Clearances of 70 \200\223170 mL/min can be achieved during intermittent HD. During continuo us renal replacement therapies (CRRT) as currently practiced on the intensive care unit, cl earances typically only average 40 mL/min; however, these can be increased with faster blo od and dialyzate \202 ows. Intermittent HD is more ef \201 cient at clearing water-solub le toxins and drugs. In the cardiovascularly unstable patient intermittent HD may not be po ssible and continuous modes or hybrid dialysis techniques may be required. When treating pa tients with drug toxicity due to a drug with a large volume of distribution, such as methot rexate, then in cases which have not responded to leucovorin, clearances can be improved by extending the duration of the intermittent HD session to 8 \200\22312 h. This can be done by slowing down either the blood or dialyzate \202 ow rate to 200 mL/min respectively, a procedure sometimes termed hybrid therapy. An alternative is to perform two consecu- tive 4 \200\2236 h intermittent HD treatments. Further reading Godman JW, Goldfarb DS. The role of continuous renal replace- ment therapy in the treatment of poisoning. Semin Dial 2006; 5: 402 \200\223407. Goldfarb DS. Principles and techniques applied to enhance the elimination of toxic compound s. In: Goldfrank LR, Flomenbaum NE, Lewin NA, Howland MA, Hoffman RS, Nelson LS (eds), Gold frank \200\231s toxico-logical emergencies, 7th edn. New York: McGraw-Hill; 2002. pp. 58 \200\22368. A. DAVENPORT 338 Haddad LM, Shanon MW, Winchester JF (eds). Clinical management of poisoning and drug overdo sage, 3rd edn. Philadelphia: WB Saunders; 1998. National Institutes of Health information resource: http://www.nlm.nih.gov/medlineplus/poisoning. html American Association of Poison Control C enters: Winchester JF. Dialysis techniques: haemoperfusion. In: Horl WH, Koch KM, Lindsay RM, Ronco C, Winchester JF (eds), Replacement of renal function by dialysis, 5th edn. Dordrecht: Klu wer; 2004. pp. 725 \200\223738. http://www.aapcc.org/ Zimmerman JL. Poisonings and overdoses in the intensive care unit: General and speci \201 c management issues. Crit Care Med 2003; 12: 2794 \200\2232801. See also Clinical approach to acute kidney injury, p. 318 Renal replacement therapies in ac ute kidney injury, p. 328 Handling of drugs in kidney disease, p. 690 Drug-induced nephropa thies, p. 698 Internet resources International Program on Chemical Safety (IPCS) INTOX databank: http://www.intox.org/databank/index.htm IPCS directory of poison centers: European Region: http://www.intox.org/databank/documents/ supplem/supp/european.htm This page intentionally left blank A.J.P. LEWINGTON 340 Glomerulonephritis, vasculitis, and nephrotic syndrome Introduction Acute glomerulonephritis (GN) is an important cause of AKI (Table 10.4.1). Ear ly recognition and treatment is essential in order to preserve renal function. Small vessel vasculitis and systemic lupus erythematosus (SLE) are common causes of AKI whereas primary glomerular diseases are less commonly associated with AKI. AKI associated with vasculitis There may be clinical features of a multisystem disease: \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 fever; purpuric rash; uveitis; arthralgia; epistaxis; conductive hearing loss; sinusitis; m outh ulcers; hemoptysis; mononeuritis multiplex; hypertension; reduced pulsation over tempo ral artery (giant cell arteritis); reduced pulsation in brachial arteries (Takayasu \200 \231s arteritis); erythema nodosum (Beh et \200\231s disease). Epidemiology The incidence of AKI due to GN is poorly de \201 ned but it is estimated that 10% of cases of AKI are due to GN. In Europe and North America the most common GN-causing AKIs are: \200 \200 small vessel vasculitis; lupus nephritis. Worldwide, GN secondary to infection is the most common cause of AKI. Etiology The development of AKI in GN is multifactorial with variable contributions from ea ch of the following depend- ing on the cause. The presence of hemoptysis usually signi \201 es pulmonary hemorrhage and is associated wi th: \200 ANCA-associated vasculitis; \200 anti-GBM disease; \200 SLE. Glomerular injury Compression of the glomerular tuft and occlusion of glomerular capillarie s by the in \202 ux of in \202 ammatory cells (crescentic GN). Local generation and relea se of the potent vasoconstrictor endothelin secondary to vascular in \202 ammation. Reduce d production of the vasodilator nitric oxide secondary to vascular in \202 ammation. AKI associated with infectious glomerulonephritis This may be associated with: \200 \200 fever; sore throat (typically 10 \200\22321 days preceding post-strep- tococcal GN); rash; loin pain; heart murmur (infectious endocarditis); peripheral emboli (infectious endocardit is). \200 \200 \200 Tubulointerstitial injury Direct tubular epithelial cell toxicity from the contents of lyse d red blood cells (free iron, Hb). Tubular obstruction by red blood cells. Prerenal AKI due to hypovolemia (nephrotic syndrome, NSAIDs, overdiuresis). Increased intrarenal pressure d ue to interstitial edema (nephrotic syndrome). It has been proposed that an imbalance betwe en endothe- lin and nitric oxide secretion potentiates the relative hypoxia that exists in the outer medulla, which may lead to acute tubular necrosis. AKI associated with primary glomerulonephritis This may present with: \200 \200 \200 synpharyngitic hematuria (IgA nephropathy); hypertension; nephrotic syndrome. AKI associated with systemic sclerosis Clinical features that may be present include: \200 \200 \200 sclerodactyly; arthralgia; severe hypertension. Vascular injury Large vessel vasculitis with distal ischemia. Renal vein thrombosis in neph rotic syndrome (hypercoag- ulable state). Fibrinoid necrosis of afferent arterioles resulti ng in glomer- ular ischemia (systemic sclerosis). Differential diagnosis The differential diagnosis can be dif \201 cult due to multisystem involvement. Many of the clinical features have common causes. A careful clinical evaluatio n should elicit evidence of: \200 \200 \200 Clinical features Generalized clinical features will be dependent upon the degree of AKI. M ore speci \201 c clinical features will be dependent upon the primary disease process caus ing the GN. recent infection; foreign travel; drug use. Intercurrent disease such as sepsis and hypovolemia may precipitate AKI. CHAPTER 10.4 Glomerulonephritis, vasculitis, and nephrotic syndrome 341 Table 10.4.1 Glomerulonephritides associated with acute kidney injury \200 thrombocytopenia (SLE); thrombocytosis (vasculitis). Blood \201 lm, expect: \200 Vasculitis Small vessel vasculitis fragmented red blood cells/schistocytes (systemic scle- rosis). ANCA-associated vasculitis Wegener \200\231s granulomatosis \200 Microscopic polyarteritis \200 Churg \200\223Stra uss syndrome Immune-complex-associated Urea and electrolytes, expect: \200 elevated urea and creatinine; \200 elevated LDH (sy stemic sclerosis); \200 elevated CRP (vasculitis, not SLE unless intercurrent infection). Henoch-Sch nlein purpura \200 Anti-GBM disease \200 Mixed essential cryoglobulinemia \200 Systemic lupus erythematosus \200 Rheumatoid arthritis \200 Relapsing polychondri tis \200 Beh et \200\231s disease Liver function tests, expect: \200 elevated alkaline phosphatase (vasculitis). Immunology screen: \200 ANCA (ANCA-associated vasculitis); PR3-ANCA (Wegener \200\231s granulomatosis); MPO-ANCA (m icroscopic polyarteritis); anti-GBM antibody; (anti-GBM disease) anti-dsDNA antibody (SLE); reduced C4, normal C3 (SLE, mixed essential cryoglobulinemia (MEC)); reduced C4, reduced C 3 (SLE, MEC, mesangiocapillary GN type I); normal C4 reduced C3 (postinfectious GN, mesangi o- capillary GN type II); elevated IgG and IgM (SLE, vasculitis, postinfec- tious GN); elev ated IgE (Churg \200\223Strauss syndrome); elevated IgA (IgA nephropathy, Henoch \200\223Sc h nlein purpura); cryoglobulins (MEC); paraprotein (MEC, myeloma/lymphoma/amyloid); ASO ti ter (post-streptococcal GN). Infection-induced Hepatitis B and C \200 HIV Paraneoplastic \200 \200 Carcinoma-induced \200 Lymphoproliferative neoplasm-induced \200 Myeloproliferative neo plasm-induced Medium vessel vasculitis \200 Polyarteritis nodosa \200 Kawasaki disease Large vessel v asculitis Takayasu \200\231s arteritis \200 Giant cell arteritis \200 Infection-associated glomerulonephritis Postinfectious \200 \200 Streptococcus spp. \200 Staphylococcus spp. \200 Hepatitis B Urine Urinalysis, expect: \200 \200 Associated with active infection HIV \200 Hepatitis C \200 Infective endocarditis \200 Shunt nephritis (ventricular sh unt infection) hematuria (GN, vasculitis); proteinuria (GN, vasculitis). Urine microscopy, expect: \200 \200 Primary glomerulonephritis \200 IgA nephropathy \200 Membranous nephropathy \200 Mini mal change nephropathy \200 Focal segmental glomerulosclerosis \200 Mesangiocapillary g lomerulonephritis red-cell casts (GN, vasculitis); granular casts (ischemic AKI). Microbiology Blood cultures: \200 positive with infection-associated GN. Virology: \200 Collagen \200\223vascular disease \200 Systemic sclerosis hepatitis B (polyarteritis nodosa, membranous GN, mesangiocapillary GN); hepatitis C (membr anous GN, mesangiocapillary GN, MEC); HIV (focal and segmental glomeruloscerosis). Treatment prior to presentation with NSAIDs and antibi- otics may cause an acute interstiti al nephritis. The precise diagnosis will require appropriate investiga- tions which will us ually include a renal biopsy. Radiology CXR: \200 Investigations Blood tests Full blood count, expect: \200 \200 \200 \200 pulmonary in \201 ltrates (pulmonary edema, hemorrhage, infection); cavitating lesions (We gener \200\231s granulomatosis). anemia; neutrophilia (vasculitis); eosinophilia (Churg \200\223Strauss syndrome); lymphopen ia (SLE); CT chest: \200 may demonstrate smaller granulomatous lesions A.J.P. LEWINGTON 342 Ultrasound, expect \200 \200 \200 normal sized kidneys; increased cortical echogenicity; renal vein thrombosis (GN associa ted with nephrotic syndrome). Renal angiography: \200 arterial aneurysms (polyarteritis nodosa). Arch angiogram: \200 narrowing or occlusion of the aorta and its primary branches (Takayasu \200\231s arteritis) . Lung function tests Carbon monoxide transfer factor coef \201 cient: \200 increased transfer factor coef \201 cient (pulmonary hemor- rhage). Fig. 10.4.2 Acute kidney injury associated with minimal change nephropathy. Minimal change nephropathy occurred secondary to mercury poisoning. There is acute tubular injury with api cal cytoplasmic projections and normal glomeruli. EM con \201 rmed foot process effacement and no immune deposits. Echocardiography Transthoracic (ideally transoesophageal) echocardiogram: \200 valve vegetations (infective endocarditis). Renal biopsy The renal biopsy \201 ndings will be dependent upon the primary pathology an d is important in: \200 \200 \200 Specific treatment is dependent upon the underlying diagnosis. In the case of immunological ly mediated diseases including the vasculitides, early diagnosis and commencement of immuno suppression is essential to preserve renal function. In patients with pulmonary hemorrhage it is important to maintain very careful \202 uid balance and avoid precipitating pulmona ry oedema which may exacerbate the pulmonary hemorrhage. Close attention must be paid to in tercurrent infection, with a low threshold for removing hemodialysis catheters. Patients wh o have developed AKI will require appropriate dose adjustments to their medications. Preven tion of AKI is particularly important in patients who have nephrotic syndrome. In patients receiving diuretics the dose must be carefully titrated with regular clinical review. The p atient \200\231s weight should be measured daily and it is advisable not to diurese >3 kg/d ay. NSAIDs should be establishing the diagnosis (Figs 10.4.1 \200\22310.4.3); assessing disease activity; assess ing the degree of chronic damage. Together these will determine the likely potential for recoverability with and without trea tment. Temporal artery biopsy This may be indicated if giant cell arteritis is suspected. Management General treatment measures should include: \200 \202 uid and electrolyte imbalance may necessitate renal replacement therapy; prompt trea tment of infection; antimicrobial prophylaxis if the patient is immunocom- promised or if i mmunosuppression is planned; stress ulcer prophylaxis with proton pump inhibitors; early en teral or parenteral nutrition; \200 \200 Fig. 10.4.1 Acute kidney injury secondary to crescentic IgA nephropathy. (Right panel) The glomerulus is hypercellular with a cellular crescent. There are red-cell casts present in t he tubules. (Left panel) Immunohistochemistry demonstrates brown granular deposits of IgA i n the mesangium. CHAPTER 10.4 Glomerulonephritis, vasculitis, and nephrotic syndrome 343 Fig. 10.4.3 Acute kidney injury secondary to post-streptococcal glomerulonephritis. (Left p anel:). There are red-cell tubular casts and the glomerulus displays global endocapillary h ypercellularity with neutrophils. (Right panel:) MSB stain of a glomurulus demonstrating in tracapillary neutrophils and a subepithelial hump-like deposit. (All images courtesy of Dr D. Leitch, St James \200\231s University Hospital, Leeds, UK.) avoided in patients with nephrotic syndrome as they can precipitate AKI. Internet resources Acute Dialysis Quality Initiative: Prognosis The prognosis is dependent upon the underlying diagnosis and the response to ther apy. If there is signi \201 cant secondary acute tubular necrosis on the renal biopsy, thi s can indicate a potential for reversibility of renal function. http://www.ADQI.net Acute Kidney Injury Network: http://www.akinet.org See also Clinical approach to acute kidney injury, p. 318 Renal replacement therapies in ac ute kidney injury, p. 328 Crescentic glomerulonephritis, p. 120 Infection-related glomerulo nephritis, p. 128 Systemic vasculitis, p. 168 Systemic lupus erythematosus, p. 180 Sclerode rma \200\223systemic sclerosis, p. 186 Further reading Furuya R, Kumagai H, Ikegaya N, et al. Reversible acute renal failure in id iopathic nephrotic syndrome. Intern Med 1993; 32: 31 \200\22335. L pez-G mez JM, Rivera F . Spanish registry of glomerulonephritis. Renal biopsy \201 ndings in acute renal failure in the cohort of patients in the Spanish registry of glomerulonephritis. Clin J Am Soc Nep hrol. 2008; 3: 674 \200\223681. Haas M, Spargo BH, Wit EJ, et al. Etiologies and outcome of acute renal insuf \201 ciency in older adults: a renal biopsy study of 259 cases. Am J Kidney Dis 2000; 35: 433 \200\2234 47. Smith JD, Hayslett JP. Reversible renal failure in the nephrotic syndrome. Am J Kidney Dis 1992; 19: 201 \200\223203. A.J.P. LEWINGTON 344 Acute tubulointerstitial nephritis Introduction Acute tubulointerstitial nephritis or acute interstitial nephritis (AIN) is an in \202 ammatory condition affecting the interstitium. The in \202 ammatory in \201 ltr ate consists of lym- phocytes and monocytes with or without eosinophils and is most commonl y secondary to drugs. Investigations Blood tests Full blood count: \200 \200 differential may reveal eosinophilia (25% cases); eosinophilia is typically absent in NSAID -induced AIN. Urea and electrolytes, expect: \200 elevated urea and creatinine. Epidemiology Acute tubulointerstitial nephritis is an important cause of unexplained AKI th at occurs in males and females with equal incidence. It most commonly occurs in the 5th and 6th decades. Liver function tests: \200 may be abnormal if AIN secondary to Legionella spp. or Leptospirosis spp. infection. Bone pro \201 le: \200 \206\221 Ca2+ if AIN secondary to sarcoidosis. Etiology The in \202 ammatory cell in \201 ltrate is triggered by a number of different p rovoking factors. Drug-induced AIN is the most common cause account- ing for 70 \200\22390% of cases and is not dose dependent (Table 10.5.1). Many drugs have been reported to cause AIN. To deter- mine a causative role for a speci \201 c drug, the patient must not be on a ny other drug or have any other condition that might cause the disease, and must undergo a con \201 rmatory renal biopsy. Autoantibody screen: \200 \200 only required if autoimmune disease suspected; anti-Ro and -La, if Sj gren \200\231s syndr ome suspected. Serum ACE: \200 if sarcoidosis suspected. Urine Urinalysis, expect: \200 \200 \200 hematuria; proteinuria (<1 g/day); proteinuria (>1 g/day if concurrent nephrotic syndrome ( NSAIDs and minimal change disease) or existing underlying renal disease); can be normal in a few patients. Clinical features Classically presents as AKI associated with: \200 \200 \200 fever; rash; arthralgia. Urine microscopy, expect: \200 eosinophiliuria (low sensitivity, also seen in RPGN and atheroembolic renal disease); white cell casts. This presentation is now less common (10% of cases). The classic triad is typically absent with NSAID- induced AIN. Often there are nonspeci \201 c symptoms related to: \200 uremi c symptoms oliguria re \202 ecting AKI; \200 loin pain secondary to swelling of renal capsule. Microbiology Specific tests dependent upon suspected underlying diagnosis: \200 \200 \200 blood cultures; urinary legionella antigen; urine culture. A thorough drug history is essential. A history of drug ingestion up to 18 months before pr esentation with AIN can occur. The nephrotic syndrome can occur with NSAID-induced AIN. The re may be clinical features of an infective process or an underlying disease process: Serology: \200 \200 \200 Legionella spp.; Leptospirosis spp.; hantavirus. Radiology CXR, may show signs consistent with: \200 \200 Leptospirosis The associated AIN may rarely be associated with multiple organ involvement w ith hemolytic anemia, liver failure and AKI. respiratory infection; sarcoidosis. Ultrasound, expect: \200 Legionellosis The associated AIN may be associated with multiple organ involvement with pne umonia, liver enzyme abnormalities and AKI. swollen or normal-sized kidneys. Gallium scan: \200 \200 rarely performed; diffuse, intense uptake secondary to in \202 ammatory in \201 l- trate; positive scan suggests AIN; differentiates AIN from acute tubular necrosis (negative scan) . Hantavirus AIN may be associated with multiple organ involvement with respiratory symptoms, liver enzyme abnormalities, thrombocytopenia and AKI. Severe hantavirus infection is mainl y seen in Asia with milder forms of infection more usual in Europe. \200 CHAPTER 10.5 Acute tubulointerstitial nephritis 345 Immuno \202 uorescence and electron microscopy: \200 Table 10.5.1 Common causes of acute tubulointerstitial nephritis nonspeci \201 c \201 ndings. Management This is dependant upon the underlying disease process. Drugs NSAIDs Antibiotics Drug-induced AIN Identify and stop offending drug. A recent retrospective study has demonst rated that early steroid treatment improves the recovery of renal function with drug-induce d AIN. Therefore consider corticosteroids if worsening renal function or requiring renal re placement therapy: \200 \200 penicillins \200 cephalosporins \200 rifampicin \200 sulphonamides (including cotrimo xazole) \200 cipro \202 oxacin Allopurinol Proton pump inhibitors prednisolone 1 mg/kg/day, orally; taper over a period of 1 month dependent upon response; c onsider bone and GI protection; monitor blood glucose. Indinavir Diuretics (sulfur containing) furosemide \200 bumetanide \200 Infections Bacteria NSAID-induced AIN is less responsive to corticosteroid therapy. Mycophenolate mofetil has b een used in patients with steroid-resistant AIN. Staphylococcus spp. \200 Streptococcus spp. \200 Tuberculosis spp. \200 Legionella sp p. \200 Leptospirosis spp. \200 Chlamydia spp. \200 Mycoplasma spp. Prognosis This is dependant upon underlying disease process. Good prognosis with drug-induc ed AIN: \200 \200 Viruses majority recover renal function; 5% mortality rate. cytomegalovirus \200 Epstein \200\223Barr virus \200 hantavirus \200 hepatitis A and B \200 herpes simplex virus \200 HIV Parasites The prognosis is poorer if the AIN is not drug-induced. There is a worse prognosis if inter stitial \201 brosis is present on the biopsy. Tubulointerstitial nephritis and uveitis syndrome (TINU) Introduction Tubulointerstitial ne phritis and uveitis syndrome (TINU) is a distinct entity occurring in a subset of patients who have tubulointerstitial nephritis and uveitis. The majority of the reports of this synd rome have been small descriptive case series or single case reports. toxoplasma Autoimmune disease Sarcoidosis Sj gren \200\231s syndrome TINU (tubulointerstitial nephrit is and uveitis syndrome) Epidemiology Female preponderance, 3:1. Median age at presentation is 15 years but has been diag- nosed in the elderly. Various HLA associations have been described but there is no c onsistent haplotype across studies. Renal biopsy A renal biopsy is indicated in a patient with unexplained AKI and normal-sized kidneys on renal tract USS (Fig. 10.5.1). However, renal biopsy may not be required in the absence of severe disease, clinical presentation highly suggestive of drug-induced AIN, an d prompt improvement in renal function on discontinuing the offending drug. Light microscop y Glomerular morphology: \200 Etiology The underlying cause is unclear. Concurrent infection with Chlamydia spp. and Epst ein \200\223Barr virus has been described. There are reported associations with a number of auto- immune diseases. normal. Interstitium: \200 in \202 ammatory in \201 ltrate: \200 \200 \200 giant cells and granulomata if: \200 TB; \200 sarcoidosis; interstitial edema. Clinical features Uveitis \200 \200 T-lymphocytes; monocytes; eosinophils; Typically bilateral. Anterior uveitis is most common: \200 \200 painful eye or redness; photophobia and decreased visual acuity. A.J.P. LEWINGTON 346 In patients with progressive AKI consider: \200 \200 \200 \200 prednisolone 1 mg/kg/day, orally; taper over 3 \200\2236 months, dependent upon response; c onsider bone and GI protection; monitor blood glucose. Most patients recover renal function. Relapses are more likely to occur. Uveitis Early referral to ophthalmologist is required. Topical or systemic corticosteroids may be indicated. Relapses are common. Rarely steroid sparing immunosuppression required. Prognosis This is dependent upon the degree of tubulointerstitial \201 brosis on renal bi opsy. Fig. 10.5.1 Silver-stained renal biopsy demonstrating acute interstitial nephritis. The ren al biopsy shows tubular injury with a mononuclear cell interstitial in \201 ltrate and nor mal glomerular morphology. (Courtesy of Dr D. Leitch, St James \200\231s University Hospita l, Leeds, UK.) Further reading Clarkson MR, Giblin L, O \200\231Connell FP, et al. Acute interstitial neph ritis: clinical features and response to corticosteroid therapy. Nephrol Dialysis Transpl 2 004; 19: 2778 \200\2232783. Joss N, Morris S, Young B. et al. Granulomatous interstitial nephritis. Reported to occur between 2 months prior and up to 14 months after the onset of AIN. Clin J Am Soc Nephrol 2007; 2: 222. Rossert J. Drug-induced acute interstitial nephritis. Kidney Int 2001; Acute interstitial nephritis \200 \200 \200 \200 \200 60: 804 \200\223817. Anorexia and weight loss. Fever. Fatigue, malaise. Arthralgia, myalgia, headache. AKI. Takemura T. Okada M. Hino, S. et al. Course and outcome of tubulointerstitial nephritis and uveitis syndrome. Am J Kidney Dis 1999; 34: 1016 \200\2231021. Internet resources Acute Dialysis Quality Initiative Investigations There are no speci \201 c laboratory investigations for TINU. There are ass ociations reported with hypocomplemen- temia and positive serology for autoantibodies, incl uding ANCA, ANA and rheumatoid factor. Renal biopsy \201 ndings are as per AIN. http://www.ADQI.net Epocrates ONLINE provides continually updated infor- mation on brand and generic drugs (dosing, drug \200\223drug interactions, adverse reactions and mode of ac tion: http://www.epocrates.com A patient-friendly US-based site with drug information: Differential diagnosis http://drugs.com Ocular Immunology and Uveitis Foundation: There is a broad differential diagnosis which includes a number of renal diseases associate d with ocular disease: \200 \200 \200 \200 \200 \200 http://www.uveitis.org/ sarcoidosis; Sj gren \200\231s syndrome; systemic lupus erythematosus; Wegener \200\231s g ranulomatosis; Beh et \200\231s disease; Infectious disease (TB, toxoplasmosis, brucellosi s). See also Clinical approach to acute kidney injury, p. 318 Drug-induced nephropathies, p. 69 8 NSAIDs and the kidney, p. 228 The ocular disease manifestations are usually distinct from uveitis and there will be evide nce of other organ involve- ment. However, it can be dif \201 cult to differentiate TINU f rom sarcoidosis and Sj gren \200\231s syndrome. Management Acute interstitial nephritis This is usually self-limiting and resolves spontane ously. This page intentionally left blank A.J.P. LEWINGTON 348 Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura Factor H is a plasma protein mainly of liver origin that binds to endothelial cells in glom erular capillaries and other resident glomerular cells and regulates complement activation in the glomerulus. Similarly, membrane cofactor protein is expressed in the kidney and regu lates glomerular C3 activation. Reduced expression of either factor H or MCP leads to exces sive complement activation on glomerular endothelial cell surfaces with endothelial cell da mage and thrombosis. Introduction The thrombotic microangiopathies (TMA) describe a group of systemic disorders characterized by the presence of microangiopathic hemolytic anemia (MAHA), thrombo- cytopen ia and tissue ischemia secondary to platelet throm- bosis in the microcirculation (Table 10 .6.1). Hemolytic anemia occurs secondary to mechanical frag- mentation of erythrocytes duri ng their passage through narrowed vessels. Thrombotic thrombocytopenic purpura (TTP) and he mo- lytic uremic syndrome (HUS) are both well-recognized causes of TMA and present with ver y similar clinical features. HUS associated with diarrhea is also known as diarrhea- positi ve (D+) HUS or typical HUS and is the most frequent form of HUS. HUS not associated with di arrhea is known as diarrhea- negative (D \200\223) HUS or atypical HUS. Thrombotic thrombocytopenic purpura TTP has been associated with genetic and autoimmune- me diated de \201 ciency of the vWF cleaving metalloproteinase ADAMTS13. Inherited mutations or IgG autoantibodies (directed against ADAMTS13) lead to defective cleavage of vWF and the pres- ence in the circulation of abnormally large vWF multimers. These large vWF multimers bind and activate platelets which can result in the formation of platelet-rich thrombus in the microcirculation and tissue ischemia. Epidemiology D+/typical HUS: \200 \200 \200 Clinical features The clinical features of both HUS and TTP are very similar. HUS and TTP s econdary to genetic mutations can cluster in families and recur. incidence of 2 cases per 100 000 per year; peak incidence is in children aged <5 years; mos t frequently seen in summer months. TTP secondary to acquired de \201 ciency of vWF-cleaving protease: \200 \200 \200 Hemolytic uremic syndrome HUS may present with: diarrhea ( bloody); \200 \200 fever; \200 hypertension; \200 \202 uid overload; \200 microangiopathic hemolytic anemia; \200 thrombocytopenic purpura; \200 AKI. incidence of 0.4 cases per 100 000 per year; occurs more commonly in females; peak incidenc e in third decade. Etiology D+ hemolytic uremic syndrome This occurs most commonly due to infection with enter - opathogenic E. coli of different serotypes, usually O157:H7, or sometimes by shigellosis. These strains produce an enterotoxin called VT (verocyte toxin). The source may be contami nated meat or milk or contact with infected animal or human excretions. E.coli O157:H7 bind s to the gastrointestinal mucosa; the VT translocates across the colon and disseminates thr ough the circulation. The VT binds to vascular endothelial cells and platelets, particularl y those of the glomerular capillaries. Activated endothelial cells produce large von Willib rand factor (vWF) multimers facilitating platelet adhesion through the glycoprotein 1b (GP1 b) receptor, resulting in thrombosis and glomerular ischemia. D \210\222 hemolytic uremic s yndrome Over the last decade in the UK, pneumococcal-related HUS has become the second most common cause of HUS, accounting for 10 \200\22315% of all cases. The reason for this recen t increase is not known. HUS in the absence of diarrhea may also be associated with: \200 \200 \200 Postpartum HUS can occur up to 6 months post delivery. Thrombotic thrombocytopenic purpura CNS involvement is more typically associated with TTP, although one-third of patients with TTP have no CNS abnormalities. TTP generally has more w idespread organ involvement. Autoimmune-mediated TTP may follow exposure to speci \201 c d rugs (e.g. clopidogrel). TTP may present with: \200 \200 \200 \200 \200 \200 \200 fever; microangiopathic hemolytic anemia; thrombocytopenic purpura; CNS involvement (confus ion, \201 ts); AKI; pancreatitis; cardiomyopathy. Pregnancy-associated TTP usually occurs before 28 weeks. Differential diagnosis Careful clinical evaluation and appropriate investigations will help to make the diagnosis and identify the cause (Table 10.6.1). factor H de \201 ciency (complement regulatory protein); membrane cofactor protein (MCP) a bnormalities; numerous drugs. CHAPTER 10.6 Hemolytic uremic syndrome 349 \200 Table 10.6.1 Classi \201 cation of thrombotic microangiopathies thrombocytopenia; reticulocytosis. Blood \201 lm: \200 Thrombotic thrombocytopenic purpura Genetic fragmented red blood cells/schistocytes. ADAMTS13 de \201 ciency Clotting screen: \200 \200 \200 Autoimmune normal PT, aPTT, \201 brinogen levels; reduced haptoglobin; Coombs \200\231 test negative (except in pneumococcal-associ- ated HUS). IgG directed against ADAMTS13 (e.g. post clopidogrel) Hemolytic uremic syndrome Infection Eschericia coli 0157:H7 \200 Shigella dysenteriae serotype 1 \200 Salmonella spp. \200 Campylobacter spp. \200 Streptococcus pneumoniae (neuraminidase) \200 HIV Genetic Urea and electrolytes, expect: \200 elevated urea and creatinine; \200 elevated LDH. Liver function tests, expect: \200 elevated bilirubin. Autoantibody screen: \200 \200 \200 \200 \200 factor H de \201 ciency \200 membrane cofactor protein abnormalities dsDNA (if SLE considered); complement (if SLE considered); ANCA (if a small vessel vasculit is considered); Scl-70 (if systemic sclerosis considered); antiphospholipid antibody (if AP L syndrome considered). Autoimmune IgG directed against factor H Drugs quinine \200 ciclosporin \200 tacrolimus \200 oral contraceptive pill Pregnancy-assoc iated TMA Other: \200 \200 \200 ADAMTS13 activity (in TTP this will be < 5% normal); factor H mutations (atypical HUS); BhC G (if pregnancy-associated TTP suspected). Pre-eclampsia \200 HELLP syndrome \200 Postpartum TTP and HUS Systemic disease-associat ed TMA \200 Accelerated hypertension \200 Antiphospholipid syndrome \200 Systemic scl erosis \200 Malignancy Urine tests Urinalysis, expect: \200 \200 \200 hematuria; proteinuria (usually mild); bilirubinuria (from hemolysis). Urine microscopy, expect: \200 few casts. Microbiology Stool culture (in D+ HUS E. coli is shed for several weeks). Other cultures de pending on clinical suspicion (Table 10.6.1). A diagnosis of TTP or HUS can be made provisionally if there is thrombocytopenia and MHA in the absence of any other apparent cause. Diagnoses to exlcude include: \200 Virology Consider HIV testing if there is a clinical suspicion. vasculitis (additional clinical features: rash and arthralgia, and presence of autoantibodi es: ANCA); systemic sclerosis with renal crisis (additional clinical features: sclerodactyl y, and presence of autoantibodies: Scl-70); accelerated hypertension (history of high blood pressure and retinopathy); disseminated intravascular coagulation (associated with sepsis and multiple organ failure, associated with an elevated PT and aPTT); hantavirus infection (associated with fever, AKI and thrombocytopenia but not MHA); HELLP syndrome (occurs late in 3rd trimester of pregnancy, has features of TMA along with liver dysfunction). Radiology Ultrasound, expect: \200 normal sized kidneys. Renal biopsy A renal biopsy is only performed if the platelet count normalizes. The histolo gy is similar for all causes of TMA. Fibrin thrombi are present in the glomerular capillari es with surrounding ischemic damage (Fig. 10.6.1). In HUS microthrombi are predominantly pr esent in the kidneys. Microthrombi are more extensively distributed in TTP and found mainly in the cerebral circulation but may also be seen in the kidneys, heart, adrenals and pancr eas. Investigations Blood tests Full blood count, expect: \200 \200 Management Supportive treatment Renal replacement therapy may be required dependent upon th e degree of AKI. anemia; elevated WBC (D+ HUS); A.J.P. LEWINGTON 350 Cryosupernatant (devoid of vWF multimers and \201 brino- gen) should be used in patients resistant to plasma exchange with FFP. Monitoring levels of ADAMTS13 autoantibodies may be useful in assessing patient response to therapy. Rituximab (anti-CD20 monoclonal antibody) has been used for resistant TTP. In pregnancy-associated TTP, delivery is recommended for t hose who fail to respond to plasma exchange. HELLP syndrome HELLP syndrome requires supportive therapy and delivery of the baby. Plasma exchange is ineffective during pregnancy but may help recovery of disease following deliver y. Prognosis In childhood D+ HUS, expect: \200 \200 \200 Fig. 10.6.1 Silver stain demonstrating features of thrombotic microangiography in glomeruli and a small interlobular artery. Glomeruli are bloodless with capillary thrombosis. The in terlobular artery shows mural \201 brinoid necrosis and luminal occlusion. (Courtesy of D r D. Leitch, St James \200\231s University Hospital, Leeds, UK.) a good initial recovery ( 90%); 3% mortality; 40% to develop hypertension and progressive CKD. Factors associated with a poor renal prognosis in HUS: \200 \200 \200 \200 \200 \200 age <2 years; high white cell count; D \200\223 (atypical HUS); anuria at presentation; HUS secondary to S. pneumoniae infection; HUS secondary to Shigella infection. Blood transfusions are required for symptomatic anemia. Avoid platelet transfusions unless there is life-threatening hemorrhage or an urgent need for surgery. D+ hemolytic uremic syn drome Initial management is supportive. Antibiotics should be avoided in cases of diarrhea (unless there is systemic bacteremia), due to the increased risk of precipitating HUS. Plas ma exchange should be commenced if there is any doubt concerning diagnosis (TTP or D \200 \223 HUS). There is no proven bene \201 t for treatment with plasma exchange in D+ HUS. D \200\223 hemolytic uremic syndrome Plasma exchange can be effective but for most it is a re laps- ing and remitting disease. Unlike D+ HUS, D \200\223 HUS can recur following renal tr ans- plantation. A recurrence rate of up to 50% has been reported in adults. The risk of re currence is less with mutations in the mem- brane cofactor protein gene. Combined liver and kidney transplantation following inten- sive plasma exchange has been performed successful ly in HUS secondary to factor H de \201 ciency. Liver transplantation restores normal fact or H synthesis. Postpartum HUS requires supportive care. The role of plasma exchange is unp roven. Postpartum HUS: \200 50% mortality; \200 most survivors will have CKD and hypertension . In TTP you should expect: \200 \200 90% patient survival if treatment is commenced early; relapse rate of 30%. Future prospects Advances in the understanding of the etiology of HUS/TTP will improve the prospects for speci \201 c therapy and assess- ing patient prognosis. Most recently the co mplement factor H R1210C mutation has been demonstrated to be linked with development of D \200\223 HUS. Further reading George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354: 1927 \200\2231935. Gutterman L, Kloster B, Tsai H. Rituximab therapy for refractory thrombotic thrombocytopeni c purpura. Blood Cells Mol Dis 2002; 28: 385 \200\223391. Noris M, Remuzzi G. Haemolytic uraemic syndrome. J Am Soc Nephrol 2005; 16: 1035 \200\2231050. Zipfel PF, Skerka C. Complement dysfunction in haemolytic uraemic syndrome. Curr Opin Rheumatol 2006; 18: 548 \200\223555. Internet resources Acute Dialysis Quality Initiative: Thrombotic thrombocytopenic purpura TTP requires prompt treatment which is aimed at: \200 \200 http://www.ADQI.net Acute Kidney Injury Network: removing vWF multimers; restoring the ability to cleave vWF multimers. Plasma exchange should be performed daily with FFP until normalization of platelets and LDH . http://www.akinet.org CHAPTER 10.6 Hemolytic uremic syndrome 351 HUSH (Haemolytic Uraemic Syndrome Help); UK E. Coli Support Group: See also Clinical approach to acute kidney injury, p. 318 Acute kidney injury in infants an d children, p. 372 Acute kidney injury in pregnancy, p. 378 http://www.ecoli-uk.com/ About TTP website: http://www.about-ttp.com/ A.J.P. LEWINGTON 352 Hepatorenal syndrome The onset of HRS is generally insidious but can be precipi- tated in patients with advanced liver disease and ascites by a number of different insults including: \200 \200 \200 \200 Introduction Hepatorenal syndrome (HRS) is the development of AKI in the setting of advance d liver disease most commonly secondary to cirrhosis, but can also occur in patients with f ulminant liver failure from any cause. The AKI is initially entirely prerenal secondary to renal hypoperfusion with normal renal histology and preserved tubular cell integrity and fu nction. HRS may progress to acute tubular necrosis (ATN). Acute kidney injury can complicat e the postoperative course of patients with obstructive jaundice or those undergoing liver transplantation. Acute kidney injury may also occur secondary to IgA nephropathy associated with liver disease and also secondary to cryoglobulinemia asso- ciated with hepatitis C. gastrointestinal hemorrhage; sepsis (e.g. spontaneous bacterial peritonitis); overdiuresis; nephrotoxins (aminoglycosides, NSAIDs, ACEIs, ARBs, contrast). Clinical features Stigmata of chronic liver disease: \200 \200 \200 \200 \200 jaundice, spider nevi, etc.; ascites; wasting (secondary to poor nutritional intake); edema (sodium and water retention); hypotension ( \206\223 effective circulating volume and syst emic vascular resistance).