filtrate fresh dialyzate blood flow blood flow Postdilution replacement fluid Convective blood purification Diffusive blood purification Fig. 10.2.2 Convective and diffusive blood puri \201 cation. A. DAVENPORT 330 convection, high flux membranes are required. Inappropriate use of a dialyzer designed for dialysis as a hemo \201 lter, will result in excessive clotting problems. Pure unadulterat ed cellulosic membranes have been shown to reduce renal recovery in patients with AKI. Howe ver, these membranes have generally been replaced by modi \201 ed cellulose, and such memb ranes compare favo- rably with the synthetic membranes. Septic patients and those with live r failure may have increased nitric oxide levels, and can be more prone to hypotension when \201 rst connected to the dialysis circuit, due to the generation of bradykinin. This ca n be minimized by priming the dialyzer with isotonic sodium bicarbonate, rather than 0.9% s aline (pH 5.4). Intermittent HD vs intermittent HF Initially it was thought that IHF provided greater cardi ovas- cular stability than IHD. However, it is now established that postdilutional IHF caus es greater cooling than IHD, and the predilutional mode even more cooling. In addition ther e are differences in sodium exchange between IHD and IHF. There is an obligatory sodium los s with any ultra \201 ltration. During IHF, plasma water passes across the hemo \201 lter membrane due to a hydrostatic pressure gradient (convection). However, not all sodium in p lasma water is freely available to move, as it may be asso- ciated with negatively charged proteins and other com- pounds. Thus for the same dialyzate/replacement \202 uid sodium c oncentration, patients treated by IHF will have a greater sodium gain than those by IHD, an d this is greatest in the postdilution mode. This is compounded by the fact that compared t o healthy dialysis patients, patients with AKI have a low dietary sodium intake. Continuous renal replacement therapies Continuous renal replacement therapies (CRRT) includ e: \200 continuous arteriovenous hemo \201 ltration (CAVH); \200 continuous venovenous hemo \201 ltration (CVVH); \200 continuous venovenous hemodialysis (CVVHD); \200 cont inuous venovenous hemodia \202 tration (CVVHDF). CAVH was the first CRRT, but often did no t provide adequate clearances, so IHD was still required. CAVH has now been superseded by p umped venovenous systems which provide adequate clearances (Fig. 10.2.3). Typically CRRT pr ovides greater cardiovascular stability than conventional IHD. This is most likely due to t he increased patient cooling associated with CRRT, despite warming of replacement \202 ui ds and dialyzates. While no study to date has shown an improved patient survival with CRRT compared to IHD, there are data to show that recovery of renal function is greater with CRR T when compared to standard IHD. Hemodia \201 ltration Hemodia \201 ltration (HDF) is a technique in which there is both d ialysis and \201 ltration (convection). Membranes Hemodialysis Diffusion is increased by having a large surface area, with a short distance for solutes to move, and thus dialyzer mem- branes designed for diffusion typicall y have long fiber lengths of narrow diameter. Typically dialyzer membranes restricted the p assage of small solutes, and were therefore termed low flux, but over time the membranes ha ve changed, so that many IHD treatments in AKI use high \202 ux membranes. Hemo \201 ltration For convective therapies, hydrostatic pressure is better maintained by shorter, wider diameter \201 bers. To allow Postdilutional replacement Venous line Filter Ultrafiltrate Peristaltic pump Arterial line Fig. 10.2.3 Continuous venovenous hemo \201 ltration. CHAPTER 10.2 Renal replacement therapies in acute kidney injury 331 Although there are differences between CVVH and CVVHD in terms of solute removal, it does n ot appear that one modality is superior to the other in clinical practice. Whereas there ar e guidelines as to the dose of RRT required for patients with CKD, it was unknown until rel a- tively recently whether the dose of CRRT impacted on patient survival. However, it has n ow been shown that the dose of treatment delivered has an impact on outcome, with greater p atient survival during postdilutional CVVH with a delivered dose of >20 mL/kg/h or an equiv alent dose of CVVHDF. Although CRRT generally provides an effective RRT, with cardiovascula r stability, it must be recognized that drugs, particularly antibiotics, may have a substan tial clearance, and therefore dosages need adjusting, and that water- soluble vitamins and trace elements such as selenium are lost and may need replacing. will produce a hyperchloremic acidosis. These changes will occur more rapidly if high volum es are exchanged, and if predilutional \202 uid replacement is used during CRRT, as chlor ide mass balance is more positive when compared to postdilutional replacement. Latterly bic arbonate-based, of buffer-free solutions have been developed, and although more costly have been shown to improve acid \200\223base status and cardiovascular stability in critically ill patients with AKI, compared to standard lactate-based \202 uids. The advent of citrat e as an anticoagulant for CRTT has again required further \202 uid development, as trisod ium citrate leads both to sodium gain and to metabolic alkalosis, as each citrate molecule is indirectly metabolized to three bicarbonates. Thus \202 uids for citrate-based CRRT no t only need to be calcium free, but also lower in both sodium and bicarbonate. Anticoagulation for CRRT Although unfractionated heparin (UFH) remains the most common anti coagulant used worldwide, CRRT systems can be run anticoagulant free. In AKI the platelet c ount may be reduced, and baseline clotting studies abnormal. Replacement \202 uids and/or dialyzates Whereas dialyzates for IHD have been bicarbonate- based for some time, the original \202 uids used for CRRT, as both replacement \202 uid s and/or dialyzates, were derived from peritoneal dialyzates, containing high concentration s of glucose, and were lactate-based. Over time, specialized \202 u- ids have been develo ped, nevertheless there is a marked range in electrolyte composition, particularly lactate and chloride concentrations. For the same blood \202 ow, hematocrit and ultra \201 ltrat ion volume, the \201 ltration fraction is greater for postdilutional hemo \201 ltration. (Fig. 10.2.4) A hemo \201 ltration replacement \202 uid containing a relatively high la ctate and low chloride concentration will, after several days of CRRT, result in a hypochlo remic alkalosis, and conversely a relatively low lactate \200\223high chloride solution Simple measures to reduce clotting in the circuit Adequate vascular access is required, usi ng large French gauge catheters, preferably with no side port-holes. Femoral access is more reliable than internal jugular or subclavian, but the femoral catheters need to be long en ough for the tips to lie in the inferior vena cava. A hemo \201 lter rather than a dialyse r membrane is required, and the \201 ltration fraction should be <30% (Fig. 10.2.4). Pred ilutional \202 uid replacement prolongs circuit survival compared to postdilutional CVVH, by preventing hemoconcentration and limiting protein deposition on the hemo \201 lter mem brane, and increasing cooling. Filtration fraction in CVVH Protein deposition on membrane Plasma flow QP FF = QUF/QP Ultrafiltrate QUF Predilutional Blood flow rate = 100 mL/min HCT 24% Ultrafiltration rate = 1500 mL/h FF = 15 00/[7500 x (1 \200\223 0.24)] = 0.26% Postdilutional Blood flow rate = 100 mL/min HCT 30% Ultrafiltration rate = 1500 mL/h FF = 1 500/[6000 x (1 \200\223 0.30)] = 0.36% Fig. 10.2.4 Filtration fraction in continuous venovenous hemo \201 ltration (CVVH). A. DAVENPORT 332 of 5 \200\22310 mg for CRRT, and then repeat when the aPTT ratio falls back to <1.2. For IH D of HDF, a bolus dose of 02 \200\2230.3 mg should suf \201 ce in AKI. Lepirudin. This dru g is used in a similar manner to hirudin. There is no antidote in cases of hemorrhage due t o lepiru- din (or hirudin) overdosage. There are reports that the combination of activated factor VIIa and tranexamic acid may help reduce bleeding, and high \202 ux IHD or predilu - tional HDF may increase lepirudin clearance. Argatroban. Argatroban has to be given by co ntinuous infusion, and is mainly hepatically cleared, so dose reduction is required in pati ents with hepatic disease. Citrate. Due to the problems with heparin in the critically ill patient with AKI, citrate has become a favored regional anticoagulant for CRRT, as it has m inimal risk of hemorrhage, and is an effective anticoagulant (Fig. 10.2.5). However, citrat e requires a degree of complexity, with low or zero calcium dialyzates/replacement solution s. The rate of citrate is adjusted according to blood \202 ow (Table 10.2.1), and both th e total and ionized calcium must be measured. If citrate accumulates then total plasma calc ium rises due to the presence of an unmetabolized calcium citrate com- plex, and the rate o f citrate should be reduced. Anticoagulation Unfractionated heparin. The main disadvantage of anticoagulation with UFH i s an increased risk of hemor- rhage especially when aPTT >65 s, while there is an increased risk of circuit clotting when aPTT <55 s. A typical regime would be a bolus dose of UFH of 15 \200\22330 IU/kg followed by a maintenance infusion of 5 \200\22315 IU/kg/h. Heparin is negatively charged and may adsorb onto the plastic tubing of the infusate line. To avoid t his problem, and to achieve better mixing, UFH should be administered in a dilute rather th an a concentrated solution. Higher doses of UFH are required for hemoperfusion due to adsor ption to the sorbent, and similarly some UFH may be lost in predilutional HDF. In the ICU, particularly with septic patients, antithrombin (AT) levels may be reduced, and therefore h eparin may not be as effective an anticoagulant when compared to its use in the chronic dia lysis patient, with an increased risk of circuit clotting once AT levels have fallen to <60 %. Low molecular weight heparins (LMWHs). Although LMWHs are easier to administer when used for intermit- tent therapies in patients with AKI (single bolus of enoxa- parin 0.5 mg/kg and/or tinzaparin 2500 IU), they require antiXa monitoring when used for CRRT, and with the ir increased half-life have no clinical advantage over UFH. As LMWHs are smaller than UFH, some may be lost when hemo \201 ltration is used, and therefore higher initial bolus doses may be required. The other major problem that can occur with UFH, and to a lesser extent L MWHs, is the development of auto- immune thrombocytopenia. In this case, all heparin admini stration must be withdrawn, including LMWHs. Thrombocytopenia occurs due to platelet activa tion, and patients are at risk of thrombosis, so require an alternative systemic anticoagul ant. Alternative anticoagulants include: 1 Synthetic heparinoids: danaparoid. 2 Direct thro mbin inhibitors: High volume CRRT Animal experiments have shown improved cardiovascular stability during CVV H, when high volumes of ultra \201 ltrate were obtained. This could have been due to the h igh volume of \202 uid replacement (6 L/h), resulting in additional cooling, and positive sodium and calcium balances. However, the studies also showed that injection of the ultra \201 ltrate into healthy animals caused hypotension, suggesting that the improvement was d ue to the removal of a vasodilatory or in \202 ammatory substance. CVVH can remove cytokin es, both pro-in \202 ammatory, such as IL-6, and anti-in \202 ammatory, including IL-10. A study showed that patients with the highest levels of cytokines, whether in \202 ammator y IL-6 or anti-in \202 ammatory IL-10, had the greatest mortality. The question arose as t o whether high dose hemo \201 ltration, often given in pulses of 6 \200\2238 h, could alte r the in \202 ammatory milieu, and thereby improve patient survival by reducing the peak c ytokine levels. Several uncontrolled studies reported improved patient hemodynamics and sur vival in those patients with AKI and severe hypotension refractory to vasopressors. Current ly several multicenter prospective trials are under- way to investigate the role of high vo lume hemo \201 ltration on patient outcomes and to test the validity of the \200\230peak cytokine hypothesis \200\231. hirudin (from the medicinal leech Hirudo medicinalis); lepirudin (recombinant hirudin); arg atroban (synthetic molecule, available in the USA). \200 \200 3 Citrate. Danaparoid. Although the half-life of danaproid is increased in AKI, following a bolus dose of 1500 IU, studies have shown that a similar maintenance dose of 140 IU/h is r equired for both CVVH and CVVHD, thereafter adjusted according to antiXa level (target: 0.3 \200\2230.4). For IHD or HDF, a bolus dose of 2500 IU for patients >55 kg is recommended, with a lower dose of 2000 IU for smaller patients. Hirudin. The half-life of hirudin is ext ensively elongated in AKI. Hirudin dosing is problematical for CRRT, as there is some hirud in clearance during CVVH, and antihirudin antibodies may develop after a few days, which re duce clearance and prolong biological activity even further. The plasma hirudin concentrati on is not linearly related to the aPTT, and once the aPTT ratio is >2.0, hirudin concentrat ions increase the aPTT ratio exponentially, so increasing the risk of hemorrhage. Thus a sp ecial test of thrombin activation, the ecarin clotting time, is required to monitor hirudin . Many centers give a single bolus dose Super \202 ux membranes for CRRT High volume hemo \201 ltration requires high volume \202 uid exchange, which is expensive, increases the risks of circuit clotting due to hemoc oncentration and requires accurate \202 uid balance assessment. Thus those centers with e xperi- ence of this technique usually perform pulses of therapy lasting 6 \200\2238 h. An a lternative method of removing in \202 ammatory media- tors is to use a super \202 ux memb rane. Whereas the typical hemo \201 ltration membrane will allow the passage of molecules up to 30 kDa in clinical practice, super \202 ux membranes will allow molecules up to 100 kDa to pass into the ultra \201 ltrate. CHAPTER 10.2 Renal replacement therapies in acute kidney injury 333 Step 6 Ca2+ is infused through a separate central line to replace Ca2+ lost in dialyzate Step 1 Infuse citrate \210\235 blood flow Step 2 Citrate chelates free Ca2+ as iCa2+ \206\223 to 0.2 mmol/L Bleeding time \206\221 Zero Ca2+ dialyzate in Step 5 Citrate is metabolized primarily in liver and also muscle to \210\222 HCO3 bound Ca 2+ is released Effluent dialyzate out Step 4 Returning blood combines with mixed venous blood, normalizing iCa2+ so preventing systemic anticoagulation Step 3 Postfilter iCa2+ is monitored and used to titrate citrate rate to assure anticoagulation Fig. 10.2.5 Citrate anticoagulation for continuous renal replacement therapy (CRRT). iCa2+: ionized calcium. using slower blood and dialyzate flows compared to standard IHD (Table 10.2.2). When not on the hybrid technique, patients could sit out of bed, go for scheduled scans, etc. Table 10.2.1 Citrate dose for varying blood \202 ows Blood \202 ow (mL/min) 4% trisodium citrate (mL/h) Acid citrate dextrose (mL/h) 100 125 150 175 218 262 210 262 315 160 200 350 420 140 ) n m / L m 120 i The advantage of the super \202 ux membranes is that other cytokines, such as TNF-A which exist as a trimer (51 kDa), can be removed using standard exchange volumes. One disadvantag e of such permeable membranes is the potential loss of albumin- and protein-bound hormones. 100 ( e c n a r a e l c 80 60 a e r U 40 Hybrid techniques Optimal clearances with CRRT depend upon the therapy continuing for 24 h. CRRT may be interrupted, and solute clearances compro- mised, for many reasons including: \200 \200 20 0 IHD CVVHDF CAVHDF PD Hybrid CVVHF CAVHF clotting of the extracorporeal circuit; patients having to leave the ICU to go to theater, or for radiological investigations, e.g. CT scanning. Fig. 10.2.6 Relative urea clearances for the different modalities of renal replacement ther apy in AKI. Also, during CRRT the patient is bed-bound and therefore may be at greater risk of developi ng nosocomial pneumo- nia, disuse atrophy and be less able to participate in physical thera py. To overcome these problems a series of hybrid techniques was introduced, ranging from s imply slowing down con- ventional hemodialysis \200\223 slow low ef \201 ciency daily dia lysis (SLEDD), extended daily dialysis (EDD) \200\223 to specially designed systems, such as the Genius Batch dialysis system. Essentially these treatments were designed to produce a very effective dialysis treatment lasting 8 \200\22316 h (Fig. 10.2.6), Table 10.2.2 Comparison of different modalities used for treating patients with AKI Modality Intermittent HD/HF/HDF CRRT Hybrid 200 \200\223300 Blood \202 ow (mL/min) 500 \200\223800 Dialysate \202 ow (mL/min) Filtr ation \202 ow (mL/min) 75 \200\223250 Treatment duration (h) 75 \200\223150 16 \200\22340 16 \200\22340 24 100 \200\223150 200 40 \200\223100 8 \200\22312 4 \200\2235 Alternate day \200\223 daily Daily Daily Treatment frequency A. DAVENPORT 334 usually used in combination with other forms of RRT (see combination therapies). Adjunctive therapies Plasma exchange/immunoadsorption For some conditions, including hemoly tic uremic syndrome, plasma exchange (PE) is the treatment of choice. For other conditions such as the pulmonary renal syndromes, anti-GBM nephritis, Wegner \200\231s granulomatosis, and other vasculitic and/or crescentic glomerulonephritides, immu- noadsorption with a sta phylococcal A adsorption column may be equally effective as PE. Plasma exchange has not bee n shown to improve outcome in septic patients with AKI. Plasma exchange can be performed by either a centrifugal spinning bowl technique, or using a PE hemo \201 lter. Typically 30 \200\22345 mL/kg of plasma is removed during a treatment session and replaced with a compos ite of both colloid and crystalloid including fresh frozen plasma, albumin, or colloid subs titute and 0.9% saline. Approximately 30% of PE treatments using fresh frozen plasma are as sociated with adverse reactions, ranging from anaphylaxis, and adult respiratory distress s yndrome, to fevers, chills and rigors. Patients who are IgA de \201 cient can react to IgA in pooled plasma. A pulmonary leak syndrome is relatively common due to the combination of the under- lying condition, administration of fresh frozen plasma which contains both in \202 ammatory cytokines and chemokines, coupled with the oncotic load of the colloid replac ement solutions if not diluted with 0.9% saline. Thus it is impor- tant to achieve a negati ve fluid balance during PE, to prevent pulmonary leak syndrome, provoking pulmonary hemorrh age. Immunoadsorption is an alternative technique for those conditions which do not require the addition of plasma factors. This avoids the use of plasma products which may potential ly be contaminated with prions. Combination therapies In an effort to remove in \202 ammatory mediators in patients with s epsis and AKI, combination therapies have been developed, using a PE hemo \201 lter, and t he ultra \201 ltrated plasma is then passed over an HP cartridge before return- ing to the patient. These systems are currently in phase III clinical trials, as the initial phase I and II studies suggested improved patient survival. The MARS and Prometheus albumin dialysi s treatments are also examples of combination therapies, both using a conventional hemo \201 lter in the extracorporeal circuit. The bioarti \201 cial kidney David Humes in Michigan has developed a bioreactor coated wit h proximal tubular cells, and this is currently being assessed in phase II and III clinical trials. Further reading Bellomo R, Tetta C, Brendolan A, Ronco C. Coupled plasma \201 ltra- tion adsorption. Blood Purif 2002; 20: 289 \200\223292. Davenport A. Replacement and dialysate \202 uids for patients with acute renal failure tr eated by continuous veno-venous haemo \201 l- tration and/or haemodia \201 ltration. Cont rib Nephrol 2004; 144: 317 \200\223328. Fliser D, Kielstein JT. Technology Insight: treatment of renal failure in the intensive car e unit with extended dialysis. Nat Clin Pract Nephrol 2006; 2: 32 \200\22339. Honore PM, Joannes-Boyau O. High volume hemo \201 ltration (HVHF) in sepsis: a comprehensi ve review of rationale, clinical applicability, potential indications and recommendations f or future research. Int J Artif Organs 2004; 27: 1077 \200\2231082. Morgera S, Haase M, Kuss T, et al. Pilot study on the effects of high cutoff hemo \201 ltr ation on the need for norepinephrine in septic patients with acute renal failure. Crit Care Med 2006; 34: 2099 \200\2232104. Albumin dialysis Albumin binds not only hormones and drugs, but also many toxins, and scave nges nitric oxide. Patients with hepatorenal syndrome may bene \201 t from vasopressor the r- apy in combination with albumin infusions. Unfortunately the number of potential binding sites is markedly reduced in stored albumin. More recently a number of dialysis systems wh ich use albumin in the dialyzate have been developed, particularly for treating patients wi th liver failure. These include single pass albumin dialysis (SPAD) and two systems that re generate albumin by passage of the spent dialyzate through charcoal and resin cartridges: M ARS and Prometheus. Although MARS has been shown to improve outcome in a small series of pa tients with hepatorenal failure, further prospective studies with the Prometheus system are currently in progress to determine whether these systems have a bene \201 cial role to pl ay in the management of patients with combined liver and kidney failure. Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous ha emo \201 ltration on outcomes of acute renal failure: a prospective randomized trial. Lanc et 2000; 356: 26 \200\22330. Swartz R, Pasko D, O \200\231Toole J, Starmann B. Improving the delivery of continuous rena l replacement therapy using regional citrate anticoagulation. Clin Nephrol 2004; 61: 134 \200\223143. Tiranathanagul K, Brodie J, Humes HD. Bioarti \201 cial kidney in the treatment of acute r enal failure associated with sepsis. Nephrology (Carlton) 2006; 11: 285 \200\223291. VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically all pati ents with acute kidney injury. N Engl J Med 2008; 359: 7 \200\22320. Internet resources Acute Dialysis Quality Initiative: http://www.ADQI.net Acute Kidney Injury Network: http://akinet.org/index.php Hemoperfusion Dialysis and filtration techniques essentially remove water-soluble compounds , whereas hemoperfusion (HP) cartridges remove lipophilic substances. The earlier HP cartri dges were associated with increased clotting, throm- bocytopenia and leukopenia. Today HP i s predominantly used in Japan to remove endotoxin and peptidoglycans in Gram-negative and G ram-positive sepsis respectively, whereas in Europe HP is See also Clinical approach to acute kidney injury, p. 318 Hemodialysis, hemo \201 ltration , and hemodia \201 ltration, p. 494 Peritoneal dialysis, p. 506 Adequacy of dialysis, p. 578 This page intentionally left blank A. DAVENPORT 336 Dialysis and hemoperfusion treatment of acute poisoning \200 \200 Introduction The standard treatment of intoxications and acute poison- ings is based on sym ptomatic and supportive therapy, cou- pled where appropriate with speci \201 c measures de signed to remove toxins including: \200 \200 \200 aminoglycosides; atenolol; lithium. Alcohols, such as methanol and ethylene glycol, are readily removed by HD. However, alcohol dehyrodgenase can also be blocked by the administration of ethanol, and fomepiz- ole. Thus HD should be reserved for cases which have not responded to conservative therapy, with cli nical deteriora- tion, metabolic acidosis and methanol or ethylene glycol levels >500 mg/L (Table 10.3.2). Larger molecular weight drugs such as amphotericin (9241 Da) can be cleared using high \202 ux dialyzers and adding in predilutional hemodia \201 ltration (HDF). H DF has advantages over HD, in terms of clearing higher molecular weight drugs and toxins, a nd is the preferred choice for overdoses of valproate, vancomycin, amphoter- icin and hirud in. gastric lavage; instillation of adsorbents, such as activated charcoal; stimulation of endo genous pathways of elimination (typ- ically a forced diuresis); administration of antidotes and/or chelating agents; extracorporeal circuits; \200 Extracorporeal circuits commonly used are: \200 \200 \200 hemodialysis (HD); hemodia \201 ltration (HDF); hemoperfusion (HP). All can be used to treat patients suffering from drug intox- ication and/or poisoning when the clinical condition fails to respond to maximum supportive care, particularly when patie nts have developed hypoventilation, hypotension and hypothermia. Extracorporeal therapies c an also be used when patients have serum levels of drugs and/or poisons which are known to result in signi \201 cant risk of patient mortality and/ or organ failure, and the rate of extracorporeal clearance exceeds that of endogenous hepatic and/or renal clearance (Tables 10.3.1 and 10.3.2). Hemoperfusion During hemoperfusion blood passes through a cartridge containing a sorbent. C ommonly used sorbents include: \200 \200 \200 charcoal; ion exchange resins; nonionic exchange macroporous resins. These sorbents can bind drugs and toxins which are normally protein-bound. Examples of toxi ns with high protein binding are: \200 \200 \200 \200 \200 Volume of distribution Although extracorporeal therapies are most effective when treating d rugs and toxins with a small volume of dis- tribution, e.g. con \201 ned to the plasma vol ume, they may have a role in treating tissue/protein-bound compounds: although only a small fraction of the total body load will be removed, a temporary reduction in plasma concentra tion may be useful in reversing life-threatening toxic effects. arsenic; calcium channel blockers; benzodiazepines; phenytoin; tricyclic antidepressants. Hemoperfusion will also remove lipophillic drugs and tox- ins more effectively than HD. The re are no data comparing one manufacturer \200\231s hemoperfusion column with another in te rms of drug and toxin removal. HP columns differ not only in the sorbent used, but also the amount and volume of the cartridge. Compared with HD, much more heparin is required to pre vent clotting in the HP circuit, due to heparin absorption to the sorbent. Peritoneal dialysis Peritoneal dialysis (PD) is not an effective therapy for drug/ toxin re moval from the blood, as it is only 10% as ef \201 cient as high \202 ux HD. However, i n small children, due to vascular access dif \201 culties, PD may have an adjunctive role. The ef \201 ciency of PD can be increased by using rapid cycles and maximizing the dwell volume, and also by using continuous \202 ow-through techniques. As peritoneal dialysis d rug clearances are less than those with hemodialysis, peritoneal dialysis patients are more at risk of developing neurotoxicity with acyclovir, ganciclovir and high doses of penicill ins and cephalosporins. Albumin dialysis More recently a variety of albumin dialysis-based systems have been introd uced, ranging from single pass albumin dialysis (SPAD) to regeneration of the albumin-based dia- lyzate, using sorbents such as the MARS and Prometheus systems. These albumin dialysi s systems can also be used to remove protein-bound and lipophillic drugs and/or toxins, and have been reported to improve the prognosis following Amanita phalloides (the deathcap mus hroom) poisoning. Hemodialysis Hemodialysis is the modality of choice for removal of drugs and toxins that: \200 \200 \200 Plasma exchange Plasma exchange (PE) can speed up the elimination of dig- oxin in severe ca ses where digoxin-speci \201 c antibodies have been administered, by removing the digoxin \200\223antibody complexes. If the digoxin \200\223antibody complexes are not endogenously cleared, then there is a risk of later digoxin toxicity, as digoxin is subsequently release d from the anti- body complex. are water soluble; are low molecular weight; have a small volume of distribution. Examples of compounds for which there is virtually no protein binding include: \200 \200 alcohols; organic acids (which accumulate in urea cycle defects of metabolism); CHAPTER 10.3 Dialysis and hemoperfusion treatment of acute poisoning 337 Table 10.3.1 Drugs and toxins preferentially removed by hemodialysis and hemoperfusion Table 10.3.2 Serum drug and poison concentrations at which extracorporeal removal may be be ne \201 cial Hemodialysis more effective Hemoperfusion more effective Classes of drugs and toxins amenable to removal by extracorporeal circuits Drug Serum concentration mg/L mmol/L Phenobarbital Glutethimide Methaqualone Salicylates Theophylline Paraquat Methanol Ethylene glycol Meprobomate Lithium acute chronic Phenytoin Valproate 100 40 40 800 40 0.1 500 500 100 0.43 0.18 0.16 4.4 0.22 0.5 16 8.1 0.46 Barbiturates Sedatives Hypnotics Tranquilizers Antimicrobials Anticancer drugs Antidepressa nts Cardiovascular Plant toxins Animal toxins Solvents and gasses Herbicides Insecticides M etals Lithium Bromide Ethanol Methanol Ethylene glycol Salicylates Antimicrobials Antivirals Valp roate Carbamazepine Metformin Barbiturates Sedatives Tranquilizers Theophyline Paraquat Deathcap mushroom Phenytoin Trich loroethanol Disopyramide 4.0 >2.5 30 1000 4.0 >2.5 120 7.0 Continuous extracorporeal therapies Most extracorporeal therapies for drug intoxications an d poisonings have been used as intermittent therapies. Once the HP cartridge has become sat urated, typically between 4 and 6 h, the treatment is terminated. However, for some drugs s uch as lithium, with a large vol- ume of distribution, a continuous or extended form of HD would potentially prevent a rebound in drug serum con- centration following a standard inte rmittent HD. Continuous methods are useful for intoxicants such as: \200 \200 \200 \200 Complications of extracorporeal circuits In addition to complications associated with vascu lar access and anticoagulation, many patients will have normal renal function, and therefor e HD can result in electrolyte abnormalities, including hypokalemia and hypophos- phatemia, which may need to be corrected. HD also results in bicarbonate gains, which may be bene \201 cial in patients with a metabolic acidosis, but could exacerbate a metabolic alkalosis , as in cases of salicylate toxicity. HP is associated with transient leukopenia and thromb ocy- topenia. Hypoglycemia may also occur during HP and the albumin dialysis therapies. Hyp ocalcemia may develop during PE due to calcium complexing with citrate. paraquat; thallium; methotrexate; procainamide. They can be useful even if initiated many hours or days after exposure. Future prospects Only a minority of self-poisonings and drug toxicities are with low molecu lar weight water-soluble agents with a small volume of distribution. So in many cases after an ini- tial reduction in plasma concentrations with intermittent HD, there is redistribut ion and a rebound in the plasma concentration. To overcome this rebound, some centers use a n initial intermittent HD treatment, followed either by a hybrid therapy or continuous RRT. Future developments are underway to combine plasma \201 lters within the dialysis/ \201 ltration circuit, so that the \201 ltered plasma is passed across sorbent columns, and t hen returned to the patient. This technology will potentially help remove even protein-boun d toxins. 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 