HBV serology explained \200 The diagnosis and monitoring of HBV is based on the collectiv e interpretation of several serologic markers (+ HBV DNA + liver enzymes) (see Table 8.10). HBsAg may appear \211 1 week post-exposure but usually \211 4 \200\223 6 weeks. \200 HBsAg positivity indicates that an individual is infected ( (cid:2) and 6 potentially infectious). HBsAg persistence (>6 months) separates acute infection from chronic \200\230 carrier \200\231 status. Quantitative HBsAg testing is available, with lower levels associated with better host immu ne HBV control. Its utility for monitoring of therapy (esp. nucleoside/nucleotide analogs) is increasing. The immune response to HBsAg produces anti-HBs (as does vaccination). This usually persists inde \201 nitely. The \201 rst antibody identi \201 ed is actually anti-HBc. IgM anti-HBc indicates acute infection \200\224 and it may be the evidence of HBV acutely, before HBsAg and anti-HBs ap pear. Subsequent IgG anti-HBc persists inde \201 nitely (signifying either historical or o ngoing infection). HEPATITIS B 681 HBeAg is a marker of viral replication ( (cid:2) and 6 infectivity). Although HBeAg is often present acutely (suggesting i infectivity), that is not its main clinical utility. HBV within liver cells may be in a replicating (i.e. virus-producing) and non-replicating ( host DNA-integrated) form. As HBeAg is produced only during viral replication, it is an ext remely useful marker of viral activity during surveillance of chronic HBV carriers. HBeAg disappearance and appearance of anti-HBe is termed seroconversion. This may occur during acute HBV or years later in chronic carriers. Serocon version is good news \200\224 associated with d HBV replication, HBV clearance, clinical i mprovement, and favorable response to treatment. 2 General rule: +ve HBeAg = infectivity; +ve anti-HBs = immunity. \200 HBV DNA estimates viral burden and viral replication. It can be quantitatively measured via sensitive PCR assays. \200 HBV DNA helps: (i) to determine re covery from acute infection; (ii) to distinguish inactive carriers from those with active d isease; and (iii) to assess the appropriateness of antiviral therapy. Table 8.10 Interpretation of HBV serology Serology Status Implication HBsAg Anti-HBc Anti-HBs Negative Negative Negative Susceptible HBsAg Anti-HBc Anti-HBs Negative Positive Positive Immune due to natural infection HBsAg Anti-HBc Anti-HBs Negative Negative Positive Immune due to HBV vaccination HBsAg Anti-HBc IgM anti-HBc Anti-HBs Positive Positive Positive Negative Acutely infected HBsAg Anti-HBc IgM anti-HBc Anti-HBs Positive Positive Negative Negative Chronically infected HBsAg Anti-HBc Anti-HBs Negative Positive Negative Interpretation unclear; four possibilities 1. Resolved infection (most common) 2. False pos itive anti-HBc, 6 susceptible 3. \200\230 Low level \200\231 chronic infection 4. Resolvi ng acute infection Adapted, with permission, from the CDC. See M www.cdc.gov/hepatitis/HBV/PDFs/SerologicChart v8.pdf . CHAPTER 8 The kidney in systemic disease 682 HBV-related renal disease Introduction Three common nephropathies are described: membranous GN, MCGN, and polyarteritis nodosa (PAN). An association between HBV and IgAN has also bee n reported but may be coincidental, as IgAN is common in many populations. Minimal change, FSGS, and amyloid are also described. Pathogenesis Direct HBV renal tissue invasion does not occur (unlike HIV). Instead, viral a nd host factors (including genetic predisposition) play a role in glomeru- lar immune compl ex deposition. These complexes comprise viral anti- gens and host antibodies, either formin g in situ in the kidney or becoming trapped after circulation. The location of the immune d eposit depends on its size, which, in turn, depends on the involved antigen. Investigations Full HBV serology and HBV DNA PCR ( b p. 680). HCV and HIV serol- ogy. U&E, SCr, LFT. uPCR or uACR. FBC, INR. Full immunological screen may be required ( b p. 40). USS liver and kidneys. Renal biopsy. Membranous glomerulonephritis (MN) HBeAg \200\223 antibo dy immune complexes are small enough to pass through the capillary basement membrane and de posit in the subepithelial space and cause MN. The clinical course of HBV-associated MN dif fers between children and adults. MN is common in children aged 2 \200\223 12 years ( \231\202 > \231\200 ), presenting with proteinuria. Usually HBeAg +ve. Tends to remit spon tane- ously with seroconversion (i.e. clearance of HBeAg and development of anti-HBe). Prot einuria may persist for >1 year. Adults often present with a more chronic nephrotic syndrom e and progressive CKD in association with liver disease. >50% will reach ESRD in 3 years. Mesangiocapillary glomerulonephritis (MCGN) Immune complexes involving HBsAg are too large to traverse the base- ment membrane so settle in the subendothelial space. MCGN is more com mon in adults (>MN in that age group), presenting with i BP, heavy proteinuria, microhaemat uria, and progressive CKD (i.e. a more nephritic presentation than MN). Histology is simila r to type I MCGN ( b p. 550), with a \200\230 streetcar track \200\231 pattern \200\224 some normal capillary loops with thin BM, oth- ers with split BM. Unlike MCGN with HCV, cry oglobulins are not present. Polyarteritis nodosa (PAN) Occurs within 4 months of HBV infection in adults, presenting as a medium-vessel vasculitis attributed to immune complex deposition ( b p. 652). ANCA \200 \223 ve. Relapse rare \200\224 never once viral replication has stopped/seroconversion has occurred. Incidence appears to be falling along with the incidence of acute HBV. IgAN The liver metabolizes IgA, so serum IgA levels increase in hepatic disease of any caus e, potentially ending up secondarily deposited within the renal mesangium and capillary loo ps. Clinically signi \201 cant disease is rare. HBV-RELATED RENAL DISEASE 683 Treatment of HBV-associated disease in adults Cessation of immune complex formation require s treatment of HBV. Remission should follow seroconversion from HBeAg to anti-HBe and a red uction in, or disappearance of, HBV DNA. Long-term nucleoside analogs are often used for th is purpose (see below). Response rates are higher in MN than MCGN. Standard treatment of pr oteinuric disease with ACE-I/ARB to achieve BP <130/80mmHg and reduce urinary protein excre tion also applies. Immunosuppression should be avoided ( l i viral replication 9 hepatic de compensation \200\224 may occur on treatment with- drawal). PAN is a possible exception wh ere severity of disease may neces- sitate steroid and cytotoxic therapy, with concomitant a ntivirals. Treatment of HBV-related liver disease: a primer \200 Decisions are based on HBV DNA, ser um ALT, and assessment of liver disease (including histology). Some guidelines have slightly different criteria, a ccording to HBeAg status (with lower HBV thresholds in HBeAg \200\223 ve individuals). In general, patients should be considered for treatment when HBV DNA levels are above 2,000 IU/mL ( 7 10,000 copies/mL) 9 serum ALT is above the upper limit of normal, with evidence o f active liver in \202 ammation or \201 brosis. Anti-HBV therapy (cid:2) Much of the long-term data exclude renal patients. Treatment inclu des antivirals and immune modulators (to enhance host responses). Response rates are modest . Interferon alfa 5 million U x 6/week or 10 million U x 3/week SC for 4 months leads to un detectable HBV DNA levels and HBeAg clearance in 30 \200\223 40%. 5 \200\223 10% of patie nts relapse after treatment. SE: fatigue, \202 u-like illness (can be severe and debilita ting), depression, leucopenia, thrombocytopenia, GI upset, alopecia, transient liver \200 \230 \202 are \200\231 at outset. Peginterferon alfa A 48-week regimen has similar ef \201 cacy to interferon alfa. Peginterferon alfa 2a has an i half-life and a more stable pl asma concentration, allow- ing fewer injections and better patient tolerability. Nucleoside /nucleotide analogs Associated with lower rates of HBe and HBs seroconversion. Most evi- de nce for extra-hepatic manifestations lies with lamivudine. This inhibits viral polymerase, but ef \201 cacy is limited by the emergence of drug-resistant mutants ( 7 15% per year). Usual dose 100mg PO daily, but (cid:2) dose reduc- tions for d GFR. Adefovir is also associ ated with resistance, and renal toxicity is recognized. Entecavir and tenofovir are potent antivirals, with good safety pro \201 les and a low resistance rates thus far. Entecavir r equires a dose adjustment, according to GFR, but has not been associated with renal toxicit y so may be the treatment of choice in renal disease. Nucleoside analogs are usually continued inde \201 nitely, unless anti-HBe seroconversion is achieved. There is currently no strong evi- dence that combination therapy is superior. CHAPTER 8 The kidney in systemic disease 684 HBV and ESRD Introduction There were multiple documented HBV outbreaks on haemodialysis uni ts in the 1960s and 70s, and they occur sporadically to this day (usually because of poor i nfection control practices). Such historical outbreaks were associated with considerable mo rbidity and mortality among both staff and patients alike. By de \201 nition, blood contac t is not uncommon in this setting, and HBV is a tenacious virus ex vivo , remaining infecti ous on surfaces, even after drying, and requiring potent disinfection to inactivate. Prevention 3 The best means of controlling HBV-related renal disease is to prevent it. Offe r immunization against HBV early in CKD ( b p. 685). Household contacts and family members of HBsAg-positive patients should also be immunized. Avoid sharing potentially blood-contam inated items (tooth- brushes, etc.). Protected intercourse. Haemodialysis Haemodialysis patients are usually screened annually for HBV (and HCV) as wel l as on return from dialysing abroad. In the UK, <1% of the HD pop- ulation are HBV-infecte d. HBV patients require isolation on haemodialysis units, in addition to standard universal precautions. Dedicated machines are used and dialyser re-use avoided. Peritoneal dialysis is an option. Transplantation in patients with hepatitis B infection Transplantation is thought to offer a survival bene \201 t over remaining on dialysis, but patient selection is crucial. Patie nts with evidence of active viral replication (HBeAg +ve or HBV DNA +ve) must be treated pr ior to transplantation and should remain on a nucleoside/nucleotide analog post-transplant. IFN- A is an immune modulator and can provoke rejec- tion if used after transplantation. I n addition, patients who are HBsAg and/or anti-HBc +ve should be considered for nucleoside/ nucleotide analog prophylaxis post-transplant. Most data in this context concern lamivudine (the dose of which should be adapted to GFR). HBsAg +ve patients have about twice the mort ality of non-HBsAg patients 5 \200\223 15 years post-transplantation (probably partly due to reactivation of latent disease). Cirrhosis is a contraindication to renal transplantatio n. New acquisitions of HBV post-transplant can present with severe disease on immune sup- p ression. HBV-related GN can recur/occur in transplants. HBsAg-positive kidney donors It is acceptable practice to use HBsAg +ve donor to HBsAg +ve recipient, with using antiviral prophylaxis. However, the safety pro \201 le is less clear when using an HBsAg +ve donor for a recipient who is anti-HBs +ve (i.e. potentially immune \200\224 either as the result of prior infection or of immu- nization), as pre-existing i mmunity may not be suf \201 cient to overcome the viral load transferred with the transpla nted kidney in the presence of immunosuppression. X Small case series suggest that outcomes may be favorable. HBV AND ESRD 685 HBV vaccination in CKD Patients who are likely to require renal replacement therapy (RRT) s hould be immunized against HBV \200\224 a strategy that has been associated with a reduced incidence of HBV infection in dialysis units. Despite the lower probability of HBV infection in peritoneal dialysis patients (and patient s destined for pre-emptive transplantation), there is suf \201 cient potential they may re quire haemodialysis at some point in their life that they should also be offered immunizati on. Patients should be immunized early in the course of progressive CKD, as the proportion of p atients achieving adequate anti-HBs antibody titres is lower, compared with the general pop ulation (and lower in advanced, compared with early, CKD). Although it is desirable to know a patient \200\231 s anti-HBc status before- hand (to pre vent unnecessary immunization), HBV prevalence is so low in many populations that pre-immun ization screening may not be war- ranted. Local protocols will apply. Most HBV immunization schedules typically involve high doses or fre- quent doses (or both). Vaccines are generally administered IM (deltoid muscle), but the intradermal route may be more effective. Examples: Engerix B 40 micrograms at 0, 1, 2, and 6 months. \200 HBvaxPRO 40 micrograms at 0, 1, and 6 months. \200 Fendrix 20 micrograms at 0, 1, 2, and 6 months ( X possibly mor e immunogenic). Response is assessed through measurement of anti-HBs antibody 8 weeks after course completi on. >100mIU/mL was conventionally regarded as immunity ( \200\230 responder \200\231 ), but t here is evidence that patients who have a lower (partial) response (10 \200\223 100mIU/mL) are less likely to become chronic HBV carriers. Such partial responders (and those in whom anti-HBs titres diminish over time) should receive a further booster dose if the annual an ti-HBs titre is <100mIU/mL. \200\230 Non-responders \200\231 (<10mIU/mL) generally receive no further immuni- zation, although some protocols give a further full course before accept- ing this status. CHAPTER 8 The kidney in systemic disease 686 Hepatitis C-related renal disease Introduction HCV is an RNA virus with six different genot ypes, causing hepatitis, cirrho- sis, hepatocellular carcinoma, and various extra-hepatic d isorders. 150 \200\223 170 million people are HCV-infected worldwide, with large geographi cal variation. Transmission is parental and associated with IVDU, accidental infection duri ng healthcare (e.g. needle or multidose vial re-use, contami- nated blood products, or poor ly sterilized instruments), and regional cul- tural practices. Perinatal and sexual transmi ssion also occur but are less important than for HBV and HIV. Infection is mild (often subclinical), following an incubation period (6 \200\223 9 weeks) . 70 \200\223 85% fail to clear acute infection and become chronic carriers. Hepatitis C-related glomerulonephritis HCV is associated with several types of renal diseas e, predominantly: MCGN with mixed (type II) cryoglobulinaemia, membranous nephropathy (MN), and polyarteritis nodosa (PAN). Also recognized: FSGS, proliferative GN, \201 brillary a nd immunotactoid GN, IgAN. Chronic HCV and associated mixed cryoglobulinaemia are now known to be the principal cause of type I MCGN (previously thought to be idiopathic). Renal involvement in some may be mild or clinically silent; in others, there is a signi \201 cant risk of progression to ESRD (worse if co-infected with HBV/HIV). HCV-related type I MCGN 2 to type II (mixed) cryoglobulinaemia Cryoglobulins are one (mon oclonal) or more (polyclonal or mixed) immu- noglobulins in serum that reversibly precipita te at <37 * C ( b p. 634). Pathogenesis HCV-induced clonal expansion of rheumatoid factor ( RhF)-expressing B cells in the liver, lymph nodes, and circulation causes excess secretion of immunoglobulins (predominantly IgM kappa ( ) directed against IgG, which is itself di rected against HCV). These proteins (IgM , IgG, and viral antigens) aggregate into large cryoglobulins. HCV may also be responsible for type III mixed cryoglobulinaemia comprising polyclonal immunoglobu- lins (see b p. 634). The cryoglobulins deposit in small and medium -sized vessels in the skin, joints, and glomeruli, where they \201 x complement and cause local in \202 ammation and injury. Prolonged clonal expansion of B cells can eventually l ead to B cell lymphoma ( 7 5%). Pathology Renal biopsy shows a type I MCGN pattern of injur y ( b p. 550). \200 Light microscopy: glomerular hypercellularity, lobular accentuation o f glomerular tuft, increased matrix and mesangial proliferation, splitting of capillary basem ent membranes (termed double contouring), intracapillary thrombosis (from cryoglobulin depo sition), vasculitis, and \201 brinoid necrosis. Immunostaining: deposits of IgG, IgM, and C3 in the mesangium and capillary walls. HEPATITIS C-RELATED RENAL DISEASE 687 EM demonstrates large subendothelial deposits that may have a tactoid distribution/size pat tern, characteristic of cryoglobulin deposition (measuring 15 \200\223 30 microns, distinc t from smaller \201 brillary deposits measuring 12 \200\223 25 microns). These are so la rge they may protrude into the capillary lumen, causing thrombosis. This appearance is diff erent from idiopathic MCGN where the subendothelial deposits are much smaller (and more com monly encountered in children and young adults). Symptoms and signs 2 Usually a systemic disease. \200 Extrarenal: fatigue, weight loss, e pisodic purpuric rash (leucocytoclastic vasculitis on biopsy), arthralgia, myalgia, mononeuritis multiplex, Raynaud \200\231 s phe nomenon. Hepatosplenomegaly and stigmata of liver disease. Renal: the kidney is affected in 60%. Manifestations include haematuria, proteinuria (often nephrotic range), (i BP, renal impairment (often progressive), and AKI (5%). In general, H CV-associated MCGN has a nephritic presentation, whilst MN is usually nephrotic. Investigations \200 Urinalysis (haematuria, proteinuria) and microscopy (red cells casts) . \200 U&E, SCr, eGFR, Alb, LFT ( i ALT/AST), FBC, ESR, CRP. \200 Rheumatoid factor (Rh F) may be +ve. \200 Complement (normal C3, low C4) ( b p. 41). \200 Cryoglobulins ( b p . 634). The cryocrit may be surprisingly low. \200 Anti-HCV antibody, HCV RNA PCR (in ser um and cryoprecipitate). \200 If HCV viral load is low, an alternative diagnosis should b e considered, so a full immunological screen may be helpful ( b p. 40). HCV genotyping (types 2 and 3 associated with i sustained remission). \200 HBV and HIV. \200 USS liver and kidneys. \200 Renal biopsy ( b p. 80). Other HCV-related glomerulopathies \200 Non-cryoglobuminaemic MCGN occurs. It will still be associated with HCV antibodies and HCV RNA. Membranous nephropathy is uncommon. Presentation, pathology, and outcomes are similar to idiopathic MN. It is thought to result from HCV-containing immu ne complexes depositing in the glomerular basement membrane (HCV can be demonstrated by in situ hybridization). Cryoglobulins are not detected, and complements are normal. Antiviral treatment is usually recommended. HCV-associated PAN is well described ( b p. 652). It tends to be an acute, severe illness, presenting >2 years post-HCV diagnosis (with no cryoglobulins). Remi ssion rates with treatment are high. Diabetic nephropathy: HCV infects pancreatic islet cells, causing reduced insulin production, and a post-insulin receptor defect also operates. Diabetic rena l disease is 6 a consideration in long-standing HCV patients. CHAPTER 8 The kidney in systemic disease 688 HCV-related disease: management Introduction Before the link between HCV infection and cryo globulinaemia MCGN was discovered, treatments were similar to those used for other small to medium-vessel vasculitides \200\224 namely corticosteroids, alkylating agents, and plasma exchange (to remove circulating cryoglobulins). Insight into the relationship between HCV and cryoglobulinaemia has led to direct treatment of HCV, with immune suppression now reser ved for severe or refractory presentations. Several issues need to be considered prior to treatment: (1) viral genotype (some respond b etter than others); (2) degree of viraemia; (3) presence of chronic liver disease; (4) seve rity of CKD (and if dialysis or transplantation is being considered); (5) extra-hepatic man ifestations; and (6) other comorbidities (e.g. CV disease). If liver status does not warrant antiviral therapy, then parameters favoring treatment for renal involvement are nephrotic syndrome, i SCr, new i BP, and the nature and severity of t he injury on renal biopsy. If HCV viraemia is not present, the renal diagnosis should be re considered. No known therapy speci \201 cally alters renal outcome in MCGN, although antiv iral therapy may clear HCV and have modest effects on proteinuria and renal function. Relap se of HCV RNA and cryoglobulins on cessation of treatment is common. Antiviral treatment The aim is to reduce or eliminate viraemia and decrease the formation o f immune complexes. Patients with HCV infection are generally treated with peginterferon al fa (e.g. 180 micrograms/week) 9 the oral antiviral agent ribavirin (e.g. 1,000 \200\223 1, 200mg/day) for 24 \200\223 48 weeks. (cid:2) However, ribavirin is not recommended if GFR <50mL/min, and most studies have 6 excluded renal patients. There is some evidence that it is safe in hae- modialysis patients. Treatment ef \201 cacy is measured in terms of sustained virologic response (SVR) \200 \224 HCV RNA levels should be undetectable for a minimum of 6 months after cessation of the rapy. Of the six known HCV genotypes, types 2 and 3 are more responsive than types 1 or 4, with SVR rates of 80% vs 45%, respectively. SE are common: for interferon alfa, see b p. 68 3); ribavirin: haemolysis and anemia. KDIGO guidelines for HCV treatment in CKD \200 CKD stage 1 \200\223 2: peginterferon alf a and ribavirin. \200 CKD stages 3 \200\223 4: peginterferon alfa monotherapy. \200 Ha emodialysis: standard interferon alfa. \200 Ribavirin ( 9 ESA support) may be considered for all stages in specialized centers. See M < http://kdigo.org/home/guidelines/ >. HCV-RELATED DISEASE: MANAGEMENT 689 Additional treatments Adjunctive therapy should be considered for severe active disease (e. g. rapidly progressive GN, severe neuropathy, widespread cutaneous vas- culitis with ulcera tion). Antivirals will not deal with the circulating cry- oglobulins already formed (PEX), and there may be an urgent need to target B cell production (rituximab) and attenuate tissu e injury (steroids). Commencement of antivirals may need to be delayed until these goals ha ve been achieved. Options \200 Plasma exchange x 3/week for 2 \200\223 3 weeks to remove cryoglobulins. \200 Rituximab 375mg/m 2 weekly for 4 weeks to stop further B cell production (also an option if intolerant/resistant to interferon alfa/ribavirin). Corticosteroids as methylprednisolone 0.5 \200\223 1g/day for 3 consecutive days, then oral. Cyclophosphamide 1.5 \200\223 2.0mg/kg daily orally for 2 \200\223 4 months. \200 Two n ovel direct-acting antivirals \200\224 boceprevir and telaprevir \200\224 have recently b een licensed for use in combination with PEG-IFN- and ribavirin to increase the viral re sponse in genotype 1 HCV infection. Use currently limited to patients with normal renal fun ction. Low-dose IL-2 is another potential future treatment. Patients with HCV-induced vasculitis h ave reduced regulatory T cells (Tregs) function. IL-2 promotes Treg survival. Additional st udies awaited. Other considerations \200 ESA to maintain Hb >110g/L (ribavirin causes red cell fragility ). Anemia can be very problematic. ACE-I/ARB to reduce proteinuria (aim uPCR <50mg/mmol). \200 Aim BP <130/80mmHg (esp. if p roteinuria). \200 Recommend alcohol avoidance. \200 Avoid sharing potentially blood-con taminated items (toothbrushes, etc.). Protected intercourse. Screen for hepatocellular carcinoma (liver USS and serum A -fetoprotein) at 12-monthly intervals. CHAPTER 8 The kidney in systemic disease 690 HCV and ESRD Introduction As a result of potential exposure to blood-contaminated equipment , haemodialysis patients are at risk of acquiring blood-borne viruses (BBV). The prevalence of HCV infection in HD patients varies widely (5 \200\223 60%), in \202 uenced by factor s, such as regional HCV prevalence, infection control techniques, and historical blood tran sfusion screening. Standard universal precautions should always be undertaken, but HCV-infected patients do no t require isolation on haemodialysis (unlike HBV) or to be dialysed on dedicated machines, as there is no convincing evidence that this affects transmission rates (although the Europ ean Best Practice Work Group have suggested it should be considered in centers with high HC V prevalence). ALT should be checked 6-monthly, with annual screening for hepatocellular ca rcinoma (USS and serum A -fetoprotein). Hepatitis C-infected patients and transplantation Renal transplantation may offer selected HCV+ ESRD patients superior survival and quality of life, compared to maintenance HD or CAP D. It is important to assess the degree of liver damage (usually with a liver biopsy), and tho se patients with advanced disease, e.g. cirrhosis or portal hypertension, should be conside red for combined liver \200\223 kidney transplan- tation (single renal transplantation is contraindicated). Patients with active HCV will require antiviral therapy prior to trans- plantation, althoug h treatment in CKD and dialysis patients is associated with low sustained virologic respons e rates ( 7 20%) and signi \201 cant drug intolerance ( 7 30 \200\223 50% of dialysis pat ients stop treatment). (cid:2) IFN- A treat- ment post-transplant is strongly associated wi th acute rejection ( 7 50%). Post-transplantation, HCV+ transplant recipients have inferior short- and long-term outcome s, compared to HCV \200\223 patients. There is a sig- ni \201 cant increase in early ( \201 rst 6 months) infection-related deaths. Patient survival at 3 years is 7 70%. 10 \200 \223 20% progress to cirrhosis within 7 5 years. The incidence of new-onset diabetes post-transplant (NODAT) is higher in HCV+ recipients. HCV-related glomerular disease can recur/occur post-transplantation and is extremely dif \201 cult to treat (see Table 8.11). HCV-positive kidney donors X Rejecting organs from all HCV seropositive (potential) decease d donors will mean discarding organs from many who do not actually have active viral replic ation at the time. Limited experience suggests these kidneys may actually be acceptable for viraemic HCV+ reci pients, although this risks superinfection with an HCV genotype from the donor that is diff erent from the genotype of the recipient. HCV AND ESRD 691 Table 8.11 Glomerular disease related to viral infection Acute GN MCGN 9 endocapillary GN Mesangial proliferative GN Parvovirus B19 Hepatitis A IgA type GN AKI Dengue fever Mesangial proliferative GN Measles Yellow fever Epstein \200\223 Barr virus (EBV) Chronic GN Hepatitis B virus ( b p. 682) Membranous GN MCGN PAN Mesangial proliferative GN Minimal change disease IgAN MCGN 9 cryoglobulinaemia Membranous GN Hepatitis C virus ( b p. 686) Mesangial proliferative GN FSGS Fibrillary and immunotactoid GN Minimal change disease IgAN PAN HIV ( b p. 676) HIVAN HIVICK Thrombotic microangiopathy Parvovirus B19 Collapsing glomerulopathy FSGS Reproduced from Oxford Desk Reference: Nephrology, Jonathan Barratt, Kevin Harris, and Pete r Topham (2008), with permission of Oxford University Press. CHAPTER 8 The kidney in systemic disease 692 The kidney in infective endocarditis Introduction Infective endocarditis (IE) is de \201 n ed as infection of the endocardial surface of the heart. If left untreated, valvular insuf \201 ciency develops and is generally fatal. IE is mainly an infection of the left side of the heart, involving the mitral or aortic valve (or both). Right-sided endocarditis is oft en associated with IVDU, but other risk factors include pacemakers, other cardiac devices, and central venous catheters. Common causes include S. aureus in acute IE or vir- idans str eptococci and coagulase-negative staphylococci in more chronic IE. Renal dysfunction occurs due to a variety of mechanisms, including: Immune complex-mediated GN. \200 Aminoglycoside-induced AKI. \200 Drug-induced AIN. \200 Emboli (from infected valves). \200 Renal abscess formation. Epidemiology In the era of effective antibiotic therapy for IE, the incidence of renal com- plications has been variably reported (ranging from 2 to 60%). The severity of IE-associat ed GN is related to the duration of infection prior to the institution of antibiotics. Cont rol of infection usually leads to rapid resolu- tion, with recovery of renal function. Howe ver, irreversible renal damage may occur if appropriate therapy is delayed. Mortality is hi gher in those who develop renal disase. Symptoms and signs The manifestations of IE are not always classical \200\224 and they are often very similar to those found in many other systemic diseases. \200 2 Suspect IE if fever, new murmur, splenomegaly, and haematuria (especially if known to have a valvular abn ormality or prosthesis). \200 Careful examination may reveal splinter hemorrhages ( \201 ngers and/or toes), although classical stigmata of IE are often absent. Microscopic haematuria points towards GN. A bland urinalysis is unusual \200\224 suggesting an alternative diagnosis, e.g. aminoglycoside toxicity. Rash, eosinophilia, and a new fever after starting antibiotics may indicate AIN. Acute (unilateral) \202 ank pain and frank haematuria suggest emboli. This should prompt a search for evidence of emboli in other organs (check extremities). Infarction at the site of embolization is common; abscess formation is rare. Cerebral emboli occur in 7 33% of pa tients. Emboli may occur after microbiological \200\230 cure \200\231 . Investigations \200 Repeated blood cultures (and sensitivity testing) are the key to management. Use CRP to monitor treatment response. \200 Echocardiography: transthoracic echo (TTE), b ut transoesophageal echo (TOE) has superior sensitivity. Daily ECG if suspected aortic root abscess. THE KIDNEY IN INFECTIVE ENDOCARDITIS 693 Urinalysis + microscopy. Microscopic haematuria 9 proteinuria, ? GN. \200 Sterile pyuria or eosinophiluria, ? AIN. \200 FBC: anemia common. If eosinophilia, ? AIN. \200 SCr, U&E, albumin. \200 Dilige nt therapeutic monitoring of aminoglycosides if used ( b pp. 880 \200\2231). Complement components: C3, C4 (often low) ( b p. 41). \200 RhF and cryoglobulins in 7 50% (type III). \200 Renal USS. CT or DMSA if emboli suspected (focal perfusions defects). \200 Renal biopsy if diagnosis unclear or response to therapy suboptimal. Pathogenesis S. aureus IE: staphylococcal enterotoxins are \200\230 superantigens \200 \231 that bind directly to MHC class molecules of antigen-presenting cells and the speci \201 c V B chain of the T cell receptor (TCR), causing T cell activation and T cell-derived cytokine release (e.g. IL-1, IL-2, IL-6, TNF, and IFN- G ). Cytokines cause polyclonal B c ell activation and immune complex forma- tion, resulting in GN. Histology Table 8.12 shows the different histological patterns of renal disease associ- ate d with IE. Immune complex-driven GN has a spectrum of presentation from mild focal prolifer ative glomerulonephritis ( l urinary abnormalities) to diffuse crescentic necrotizing glome rulonephritis ( l AKI). It may be similar to post-streptococcal GN ( b p. 548) or MCGN ( b p. 550), with hypercellularity (due, in part, to the in \202 ux of circulating in \202 am matory cells) and immune deposits in the glomerular capillary wall. Fibrinous thromboemboli within arteries, with in \202 ammation of the adja- cent renal tis sue, may also occur as a consequence of septic emboli \200\224 renal abscesses can form at these sites. Thrombotic microangiopathy with cortical necrosis can complicate severe sepsi s. Acute tubular injury is a consequence of haemodynamic compromise (as well as nephrotoxic drugs (aminoglycosides or others). Treatment \200 If GN, cure IE, using appropriate antibiotics. There is no role for adjunctive treatments, even if crescentic change on biopsy. If ATN, tailor aminoglycoside doses to levels or change antibiotic. \200 IF AIN, change a ntibiotic. No role for steroids. \200 Valve surgery may be required. MRSA glomerulonephritis MRSA glomerulonephritis presents either as rapidly progressive glo- merulonephritis (RPGN) and/or as nephrotic syndrome with various degrees of proteinuria, u sually in the context of a severe MRSA infec- tion. Normal complement levels and polyclonal elevation of serum IgG and IgA are often seen. Histological changes are described in Table 8.12. CHAPTER 8 The kidney in systemic disease 694 e r a c h t i h t i h t i h t i w s e v o r p m w s e v o r p m w s e v o r p m w s n e s r o W e v i t r o p p u s e m o c t u O s c i t o b i t n a s c i t o b i t n a s c i t o b i t n a e b a i r a V l i i i I I I i l o b m e o b m o r h t s i t i r h p e n o u r e m o l g s a n o i t a r t l \201 n s i t i r h p e n y r a l l i l r e d r o s i d s i t i r h p e n o u r e m o l g p a c o d n e / l a g n a s e M i l a i t i t s e t n o u b u t s t n e c s e r c l a i t i t s r e t n o u b u T s u o n i r b \201 e s u f f i s i t i d r a c o d n e 7 0 1 e v i t a r e f i l e h t y g o o t s i H d . i p l r o i i l a i r e t r A l e b b f l o t r a p l l a c o F y a M e e S o r p e v i t c e f n s n i l i u b o l g o n u m m h t i M g I M g I w d e t a c o s s a , , A g I A g I A g I , , , G g I i G g I i G g I i i n n I t n e m e l p m o C e s a e s i d l a n e r n n n n d f o s e r u t a e f s t s a c e g n a r s t s a c a i r u s t s a c l l e c a i r u t a m e a H a i r u n e t o r p s i s y l a n i r U c i t o r h p e N l i h p o n i s o E r a l u n a r G l a i l l a c g o o h t a p o c n l l e c e h t i p E i i d e R l n o i t c r a f n N G x e p m o c - e n u m m y r u n i s i t i r h p e n o u r e m o l g i l j l a i t i t s r e t n C ) l i i N A r a l u b u t l a n e r 2 1 8 I ( . l s i t i r h p e n c i l i e l b a T A S R M e t u c A e t u c A o b m E I THE KIDNEY IN INFECTIVE ENDOCARDITIS 695 Table 8.13 Bacterial infection-related glomerular disease Mycobacterium leprae Amyloidosis (AA): \210\222 Glomerulonephritis \210\222 Diffuse proli ferative GN \210\222 Focal proliferative GN \210\222 MCGN \210\222 Mesangial proliferati ve GN Mycobacterium tuberculosis Amyloidosis (AA) MCGN type II Treponema pallidum Congenital syphilis: \210\222 Membranous nephropathy Acquired syphilis: \210\222 Membranous nephropathy \210\222 Diffuse endocapillary GN \210\222 MCGN \210 \222 Mesangial proliferative GN \210\222 Amyloidosis (AA) Salmonella typhi Mesangial proliferative GN IgA nephropathy Streptococcus pneumoniae Mesangial proliferative GN Diffuse proliferative GN Others reported in association with GN Brucella melitensis E. coli Klebsiella pneumoniae Yersinia enterocolitica Mycoplasma pneumoniae Legionella Bartonella henselae Reproduced from Oxford Desk Reference: Nephrology, Jonathan Barratt, Kevin Harris, and Pete r Topham (2008), with permission of Oxford University Press. CHAPTER 8 The kidney in systemic disease 696 Renal tuberculosis Introduction Tuberculosis is caused by Mycobacterium tuberculosis and af fects 8 \200\223 10 mil- lion people every year, usually presenting as pulmonary disease. The global burden of TB has risen sharply as a result of HIV infection and the increased nu mber of patients with solid organ transplants taking long-term immu- nosuppressive medicati on. (cid:2) Data from the World Health Organization (2010) suggests that one-third of the w orld population has been exposed to TB and has at least latent disease. After lymph node involvement, the most common site of extrapulmo- nary TB is the genitourin ary system (15 \200\223 30% all cases). Renal dysfunction can occur through a variety of m echanisms, including direct infection of the kidney or lower urinary tract, obstructive uro pathy, tubulointerstitial nephritis, and secondary amyloidosis. Genitourinary TB (GUTB) Pathogenesis Mycobacterium tuberculosis bacilli are inhaled into th e alveoli. Initially, the bacilli are locally contained by leucocytes and macrophages, but, over time, they are carried to regional lymph nodes and the thoracic duct before delivery into venous blood and seeding of distant organs. In the kidneys, multiple granuloma form at the site of metastatic foci. These are typically bilateral, cortical, and adjacent to the glomeruli. They can remain inactive for decades. Active granulomas may grow to invade the calyceal systems, resulting in the spread of bacil li to the renal pelvis, ureters, bladder, and other genitourinary organs, including the epi didymis and prostate. The renal medulla is preferentially affected, but subsequent papillary and pelvic involveme nt causes progressive scarring, calci \201 cation, \201 brosis, and chronic abscess form ation. Extensive lesions will result in ESRD. Ureteral TB may cause strictures (can be extensive), hydronephrosis, and obstruction. Often unilateral. Symptoms and signs Classical TB symptoms, e.g. fever, weight loss, and night sweats, are un common. Pulmonary symptoms may be absent (although 7 30% will have an abnormal CXR). Sympto ms are often non-speci \201 c, with >25% asympto- matic. It is 6 essential to maintain a h igh index of suspicion in those at risk. Abdominal (particularly back and \202 ank) pain, LUTS, recurrent UTIs that are poorly antibiotic-responsive, macro- and microscopic haematu ria, incontinence (bladder \201 brosis), infertility in both sexes. Investigation \200 Sterile pyuria (WCC on microscopy but negative culture) is characteristic ( b p. 24). Three consecutive early morning urine samples (EMUs). Microscopy for acid-fast bacilli on centrifuged urine (Ziehl \200\223 Neelsen stain) and c ulture on L wenstein \200\223 Jensen media (takes 2 \200\223 6 weeks). RENAL TUBERCULOSIS 697 EMUs for AFBs have a sensitivity of only 65% (although speci \201 city is 7 100%). More rapid results (<1 week) with a radiometric culture system (BACTEC). PCR for mycobacterial DNA can be helpful when available. It is a rapid test with high sensitivity and speci \201 city. U&E ( d Na + s to SIADH), SCr, LFTs, CRP, FBC, ESR. \200 2 Consider HIV testing. \200 T uberculin skin testing is usually undertaken; however, beware false positives in those pati ent vaccinated with BCG and false negatives in those on immune suppression. \200 Plain KU B may show calci \201 cation. \200 IVU or CT-IVU: abnormal (70 \200\223 90%), with caly ceal tip erosions ( \200\230 moth-eaten \200\231 calyx), pelvic distortion (e.g. the \200\230 hiked-up \200\231 appearance), strictures, \201 lling defects, and calci \201 cation. \200 Rena l tract USS if obstruction suspected. CHAPTER 8 The kidney in systemic disease 698 Renal tuberculosis: TB-TIN and TB in patients with ESRD Tuberculous interstitial nephritis (TB-TIN)