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). De \201 nition HRS has been classi \201 ed into two types dependent upon the rapidity of onset, the severity of AKI and prognosis. Signs of the precipitating factor may also be present: \200 \200 GI hemorrhage (portal hypertension and coagulopathy); sepsis ( \206\221 susceptibility, spo ntaneous bacterial peritonitis and pneumonia). Type I HRS \200 \200 \200 \200 AKI is the dominant clinical feature. Rapid fall in GFR <20 mL/min in <2 weeks. Progressive oligoanuria. Median survival 2 weeks. A diagnosis of HRS is based upon the presence of prede- termined major criteria. These incl ude the demonstration of a markedly reduced GFR and the exclusion of other causes of AKI in the setting of acute or chronic liver disease with advanced liver failure and portal hyper tension (Table 10.7.1). It is important to recognize that: Urine Na <10 mmol/L (off diureti cs) is only a minor criteria. Fractional excretion of sodium (FENa) may remain <1% in patie nts with ATN superimposed on HRS secondary to persistent vasoconstriction. Patients with li ver cirrhosis have reduced muscle mass and therefore serum Cr may underestimate GFR. Serum urea will also be affected by: \200 \200 \200 Type II HRS \200 \200 \200 \200 \200 Ascites is the dominant clinical feature. Protracted clinical course. AKI is less acute and severe. Potential to convert to type I HRS. Median survival 6 months. Epidemiology HRS is reported to occur in 20% of patients with liver cir- rhosis and ascites at 1 year. The incidence increases to 40% at 5 years. Etiology With progressive liver disease there is a rise in cardiac out- put and a fall in s ystemic vascular resistance (SVR). Falling SVR results from the splanchnic vasodilatation t hat occurs in association with liver disease and has been pro- posed to be secondary to an increased secretion of a number of mediating factors including: \200 vasoactive gut pepti de secretion; \200 glucagon; \200 prostacyclin; \200 nitric oxide (NO) secretion loca lly; \200 bacterial translocation. GI hemorrhage; \206\223 production by the liver; \206\223 dietary intake. Differential di agnosis Distinguishing HRS from other causes of AKI in patients with liver disease presents a diagnostic challenge. The diagnosis of HRS is essentially one of exclusion and must be d istinguished from other causes of combined liver disease and AKI. Other common causes inclu de: \200 \200 \200 \200 \200 sepsis leading to relative hypovolemia and ATN; GI hemorrhage leading to hypovolemia and AT N; overdiuresis leading to hypovolemia and ATN; nephrotoxins leading to ATN; glomerulonephr itis (suspect if active urinary sediment with red cell casts); mesangiocapillary glomerulon ephritis and hepatitis C; IgA nephropathy and alcoholic liver disease. Low SVR in turn results in renal vasoconstriction and a fall in renal blood \202 ow (RBF) secondary to secretion of: \200 \200 \200 \200 catecholamines (A-agonism); angiotensin (2 hyperaldosteronism); endothelin; ADH (nonosmot ic stimulation). \200 A resultant fall in RBF results in a parallel fall in GFR and prerenal AKI. Establishing the correct diagnosis is important clinically as patients with HRS have a poor prognosis. Most patients die CHAPTER 10.7 Hepatorenal syndrome 353 Table 10.7.1 Criteria for the diagnosis of hepatorenal syndrome Microbiology It is essential to exclude sepsis with: \200 \200 \200 blood cultures; urine culture; cultures of ascitic \202 uid. Major criteria Acute or chronic liver disease with advanced liver failure and portal hypertension. Progressive AKI over days to weeks (CrCl <40 mL/min). Absence of other causes of AKI includ ing: Radiology CXR: \200 \200 shock \200 GI \202 uid losses \200 overdiuresis \200 sepsis (exclude spontaneous ba cterial peritonitis) \200 nephrotoxins (NSAIDs, aminoglycosides) \200 obstruction or pa renchymal disease on ultrasound. to aid volume assessment; to detect pneumonia. Ultrasound, expect: \200 normal sized kidneys. Renal biopsy A renal biopsy is not usually required and may represent a significant risk in a patient with liver disease and coagulopathy. Renal biopsy \201 ndings in patients with HRS are normal initially but prolonged renal hypoperfusion will result in ATN. No sustained recovery of renal function ( \206\221 CrCl >40 mL/min) following adequate \202 uid resuscitation and discontinuation of potential nephrotoxins. Proteinuria <500 mg/dL (no evidence of renal parenchymal disease). Minor criteria Urine output <500 mL/day. Urine Na <10 mmol/L (off diuretics). Urine osmolal ity > plasma osmolality. Urine red blood cells <50/HPF. Serum Na <130 mmol/L. Management Prevention It is important to identify patients at risk of developing HRS; usual ly these are those with liver cirrhosis and ascites: \200 \200 \200 \200 \200 check medications; beware of over diuresis; beware of esophageal varices \206\222 GI hemor rhage; prompt diagnosis and treatment of sepsis; increased risk associated with surgery. within weeks of the onset of AKI, usually from a complica- tion of their liver disease, e.g . GI hemorrhage, unless they receive effective treatment. Other causes of AKI such as ATN o r prerenal disease are usually reversible. Ensure adequate volume replacement with 100 mL 20% salt poor human albumin solution (HAS) p er 1.5 L paracentesis. If spontaneous bacterial peritonitis is suspected: \200 Investigations Blood tests Full blood count, expect: \200 \200 IV salt poor HAS 1.5 g/kg at diagnosis and 1 g/kg at 48 h; antibiotic treatment. anemia (GI hemorrhage); neutrophilia (sepsis). In alcoholic hepatitis: \200 Urea and electrolytes, expect: \200 elevated urea and creatinine; \200 hyponatremia (di lutional). Liver function tests, expect: \200 \200 \200 consider pentoxifylline (TNF-A inhibitor) 400 mg PO tds. Treatment It is important to establish the diagnosis of HRS early and exclude other causes of liver disease and AKI. Recovery of renal function is dependent upon prompt treatment of precipitants and recovery of liver function through the resolution of the primary liver dis ease or liver transplantation. Improvement in the primary liver disease is most dramatic in patients with: \200 \206\221 bilirubin; hypoalbuminemia; \206\221 INR. Autoantibody screen: \200 only required if autoimmune liver disease suspected. Urine Urine biochemistry, expect: \200 urine Na <10 mmol/L; \200 urine osmolality > pla sma osmolality. alcoholic liver disease when patients abstain from alco- hol consumption; decompensated liv er cirrhosis secondary to hepatitis B virus infection treated with antiviral therapy. Urinalysis, expect: \200 \200 \200 bland urinary sediment; no hematuria; proteinuria (<500 mg/day). General measures Volume assessment and \202 uid resuscitation: \200 IV 20% salt-poor human albumin solution (HAS). Urine microscopy, expect: \200 red blood cells <50/HPF. Stop nephrotoxic medications. A.J.P. LEWINGTON 354 Septic screen: \200 \200 It should only be considered if: \200 \200 culture blood, urine and ascitic \202 uid; consider prophylactic antibiotic treatment wit h cefotax- ime 1 g bd or piperacillin/tazobactam 4.5 g tds. liver transplantation is awaited; there is a possibility of recovery of liver function. Continuous renal replacement therapy is preferred due to hemodynamic instability. Molecular adsorbent recirculating system (MARS). This removes in \202 ammatory cytokines. There is a lack of convincing data regarding effect on outcome. Liver transplantation. This is an ef fective therapy. There is an improvement in GFR following transplantation, but the majority do not regain normal renal function. There is a 10% incidence of ESRD. Long-term mortality is increased when pre-transplant renal dysfunction is present. Exclude intra-abdominal hypertension: \200 \200 check intra-abdominal pressure if there is tense ascites; if intra-abdominal pressure is >3 0 cm H2O paracentesis is indicated. Speci \201 c measures Vasoconstrictors should be administered in combination with salt-poo r HAS to improve systemic hemodynamics and improve renal perfusion. However, these drugs sh ould be avoided in patients with ischemic heart disease, periph- eral arterial disease and/ or cerebrovascular disease due to the risk of precipitating an ischemic event. Midrodine in combination with octreotide. A small number of studies support the ef \201 cacy and safet y. Midrodine: \200 \200 \200 Prognosis Patients with liver disease who develop HRS have a signi \201 - cantly worse pro gnosis. Type I HRS: \200 selective A1-agonist; systemic vasoconstrictor; dose: 7.5 \200\22312.5 mg PO tds. Octreotide: \200 \200 \200 median survival 2 weeks. somatostatin analog; inhibitor of endogenous vasodilator release; dose: 100 \200\223200 g SC tds. Type II HRS: \200 median survival 6 months. Obstructive jaundice and acute kidney injury Obstructive jaundice secondary to intra- or ex trahepatic biliary system obstruction is the most commonly encoun- tered form of jaundice. Surgery performed in the setting of obstructive jaundice is associated with an 8% incidence of AKI. The cause of AKI in such patients is multifactorial and includes: \200 \200 \200 \200 \200 Both drugs are titrated to increase MAP by >15 mmHg. Administer for 3 \200\22315 day trial with daily IV salt poor HAS (20 \200\22340 g). Studies suggest they signi \201 cantly impr ove renal function and reduce mortality. Minimal side-effects have been reported. A trial o f therapy should be considered in selected patients. Terlipressin. There are a small number of studies with variable out- comes. \200 \200 \200 hypovolemia; endotoxinemia; hyperbilirubinemia; release of renal prostaglandins; activation and endothelin system. There is no speci \201 c or effective therapy. Preoperative optimi zation of fluid balance is essential preventative therapy. The use of mannitol (osmotic diu retic) is controversial and cannot be routinely recommended. Vasopressin analog acts via V1 receptors. Dose: 0.5 \200\2231 mg IV 4 \200\2236 times per d ay. Daily IV salt poor HAS (20 \200\22340 g/day) for 3 \200\22315 days. Responders appear to have a better prognosis. Repeat courses can be given and are effective in selected patients. It is not recommended as routine practice. Transjugular intrahepatic portosystemic shunt (TIPS). This is used in combination with vasoconstrictors when pharmac otherapy alone has failed. There is little data available on outcomes. Many patients are co nsidered too unwell to undergo the procedure. There is improved short-term survival in sele cted patients. N-Acetylcysteine. There are few data available on effectiveness in HRS. Dose : 100 mg/kg IV bd. It is not recommended as routine practice. Renal replacement therapy. Th is has no effect on outcome. Liver transplantation and acute kidney injury Acute kidney injury is one of the most common postop- erative complications of liver transplantation with an incidence reported between 21 \200\22370%. Pretransplant renal function has an impact on the immedi- ate and longer-te rm outcome post liver transplantation. Patients undergoing liver transplantation are at ris k of developing AKI in the setting of: \200 pre-existing renal dysfunction (prevalence of 10 \200\22320%); intraoperative hypotension; postoperative sepsis and exposure to nephrotoxic med- ications (calcineurin inhibitors). \200 CHAPTER 10.7 Hepatorenal syndrome 355 A signi \201 cant proportion of patients will have HRS prior to surgery. Therefore preoper ative optimization of \202 uid balance is essential. 10 \200\22318% of patients require r enal replacement therapy following liver transplantation and the mortality in these patient s is high (40 \200\22390%). In the setting of severe AKI treatment with corticosteroids, cyclophosphamide with or witho ut plasmapheresis may be considered. Further reading Arroyo V, Gines P, Gerbes AL, et al. De \201 nition and diagnostic criteri a of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996; 23: 164 \200\223176. Glomerulonephritis and acute kidney injury IgA nephropathy This is the glomerulonephritis m ost commonly associated with liver disease, invariably alcoholic liver disease. IgA contain ing complexes are normally removed by the liver. Failure to remove these complexes in liver disease results in persistence of complexes in the circulation and mesangial IgA depositio n. Most patients are asymptomatic and present with micro- scopic hematuria, mild proteinuri a and varying degrees of renal dysfunction. Management is as for idiopathic IgA nephropathy . Pouria S, Barratt J. Secondary IgA nephropathy. Semin Nephrol 2008; 28: 27 \200\22337. Salerno F, Gerbes A, Gines P, et al. Diagnosis, prevention and treatment of hepatorenal syn drome in cirrhosis. Gut 2007; 56: 1310. Wadei HM, Mai ML, Ahsan N, et al. Hepatorenal syndrome: pathophysiology and management. Cli n J Am Soc Nephrol 2006; 1: 1066. Internet resources Acute Dialysis Quality Initiative: http://www.ADQI.net Acute Kidney Injury Network: http://akinet.org/index.php Cochrane Review of Terlipressin in hepatorenal syndrome: Mesangiocapillary glomerulonephritis Cryoglobulins can be found in up to 40% of patients wi th chronic liver disease. It is associated with viral hepatitis, particularly hepatitis C. Most commonly type II cryoglobulinemia is found. Patients with chronic liver disease and cr yoglobulinemia may present with an acute nephritic syndrome and AKI. The clinical presentat ion is characterized by: \200 \200 \200 \200 \200 \200 \200 \200 http://www.cochrane.org/reviews/en/ab005162.html US government register of clinical trials in hepatorenal syndrome: http://clinicaltrials.gov/ct2/results?cond=%22 Hepatorenal+Syndrome%22 arthritis; purpuric skin rash; lymphadenopathy; splenomegaly; liver dysfunction; peripheral neuropathy; microscopic hematuria; mild proteinuria (20% have nephrotic range). See also Clinical approach to acute kidney injury, p. 318 Renal replacement therapies in ac ute kidney injury, p. 328 IgA nephropathy and Henoch \200\223Sch nlein purpura, p. 100 Mes angiocapillary glomerulonephritis, p. 112 Investigations demonstrate hypocomplementemia and circulating cryoglobulins. Renal biopsy r eveals a mesangiocapillary glomerulonephritis. A.J.P. LEWINGTON 356 Ischemic acute kidney injury Introduction Ischemic AKI may result from either systemic hypotension (causing ATN) or dise ase of the renal vasculature. This chapter will discuss AKI due to arterial occlusive disea se (atheromatous, thromboembolic and atheroembolic) and renal vein thrombosis. Atheromatous renovascular disease (ARVD) may involve large, medium-sized and small renal vessels and ca n be associated with both slowly progressive CKD and AKI. Thromboembolic AKI refers to occl usion of the renal artery or branch vessel secondary to a thrombus originat- ing in the hea rt or aorta. Atheroembolic AKI refers more speci \201 cally to renal arterial occlusive di sease secondary to cholesterol emboli. Cholesterol crystals may break off from atherosclero tic plaques either spontaneously or following manipulation of the vascular tree and emboliz e resulting in occlusion of distal small vessels. Renal artery occlusion In situ renal artery (and vein) thrombus formation may occur in pati ents with a hypercoagulable state. Renal artery occlusion can occur following direct trauma or following a deceleration injury when patients land on their feet following a fall from a height. On impact the renal arteries are acutely stretched and recoil resulting in acute thrombosis which is typically bilateral. Atheromatous renovascular disease While ARVD is usually associated with progressive CKD it does increase the risk of AKI when renal perfusion is compromised: \200 \200 \200 \200 hypovolemic states; ACEIs or ARBs; NSAIDs; radiological contrast administration. Prescription of ACEIs in the presence of renal artery stenosis (RAS, bilateral or in a sing le functioning kidney) can precipitate AKI. This process is generally but not always revers ible. Patients with RAS are dependent upon angi- otensin II to maintain the efferent arteri olar tone and therefore glomerular capillary pressure and \201 ltration. Patients with at heromatous renovascular disease are also at increased risk of contrast-induced AKI due to b oth contrast-induced vasoconstriction and direct tubular toxicity. Epidemiology The incidence of atheroembolic AKI has been estimated at 1.4% of the general p opulation based on postmortem studies. Factors associated with an increased incidence inclu de: \200 \200 \200 \200 \200 \200 Caucasian males >60 years; diabetes mellitus; hypertension; peripheral vascular disease; is chemic heart disease; cerebrovascular disease. Clinical features Clinical manifestations will differ between atheroembolism (cholesterol e mbolization), thromboembolism and throm- bosis in situ. Thromboembolism and thrombosis in s itu more commonly result in complete arterial occlusion whereas atheroembo- lism more commo nly leads to partial occlusion of distal vessels and more widespread extrarenal ischemia. R enal manifestations of the disease are dependent upon whether the arterial occlusion is acu te or occurs suba- cutely on the background of underlying atherosclerotic arterial disease. Acute renal artery occlusion secondary to thromboembo- lism or thrombosis in situ in the a bsence of pre-existing renal artery stenosis is associated with: \200 \200 \200 \200 \200 \200 The incidence of thromboembolic AKI has been estimated at 2%. It is most commonly secondary to atrial \201 brillation and associated with underlying atherosclerotic disease. Etiology A number of different diseases may be associated with the development of ischemic AKI (Table 10.8.1). Atheroembolic AKI Most commonly occurs following: \200 \200 \200 arterial instrumentation such as vascular surgery; angiography; renal angioplasty, and sten t placement. fever; loin or \202 ank pain; low back pain or abdominal pain; nausea and vomiting; hyper tension (secondary to renin release); AKI with oliguria/anuria (if bilateral occlusion or o cclusion of single functioning kidney). The procedures may result in arterial dissection or cholesterol embolization. Cholesterol e mbolization results in partial or total occlusion of multiple small arteries due to the non distensible nature of the crystals. Thromboembolic AKI The kidneys are at increased risk of thromboembolism originating from th e heart or aorta because of their relatively high blood \202 ow. The left renal artery is more commonly involved due to the angle at which it joins the aorta. Thromboembolism is mo st commonly secondary to atrial \201 brillation but can also occur secondary to emboli fr om valvular vegetations in infectious endocarditis and rarely tumor and fat embolization. Atheroembolism (less common with thromboembolism) may be associated with the following extr a-renal features: \200 \200 \200 \200 \200 \200 livedo reticularis; necrotic skin ulceration; Hollenhorst plaques (yellow deposits on fundo scopy); digital ischemia; gastrointestinal bleeding; hepatitis; CHAPTER 10.8 Ischemic acute kidney injury 357 Table 10.8.1 Arterial causes of ischemic acute kidney injury Differential diagnosis Clinical features may closely resemble that of systemic vasculitis. Atheroembolic AKI is favored by the presence of athero- sclerotic disease elsewhere. Athero embolic AKI following surgery or a radiological procedure needs to be differentiated from p ostischemic acute tubular necrosis (ATN) and contrast nephropathy. Unlike postischemic ATN and contrast nephropathy the renal dysfunction associated with atheroembolic AKI generally fails to recover. Thromboembolic AKI needs to be differentiated from renal stone disease (r enal colic) and acute pyelonephritis (loin pain). Unlike thromboembolic AKI the latter two conditions are not associated with a rise in LDH. Embolic Thromboembolic Cardiac source atrial \201 brillation \200 infective endocarditis \200 left ventricular mural thromb us Atheroembolic Cholesterol embolus Fat embolus Tumor embolus Thrombotic Renal artery stenosis Hypercoagulable states Nephrotic syndrome Protein S and C de \201 ciency Factor V Leiden de \201 ciency Antithrombin III de \201 ciency Antiphospholipid syndrome Investigations Blood tests Full blood count, expect: \200 anemia (normocytic); \200 leu kocytosis; \200 eosinophilia (atheroembolism, 80%). Homocystinuria Dissection of aorta or renal artery Marfan syndrome Ehlers \200\223Danlos syndrome Traumatic Surgical intervention Radiological intervention Clotting screen (perform if hypercoagulable state suspected): \200 \200 \200 \200 protein S and C de \201 ciency; antithrombin III de \201 ciency; factor V Leiden de \201 ciency; lupus anticoagulant. Vasculitis Polyarteritis nodosa Takayasu \200\231s disease Necrotizing vasculitis Urea and electrolytes, expect: \200 elevated urea & creatinine; \200 elevated CK (ather oembolism); \200 elevated LDH (renal infarction); \200 elevated amylase (atheroembolism ); \200 elevated CRP (atheroembolism, pyelonephritis). Thrombotic microangiography Accelerated hypertension Hemolytic uremic syndrome Thrombotic t hrombocytopenia purpura Scleroderma Polycythemia vera Hyperacute vascular allograft rejecti on Liver function tests, expect: \200 elevated alkaline phosphatase. Autoantibody screen: \200 \200 \200 \200 \200 angina; pulmonary edema; neurological dysfunction. hypocomplementemia (atheroembolism); antiphospholipid antibody (spontaneous thrombosis); AN A, ANCA (to exclude vasculitis). Digital ischemia may lead to gangrene or ulceration. Livedo reticularis is the most common cutaneous manifes- tation, occurring in up to 50% of cases. Cardiac failure and severe hype rtension contribute to the high mortality. The presence of pre-existing arterial disease re sults in chronic renal ischemia and promotes the development of a collateral renal blood su pply. Therefore subacute renal artery occlusion in the presence of pre-existing renal arter y stenosis may present with very few signs and symptoms unless it occurs in a solitary func tioning kidney. In this scenario clinical features will be secondary to AKI. Additional sig ns and symptoms will depend upon the extrarenal extent of atheroembolism. Urine Urinalysis, expect: \200 \200 hematuria; proteinuria. Urine microscopy, expect: \200 \200 \200 hematuria; pyuria (pyelonephritis); eosinophiluria (atheroembolism). Urine culture, expect: \200 negative culture (exclude acute pyelonephritis). Radiology CXR: \200 \200 \200 cardiomegaly/LV aneurysm (mural thrombus); pulmonary edema (may be present); tortuous aorta (may be present). A.J.P. LEWINGTON 358 Ultrasound, expect: \200 \200 \200 asymmetrical kidneys (if pre-existing ARVD); normal kidneys (if acute athero/thromboembolis m); renal Doppler may demonstrate renal artery occlusion (less sensitive). CT: \200 spiral CT without contrast will exclude renal stone disease; enhanced CT will identify perf usion defects and areas of renal infarction. MRA: \200 will demonstrate renal artery occlusion. Renal angiography: \200 \200 \200 provides a de \201 nitive diagnosis; carries a risk of contrast nephropathy; increases the risk of further atheroembolism. Fig. 10.8.1 Renal biopsy demonstrating cholesterol embolization within renal arterioles. Th e arteriolar lumen contains several cholesterol clefts. (Courtesy of Dr D. Leitch, St James \200\231s University Hospital, Leeds, UK.) Radioisotope (DTPA) scan: \200 will demonstrate segmental or generalized decreased renal perfusion. Other ECG: \200 Thromboembolism and in situ thrombosis Immediate management of thromboembolism and throm- b osis in situ will be dictated by the clinical scenario and other organ systems affected. Th e urgency of intervention depends upon whether there is a signi \201 cant collateral blood supply to the kidney. Anticoagulation is necessary if there is a hypercoagulable state or if the occlusion is secondary to an acute throm- boembolic event (atrial \201 brillation, mural thrombus). Otherwise anticoagulation is not advisable in the acute set- ting if ther e is widespread atherosclerosis due to its desta- bilizing affect on atherosclerotic plaque s. Thrombolysis with intra-arterial recombinant tissue plas- minogen activator is indicated if the occlusion has occurred to previously normal renal arteries or is related to recent renal artery instrumentation. The procedure is minimally invasive but there are no large se ries to support its ef \201 cacy. Angioplasty may be successful following acute occlusion of an atherosclerotic renal artery. However, there are signi \201 cant risks of precipitat ing atheroembolism related to the instrumentation. Revascularization has been successfully performed follow- ing acute renal artery occlusion, up to several weeks after the event. Su rgical intervention is not recommended if the occlusion is unilateral in the setting of two previously normal functioning kidneys due to the relatively high oper- ative mortality. atrial \201 brillation (thromboembolism). Renal biopsy Often not required when there are strong clinical and radiological grounds for diagnosis. In atheroembolic AKI, birefringent, biconvex, elongated cho- lesterol crystals (frozen sections) will be seen on polarized light microscopy or cholesterol clefts (fixed s ections) (Fig. 10.8.1). Cholesterol clefts represent areas of cholesterol embolization with in vascular lumina. The cholesterol is dis- solved during the processing of the histologica l specimen. Eosinophilic in \201 ltrates and surrounding tissue ischemia are often seen in association with cholesterol emboli. Muscle biopsy Lower limb muscle biopsy has a sensitivity of nearly 100%, but is rarely perf ormed to diagnose atheroembolism. Skin biopsy Will be diagnostic in 75% of atheroembolism. Management Identifying patients at risk of atheroembolism and throm- boembolism is essentia l to allow prompt diagnosis and treatment. In particular it is important to recognize that the majority of these patients will be at an increased risk of developing contrast-induced nephropathy if undergoing angiography. The appropriate prophylactic measures to reduce the risk of radiocontrast induced nephropathy include: \200 Atheroembolism There is no speci \201 c therapy for renal atheroembolism, but there are a number of general measures that can be considered. ACEIs need to be stopped if implicated i n the etiology. If not implicated they may be effective in managing the hypertension trigge red by the atheroembolism. Corticosteroids have been used in patients with an acute inflamm atory response or those with gastrointestinal assessment to confirm that the investigation is appropriate; avoidance of nephrotoxic drugs , e.g. NSAIDs; adequate volume expansion prior to and following the procedure with 0.9% sod ium chloride 1 mL/kg/h (volume administered will be dependent upon volume status); minimiza tion of the volume of contrast media used; use of iso-osmolar contrast media. \200 \200 CHAPTER 10.8 Ischemic acute kidney injury 359 involvement. Their use is controversial and is based on small series and case reports. Nutr itional support should be considered as patients are often malnourished prior to the event. Statins should be started or continued due to their anti- in \202 ammatory properties and ability to stabilize plaques. Hemodialysis is the preferred form of renal replacement ther apy but should be performed with minimal anticoagu- lation if atherosclerotic disease is wi despread. Peritoneal dialysis is usually not practical due to previous abdominal surgery, g astrointestinal ischemia and nutritional compromise. Table 10.8.2 Causes of renal vein thrombosis Nephrotic syndrome Membranous nephropathy Lupus nephritis Amyloidosis Malignancy Renal cell carcinoma Retroperitoneal tumor Hypercoagulable states Oral contraceptive Pregnancy Antiph ospholipid syndrome Protein S and C de \201 ciency Antithrombin III de \201 ciency Factor V Leiden mutation Trauma Surgical Blunt Renal transplantation Acute pancreatitis Prognosis The overall prognosis of atheroembolic AKI is dif \201 cult to quantify and is d ependent upon the associated comorbidi- ties and extrarenal organ involvement. Patients who develop cardiac failure and AKI following atheroembolism have a 1 year mortality of 50%. P atients developing ESRD following atheroembolism have a 5 year mortality rate of 40%. Indic ators of a poor prognosis include: \200 \200 Thrombosis of inferior vena cava recurrent atheroembolism; gastrointestinal involvement. Urine Urinalysis, expect: \200 \200 One-third of patients with AKI due to atheroembolism remain dialysis dependent. hematuria; proteinuria. Renal vein thrombosis Renal vein thrombosis (RVT) is a rare and often undiag- nosed cause o f AKI. Radiology Ultrasound and Doppler: \200 \200 \200 may demonstrate increased renal size and echogenicity; \201 lling defect in renal vein; \206\221 resistive indices. Epidemiology This is poorly de \201 ned. There is a reported incidence of 22% in patients with nephrotic syndrome. MRA: Can be used to make the diagnosis but is rarely necessary. Etiology RVT may occur in patients who have a hypercoagulable state including: \200 \200 \200 Renal biopsy Not indicated. nephrotic syndrome; malignancy; pregnancy. Management Management is dependent upon the underlying disease process. Systemic anticoagul ation to prevent thrombus extension and embolization. Anticoagulation must be continued ind e \201 nitely if there is a hypercoagulable state. Nephrectomy may be required for tumor-r elated RVT, capsular rupture or longer-term consequences of a non- functioning kidney such as hypertension or infection. Catheter-directed thrombolysis with percutaneous thrombectomy has been reported to be successful in some cases. Conservative therapy may be favored in t he case of a left RVT because its extensive collateral venous supply may allow venous drain age and partial recovery of renal function. Patients with nephrotic syndrome secondary to membra- nous nephropathy and lupus nephritis are particularly at risk. Extrinsic compression of the renal vein can occur secondary to re troperitoneal \201 brosis and tumor. Clinical features \200 \200 \200 \200 \200 \200 loin, testicular or \202 ank pain; low grade fever; AKI with oliguria/anuria (bilateral o r single functioning kidney); hematuria (microscopic); pulmonary embolus (as a consequence) . Investigations Blood tests Clotting screen if thrombophilia suspected. A.J.P. LEWINGTON 360 Further reading Harris R, Ismail N. Extrarenal complications of nephrotic syndrome. Acute Kidney Injury Network: http://akinet.org/index.php Renovascular Forum: Am J Kidney Dis 1994; 23: 477 \200\223497. Modi KS, Rao VK. Atheroembolic renal disease. J Am Soc Nephrol 2001; 12: 1781. http://www.renovascularforum.org Journal of Renovascular Disease: Paris B, Bobrie G, Rossignol P, et al. Blood pressure and renal out- comes in patients with kidney infarction and hypertension. J Hypertens 2006; 24: 1649. http://www.journalrenovasculardisease.com/ Scolari F, Tardanico R, Zani R, et al. Cholesterol crystal embolisa- tion: a recognizable c ause of renal disease. Am J Kidney Dis 2000; 36: 1089. See also Clinical approach to acute kidney injury, p. 318 Renovascular disease, p. 292