Etiology There are several factors which are recognized to increase the risk of developing PeT in pregnancy (Table 9.5.2). PeT is characterized by: \200 Epidemiology PeT complicates 2 \200\2233% of all pregnancies and 5 \200\2237% of \201 rst pregnancies. PeT is a major cause of maternal and perinatal morbidity and mortality worldw ide with >4 million women develop- ing PeT each year, mainly in developing countries. vasoconstriction (increased peripheral vascular resist- ance); maternal volume contraction; platelet activation and intravascular coagulation; generalized dysfunction of the endothel ium (the hall- mark of the systemic syndrome of PeT). \200 \200 Maternal morbidity and mortality PeT is responsible for 25% of maternal deaths in the USA a lthough in developed countries the absolute rate of maternal death is quite small. In the U K, PeT accounts for 12 per 100 000 maternal deaths but the risk is up to 20 times higher in developing countries. 2% of women with PeT will develop eclampsia. Women with PeT have a d oubling of risk of death from cardiovascular disease in later life. This risk is highest in women with PeT who deliver preterm and those with recurrent PeT. PeT can be considered as a two-stage disorder. Stage I: There is placental hypoperfusion du e to inadequate tro- phoblast invasion leading to reduced placental blood \202 ow. Stage II: In some but not all women this progresses to the multisys- tem disorder of PeT and HELL P syndrome. The clinical presentation of PeT depends upon the extent of involvement of diff erent organ systems. Perinatal morbidity and mortality Fetal mortality and morbidity is considerable and related to the effects of the disease on the fetus and associated early delivery and prematurity P eT accounts for 15% all preterm births. Table 9.5.2 Factors associated with an increased risk of pre-eclampsia (PeT) Genetics There is some evidence to support the role of maternal and paternal genetic factor s in the pathogenesis of PeT. A number of genetic polymorphisms have been reported to be mo re common in women with PeT. Genes involved include those related to: \200 Primigravida Previous PeT Family history of PeT (mother or sister) High body mass index (>3 5 kg/m2 at booking) Older maternal age >40 years >10 years since previous pregnancy Multipl e pregnancy Underlying medical conditions: \200 diabetes \200 renal disease \200 chro nic hypertension \200 connective tissue diseases (SLE, especially in presence of coagulation (5,10-methylene-tetrahydrofolate reductase and factor V); folate metabolism; ox idative stress; components of RAS system. However, \201 ndings are inconsistent. \200 \200 antiphospholipid antibodies) Smoking: reduced risk of PeT S. J. CARR 312 Pathogenesis of reduced placental perfusion \200 Clinical observations: Table 9.5.3 Factors implicated in the pathogenesis of pre-eclampsia Reduced placental perfusion and placental hypoxia are important early features of pregnanci es complicated by PeT and intrauterine growth retardation. PeT is more common in conditions associated with larger placentas, e.g. twin pregnancies. There is an increased incidence o f PeT in women with medical diseases associated with microvascular disease (e.g. diabetes). Increased activity of the sympathetic nervous system Increased responsiveness to angiotensi n II and noradrenaline Decreased activity of the nitric oxide system Increased levels of: \200 endothelin \200 proin \202 ammatory cytokines \200 circulating microparticles \200 circulating antiangiogenic proteins Reduced levels of: \200 relaxin \200 antioxid ants Increased ratio of thromboxane : prostacyclin (increased urinary thromboxane B2 in pre gnancy-induced hypertension) Abnormalities in the coagulation cascade with thrombophilia Hy pocalciuria and abnormalities in PTH Remodeling of spiral arteries: Normally, the spiral arteries in the intervillous space reduce their muscular coat and beco me capacitance ves- sels, thereby enabling greater blood \202 ow in pregnancy. This remod eling of spiral arteries fails to occur in PeT and consequently there is increased resistan ce in these intervillous space vessels. The physiological control of trophoblast endovascul ar invasion depends on interactions between maternal decidua and fetal trophoblast. In PeT a number of abnor- malities in trophoblast invasion have been described. These changes invo lve both ambient local oxygen ten- sions and local immune reactions. The oxygen tension inc reases in the intervillous space at 10 \200\22312 weeks and is associated with an increase in con- centration of reactive oxygen species. The maternal antioxidant capacity is believe d to be an important factor in the regulation of trophoblast inva- sion and defects in anti oxidant capacity may impair remodeling of intervillous space vessels. Many factors have been suggested as potential triggers for this endothelial dysfunction inc luding: \200 \200 \200 \200 the renin \200\223angiotensin system; circulating antiangiogenic proteins; circulating micr oparticles; oxidative stress. The renin \200\223angiotensin system (RAS): There are changes in the decidual and maternal RAS in pregnancy. Progesterone regulates the RAS and is increased in PeT which may stimulate activation of decidual RAS. In PeT there i s a reduction in plasma renin levels and to a lesser degree aldosterone levels suggesting i ncreased adrenal gland sensitivity to angiotensin II. This increased sensitivity to angiote nsin II is important in generating the increased tendency to vasoconstriction in PeT. Incre ased heterodimerization of the angiotensin I recep- tor AT1 and bradykinin B2 receptor has been proposed as a mechanism for the increased sensitivity to angi- otensin II in PeT. In a ddition, antibodies may develop against the AT1 receptor in PeT. These antibodies may play a role in enhancing vascular sensitivity to angiotensin II. Uterine natural killer cells: Uterine natural killer cells (uNK) reside within the decidua and interact with fetal tropho blasts through spe- ci \201 c receptor \200\223ligand interactions and in \202 uence trop hob- last invasion. Normal placentation requires a balance of inhibition and activation of uNK cells that is mediated by maternal and fetal factors. It has been suggested that this b alance is defective in PeT. Pathogenesis of the maternal systemic disorder of PeT Numerous factors have been implicated in the pathogene- sis of PeT (Table 9.5.3). Several of the more recently reported factors are consid- ered in more detail below. \200 Endothelial dysfunction: Circulating antiangiogenic proteins: Normal placentation involves both angiogenesis and vas- culogenesis. There are several rece ptor \200\223ligand systems that are vital to this process including: vascular endothelial growth factor (VEGF); placental growth factor (PGF). VEGF and PGF are proangiogenic growth factors and bind to the receptor Flt-1 (fms-like tyrosine kinase 1) in target tissues. Inte raction of VEGF and PGF with Flt-1 can be antago- nized by the presence of a soluble form o f the Flt-1 receptor, sFlt-1. In PeT there is generalized dysfunction of the endo- thelium. Alteration in the normal func tions of the endothelium in pregnancy can lead to: vasoconstriction; \200 \200 increase d sensitivity to pressor agents including angi- otensin II; activation of the coagulation c ascade. The activated endothelium also induces the production of in \202 ammatory mediators, growt h factors and cytokines which can in \202 uence vascular tone. CHAPTER 9.5 Hypertensive disorders in pregnancy 313 sFlt-1 is a secreted splice variant of Flt-1 that binds VEGF and PGF and therefore acts as an antiangiogenic factor. The normal placenta induces a 20-fold increase in circu- lating s Flt-1 levels by the end of the third trimester of pregnancy. Increased circulating levels o f sFlt-1 are found in PeT and infusion of sFlt-1 in pregnant rats induces a PeT-like syndro me which can be reversed by VEGF admin- istration. Soluble endoglin (sENG) is another antia ngiogenic pro- tein which along with sFlt-1 can induce a severe PeT-like syndrome in pregna nt rats. In human pregnancy it is hypothesized that sENG could act with sFlt-1 to amplify e ndothelial dysfunction in PeT. Rising circulating levels of sENG and ratios of sFlt1: PGF h ave been shown in some studies to herald the onset of PeT. It is possible that if used toge ther these markers could be of predictive value for development of PeT. However, it is not clear if they are markers of the sys- temic syndrome of PeT or are involved in the pathogen - esis of the syndrome. \200 Circulating microparticles: The kidney in PeT In the systemic syndrome of PeT there is a reduction in GFR caused by: \200 \200 \200 decreased renal blood \202 ow due to vasoconstriction; volume contraction; decreased card iac output. In addition, abnormal glomerular morphology leads to a reduction in ultra \201 ltration ca pacity, further reducing the GFR. Renal biopsy features \200 Light microscopy: There is marked swelling of the glomerular endothelial cells which is suf \201 cient to oc clude the capillary lumen and result in hypoperfusion, so-called \200\230glomerular endoth eliosis \200\231. This change is not seen in any other form of hypertension and points to t he endothelium as the primary target for the disorder. There may also be mesangial expansio n and inter- position, thickening of capillary walls and diffuse \200\230double contours \200\231. Subendothelial \200\230 \201 brinoid \200\231 deposits and endothelial and mesa ngial fat vacuoles may also be seen. These changes may progresses to acute tubular necrosis or cortical necrosis in severe cases of PeT. Immuno \202 uorescence: Small membrane vesicles released from apoptotic syncy- tiotrophoblast or endothelial cells have been found to circulate in excess in PeT and to impair endothelial function. Micropart icles have also been found to be procoagulant, inducing disturbances in the coagulation cas cade. There may be IgM and \201 brin deposition but no evidence of other immunoglobulin or comp lement deposition. Electron microscopy: Thickening of glomerular capillary walls due to mesang- ial cell interposition is commonly seen. Endothelial cell hyperplasia and hypertrophy, exudation of foamy macrophages, lymphoc ytes and polymorpho- nuclear cells and increased glomerular volume have all been reported. Oxidative stress: There are many reports of increased oxidative stress in PeT. In general, therapeutic interv entions to reduce oxidative stress have not reduced risk of PeT except in one small study o f combined vitamin C and vitamin E therapy after 20 weeks gestation. Other systemic manifestations of PeT In PeT there may also be: \200 generalized vasoconstriction leading to hypoperfusion of numerous organs; activation of the coagulation cascade and formation of occlusive microthrombi in small vessels; loss of \202 uid from the intravascular compartment, leading to hypovolemia; metabolic syndrome wit h dyslipidemia; hyperuricemia. Clinical features Raised BP >140/90 mmHg and proteinuria after 20 weeks gestation. Persiste nt severe headache. Visual disturbances (blurred vision, diplopia). Epigastric pain, tender ness and vomiting. Hyper-re \202 exia. Edema. Bleeding diathesis. Jaundice. Placental abru ption. Reduced fetal movements. Intrauterine death. \200 Investigations It is important to assess for: \200 \200 thrombocytopenia; microangiopathy (blood movie: fragmented red blood cells); abnormal renal function; abnormal liver function tests; raised urate level (values >270 mol/L suggestiv e of PeT); proteinuria on either dipstick, spot PCR or 24 h urine protein estimation; disse minated intravascular coagulation. \200 \200 HELLP syndrome Hemolysis, Elevated Liver enzymes, Low Platelets. This is a severe form of P eT in which liver and platelet abnormalities are predominant. S. J. CARR 314 Treatment of hypertensive disorders in pregnancy Delivery The only de \201 nitive treatmen t for PeT is delivery. If PeT presents after 32 weeks this is relatively straightfor- ward. However, PeT presenting at earlier stages of gesta- tion requires a dif \201 cult balance between delivery and medical management of HTN and maternal and fetal well- being. It can also be given as a 50 mg IV dose repeated every 10 \200\22320 min to a maximum dose of 200 mg. Hydralazine This is given as a slow IV injection of 5 \200\22310 mg repeated after 30 min t o maximum of 20 mg. This can be followed by an IV infusion if required (50 \200\223100 g/ min). Magnesium sulfate In women at high risk of seizures magnesium sulfate is the anticonv ulsant of choice for both prevention and treat- ment of eclampsia. Indications for delivery Dif \201 culty in controlling BP. Reduced fetal growth, reversed end-diastolic \202 ow on fetal ultrasound. Evidence of maternal organ dysfunction: \200 \200 \200 Management of mild \200\223moderate hypertension in pregnancy Methyldopa This is generally recommended as \201 rst-line treatment for mild \200\223moderate HTN in pregnancy (0.5 \200\2232.0 g/day). Side-effects of drowsiness and depression may occur. The safety of meth yldopa has been established in case con- trol studies. Long-term follow-up studies of child ren of mothers taking methyldopa have identi \201 ed no adverse effects. deteriorating renal function; deteriorating liver function; thrombocytopenia. Antihypertensive medication in pregnancy Antihypertensive drugs are used for the treatment of mild \200\223moderate and hypertensive emergencies HTN in pregnancy. The aim is to smoot hly reduce BP to levels safe for mother and fetus, avoiding sudden falls. The ideal target BP remains controversial: \200 b-Blockers A Cochrane Review demonstrated an increase in small for gestational age infants in association with atenolol treat- ment and this should be avoided in pregnancy. Labetolol 0.2 \200\2231.2 g/day orally may be used. treatment is mandatory when BP >160/100 mmHg. The ideal BP target in pregnant women with chronic HTN and underlying renal disease is unkn own. Concerns have been reported about the impact of lower- ing BP upon fetal growth, altho ugh evidence is con \202 icting. One meta-analysis demonstrated that lowering maternal BP resulted in an increased incidence of small-for- gestational-age infants whereas a separate analysis showed no overall risk of a small baby in women taking antihyper- tensive medicat ion. Treatment of high BP in pregnancy probably has maternal bene \201 ts. Treatment may r educe the risk of severe HTN compared to placebo or no treatment but it is not clear whethe r it delays the progression or the development of PeT. Treatment may reduce the risk of fet al or neonatal morbid- ity (respiratory distress syndrome). Calcium channel blockers These are frequently used in pregnancy. E.g. nifedipine 40 \200 \22380 mg/day orally. Diuretics These should be avoided in pregnancy. Hypovolemia secondary to diuretics may comp romise pla- cental blood \202 ow. Some women with severe edema due to nephrotic syn- drom e or PeT at an early stage of pregnancy may require diuretic therapy for treatment of sever e \202 uid retention or pulmonary edema. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) T hese are contraindicated in pregnancy and should be avoided. Previously, ACEIs/ARBs were no t considered teratogenic in the \201 rst trimester. However, a recent study reported a 2. 7-fold greater risk of serious congenital malformation with exposure to ACEIs in the \201 rst trimester of pregnancy. Malformations were reported in the cardiovascular and central nervous systems (and in renal tract on post hoc analysis). Exposure in the 2nd and 3rd trim esters of pregnancy is associated with ACEI fetopathy. Fetuses with this syndrome have had: \200 \200 \200 \200 \200 \200 Management of hypertensive emergencies in pregnancy When a patient has seizures or is at ri sk of stroke or eclampsia from acutely raised or very high BP in pregnancy (>170/110 mmHg) then IV treatment may be required as an emergency. Intravenous medication should be given i n a high depend- ency care setting with the aim to reduce the BP over a period ranging from minutes to 1 \200\2232 h. Drug dosage should be titrated against the BP. Aim for a target diastolic BP of 90 mmHg. The patient will require intensive monitoring of cardiovas- cular, neurological, obstetric status and careful monitoring of urine output. oligohydramnios; intrauterine growth retardation; hypocalvaria; renal dysplasia; renal fail ure with anuria; intrauterine death. Labetolol This is given as an IV infusion at 2 mg/min. It should be stopped when target BP is reached and oral therapy commenced. CHAPTER 9.5 Hypertensive disorders in pregnancy 315 Counseling for future pregnancies Women with a history of PeT are at increased risk of PeT in future pregnancies and should be warned of this postnatally. The presence of underlying medical conditions should be considered (Table 9.5.1). The exact risk of PeT in future preg nancies is dif \201 cult to determine but is generally lower in a second pregnancy with th e same partner. However, in the presence of an underlying medical condition such as CKD the risk may increase with disease progression and increasing age. Prevention of PeT Dietary calcium supplementation Initial reports showed that supplementati on with 1 g daily reduced risk of PeT. However, subsequent trials produced con \202 icting results. Secondary analyzes have shown that calcium supplements may be bene \201 cial in women with extremely low dietary calcium intake. Antioxidants Vitamin C and E: there is some evidence of reduced risk of PeT and several lar ge trials are underway. Further reading Atallah A, et al. Calcium supplementation during pregnancy for pre- venting hypertensive disorders and related problems. Cochrane Database Syst Rev 2002; (1): CD00105 9. Low dose aspirin Trials have shown con \202 icting results. A meta-analysis in 1991 demons trated that low dose aspi- rin reduced the risk of PeT but two subsequent larger mul- ticen ter studies reported minimal effects. Secondary analyzes identi \201 ed that certain group s may derive some bene \201 t from low dose aspirin. Further studies have shown that a lar ge number of women require treatment to prevent one case (need to treat 69 women to prevent one case of PeT and to treat 227 women to prevent one neonatal death). Low dose aspirin ma y be prescribed to women at high risk of PeT: \200 \200 \200 Broughton-Pipkin F, Roberts JM. Hypertension in pregnancy. J Hum Hypertens 2000; 14: 705 \200\223724. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congeni- tal malformations after \201 rst trimester exposure to ACE inhibi- tors. N Engl J Med 2006; 354: 2443 \200\2232454. Duley L, Meher S, Abalos E. Management of pre-eclampsia. Br Med J 2006; 332: 463 \200\223468. Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulat- ing antiangiogenic fa ctors in pre-eclampsia. N Engl J Med 2006; 355: 992 \200\2231005. [Erratum: 355: 1840.] Shah D. Pre-eclampsia: new insights. Curr Opin Nephrol Hypertens 2007; 16: 213 \200\223220. previous history of severe PeT; diabetes; chronic hypertension. Ventakatesha S, Toporsian, Lam C, et al. Soluble endoglin contributes to the pathogenesis o f pre-eclampsia. Nat Med 2006; 12: 642 \200\223649. Von Dadelszen P, et al. Fall in mean ar terial pressure and fetal growth restriction in pregnancy hypertension. Lancet 2000; 355: 8 7 \200\22392. Wolf M, Shah A, Lam C, et al. Circulating levels of the antiangiogenic marker sFlt-1 are increased in \201 rst versus second pregnancies. Am J Obstet Gynecol 2005; 19 3: 16 \200\22322. Aspirin should be started after 12 weeks if there are no contraindications. Follow-up It is important that women with de novo HTN during preg- nancy or PeT are followe d postnatally to determine whether ongoing medication or further investigation are required . Investigation may be required to identify secondary or pre-existing HTN. The BP should be monitored and antihypertensive medica- tions reduced as BP falls. When the BP is stable, a ntihypertensive medication should be converted back to the most appropriate regime for the nonpregnant women, i.e. restart ACEI/ARB, diuretic, etc. Advice regarding safety of antihyp ertensive medication in breastfeeding women should be sought from a pharmacist. Proteinuria following PeT can persist for a prolonged period, frequently \211 3 \200\2236 months. In this situation referral to a nephrologist should be made as a renal biopsy may be considere d to exclude an underlying renal pathology. Internet resources Cochrane Library, sets of reviews on pre-eclampsia: http://www.thecochranelibrary.com Geneva Foundation for Medical Education and Research: http://www.gfmer.ch/guidelines/pregnancy_newborn Royal College of Obstetricians and Gynecol ogists. Pre- eclampsia Study Group recommendations September 2003: http://www.rcog.org.uk Action on Pre-eclampsia: http://www.apec.org.uk Pre-eclampsia Foundation: http://www.Preeclampsia.org See also Acute kidney injury in pregnancy, p. 378 CKD in pregnancy, p. 476 This page intentionally left blank 317 Chapter 10 Acute kidney injury (AKI) Chapter contents Clinical approach to acute kidney injury 318 Renal replacement therapies in acute kidney in jury 328 Dialysis and hemoperfusion treatment of acute poisoning 336 Glomerulonephritis, va sculitis, and nephrotic syndrome 340 Acute tubulointerstitial nephritis 344 Hemolytic uremi c syndrome and thrombotic thrombocytopenic purpura 348 Hepatorenal syndrome 352 Ischemic ac ute kidney injury 356 Pigment-induced acute kidney injury 362 Acute kidney injury in tropic al countries 366 Acute kidney injury in infants and children 372 Acute kidney injury in pre gnancy 378 Acute kidney injury in the elderly 384 A. DAVENPORT 318 Clinical approach to acute kidney injury Other studies have observed that the risk of developing AKI severe enough to require dialys is, plus failure to recover residual renal function following AKI, is greater in those pati ents who generate more free radical-derived nitrosotyrosine in response to in \202 ammatio n and who also have reduced catalase, one of the enzymes involved in lim- iting hydrogen pe roxide activity. Introduction The term acute kidney injury (AKI) has been introduced to make clinicians awar e of developing renal injury, and therefore potentially allow interventions designed to pre vent the development of renal failure requiring dialysis. AKI is associated with a rapid re duction in renal function, characterized by a fall in glomerular \201 ltration rate (GFR) , with corresponding increases in serum urea, creatinine and cystatin C. Clinical features History Clinical history is vital in helping to differentiate intrinsic A KI from CKD, in terms of obstruction, prerenal causes and also its time course (Fig. 10.1.3 ). Prerenal AKI is due to a reduction in renal perfusion, either in terms of renal artery b lood \202 ow and/or renal perfusion pressure, or due to intrarenal ischemia (Table 10.1.3 ). Similarly the history may reveal causes of intrinsic renal disease: drug-induced toxic o r interstitial renal injury, pyelonephritis, and/or underlying vasculitis (Table 10.1.4). S ome drugs predispose to AKI, such as tenovir in HIV patients, due to its mitochondrial effe cts, intravenous immunoglobulins due to osmotic damage, and some herbal remedies. Total anu ria and loin pain may suggest obstructive causes of renal failure (Table 10.1.5). Although obstruction can cause AKI, typically it causes acute on chronic kidney damage. De \201 nition One of the major dif \201 culties in studying AKI has been the lack of a c onsensus de \201 nition of AKI. The Acute Dialysis Quality Initiative (ADQI) has pro- posed that for clinical research purp oses AKI be de \201 ned as an \200\230abrupt (1 \200\2237 days) and sustained (>24 h) dec rease in GFR, urine output or both \200\231. They have produced a classi \201 cation system divided into three levels of severity (risk , injury and failure) and two clinical outcomes ( \200\230loss \200\231 and \200\230end-st age renal failure \200\231) (RIFLE Classi \201 cation, Table 10.1.1). However these criter ia are not intended to guide clinical management of individual patients. More recently the Acute Kidney Injury Network (AKIN), simpli \201 ed the RIFLE criteria to use just the \201 rst three grades of RIFLE: risk, injury and failure (Table 10.1.2). Epidemiology In the USA, the recorded incidence of AKI requiring dialysis has been steadily increasing from 14 per 1000 Medicare hospital discharges in 1992 to 35 per 1000 in 2001. T he annual incidence of AKI in the UK has been reported to be 500 per million population (pm p), with some 200 pmp requiring dialysis. Risk factors for developing AKI include: \200 Clinical assessment Thorough physical examination is required, not only to assess volume st atus (see below), but also to look for signs of small vessel vasculitis and/or systemic dis orders: \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 nail-fold infarcts; skin vasculitis; arthritis; oral ulceration; retinopathy; atrial \201 brillation; hypo- and/or hypertension; cardiac murmurs; hemoptysis; abdominal distension; organomegaly and/or ascites. age (more than doubling in patients aged >85 compared with those <65 years); male sex; ethn icity (more common in African-Americans than in other racial groups in the USA). \200 Following the introduction of the modi \201 ed MDRD equation, used to estimate GFR from se rum creatinine, it is now generally recognized that many patients who develop AKI do so on a background of pre-existing CKD. Traditionally the causes of AKI are divided into prerenal , intrinsic and postrenal etiologies (Fig 10.1.1). AKI in the hospital setting: \200 \200 \200 A pelvic examination is mandatory to exclude an enlarged bladder, abnormal prostate and/or gynecological malignancy. Bedside urine dipstick testing may detect: \200 40 \200\22370% prerenal; 10 \200\22350% intrinsic; 10% obstruction. hematuria (due to excess red blood cells, hemolysis and/ or myoglobin); protein (glomerular , tubular or over \202 ow); leukocytes and nitrites (indicating infection). In the community, obstruction is a much more common cause of AKI (Fig. 10.1.2). \200 Genetics Recent work has shown that single point mutations, typically in the promoter regio n of various genes, can in \202 uence mortality in AKI. Volume assessment In the early stages of AKI due to prerenal etiologies, appropriate \202 uid resuscitation may well prevent progres- sion to established AKI, and similarly minimiz e AKI in cases of myeloma/light chain disease, rhabdomyloysis, and post- tumor lysis syndro me. There is evidence that mortality in AKI is much higher in those patients with a high TNF-A and low IL-10 producer phenotype, whereas there is a survival advantage for those who are l ow TNF-A and high IL-10 producers. CHAPTER 10.1 Clinical approach to acute kidney injury 319 Table 10.1.1 RIFLEa grading of AKI Table 10.1.2 Acute Kidney Injury Network (AKIN) grading of AKI RIFLE grade GFR Serum creatinine Urine output AKI stage Serum creatinine criteria Urine output criteria <0.5 mL/kg/h for 6 h Risk >25% \206\223 \2271.5 \206\221 >50% \206\223 \2272.0 \206\221 Absolute \206\221 Cr \211 25 mol/l or \206\221 Cr \211 150 \200\223200% above baselin e \206\221 Cr >200 \200\223300% above baseline <0.5 mL/kg/h for >12 h <0.3 mL/kg/h for 24 h or anuria for 12 h <0.5 mL/kg/h for >6 h 1 <0.5 mL/kg/h for 12 h Injury <0.3 mL/kg/h for 24 h or anuria for 12 h Failure >75% \206\223 \2273.0 \206\221 or 2 Cr >350 with acute \206\221 >45 mol/l Persistent loss of kidney function >4 weeks 3 \206\221 Cr >300% above baseline or Cr \211 350 mol/l with an acute rise of \211 45 mol/l Loss refers to increase in serum creatinine within a 48 h period Dialysis dependent >3 months ESRD aRisk, injury, failure; loss, end-stage renal disease. Acute kidney injury Prerenal causes Intrinsic renal causes Postrenal causes Interstitial nephritis Toxic tubular injury Glomerulonephritic vasculitis Vasomotor nephropathy Fig. 10.1.1 Broad categories of AKI. Other obstructive causes 11% Prostatic obstruction 25% Unknown 4% Medical causes 25% Surgical causes 25% Cardiac/vascular causes 25% Fig 10.1.2 Causes of AKI in a community-based survey. A. DAVENPORT 320 \206\223 Intravascular volume & \206\223 BP GI, renal, dermal fluid losses burns, hemorrh age, shock Large vessel renal vascular disease Renal artery stenosis, thrombosis and embolus, operativ e cross-clamping \206\223 Effective intravascular volume congestive cardiac failure, cirrhosis, nephrotic s yndrome, peritonitis, pancreatitis Small vessel renal vascular disease vasculitis, renal transplant rejection, cholesterol, em boli, HUS, HbSS, malignant hypertension, scleroderma, hypercalcemia Generalized or local \206\223 renal blood flow Drugs calcineurin inhibitors, ACEIs, ARBs, NSAIDs, contrast agents, amphotericin Hepatorenal syndrome Abdominal tamponade gross ascites, postoperative bowel dilatation, laparoscopic surgery Sepsis systemic, pyelonephritis Fig. 10.1.3 AKI due to causes of reduced renal blood \202 ow. Typically hypovolemic patients have cooled peripheries, but patients with septic shock and/ or liver failure, who may also have renal hypoperfusion, may have warm peripheries. The cap illary re \201 ll test is a quick bedside test used to assess volume status; a normal re \201 lling of the nail-bed cap- illaries takes <2 s after release of pressure. In hypovolem ic patients the jugular venous pulse (JVP) may well be depressed, and patients may need to be tilted head-down before it becomes visible. However, the JVP is an assessment of right a trial \201 lling pressure, and not a measurement of cardiac output. Thus although a low J VP is associated with circulatory under \201 lling, an elevated JVP does not equate with a dequate cardiac output and renal perfusion, particularly in cases of systemic sepsis, liver failure, hypoalbuminemia, severe metabolic acidosis and cardiac failure. Fluid resuscitati on should be designed to restore tissue perfusion (Fig. 10.1.4) and maintain tissue viabili ty (Table 10.1.6). In clinical practice, it can be very dif \201 cult to assess the adequa cy of the circulating volume, as this depends upon both vasomotor tone (systemic vascular r esistance) and cardiac contractile performance. In a previously normotensive patient, tissu e organ \202 ow, including renal perfusion, should be maintained with a mean arterial pre ssure of \211 65 mmHg, with \202 uid and/or vasopressors. If patients are preload (volum e) responsive (Table 10.1.3), then \202 uid resuscitation will be bene \201 cial, by inc reasing cardiac output and renal perfusion, whereas if they are not, then vasopressors shou ld be tried, as additional \202 uids may well be detrimental (treatment algorithm Fig. 10 .1.4). In the nonventilated patient, preload responsiveness can be assessed by monitoring t he dynamic CVP during spontaneous respiration, and also by assessing the change in pulse de nsity of the \201 nger oxygen saturation probe (a change in CVP of >1 mmHg and a change i n pulse Table 10.1.3 Causes of prerenal AKI Reduced renal artery blood \202 ow Volume losses Hemorrhage GI \202 uid losses: vomiting/diarrhea Burns Excessive diuresis R enal arterial obstruction Renal artery thrombosis/embolus Renal artery stenosis Aortic aneu rysm Intra-renal ischemia Cardiogenic shock Systemic sepsis Hepatorenal failure Anaphlyactic sho ck Nephrotic syndrome Abdominal compartment syndrome Page kidney Renal vein thombosis Drugs COX-1 and -2 inhibitors \200 ACEIs and ARBs \200 Calcineurin inhibitors However, in cases of established AKI, rapid \202 uid administra- tion may well result in pulmonary edema. Review of clinical \202 uid balance charts and daily weights aids assess ment along with history of \202 uid losses and reduced \202 uid intake. Young patients can compensate for volume depletion to a far greater extent than the elderly, and may well maintain a \200\230normal \200\231 brachial arterial pressure with no demonstrable postura l hypotension. However, the pulse pressure may be narrowed due to increased sympathetic ner vous activity. CHAPTER 10.1 Clinical approach to acute kidney injury 321 Table 10.1.4 Causes of intrinsic AKI Table 10.1.5 Causes of post-renal (obstructive) AKI Small vessel vascular disease Occlusion Intrinsic Intraluminal \200 Calculus \200 Blood clot \200 Sloughed papilla Cholesterol emboli \200 Cryoglobulinemia \200 HUS/TTP \200 DIC \200 Plasmodium mala ria \200 Sickle cell crisis \200 Eclampsia Intramural \200 Ureteric malignancy \200 Ureteric stricture (TB) \200 Post-irradiatio n \201 brosis \200 Bladder cancer \200 Prostatic hypertrophy Vasculitis Microscopic polyangiitis Wegeners granulomatosis Extrinsic Extramural SLE \200 Henoch \200\223Sch nlein purpura \200 Hyperacute renal transplant rejection Retroperitoneal \201 brosis \200 Pelvic malignancy \200 Ureteric ligation Hypertension Malignant hypertension \200 Scleroderma Acute glomerulonephritis Crescentic rapidly progressive GN density >10% suggests that the patient will be preload responsive). Volume loading in patie nts with CVP >12 mmHg is unlikely to increase cardiac output. During mechanical ventilation , the variation in cardiac stroke volume, or \201 nger pulse pressure variability during the venti- latory cycle, can also predict preload responsiveness. In patients predicited to be volume responsive, a \202 uid bolus of 2 mL/kg of colloid or 3 mL/kg of crystalloid o ver 10 min should be given, and then the patient should be reassessed. Anti-GBM disease \200 Postinfectious GN \200 Idiopathic Interstitial nephritis Drug-ass ociated \200 Antibiotics \200 NSAIDs Post-infection Leptospirosis \200 Epstein \200\223Barr virus Drug toxicity Aminoglycosides \200 Tenovir Investigations All patients should have urine stick testing performed to detect blood, prot ein, glucose and nitrites. Depending upon the history and physical examination other invest iga- tions may be required (Table 10.1.7). Toxins Radiocontrast media \200 Myoglobin \200 Hemolysis \200 Myeloma/light chains \200 Sn ake/spider venom Urinary electrolytes Urinary electrolytes may be helpful in determining those patients with reversible prerenal AKI. Heavy metals \200 Cisplatin Spot urinary sodium Urinary sodium excretion can be affected by pre-existing CKD and prior treatment with diuretics. Urinary sodium concentration on a spot urine sample may not be di scriminant if normal or increased, but would suggest possible volume responsive in AKI if: \200 \200 Poisons \200 Plant \200 Drugs \200 Chemical (e.g. ethylene glycol) Crystals \200 Urate \200 Indinavir \200 Oxalate In \201 ltration \200 Sarcoid \200 Lymphoma <10 mmol/L in a healthy young adult; <20 mmol/L in an elderly patient. Importantly, following relief of urinary obstruction, the patient may be intravascularly vo lume-depleted but still have a normal or increased spot urine sodium concentration. Infection Acute pyelonephritis \200 Bacterial infection Spot urine osmolality Spot urine osmolality may be increased in volume respon- sive AKI, bu t is also normally increased in the immediate postsurgical period, due to changes in vasopr essin release and renal free water clearance. Immunological Renal transplant Cellular rejection A. DAVENPORT 322 Hemodynamic (and volume) assessment of the patient with AKI Is the patient hemodynamically stable? YES NO Is patient preload (volume) responsive? monitor YES NO give fluids and reassess Is there reduced vasomotor tone? YES NO add vasopressor and consider further fluid add inotrope Fig. 10.1.4 Clinical approach to volume and vasopressor management in the patient with AKI. After each step, reassess patient. Typical vasopressor: noradrenaline. Typical inotrope: d obutamine. Vasomotor tone typically assessed invasively as SVR (systemic vascular resistanc e). Table 10.1.6 Assessment of tissue perfusion FEUrea <35%. Other causes of a FENa <1% include: \200 \200 \200 Measured variable Desired range cardiac failure; contrast nephropathy; heme pigment nephropathy. Mean arterial blood pressure SVO2 mixed venous oxygenation SCVO2 central venous oxygenation Arterial/venous lactate >65 mmHg >70% sat. (4 \200\2236 kPa) >65% sat. <2 mmol/L(A) or <2.5 mmol/L (V) 2 mmol/L <2 s <100 beats/min The FEUrea is a better discriminant of prerenal AKI than FENa, as even when patients have b een given diuretics the FEUrea will be <35%, whereas the FENa is often >2%. In established AKI, both are elevated. In the hepatorenal syndrome the FEUrea is low, and the urinary sodi um concentration is typically 10 mmol/L. Metabolic acidosis \200\223 base excess Capillary re \201 ll time Tachycardia Novel biomarkers of AKI Traditionally urea and creatinine have been used to assess renal fu nction. However, following AKI, serum creatinine does not increase for some 24 \200\22372 h , and similarly there is a delay between the recovery of residual renal function and a fall in serum creatinine. This has led to the search for other biomarkers to detect AKI at an e arlier stage. For example, cystatin C tends to increase \211 24 h prior to cre- atinine ri ses. Other urinary biomarkers investigated include: \200 neutrophil gelatinase-associated lipocalin; \200 IL-18; \200 kidney injury molecule-1; N-acetyl-B-(D)-glucosinidase. \200 Fractional excretion of sodium and urea To try and improve the diagnostic accuracy of urine biochemistry in AKI, ratios of sodium and urea excretion relative to creatinine have been evaluated. The fractional excretion of sodium (FENa) and fractional excretion of urea (FEUr ea) are useful parameters. FENa = urinary Na \227 plasma Cr \227 100 plasma Na \227 urin ary Cr The normal FENa is >1% and FEUrea is >45%. In those patients with prerenal AKI: \200 FENa <1%; CHAPTER 10.1 Clinical approach to acute kidney injury 323 Table 10.1.7 Investigation Comment Urine Urine stick testing Renal or lower urinary tract in \202 ammation/myoglobin Glomerular or renal tubular protei nuria Urinary infection Urinary infection Red cell casts in glomerulonephritis and vasculit is Oxalate/indinavir/uric acid stones Malignant cells Eosinophiluria in interstitial nephri tis Blood Protein Nitrites Urine culture Microscopy/cytology Biochemistry Serum Urea, creatinine, cystatin C raised in AKI Hyperkalemia and metabolic acidosis Hypocalcemia and hyperphosphatemia in rhabdomyolysis Hypercalcemia in myeloma, sarcoid, malignancy Hypo albuminemia in nephrotic syndrome, cirrhosis Bilirubin raised in liver disease, leptospiros is LDH raised in malignancy and hemolysis CPK raised in rhabdomyloysis, sickle cell crisis Haptoglobins reduced in hemolytic uremic syndrome ACE raised in sarcoid CRP raised in in \202 ammation and sepsis Uric acid raised in tumor lysis syndrome, sickle cell crisis Fract ional excretion of sodium and urea Proteinuria; quantitation: protein/creatinine ratio Urine Hematology Full blood count