (spon- dyloarthropathies, dermatitis herpeti formis, psoriasis). (cid:2) Previously considered relatively benign, it is now recognized t hat 30 \200\223 50% will progress to signi \201 cant CKD over time. The remainder will ei ther enter remission or have persistent low-grade haematuria/proteinuria Pathogenesis The majority of IgA (both IgA1 and 2) is produced by plasma cells and freely c irculates before hepatic metabolism. In IgAN, abnormally glyco- sylated polymeric IgA1, wit h an increased tendency for self-aggregation and complex formation , is deposited in the gl omerular mesangium. These deposits are seen in 3 \200\223 16% of healthy individuals with no renal disease, suggesting that deposition of IgA alone is insuf \201 cient to induce in jury. Co-deposits of IgG and C3 may contribute to severity. The predominance of IgA1 over I gA2 is due to the abnormal glycosylation of O-linked poly- saccharides that are unique to t he hinge region of IgA1. IgA binding of mesangial Fc receptors l mesangial cell activation l pro- duction of platele t-derived growth factor and other cytokines l mesangial cell proliferation, matrix synthesi s, in \202 ammatory cells recruitment, and local injury (see Fig. 7.4). Infection, particularly mucosal, and hypersensitivity are suggested pre- cipitants. However , it seems likely that an aberrant IgA immune response is more important than a particular antigen, with polymeric IgA found in plasma cells. There is evidence of a genetic in \202 uence, but it is complex and polygenic and dif \201 cult to study, owing to the often \200\230 latent \200\231 nature of the di sease. Symptoms and signs \200 Often presents as asymptomatic urinary abnormalities, particularl y microscopic haematuria. Haematuria may be macroscopic, classically timed with upper respiratory illnesses (so-calle d \200\230 synpharyngetic haematuria \200\231 ). \200 Associated proteinuria is common, although nephrotic range proteinuria (>3g/day) is unusual (<15%). Consider in young adults presenting with urinary abnormalities 9 CKD. \200 i BP is common and often dif \201 cult to control. \200 2 IgAN may present as a rapidly progressive GN with AKI ( b p. 71). Extrarenal manifestations, including a purpuric skin rash, can occur, and there appears to be overlap with Henoch \200\223 Sch nlein purpura (HSP). For discussion, see b p. 651. IGA NEPHROPATHY 545 Investigations \200 SCr, U&E, eGFR, serum albumin, bone pro \201 le, lipid pro \201 le. \200 Elevated serum IgA in 7 50%. \200 Urine microscopy for dysmorphic RBCs and red ce ll casts ( b p. 22). \200 Elevated uPCR or uACR. \200 Biopsy of associated skin rash, i f present, may show IgA deposition on immuno \202 uorescence. \200 Renal biopsy ( b p. 80). Histology \200 Light microscopy: mesangial cell proliferation and increased mesangial matrix (may be focal or diffuse). Immunostaining: con \201 rms mesangial IgA deposits with C3. Possible co-deposition of IgG and IgM. Electron microscopy: mesangial deposits near the paramesangial GBM. GBM Capillary lumen Mesangial deposits Endothelial cell Podocyte Fig. 7.4 Cartoon of mesangial IgA deposits. Classi \201 cation A lack of historical agreement concerning precise histological classi \201 cation has rendered trial data dif \201 cult to interpret and accord on best treatmen t dif \201 cult to reach. The 2009 Oxford Classi \201 cation was based on a consen- sus v iew of 265 biopsy specimens. The following variables were associated with renal outcome, in dependent of baseline features and control of BP and urinary protein excretion: \200 Mesa ngial hypercellularity score. \200 Segmental glomerulosclerosis. \200 Endocapillary hyp ercellularity. \200 Tubular atrophy/interstitial \201 brosis. \200 (One drawback is t hat the classi \201 cation does not include crescentic/ necrotic lesions.) It is hoped that this classi \201 cation may help to stratify an individual patient \200 \231 s prognosis and determine their treatment at the time of biopsy (e.g. endo- capillary proliferation may help to predict steroid responsiveness). CHAPTER 7 Diseases of the kidney 546 IgA nephropathy: management Introduction The treatment of IgAN is unsatisfactory because of the heterogeneity of the disease itself and the paucity of good clinical trial data. Preve ntion of progressive renal impairment is the key therapeutic goal. However, many patients h ave slowly progressive disease (decline in GFR of 7 1 \200\223 3mL/min/ yr), so long-term studies are urgently required. Current options are broadly divided into non-immunosuppressive and immunosuppressive strategies. Stratifying patients: key features of a poor prognosis at presentation \200 Impaired rena l function. \200 Heavy proteinuria (>3g/day). \200 (Dif \201 cult to control) hyperten sion. \200 Signi \201 cant tubulointerstitial \201 brosis and glomerulosclerosis on re nal biopsy (see Oxford classi \201 cation, b p. 545). Rapidly progressive crescentic IgAN. Low-risk patients (no poor prognostic features) \200 Normal GFR. \200 Isolated microsco pic, or episodic macroscopic, haematuria. \200 Proteinuria <500mg/day (uPCR <50mg/mmol). \200 Normotensive. No speci \201 c treatment is necessary in this group, but regular surveillance (e.g. annua l BP, SCr, eGFR, uPCR) is recommended. X Many centers will manage these patients without a renal biopsy and, therefore, without a speci \201 c diagnosis of IgAN ( b p. 67). Persiste nt haematuria implies ongo- ing immune activity. Proteinuria implies more severe disease, a nd the amount will increase with activity and progression. Medium-risk patients (no poor prognostic features) \200 Older age. \200 Normal GFR or o nly slight d . \200 Proteinuria >500mg/day (uPCR >50mg/mmol). \200 Hypertension. Non-immunosuppressive treatment \200 2 Reduce BP and proteinuria. Aim for target BP of \211 125/75mmHg, ideally with ACE-I as \201 rst agent (ARB if not tolerated). If normal BP, but proteinuria, ACE-I for proteinuria reduction. \200 X Dual blockade of A 2, using combined ACE-I + ARB, may offer additional bene \201 t ( d proteinuria but no dat a on renal outcomes). \200 If tolerated, titrate therapy to reduce proteinuria to <1g/day (uPCR <100mg/mmol) and ideally <0.5g/day (uPCR <50mg/mmol). IGA NEPHROPATHY: MANAGEMENT 547 X Fish oils (omega-3 fatty acids): Limited data to suggest a role in the prevention of progression. \200 However, study data are con \202 icting \200\224 and not all patients included were on ACE-I/ARB. Presumed to modulate the production/action of eicosanoids. \200 Given as \201 sh oil (e .g. Maxepa 5g bd). \200 GI intolerance (including halitosis) often limits patient acce ptability. \200 Overall, a safe and justi \201 able adjunct to ACE-I. Consider in those where uPCR >100mg/mmol despite ACE-I/ARB. High-risk patients \200 Dif \201 cult to treat, with progression to ESRD not uncommon. \200 Signi \201 cant proteinuria, e.g. >1g/day (uPCR >100mg/mmol), esp. if nephrotic range (>3g/day; uPCR >300mg/mmol). \200 Proteinuria fails to decrease with ACE- I/ARB therapy. \200 Signi \201 cantly impaired renal function at outset or progressive d in GFR. \200 Crescentic change on biopsy. \200 Signi \201 cant chronic histological d amage, such as glomerulosclerosis, heralds a poor prognosis, regardless of treatment. Non-immunosuppressive treatment \200 As for medium-risk patients. Immunosuppressive treatment \200 Give in conjunction with ACE-I/ARB. \200 Optimum thera py uncertain. Con \202 icting data from small studies of inadequate duration where inclusion of low-risk patients skews outcomes. Corticosteroids: Some evidence of bene \201 t if proteinuria >1g/day and eGFR >50mL/ min. Trial of 0.5mg/kg prednisolone alternate days for 6 months or, if nephrotic range proteinuria, 0.5 \200\223 1mg/kg/day for 8 weeks. X Cyclophosphamide: Reserved for severe active disease (rapidly progressive clinical course and >50% crescentic change, with severe active in \202 ammation) where aggressive t reatment may spare renal function. Prednisolone 0.5 \200\223 1mg/kg/day + cyclophosphamide 2mg/kg/day for 8 weeks, followed by tapering prednisolone and conversion to maintenance azathioprine 2 mg/kg/day. Severity of renal dysfunction and degree of chronic damage on kidney biopsy will signi \201 cantly in \202 uence outcomes. Limited evidence that treating as an RPGN with pulse MP/ cyclophosphamide 9 PEX may improve renal prognosis. Other: MMF may d proteinuria and rate of GFR decline \200\224 however, data are not consistent, so further studies are awaited. Tonsillectomy is not generally recommended for synpharyngetic disease. CHAPTER 7 Diseases of the kidney 548 Post-infectious glomerulonephritis Introduction PIGN is classically associated with strepto coccal infection, but infection of almost any cause may be associated with an acute nephrit ic syndrome and a diffuse proliferative GN on kidney. 2 Beware chronic, deep-seated, and concealed sources of sepsis, e.g. endocarditis ( b p. 69 2), foreign bodies (e.g. ventriculoatrial shunt), and abscesses. Common associations of post-infectious GN \200 Bacterial: streptococcal, staphylococcal, pneumococcal, meningococcal, salmonella, mycobacterial, syphilis. Viruses: in \202 uenza B, mumps, rubella, coxsackie, hepatitis B, EBV, CMV. Fungi: candida , Coccidioides, Histoplasma. \200 Parasites: malaria, \201 liariasis, to xoplasmosis, or schistosomiasis. Acute post-streptococcal GN Introduction An immune complex-mediated GN that usually occurs in childhood (age <7 years). Now rare in developed countries. Classically, follows 10 \200 \223 21 days after a streptococcal sore throat but often occurs after infection elsewhere, e.g. tonsillitis, pharyngitis (commonly), impetigo, otitis media, and cellulitis. Pathophysiology B -haemolytic Infection with nephritogenic Lance \201 eld group A Streptoc occus (esp. types 12 and 49) is followed by a latent period during which immune complexes f orm, circulate, and then deposit in glomeruli. Nephritis-associated plasmin receptor (NAPIr ) and streptococcal pyro- genic exotoxin B (SPE-B) are two suggested culpable antigens. Clinical presentation Varies from asymptomatic microscopic haematuria through to an acute n ephritic syndrome, with frank haematuria, oliguria, oedema, i BP, pul- monary oedema, and A KI. Bilateral loin pain or renal angle tenderness s renal engorgement may occur. Investigations Urinalysis. Urine microscopy for red cell casts 9 pyuria. SCr, U&E, FBC, Ca 2+ , LFT. uPCR. Anti-streptolysin O titre (ASOT) or anti-DNase B (for group A streptococci) may be positive. (cid:2) Note if only ASOT is used to screen, it can be falsely negative o r blunted, particularly in skin infections (or if antibiotics have been given). Complement components: d C3, with normal C4. Rheumatoid factor may be positive. Consider full immunolo gi- cal and serological screen if in diagnostic doubt, particularly in adults (see b p. 40) . POST-INFECTIOUS GLOMERULONEPHRITIS 549 In children, suspect if good clinical history and documented evidence of relevant infection . A renal biopsy is rarely necessary, unless resolution does not begin within 1 week. In adults, main differentials are IgAN, MCGN, SLE, HSP, and other vascu- litides. A biopsy is more likely to be undertaken to con \201 rm the diagnosis. Histology Diffuse proliferative changes with hypercellularity. Extensive neutro- philic in \201 ltration and red cell casts. Crescentic change and frank necroses are unusual. Immuno \202 uorescence: IgG and C3 deposition in diffuse granular pattern in both the mesangium and glomerular capillary walls. EM: \200\230 dome-shaped \200\231 , electron-dense deposi ts in the subepithelial aspects of the capillary walls, with endothelial cell swelling. Sim ilar to the changes seen in MCGN (for graphic, see b p. 551). Clinical course Generally, PI GN is self-limiting once (if) the underlying infection resolves. It is associated with a fu ll renal recovery (even after AKI). Resolution usu- ally begins after 7 \200\223 10 days. Recurrence is rare. Urinary abnormalities may persist for many years after recovery, althou gh isolated microscopic hae- maturia has little prognostic value. Proteinuria, i BP, and CK D also occur, so patients should be offered follow-up. Treatment \200 2 Ensure the predisposing infection has resolved. If ongoing, treat actively with a penicillin or other appropriate antibiotic. If volume overload: restrict salt (<80mmol/day or <5g/day) and \202 uid (assess volume st atus and UO regularly to tailor restriction, e.g. 500 \200\223 1000mL/day). Treat i BP: salt and water overload is common, so start with loop diuretic (e.g. furosemide 40 \200\223 160mg PO/IV). Escalate with additional agents, such as a CCB or an ACE-I (wit h caution), as necessary. Renal replacement, as per standard indications ( b p. 172). Shunt nephritis Originally coined to describe the GN associated with a chronically infected ventriculoatrial or ventriculojugular shunt used to treat hydro- cephalus. In the modern e ra, bacterial bio \201 lms on an indwelling central venous cannula or cardiac pacing appar atus are more likely to be the source of low-grade infection ( l immune complex formation a nd glo- merular deposition). Clinical features in such scenarios include: Fever. \200 Haematuria, proteinuria, and i SCr. \200 Splenomegaly. \200 i ESR, CRP, d Hb, and d C3. \200 Histology is similar to PIGN. Removal of the foreign body is essential for resolution. CHAPTER 7 Diseases of the kidney 550 Mesangiocapillary glomerulonephritis Confusingly, also called membranoproliferative glomeru lonephritis (MPGN). Introduction MCGN is a histological term used to describe a pattern of injury, rather than a distinct GN. Can be idiopathic but commonly secondary to a variety of causes. MCGN associations With cryoglobulins \200 Hepatitis C (less commonly B) ( b p. 686). \200 Mixed cryoglobu linaemia unrelated to HCV ( b p. 634). Without cryoglobulins \200 Shunt nephritis and oth er chronic infections, including endocarditis and visceral abscesses ( b p. 692). SLE, Sj gren \200\231 s syndrome. \200 HBV, HCV, HIV, parvovirus B19. \200 TB, lepr osy. \200 Malaria, schistosomiasis. \200 Complement de \201 ciencies (e.g. factor H). \200 TMA. \200 Plasma cell dyscrasia (e.g. myeloma), lymphoma. \200 Transplant glomer ulopathy ( b p. 415). Classi \201 cation and histology The subendothelial and mesangial deposition of immune com plexes implies a common pathogenic mechanism (see Fig. 7.5 ). All subtypes have a character istic \200\230 double contour \200\231 or \200\230 basement membrane splitting \200\231 appearance of the GBM s to the interposition of mesangial cell cytoplasm between the endot helium and GBM. Type I MCGN \200 Characterized by mesangial hypercellularity and discrete immune deposits in the mesangium and subendothelial space. Monocyte in \201 ltration causes a lobular pat tern to the glomerular tufts. Crescentic change can occur. Immuno \202 uorescence shows gr anular IgG and C3 deposition within capillaries and mesangium. Commonly associated with cryoglobulinaemia (with HCV). \200 Also associated with SLE, end ocarditis, plasma cell dyscrasias (e.g. MIDD and AL amyloid), and HBV infection. Less commonly, a primary idiopathic MCGN (consider this a diagnosis of exclusion). MESANGIOCAPILLARY GLOMERULONEPHRITIS 551 Dense deposit disease (type II MCGN) \200 Continuous, dense, ribbon-like intramembranous deposits along the GBM, tubule, and Bowman \200\231 s capsule. These contain C3 but no immunoglobulin. Related to de \201 ciency in complement factor H (often with partial lipodystrophy and retinal abnormalities). Type III MCGN \200 Immune deposits, as in type I, but complete disruption of the GBM with membranous change. Three distinct varieties of type III MCGN have been described. \200 An inherited form is associated with chromosome 1q32. C3 glomerulopathy \200 Isolated deposition of C3, often with similar features to type I, but with no immunoglobulin deposition. Associated with genetic or acquired abnormalities of complement regulation. Serum C3 nephritic factor is positive (see b p. 552). \200 Probably part of the spectrum of dense deposit disease. Subendothelial deposit Capillary lumen GBM Mesangial hypercellularity Endothelial cell Podocyte Fig. 7.5 Cartoon of subendothelial deposits in MCGN. CHAPTER 7 Diseases of the kidney 552 MCGN: presentation and management Presentation Idiopathic MCGN tends to affect \231\202 = \231\200 aged 8 \200\223 30. It carries a relatively poor prognosis: 7 50% ESRD at 10 yea rs. Symptoms and signs All may present as asymptomatic urinary abnormalities, acute nephritis, nephrotic syndrome, or progressive renal failure. i BP is particularly common. For presenta tion of cryoglobulinaemia, see b p. 634. MCGN type II may be associated with partial lipody strophy (absent sub- cutaneous issue in the face and upper limbs) and retinal abnormalities (pigmentation and visual \201 eld de \201 cits). Investigations \200 SCr, eGFR, U&E, albumin, LFTs, uPCR (or uACR), microscopy for red cell casts. 2 Consider potential underlying causes: immunoglobulins, serum and urinary protein electrop horesis ( 9 serum free light chains), hepatitis serology (for HCV and MCGN, see b p. 686), rheumatoid factor, cryoglobulins, complement components, and C3 nephritic factor ( b p. 41) . Complement in MCGN \200 Type I MCGN: Classical pathway is activated by immune complexes l normal/ d C3 and d C4). Type II MCGN (dense deposit disease): Alternate pathway is activated l d C3, normal C4. \200 A stabilizing IgG binding a C3 con vertase (C3Bb) occurs in dense deposit disease l persistent cleavage of C3. This is termed the C3 nephritic factor. Type III MCGN: Findings similar to type II but without the C3 nephritic factor. Management \200 2 Exclude s causes of MCGN prior to treatment. \200 For treatment of HC V-related MCGN, see b p. 688. \200 (cid:2) Evidence-based treatment strategies are lackin g for primary MCGN. Many early studies almost certainly (inadvertently) included patients w ith s MCGN. General measures \200 Stop smoking (as in all progressive nephropathies). \200 Treat i BP vigorously. \200 Reduce proteinuria: use ACE-I or ARB. \200 Restrict s alt intake 9 diuretic ( b p. 538). \200 Dual antiplatelet therapy with aspirin and dipyri damole is no longer widely advocated. MCGN: PRESENTATION AND MANAGEMENT 553 Immune suppression The following strategies may offer bene \201 t. They are generally rese rved for patients with the nephrotic syndrome and progressive renal impairment. \200 Cort icosteroids (tapering prednisolone started at 1mg/kg/day). An alternate day, long-term corticosteroid regimen has been common in pediatric practice. Corticosteroids 9 cyclophosphamide 1.5 \200\223 2mg/kg/day for \211 6 months. \200 Cor ticosteroids 9 MMF for \211 6 months is a potentially less toxic alternative. MCGN: towards a new classi \201 cation Until recently, MCGN was generally classi \201 ed as described on b p. 550; i.e. either p (idiopathic) or s if an underlying cause could be i denti \201 ed. p MCGN was further classi \201 ed into I \200\223III based on ultrastructu ral appear- ances and distribution of electron-dense deposits. More recently, a bet- ter un derstanding of the pathogenetic role of complement in MCGN has informed a new view of the l esion, with categorization into either Ig-mediated disease (driven by the classical complem ent pathway) or non-Ig-mediated disease (driven by the alternative complement path- way) (s ee Fig. 7.6). The non-Ig-mediated group, referred to as C3 glo- merulopathy, includes dense deposit disease and C3 glomerulonephritis. C3 glomerulopathy is a proliferative lesion, us ually with a MCGN-type appearance on light microscopy. C3 alone on immunostaining suggests overactivity of the alternative complement pathway. Historically, clinical trials within MCGN have selected patients with comparable histology on light microscopy \200\223 meaning that many different etiologies were probably represen ted. It is hoped that advances in clin- icopathological understanding will foster diagnosti c clarity and generate disease-speci \201 c therapies. MCGN or other proliferative GN (e.g. mesangioproliferative GN or crescentic GN) on LM C3 + Immunoglobulin on IF C3 alone on IF C3 glomerulopathy: complement alternative pathway-mediated GN Immune-complex-mediated GN Mesangial and intramembranous highly election-dense deposits on EM Mesangial, subendothelial, subepithelial, and/or intramembranous deposits on EM DDD C3GN