Describe the biomarkers for acute kidney injury (AKI) currently in use and in development.

Discuss the agents currently used to treat AKI.

Differentiate between intermittent and continuous hemodialysis.

Utilize HBO therapy in conditions in which it is beneficial.

Discuss the effects of HBO on wound healing.

Acute Renal Failure
David M. Ward, MD, Professor, Department of Medicine, University of California, San Diego, School of Medicine

Definition: recent decline in kidney function, resulting in decreased ability to excrete nitrogenous wastes, often with fluid retention; heterogenous etiology; onset often goes unrecognized; term “acute kidney injury” (AKI) coined for entire spectrum of condition; AKI now defined in series of stages, based on creatinine (Cr)

Phases of AKI: first step—0.3-mg increase in serum Cr (SCr) or 50% increase over baseline; prerenal phase—kidney function suboptimal, but no damage yet to kidneys; extension phase—events associated with endovascular endothelial cell changes and activation and inflammation in kidney consequent on microvascular changes; prerenal phase recognized by reduced urine volume and rising SCr; necessary to measure serum electrolytes; measure Na, K, Cl, Cr, urine urea nitrogen, and osmolality; fractional excretion of Na—calculated ratio of urinary to plasma Na and Cr; amount of filtered Na found in urine

Urine osmolality: if kidney function starting to fail due to underperfusion, situation reversible if urine osmolality >500 mOsm/kg (not rescuable if <400 mOsm/kg); in prerenal phase, treatment principle to correct all reversible factors; objectives include restoring renal perfusion, optimizing hemodynamics, reducing demand on kidneys (correcting electrolytes and acid-base disturbance results in less metabolic work), excluding obstruction, and ameliorating response to injury

Pharmacologic interventions: N-acetyl cysteine (eg, Mucomyst)—used to prevent radiocontrast nephrotoxicity; all interventions for radiocontrast nephrotoxicity poorly established; ensure that patient not acidemic before giving contrast dye; osmotic diuretics—eg, mannitol; demonstrable benefit in late prerenal stage of AKI; once fluid deficit corrected, if urine osmolality >400 to 500 mOsm/kg (suggesting renal tubular ability to concentrate urine), giving mannitol increases osmotic flow in nephron, washing out any cells beginning to slough, and preventing obstruction within renal tubules; mannitol also of possible benefit after rhabdomyo-lysis; some trials show value, but not used often; loop diuretics—most controversial; eg, furosemide; convert oliguric to nonoliguric acute renal failure (ARF) in few cases and beneficial for fluid management thereafter, but do not reduce need for dialysis and mortality of ARF; side effects associated with hearing; mortality rate increased in one study as result of persistent aggressive use of diuretic in patients already oliguric; no evidence of benefit in mortality rate, length of hospital stay, or renal recovery; should be used in patients who respond to diuretics’ ability to control fluid overload and not in patients who fail to respond because of ARF; tolvaptan—vasopressin receptor antagonist; useful in hyponatremia; possibly helpful for ARF in congestive heart failure and liver failure; natriuretics—eg, anaritide (atrial natriuretic peptide); some claims of benefit; nesiritide (B-type natriuretic peptide) possibly helpful in ameliorating AKI; dopamine—meta-analysis shows low- dose dopamine increases urinary output but does not prevent renal dysfunction or affect natural history of AKI; fenoldopam— more selective dopamine agonist with fewer side effects; proposed study of infusion into renal arteries in oliguric patients unresponsive to diuretics; placebo-controlled studies of regular fenoldopam infusion showed no difference in outcomes

Early recognition of AKI: easy after cardiac surgery or contrast exposure; ≈50% of ARF in hospital practice due to sepsis, and time of onset not clear; requires biomarker system for early detection; biomarkers becoming more specific; supportive therapy helpful, but mortality high

Neutrophil gelatinase-associated lipocalin (NGAL): most up-regulated gene in renal tubules when ischemic kidney injury present in animals; protein elevated in plasma and urine before any elevation in SCr seen; protein demonstrable on renal biopsy, so helps to identify site of injury; predictive as clinical test and predicts AKI by 1 to 2 days; bedside urine test available in Europe; 2 hr after cardiac surgery, able to determine who will develop kidney failure; studies in contrast nephropathy, sepsis, and kidney transplantation show high predictive value; less predictive of sepsis; patients with highest NGAL have longest duration of ARF; greater the severity, greater the expectation of dialysis or risk for mortality

Interleukin-18: activated by caspase and induced by kidney ischemic injury; overexpressed as gene and as protein in tubular cells; appears in urine before Cr rises; no commercially available assay; in intensive care unit (ICU) setting, predicts AKI, ARF, and mortality; predicts ARF after cardiopulmonary bypass or kidney transplantation

Kidney injury molecule (KIM)-1: rapidly up-regulated gene in kidney after injury; transmembrane protein; overexpressed; domain outside of cell falls off; appears in urine as marker before Cr changes; predicts mortality, need for dialysis, and long-term graft loss

Treatment of AKI

Calcium channel blockers: evidence of reduction in delayed graft function rate in kidney transplants shown with diltiazem and verapamil; result applicable to other kinds of AKI, with some early success

Erythropoietin (EPO): has opposite action of tubular necrosis factor; makes body expend energy on healing and producing red blood cells; helps endothelium and tubular epithelium resist inflammatory stimuli; ameliorates AKI to mild extent

Growth factors: insulin-like growth factor 1 (IGF-1) only one used successfully

Deferiprone: congener of NGAL; marketed as Ferriprox in Europe and Asia; siderophore; used for thalassemia major; similar to NGAL marker; ameliorates renal injury; multinational trial soon to start on individuals undergoing cardio- pulmonary bypass surgery, with primary end point of reduction in rate of AKI and overt ARF

Mesenchymal stem cell therapy: obtained from peripheral blood and, when reinfused, contributes to repair and protection from kidney injury; intra-aortic injection of cells into rats with AKI creates robust protection against renal failure and significantly increases survival

Other management issues: include volume, electrolytes, acid-base balance, nutrition, and dialysis; peritoneal dialysis— rarely used; used if hemodialysis not available; intermittent hemodialysis (IHD)—uses standard dialysis machine; no longer preferred method in severely ill patient; slow low-efficiency dialysis (SLED)—uses regular dialysis equipment; performed for 8 to 10 hr or overnight in more controlled manner, with fewer hemodynamic consequences; continuous hemofiltration or hemodialysis—falls under general term “continuous renal replacement therapies” (CRRT)

Comparison of intermittent and continuous hemodialytic modalities: IHD—corrects volume in 3 to 4 hr; episodic, with rapid volume shifts during procedure; blood pressure (BP) can drop, with other hemodynamic consequences; continuous hemodialysis—volume balanced and even; volume shift small, with no sudden changes in hemodynamics; ischemic acute tubular necrosis (ATN) not only involves tubular necrosis but also smooth muscle cell (controls hemodynamics and autoregulation of kidney) necrosis; patient with ATN recovers faster without repeated hypotensive events; hemodynamic shifts in IHD group not good for kidney or for patient; benefit of continuous dialysis unproven, but advantages include absence of sudden shifts and facilitation of parenteral nutrition; to date, no substantial difference in outcome seen between IHD and CRRT, although several trials favor CRRT (not statistically significant); IHD requires anticoagulation for length of dialysis, while continuous hemo-dialysis requires constant anticoagulation (problem in patient who has had major surgery or trauma); in IHD, no heparin present in dialysis circuit, while in continuous hemodialysis, unable to change filters every 3 to 4 hr (reason citrate regional anticoagulation used)

Hyperbaric Oxygen Therapy: Indications and Techniques
Ian Grover, MD, Assistant Clinical Professor of Medicine, University of California, San Diego, School of Medicine, and Medical Director, Hyperbaric Medicine Center, UCSD Medical Center

Definition of hyperbaric O2 (HBO) therapy: patient breathes 100% O2 at pressures higher than that at sea level; pressurization should be 1.4 atmospheres absolute (ATA; equivalent to 13 ft below sea level)

Physiologic effects of HBO therapy: mechanical effects of pressure—Boyle’s law states that pressure and volume inversely related (as pressure increases, volume decreases by 50%); important when dealing with side effects (eg, barotrauma) of HBO therapy; effects of increased PO2 —breathing 100% O2 at 2.8 ATA (60 ft), 6 volumes percent of O2 dissolved in plasma (for every 100 mL of plasma, 6 mL of O2 dissolved); not attaching more O2 to hemoglobin (Hb), as Hb fully saturated at sea level, when breathing air; 6 vol percentage mean extraction rate of body at rest; effects—suppression of alpha toxin production (important in treatment of gas gangrene); enhancement of leukocyte killing activity; decrease in white blood cell (WBC) adherence to capillary walls; vasoconstriction in normal vessels (reduction of edema); restoration of fibroblast growth and collagen production; stimulation of free radical scavenger (eg, superoxide dismutase) production; enhancement of osteoclastic activity (O2 -dependent function); termination of lipid peroxidation in carbon monoxide (CO) poisoning; hastens removal of CO from Hb

Indications for HBO therapy: clostridial myositis and myonecrosis; necrotizing fasciitis and soft tissue infections; crush injury, compartment syndrome, and other acute traumatic ischemias; enhancement of healing in selected problem wounds; delayed radiation injury (soft tissue and bony radionecrosis); compromised skin grafts and flaps; thermal burns; exceptional blood-loss anemia

Clostridial myositis and myonecrosis: toxin-induced infectious disease caused by anaerobic, gram-positive, spore-forming bacillus; Clostridium perfringens releases ≈12 toxins; alpha toxin—most important and causes many clinical manifestations associated with gas gangrene; activates arachidonic acid cascade, causing release of inflammatory mediators and suppression of cellular inflammatory response (lyses WBCs and suppresses migration of WBCs); on Gram stain, paucity of WBCs; also enhances neutrophil adhesion, which promotes hypoxic environment in which bacteria can replicate; shown to directly inhibit myocardial contractility in rabbit studies; treatment—3-pronged approach (antibiotics, surgical debridement, and HBO therapy); antibiotics include sodium penicillin and clindamycin (inhibitory effect on alpha toxin); O2 tension >250 mm Hg inhibits alpha toxin production; body clears alpha toxin rapidly; HBO therapy at 3 ATA required to achieve tissue pressures >300 mm Hg (reason for treating gas gangrene patients at 60 ft); other benefits of HBO therapy—hyperoxic vasoconstriction, reducing edema to area, and hyperoxic protection of adjacent areas (diffusion of O2 reduces hypoxic environment); treatment protocol—3 ATA for 80 min at 60 ft; broken into four 20-min treatment periods to reduce O2 toxicity and risk for seizure; 3 treatments in first 24 hr (stops alpha toxin production), then 2 treatments daily after first 24 hr; usual treatment course 2 to 5 days; treatment stopped when progression of infection stopped, wounds well demarcated, and clinical toxicity resolved

Necrotizing fasciitis: infection of superficial and deep fascia; progresses to ischemic dermal necrosis; caused by various bacteria, most of time polymicrobial; treatment—antibiotics (clindamycin and meropenem), surgical debridement, and HBO therapy; HBO therapy reduces amount of hypoxic leukocyte dysfunction, provides oxygenation to ischemic tissues, and increases antibiotic penetration into target bacteria (for aminoglycosides in Pseudomonas, O2 required for transfer of antibiotic across cell wall); treatment protocol—100% O2 at 2.4 ATA for 90 min; given bid; treatments ended once no further debridements needed

Healing of selected problem wounds: wound healing rate O2 -dependent; O2 -sensitive responses include fibroblast replication, collagen deposition, angiogenesis, epithelialization, resistance to infection, and intracellular leukocyte bacterial killing; fibroblasts and collagen—hypoxia signals fibroblasts to start collagen production; wound collagen deposition increased in well-oxygenated wounds; angiogenesis—hyperoxia acts by increasing vascular endothelial growth factor (VEGF) release or enhancing its activity; epithelialization—hypoxic epidermal cells show poor movement and mitosis; hyperoxy-genation improves epithelialization by increasing cell proliferation and improving basement membrane production; resistance to infection—ischemic wounds prone to infection; hypoxia favors growth of anaerobes and suppresses killing of aerobes; neutrophils kill bacteria in 2 ways (O2 -independent pathway, where cytoplasmic granules contain antibacterial enzymes, and O2 -dependent pathway, with respiratory or oxidative burst seen [decreased in hypoxic wounds]); study by Hopf shows that as tissue PO2 levels drop, infection rate significantly increases

Delayed radiation injuries: HBO proven beneficial; complications of radiation therapy typically seen after latent period of ≥6 mo, and often precipitated by tissue insult (eg, surgery); hallmarks include endarteritis with tissue hypoxia and secondary fibrosis; after irradiation, tissue Po2 levels drop to 30% (cutoff); at <30%, wounds do not heal and break down

Soft tissue radionecrosis: soft tissue injury from irradiation; impaired wound healing seen; study by Marx showed that in HBO-treated group, less wound infection, lower dehiscence rate, and less delayed wound healing

HBO and tumor growth: no increased likelihood of tumor recurrence or secondary tumor growth with HBO therapy; significant differences in wound healing and tumor angiogenesis; study by Feldmeier found that hypoxic tumors less responsive to treatment, less subject to death by apoptosis, and more prone to aggressive growth and metastasis

Compromised skin grafts and flaps: HBO not necessary or recommended for normal skin grafts or flaps, but extremely efficacious in maximizing viability of compromised flaps and skin grafts; HBO enhances flap survival by hyperoxygenation of ischemic tissues, preservation of tissue viability, increasing angiogenesis and tissue growth, prevention of ischemia-reperfusion injury by reducing neutrophil endothelial adherence in venules, and closing off of arteriovenous shunts; each flap problem unique, but all show improved viability with HBO therapy

Exceptional blood-loss anemia: occurs when patient refuses blood transfusion on religious grounds or cannot be cross- matched; body extracts 5 to 6 mL of O2 for every 100 mL of blood; normal levels of Hb easily supply those extraction rates; once Hb drops to <6 g/dL, normal O2 delivery to tissues problematic, and patient starts to build up O2 debt; patient treated at 2 to 3 ATA and response monitored; treatment number and frequency depend on O2 debt, clinical signs and symptoms, and O2 toxicity