CXR. mammography (in women). stool for fecal occult blood. colonoscopy. measurement of tumo r markers, such as prostate- speci \201 c antigen (PSA). These biopsy stages do not correlate with clinical disease severity, treatment response, or outcome. For patients with acutely deteriorating renal function and an active urinary sediment, anti -GBM antibodies should be sought. Development of these antibodies is a rare but well- recog nized complication of MN. For patients with suspected thromboembolic events, including thos e with flank pain and hematuria, renal venography should be considered to look for renal ve in thrombosis. Important histological variants Focal sclerosis This \201 nding predicts rapid progressio n to ESRF. Glomerular crescents The presence of anti-GBM antibodies is associated with the development of crescentic glomerulonephritis on a background of MN. A. SALMON AND S. HARPER 108 (a) (b) (c) Fig. 3.6.1 (a) Glomerulus stained with methanamine silver showing \200\230spike \200\231 f ormation. (b) Immuno \202 uorescence microscopy showing granular deposition of IgG around capillary loops. (c) Electron micrograph showing numerous subepithelial electron-dense depo sits and foot process effacement. (Courtesy of Dr Nick Mayer, Consultant Histopathologist, University Hospitals of Leicester, UK.) Patient advice General As with all causes of chronic kidney disease, patients with MN and C KD 3, 4 and 5 must pay close attention to cardio- vascular risk and: \200 stop smoking; \200 eat a healthy and balanced diet; \200 take regular exercise. Atypical deposits IgA- or C1q-positive immuno \202 uorescence, mesangial cell proliferatio n and mesangial or subendothelial deposits indicate an increased likelihood of underlying m alignancy. Panimmunoreactivity Positive immuno \202 uorescence for IgM and/or IgA, along- side IgG, p articularly in mesangial areas, indicates underly- ing SLE. Pregnancy ACEIs or A2R blockers should be avoided in women con- sidering pregnancy When pre gnant, patients should be monitored in a renal \200\223 obstetric clinic. 90% of pregnancie s in patients with MN result in live births. Repeated pregnancies do not alter the outcome of MN. Risk strati \201 cation Older age and male gender adversely affects prognosis. Persistent proteinuria (>8 g/day for >6 months, >6 g/day for >9 months, or >4 g/day for >1 year) has a high (>65%) positive predictive value for progression to ESRF. Impaired renal function is a useful index (positive predic- tive value >60%) of progression to ESRF. The rate of chang e of creatinine clearance over time is a better index of disease severity than creatinine a t presentation. Published algorithms augment the speci \201 city and positive predictive v alue of prognostically important clinical factors. The use of published methods of risk str atification is variable, both in practice and in therapeutic trials. Pharmacological treatment Nonspeci \201 c measures Blood pressure: treat to National Guide lines. \200 Dietary sodium restriction. \200 Diuretics. \200 Renin \200\223angiotensi n system blockade. CHAPTER 3.6 Membranous nephropathy 109 Secondary hyperlipidemia \200 Dietary measures. \200 HMG CoA reductase inhibitors (aim LDL-cholesterol <3 mmol/L, total cholesterol <5 mmol/L, or a 30% reduction from baseline fo r either parameter; extrapo- lated from national targets). The use of immunosuppression should be balanced against the risk of worsening the malignant disease. Systemic lupus erythematosis Evidence-based recommendations for therapy speci \201 c to SL E-related MN are lacking. The natural history and therapeutic approaches are similar to idi opathic MN. Anticoagulation \200 Decision analysis models predict bene \201 t from prophy- lactic wa rfarin therapy. Recommendations are for treatment in severe nephrotic states (serum albumin <20 g/l). HBV In the minority of children in whom MN does not spontaneously remit, interferon- ther apy is effective and well-tolerated. Successful therapy with interferon- and lamivudine h as been reported in adult patients with HBV-associated MN. Decrease urinary protein excretion \200 Renin \200\223angiotensin system blockade with AC EIs or A2R blockers should be titrated to a maximal dose (alone or in combination) as long as there are no adverse effects on systemic BP, GFR or serum potassium. Drugs Withdraw any drug therapy considered to be causative. De novo MN in renal allografts No formal evidence supports changes to immunosuppres- sive t herapy although, if accompanied by deteriorating graft function, use of calcineurin inhibit ors can be minimized. In individuals with well-maintained serum albumin the above measures may be all that is req uired. For those who are overtly nephrotic corticosteroids alone are often suf \201 cient to induce clinical remission, although the use and enthusiasm for such treatment varies bet ween centers and countries. Prognosis and follow-up Idiopathic MN Patients with partial remissions or normal renal func tion after 3 years have an excellent prognosis. Of the one-third of patients who progress t o ESRF, the proportion who are dead or dialysis dependent is 30% at 5 years, 70% at 10 year s and 80% at 15 years. Disease-speci \201 c measures Routine use of cytotoxic therapies is still controversial an d these are often reserved for those at the highest risk of progression to ESRF (usually th ose with severe and/or resistant nephrosis and those with deteriorating renal function). Th ere is often considerable delay between the start of therapy and a reduction in urinary pro tein excre- tion. Several treatment regimens have been described: Secondary MN Malignancy Nephrotic syndrome frequently, though not invariably, resolves with treatment of the malignant disease given time (6 \200\22318 months). Tumor prognosis deter mines outcome, but is often poor (75% mortality 3 months after the diagnosis of malignancy) . Corticosteroids plus chlorambucil Methylprednisolone 1 g IV for 3 days, then 0.5 mg/kg pred - nisolone orally for 1 month, alternating with 1 month of chlorambucil 0.1 \200\2230.2 mg/ kg/day for 6 months. Outcome: Decreased proteinuria, slower rate of decline of renal functi on, and decreased progression to ESRF. Systemic lupus erythematosis Monitoring for transformation into the more aggressive forms o f lupus nephritis (e.g. proliferative nephritis) is important. Corticosteroids + cyclophosphamide Methylprednisolone 1 g IV for 3 days, then 0.5 mg/kg pre d- nisolone orally for 1 month, alternating with 1 month of cyclophosphamide 2.5 mg/kg/day for a total of 6 months. Comparable ef \201 cacy to the corticosteroid + chlorambucil regi men, with a better adverse effect pro \201 le. HBV The course is more benign than idiopathic MN. Most children exhibit spontaneous remissi on within 5 years. 50 \200\22375% of patients treated with anti-HBV therapy experi- ence su stained remission. Ciclosporin 3.5 \200\2235 mg/kg/day Higher rates of complete or partial remission of nephro tic syndrome, and short-term preservation of renal function, when compared with placebo. Sh ort (<12 \200\22324 month) courses are associated with a higher relapse rate. Drugs Drug discontinuation leads to resolution of nephrotic syn- drome within 12 \200\22336 months. Progressive renal failure is very uncommon in this setting. Renal transplantation De novo MN in renal transplant recipients does not adversely affect g raft survival and is not considered a con- trainduction to retransplantation. Alternative third-line strategies Some preliminary evidence supports the consideration of m ycophenolate mofetil, IV immunoglobulin, pentoxyfylline, rituximab, and eculizumab. Further clinical trials are necessary to evaluate the utility of these agents. Further reading Burstein DM, Korbet SM, Schwartz MM. Membranous glomeru- lonephritis and malignancy. Am J Kidney Dis 1993; 22: 5 \200\22310. Cattran DC. Mycophenolate mofetil and cyclosporine therapy in membranous nephropathy. Semin Nephrol 2003; 23: 272 \200\223277. Cattran DC, Pei Y, Greenwood CM, Ponticelli C, Passerin i P, Honkanen E. Validation of a predictive model of idiopathic mem- branous nephropathy: i ts clinical and research implications. Kidney Int 1997; 51: 901 \200\223907. Underlying disease Malignancy Primary treatment should be directed at the underlying malign ancy. A. SALMON AND S. HARPER 110 Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylpred- nisolone plus cyclophosphamide in idiopathic membranou s nephropathy. J Am Soc Nephrol 1998; 9: 444 \200\223450. Cattran DC, Appel GB, Hebert LA, et al. Cyclosporine in patients with steroid-resistant mem branous nephropathy: a randomized trial. Kidney Int 2001; 59: 1484 \200\2231490. Glassock RJ. Diagnosis and natural course of membranous Reichert LJ, Koene RA, Wetzels JF. Prognostic factors in idiopathic nephropathy. Semin Nephrol 2003; 23: 324 \200\223332. membranous nephropathy. Am J Kidney Dis 1998; 31: 1 \200\22311. Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrot ic syndrome: a comparison of renal biopsy \201 ndings from 1976 \200\2231979 and 1995 \200\2231997. Am J Kidney Dis 1997; 30: 621 \200\223631. Internet resources MGN Support Group: Hariharan S, Peddi VR, Savin VJ, et al. Recurrent and de novo renal diseases after renal tr ansplantation: a report from the renal allo- graft disease registry. Am J Kidney Dis 1998; 31: 928 \200\223931. http://www.mgninfo.co.uk/ National Kidney Foundation: Jefferson JA, Couser WG. Therapy of membranous nephropathy associated with malignancy and s econdary causes. Semin Nephrol 2003; 23: 400 \200\223405. http://www.kidney.org.uk/ See also Nephrotic syndrome, p. 80 Renal biopsy, p. 32 Systemic lupus erythematosis, p. 180 Malignancy-associated glomerular disease, p. 134 Malik GH, Al-Harbi AS, Al-Mohaya S, et al. Repeated pregnancies in patients with primary me mbranous glomerulonephritis. Nephron 2002; 91: 21 \200\22324. Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study wi th methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 1995; 48: 1600 \200\2231604. This page intentionally left blank A. SALMON AND S. HARPER 112 Mesangiocapillary glomerulonephritis Mesangiocapillary, or membranoproliferative, glomeru- lonephritis (MCGN) is an uncommon cau se of glomeru- lonephritis. MCGN is typically related to complement-mediated glomerular dam age, either through immune complex (or cryoglobulin) deposition and complement activation i n situ, or through chronic activation of complement pathways. Idiopathic disease is most co mmon in children, whereas hepatitis C virus (HCV)-related disease is most common in adults. There is no clear consensus about the optimal treatment of MCGN. MCGN type II is associated with: The presence of C3 nephritic factor (often in association with partial lipodystrophy). Impaired factor H function (de \201 ciency, defect or auto- a ntibodies). MCGN type III Two lines of evidence support the hypothesis that MCGN types I and III are di fferent histological phenotypes of the same disease. \200 \200 Reports of MCGN types I and III in siblings. Similar etiological agents are associated with both MCGN types I and III. De \201 nition MCGN is a histological diagnosis, characterized by profuse glomerular hyper cellularity (proliferation of mesangial cells and matrix), thickening of capillary walls wi th dense dep- osits, and splitting of the basement membrane ( \200\230double contouring \200\231) due to mesangial interposition. It is classi \201 ed into types I, II and III, p rimarily according to the distribution and morphology of electron-dense depos- its on elect ron microscopy. Pathogenesis MCGN types I and III A number of steps contribute to the pathogenesis of MCGN type I. The persistence of either: \200 circulating immune complexes, either through continued formation (e.g. chronic infection) o r impaired elimina- tion (hepatic and splenic disease); or cryoglobulins. Epidemiology The European incidence is 0.9 cases pmp per year, where it accounts for 10% of cases of nephrotic syndrome. MCGN is more common in South America, Asia and Africa, wher e it accounts for 30 \200\22340% of cases of nephrotic syn- drome, predominantly because of associations with chronic infection. Peaks of incidence are between the ages of 6 and 30 y ears (commonly associated with nephritic factors) and in older adults (commonly associated with HCV). MCGN type I is more common in females than in males; MCGN type II occurs with ap proximately equal frequency in males and females. It is more common in Caucasian than in Bl ack individuals. Familial forms of all three types of MCGN are reported, albeit infrequentl y. Glomerular deposition of immune complexes (or cryoglobulins). Complement activation, via th e classical pathway, within the glomerular capillary wall (with the involvement of the \200\230nephritic factor of the terminal pathway \200\231 (NFt) in some cases of MCGN type III). Leukocyte recruitment. Subsequent capillary wall damage, mediated by growth fac- tors , cytokines and proteases. MCGN type II This results from persistent activation of the alternative pathway of compleme nt at the level of C3. This usually occurs because of: \200 the presence of an autoantibody (C3 nephritic factor: (C3Nef)) that binds to and activates the alternative pathway C3 convertase (C3bBb). Less commonly it occurs because of: \200 Etiology Etiology of MCGN varies according to the histological subtype. impaired function of an inhibitor of the alternative path- way (factor H). MCGN type II may occur in association with partial lipod- ystrophy, because adipocytes disp lay surface expression of complement components, the inappropriate activation of which by C 3Nef results in adipocyte cell loss. MCGN type I is associated with: Mixed cryoglobulinemia (type II or III). Viral infection (p articularly HCV, but also hepatitis B virus (HBV) and HIV). Bacterial infection (particular ly bacterial endocarditis and abscesses). Parasitic infection (Malaria (Plasmodium malariae ) and schistosomiasis). Complement de \201 ciency (hereditary or acquired). Systemic lupus erythematosis (SLE) and Sj gren \200\231s syndrome. Sickle cell disease. Chronic liver di sease (cirrhosis and 1-antitrypsin de \201 - ciency). Malignancy (chronic lymphocytic le ukemia, lymphoma). Natural history Idiopathic MCGN has a relatively unfavorable prognosis. Adverse prognostic markers include: \200 \200 \200 \200 abnormal renal function. nephrotic-range proteinuria. hypertension. interstitial \201 bro sis. MCGN may recur in a renal allograft: \200 \200 types II and III 85% risk of recurrence; type I 25% risk of recurrence. CHAPTER 3.7 Mesangiocapillary glomerulonephritis 113 Recurrent disease has a negative impact on graft survival. The addition of cyclophosphamide to standard immunosup- pressive therapy may be considered in these circumstances. C3NeF present in 75% of patients. MCGN type III \200 As for MCGN type I, except that classical pathway com- ponents (C4, C1q) are usually normal Symptoms and signs There are \201 ve major clinical patterns of presentation, which are u sually associated with signi \201 cant hypertension: \200 asymptomatic microscopic hemat uria and non- nephrotic proteinuria ( 20%). nephrotic syndrome and minor renal function imp air- ment ( 50%). acute nephritic syndrome ( 15%). recurrent macroscopic hematuria ( 10%). end-stage renal failure (either acute or chronic) ( 5%). MCGN type II, although relatively uncommon, may be associated with: \200 Serological markers provide no information about disease severity or activity. Renal biopsy \201 ndings Light microscopy Glomeruli are hypercellular and enlarged, due t o: \200 \200 mesangial cell proliferation and matrix expansion; leukocyte (neutrophil and monocyte) in \201 ltration. \200 \200 Glomerular hypertrophy is absent. Glomerular capillary walls are thickened, due to expansio n of mesangial cells and/or matrix into the capillary wall. This gives rise to the \200 \230double contour \200\231 appearance of the glomerular capillary wall that is best apprec iated with silver-methanamine staining. In MCGN type II, basement membranes in many locatio ns (e.g. Bowman \200\231s capsule, tubules, peritubular capillaries) are thickened. Crescen ts are present in <10% of biopsies. Impaired renal function is accompanied by interstitial in \202 ammation, tubular atrophy, and interstitial \201 brosis. MCGN type II is conside red by some to be a different dis- ease from MCGN types I and III, and the diseases are cla s- sified together merely because of similar histological appearances on light microscopy. absent SC tissue in the face and upper limbs (partial lipo- dystrophy). visual \201 eld d efects and mottled retinal pigmentation (Drusen bodies). Cryoglobulin-associated MCGN (usually in adults) may present with: \200 \200 \200 \200 arthralgia, weakness and purpuric rash; ulcerative skin lesions; peripheral neuropathy; Ray naud \200\231s phenomenon. Additional clinical features of underlying associated dis- eases (see \200\230Etiology \200\231) should be sought. Differential diagnosis Following renal biopsy, careful consideration should be given to the presence of: \200 \200 \200 \200 Immunohistology The classic pattern is granular C3 positivity in the capillary wall and mes angial areas. This may be accompanied by: \200 post-streptococcal glomerulonephritis; paraproteinemias; thrombotic microangiopathy; transp lant glomerulopathy (in renal allografts); other early complement components (e.g. C1q), IgG and occasionally IgM in MCGN type I; litt le or no immunoglobulin positivity in MCGN type II; C5, properdin, IgG and IgM detected in the capillary walls in MCGN type III. \200 particularly because many of these diseases also cause complement consumption. Electron microscopy Different appearances on electron microscopy de \201 ne the different types of MCGN. MCGN type I is characterized by the presence of suben- dothelial electron-de nse deposits. These are occasionally accompanied by mesangial and subepithelial deposits. M CGN type II is characterized by the deposition of amor- phous electron-dense deposits (henc e the alternative name of this disease: \200\230dense deposit disease \200\231) in the lam ina densa of the GBM, leading to basement membrane thickening. MCGN type III is characteriz ed by dense deposits in: \200 \200 \200 General investigations Assessment of renal function, blood pressure, urinary protein excret ion and serum albumin, urinalysis and renal size are mandatory for the investigation of sus pected glomerulonephritis. Special investigations The diagnosis of MCGN requires a renal biopsy. Once con \201 rmed o n renal biopsy, investigations directed towards underlying diseases associated with MCGN sh ould be instituted. Complement levels/factors help to distinguish between the different typ es of MCGN. subendothelial regions; mesangial areas; subepithelial regions. MCGN type I \200 \200 \200 \200 These deposits result in a laminated appearance of the basement membrane in MCGN type III. Low C3 in 50% of patients. Low classical pathway components (C2, C4, C1q). Low or normal t erminal components (C5, C8, C9). NFt may be present. Risk strati \201 cation Adverse prognostic clinical features include: \200 \200 \200 \200 older age; renal impairment; nephrotic syndrome; hypertension at presentation. MCGN type II \200 \200 Low C3 in 75% of patients. Normal levels of classical pathway (C2, C4, C1q) and terminal ( C5, C8, C9) components. A. SALMON AND S. HARPER 114 Bene \201 t has been demonstrated for: \200 Adverse prognostic histological features include: \200 \200 \200 \200 children with idiopathic MCGN type I treated with cor- ticosteroids; adults treated with an tiplatelet agents (small studies also demonstrate bene \201 t in children). interstitial \201 brosis; tubular atrophy; glomerular crescents; a high proportion of scl erotic glomeruli. Evidence is lacking for the use of steroids in adults. Patient advice General As with all causes of chronic kidney disease patients with MCGN and CKD 3, 4 and 5 must pay close attention to cardiovascular risk and: \200 \200 \200 Corticosteroids (in children) Alternate-day prednisolone (40 mg/m2) (for \211 3 \200\2236 months and for up to 10 years), when compared with control, has been shown to improve: \200 creatinine clearance; \200 renal survival; \200 biopsy \201 ndings. stop smoking; eat a healthy and balanced diet; take regular exercise. Antiplatelet agents Aspirin (375 \200\223925 mg/day) + dipyridamole (150 \200\223300 mg/ da y) improves: \200 Pregnancy Patients with high risk clinical pro \201 les (particularly those receiving ACE inhibitors or A2R blockers) should be offered preconception counseling and, when pregnant, undergo careful monitoring in a combined renal \200\223obstetric clinic. Adverse fetal outc ome is more likely in offspring of women with MCGN type I as compared with those with MCGN type II. Patients with MCGN are more likely to experience dete- riorating renal function, p roteinuria and hypertension dur- ing pregnancy, as compared with many other glomerular dise ases. renal survival at 5 (but not 10) years (when administered for 1 year); proteinuria. Purported mechanisms include altered glomerular hemo- dynamics, decreased mesangial prolife ration and antiplate- let effects. Alkylating agents In patients with rapidly deteriorating renal function and crescentic dise ase on biopsy, methylprednisolone followed by oral prednisolone and cyclophosphamide should be considered. Pharmacological treatment Nonspeci \201 c measures Blood pressure: treat to National Guide lines. \200 \200 \200 \200 Alternative strategies Preliminary evidence supports the use of mycophenolate mofetil, part icularly in steroid-resistant cases. Ciclosporin in combination with prednisolone may also be of bene \201 t. Further randomized controlled trials are necessary to evaluate the util ity of mycophenolate mofetil and ciclosporin. Dietary sodium restriction. Renin \200\223angiotensin system blockade. Diuretics. Additiona l agents where necessary. Secondary hyperlipidemia: \200 \200 MCGN type II Steroids and calcineurin inhibitors are ineffective. Plasma exchange has been effective when disease is due to inactivating mutations of factor H, but less effective whe n the cause is C3Nef. The utility of mycophenolate mofetil is not yet established. Rituxima b has been suggested for use in patients with C3Nef, but again its role needs to be more cl early de \201 ned. Dietary measures. HMG CoA reductase inhibitors (aim LDL-cholesterol <3 mmol/l, total choles terol <5 mmol/l, or a 30% reduc- tion from baseline for either parameter; extrapolated from current national targets). Reduce urinary protein excretion. Decrease urinary protein excretion: Renin \200\223angiotensin system blockade with ACEIs or A2R blockers should be titrated to a maximal dose (alone or in combination) as long as the re are no adverse effects on systemic BP, GFR or serum potassium. Underlying disease HCV Interferon- has been shown to improve renal function, cryoglobulin levels, and HCV RNA load. Relapse commonly occurs on drug withdrawal, although this is usu ally reversible with reinstitution of therapy. Promising anecdotes report successful therap y with inter- feron- and ribavarin in combination, although ribavarin is contraindicated once creatinine clearance is <50 mL/min. Aggressive therapy with: \200 \200 \200 Anticoagulation: Preliminary reports document improvements in renal function and proteinuri a with the combined use of antico- agulation and antiplatelet therapy in MCGN. Renal vein t hrombosis is reported in patients with neph- rotic syndrome due to MCGN. Anticoagulation sh ould be considered, as in other glomerulonephritides, in severe nephrotic states (serum alb umin <20 g/L). Disease-speci \201 c measures MCGN type I Disease-modifying treatment is recommended for t hose with nephrotic-range proteinuria or deteriorating renal function. steroids + cyclophosphamide; plasmapheresis; rituximab. has been reported in severe cases. CHAPTER 3.7 Mesangiocapillary glomerulonephritis 115 SLE and rheumatological diseases Standard treatment of the underlying disease should be ins tituted. light microscopy, but without the presence of immune deposits. References Appel GB, Cook HT, Hageman G, et al. Membranopro liferative glomerulonephritis t ype II (dense deposit disease): an update. J Am Soc Nephrol 2005; 16: 1392 \200\2231403. HBV Spontaneous remission is common, and therefore immu- nosuppression is rarely required. D \200\231Amico G, Ferrario F. Mesangiocapillary glomerulonephritis. Prognosis and follow-up MCGN type I Prognosis is heavily dependent on the presence or absen ce of nephrotic syndrome at presentation. Nephrotic syndrome \200 \200 J Am Soc Nephrol 1992; 2(10 Suppl): S159 \200\223166. Hariharan S, Adams MB, Brennan DC, et al. Recurrent and de novo glomerular disease after re nal transplantation: a report from Renal Allograft Disease Registry (RADR). Transplantation 1999; 68: 635 \200\223641. Miller G, Zimmerman R, Radhakrishnan J, Appel G. Use of myco- phenolate mofetil in resistan t membranous nephropathy. Am J Kidney Dis 2000; 36: 250 \200\223256. 50% ESRF at 10 years; 90% ESRF at 20 years. Zimmerman SW, Moorthy AV, Dreher WH, Friedman A, Varanasi U. Prospective trial of warfarin and dipyridamole in patients with membranoproliferative glomerulonephritis. Am J Med 1983; 75: 920 \200\223927. Absence of nephrotic syndrome \200 15% ESRF at 10 years. MCGN type II Prognosis is less favorable than MCGN type I (median renal survival 5 \200\223 10 years). Internet resources The British Kidney Patient Association: MCGN type III There is no concordance in the literature about the out- come of MCGN type II I. http://www.britishkidney-pa.co.uk/ National Kidney Federation: http://www.kidney.org.uk/ National Kidney Foundation: Recurrent disease post-transplantation Recurrence is both common (20 \200\22330%) and likel y to lead to graft failure ( \211 40%) in MCGN type I. Recurrence occurs in 50 \200\223100% of cases of MCGN type II, although recurrences tend to be mild and <20% of grafts are lost as a result. Recurrent MCGN must be differentiated from trans- plant glomerulopathy, which has similar appearances on http://www.kidney.org/ See also Immunological investigation of renal disease, p. 36 Mixed cryoglobulinemia and hep atitis C infection, p. 176 Systemic lupus erythematosis, p. 180 A. SALMON AND S. HARPER 116 Acute endocapillary glomerulonephritis Acute endocapillary glomerulonephritis (AEGN) is the most common form of glomerular lesion worldwide and results from an infection-stimulated immunological response that initiates in \202 ammation and cellular prolifera- tion within the glomerulus. When appropriate clinic al support is available the progno- sis is generally good, especially in children. The prim ary treatment is directed at eradicating the underlying infection. bacteria: staphylococci (occasionally MRSA), mycobac- teria, meningococci, salmonella; viru ses: Hepatitis B virus, Epstein \200\223Barr virus, cytomegalo- virus, rubella, mumps; fung i: candida, coccidioides, histoplasma; parasites: malaria, schistosomiasis, toxoplasmosis, \201 liariasis. \200 Natural history The outcome of AEGN is generally good with 100% recov- ery reported in some pediatric series. Complement levels return to normal within a few months. Proteinuria and microscopic hematuria generally resolve after 3 \200\2234 years. Even in adults the prognos is is favorable, although cases where recovery is absent or incomplete are well-recognized and this outcome becomes more common with increas- ing age. De \201 nition AEGN is a histological diagnosis, usually made in the con- text of the \200\230nephritic \200\231 syndrome. Characteristically light microscopy reveals neutrophil in \201 l- tration and immunohistochemistry demonstrates immu- noglobulin and complement deposition. Epidemiology The UK incidence is now very low although many subclini- cal cases are likely to go unnoticed. It is most commonly seen in the developing world but the incidence is fall ing with the slowly improving healthcare infrastructure and socioeconomic conditions. The m ale:female ratio is 2:1. Most cases occur in infancy, childhood and adolescence. Only 5 \200\22310% of cases occur in patients aged >40 years. Seasonal variations have been report ed but these often dif- fer between geographic regions. Symptoms and signs In addition to nonspeci \201 c symptoms of weakness, nausea and malaise , individuals usually present with features of the \200\230nephritic \200\231 syndrome and impaired renal function 1 \200\2234 weeks after onset of the infection. Common presenting features: \200 \200 \200 \200 Loin pain (thought to be due to capsular stretching). Hypertension (sometimes severe). Olig uria. Hematuria. This is said to be universal, is often asso ciated with red cell casts, an d is sometimes macroscopic. The time interval from infection to hematuria contrasts with Ig A nephropathy in which macro scopic hematuria appears hours or days post infection. Edema ( often facial). Differential diagnosis The differential diagnoses are the causes of unexplai ned rapidly declining renal function in the context of an active urinary sediment: \200 R enal vasculitis. \200 Systemic lupus erythematosis. \200 Anti-GBM disease. \200 Cryog lobulinemia. \200 Henoch \200\223Sch nlein purpura. \200 Hemolytic uremic syndrome. Etiology Glomerular lesions in AEGN are believed to result from glomerular antigen depositi on and in situ formation of immune complexes with subsequent immune-mediated glomerular inj ury. The nature of the antigen deposition is speculative except in the case of post-strepto coccal glomerulonephritis (PSGN). Pathogenesis PSGN Antigenic moieties derived from streptococcal proteins are thought to be deposited or \200\230planted \200\231 in glomeruli. Host antibodies directed against the i nfecting organism result in in situ immune complex formation. The immune complexes (and pos sibly streptococcal derivatives) activate complement and induce an in \202 amma- tory resp onse. Two prominent serotypes of -hemolytic streptococci (Lance \201 eld Grp A) have bee n highlighted as causative agents in PSGN: serotypes 12 and 49, that cause respira- tory an d skin infections respectively. Other serotypes that have been implicated are: 1, 2, 4 (res piratory), 47, 55, 57 (skin). General investigations Assessment of renal function, blood pressure, urinary protein excret ion and serum albumin, urinalysis and renal size are mandatory for the investigation of sus pected glomerulonephritis. Special investigations The diagnosis requires a renal biopsy. Investigations relating to th e underlying infection: \200 Nonstreptococcal infection-associated glomerulonephritis AEGN has been associated with a wi de variety of clinical infections including endocarditis, infected CSF shunts, infected gra fts, and tissue abscesses associated with IV drug abuse. A large number of causative organi sms have also been reported including: Infection screen of blood, urine, stool, sputum as appro- priate. Echocardiography and CXR as appropriate. Antistreptolysin antibody titers. \200 CHAPTER 3.8 Acute endocapillary glomerulonephritis 117 Other serology may be required to identify other causa- tive organisms. (a) Investigations directed at excluding the differential diag- noses would include: \200 \200 \200 \200 \200 \200 Antinuclear and anti-dsDNA antibodies. Complement levels. ANCA. Anti-GBM antibodies. Cryogl obulins. Blood \201 lm. Renal biopsy \201 ndings The principal abnormality is glomerular hypercellularity. Light microscopy Two aspects contribute to the hypercellularity of the glomeruli: \200 (b) Resident glomerular cell (endothelial and mesangial) proliferation. In \202 ammatory cell in \201 ltration (neutrophils initially, mono- cytes and lymphocytes later. A lymphocytic interstitial in \201 ltrate is also typical). The glomerular basement membrane is normal. Crescent formation is described but is rare. Immuno \202 uorescence Immune deposits are found in the GBM and mesangium. The deposits us ually contain C3, C5b \200\223C9 and immu- noglobulins (typically IgG and IgM). The pattern and distribution of immuno \202 uorescence stain- ing is said to vary according to the ti me after onset of dis- ease and with the degree of proteinuria. Electron microscopy Subepithelial deposits ( \200\230humps \200\231) are typical in post-st repto- coccal glomerular lesions. Subendothelial and intramembranous electron-dense deposit s also occur in post-streptococcal and nonstrepto- coccal AEGN. Fig. 3.8.1. (a) Methanamine-silver-stained glomerulus showing diffuse proliferative changes with endocapillary proliferation. (b) Electron micrograph demonstrating a well-demarcated subepithe- lial electron-dense deposit. (Courtesy of Dr Nick Mayer, Consultant Histopatholo gist, University Hospitals of Leicester, UK.) Risk strati \201 cation Older age, male gender, persistent proteinuria (beyond 4 years) an d long-term impaired renal function are poor prognostic markers. The presence of acute rena l failure at presentation is not necessarily associated with a poor outcome. Blood pressure: treat to levels suggested by National Guidelines. \200 \200 \200 \200 Dietary sodium restriction. Diuretics. Renin \200\223angiotensin system blockade. Additiona l antihypertensive agents where necessary. Patient advice General Those in whom renal function returns to normal can be reassured, and long-term follow-up is not required. However, in individuals in whom AEGN leads to CKD, in line with the management of other glomerular lesions that may lead to progressive renal im pairment, attention should be paid to cardiovascular risk: \200 \200 \200 Secondary hyperlipidemia: \200 \200 Dietary measures. HMG CoA reductase inhibitors (aim for LDL-choles- terol <3 mmol/L, total cholesterol <5 mmol/L, or a 30% reduction from baseline for either parameter; extrapo- late d from current national targets). stop smoking; eat a healthy and balanced diet; exercise regularly. Decrease urinary protein excretion: Renin \200\223angiotensin system blockade with ACEI or A2R blockers, titrated to a maximal dose (alone or in combina- tion) as long as adverse eff ects on systemic blood pressure, GFR or serum potassium concentration (a greater risk if ol iguric) are avoided. Pharmacological treatment Nonspeci \201 c measures For the minority in whom long-term rena l impairment develops, the general management should be as in any other GN lesion. A. SALMON AND S. HARPER 118 Anticoagulation: This is usually considered if the presentation is primarily with nephrotic syndrome and in those in whom there is signi \201 - cant hypoalbuminemia (<20 g/L) and lo w bleeding risk. considered although usually after de \201 nitive treatment for the primary infection is we ll underway. References Levy M. Infection-related proteinuric syndromes. In: Cameron JS, Glassock RG (ed s), The nephrotic syndrome. New York: Dekker; 1988. pp. 745 \200\223804. Supportive measures Acute kidney injury: supportive renal replacement therapy as required. Hypertensive encephalopathy is rare but requires aggres- sive therapy. Primary infection sh ould be appropriately treated avoiding nephrotoxic antimicrobials whenever possible. Moroni G, Pozzi C, Quaglini S, et al. Long-term prognosis of diffuse proliferative glomerul onephritis associated with infection in adults. Nephrol Dial Transplant 2002; 17: 1204 \200 \2231211. Naicker S, Fabian J, Naidoo S, Wadee S, Paget G, Goetsch S. Infection and glomerulonephriti s. Semin Immunopathol 2007; 29: 397 \200\223414. Simon P, Ram e MP, Autuly V, et al. Epidemiology of primary glomerular diseases in a Frenc h region. Variations according to period and age. Kidney Int 1994; 46: 1192 \200\2231198. Disease-speci \201 c measures The primary aim is to treat the underlying infective lesion with the notional aim of removing the offending putative antigen. There is no controlled tr ial data to suggest that the use of corticosteroids or other anti-in \202 ammatory/ immuno sup- pressant agents are of any bene \201 t and these are often rela- tively contraindicat ed by the underlying infective process. However, in severe disease in which there is widesp read crescent formation on biopsy, corticosteroids are sometimes Sotsiou F. Postinfectious glomerulonephritis. Nephrol Dial Transplant 2001; 16(Suppl 6) :68 \200\22370. Yoshizawa N. Acute glomerulonephritis. Intern Med 2000; 39: 687 \200\223694. See also Infection-related glomerulonephritis, p. 128 Glomerular disease in the tropics, p. 138 This page intentionally left blank A. D. SALAMA 120 Crescentic glomerulonephritis De \201 nitions A crescent is an area of extracapillary cell accumulation within Bowman \200\231s space, associated with severely damaged glomerular tufts (Fig. 3.9.1). It is so-n amed because of its appearance on renal biopsy. Crescents consist of: \200 proliferating parietal and visceral epithelial cells (podo- cytes); leukocytes: predominant ly monocytes, macrophages and lymphocytes; \201 broblasts; \201 brin; other serum compo nents leaking from the ruptured glomerular tuft. \200 \200 Crescents may enlarge rapidly and compress the glomeru- lar tuft, preventing effective glom erular blood \202 ow and \201 ltration. Crescentic glomerulonephritis (CGN) is a pathol ogical de \201 nition, which may result from a number of different etiological processes. Diffuse CGN (DCGN) is de \201 ned as crescent formation in >50% of glomeruli in a kidney b iopsy. DCGN is clinically associated with a rapid decline in renal function over weeks to m onths. This is known as rapidly progressive glomerulonephritis. The diagnosis of CGN requir es a renal biopsy to be performed. Further assessment by immunohistochemistry, electron mic roscopy and serological analysis is required to identify the particular underlying conditio n. A rapid assessment of the particular form of crescentic GN is essential for appropriate therapy to be instituted in order to avoid permanent renal failure. CGN may heal by scarrin g and lead to glomerular sclerosis with permanent glomerular damage and some degree of chro nic kidney disease. Treatment may lead to complete resolution of the crescen- tic change or healing with scarring. Based on the histological similarities in all forms of CGN, similar treatment protocols have initially been tried for the different underlying conditions. Mor e recently these have been refined based on our current understanding of the pathogenesis o f individual diagnoses. Fig. 3.9.1 The glomerular crescent is outlined by the dotted line and black arrow. The comp ressed glomerular tuft is shown by the solid white arrow.