will demonstrate segmental or generalized decreased renal perfusion. Other ECG: \200 Thromboembolism and in situ thrombosis Immediate management of thromboembolism and throm- b osis in situ will be dictated by the clinical scenario and other organ systems affected. Th e urgency of intervention depends upon whether there is a signi \201 cant collateral blood supply to the kidney. Anticoagulation is necessary if there is a hypercoagulable state or if the occlusion is secondary to an acute throm- boembolic event (atrial \201 brillation, mural thrombus). Otherwise anticoagulation is not advisable in the acute set- ting if ther e is widespread atherosclerosis due to its desta- bilizing affect on atherosclerotic plaque s. Thrombolysis with intra-arterial recombinant tissue plas- minogen activator is indicated if the occlusion has occurred to previously normal renal arteries or is related to recent renal artery instrumentation. The procedure is minimally invasive but there are no large se ries to support its ef \201 cacy. Angioplasty may be successful following acute occlusion of an atherosclerotic renal artery. However, there are signi \201 cant risks of precipitat ing atheroembolism related to the instrumentation. Revascularization has been successfully performed follow- ing acute renal artery occlusion, up to several weeks after the event. Su rgical intervention is not recommended if the occlusion is unilateral in the setting of two previously normal functioning kidneys due to the relatively high oper- ative mortality. atrial \201 brillation (thromboembolism). Renal biopsy Often not required when there are strong clinical and radiological grounds for diagnosis. In atheroembolic AKI, birefringent, biconvex, elongated cho- lesterol crystals (frozen sections) will be seen on polarized light microscopy or cholesterol clefts (fixed s ections) (Fig. 10.8.1). Cholesterol clefts represent areas of cholesterol embolization with in vascular lumina. The cholesterol is dis- solved during the processing of the histologica l specimen. Eosinophilic in \201 ltrates and surrounding tissue ischemia are often seen in association with cholesterol emboli. Muscle biopsy Lower limb muscle biopsy has a sensitivity of nearly 100%, but is rarely perf ormed to diagnose atheroembolism. Skin biopsy Will be diagnostic in 75% of atheroembolism. Management Identifying patients at risk of atheroembolism and throm- boembolism is essentia l to allow prompt diagnosis and treatment. In particular it is important to recognize that the majority of these patients will be at an increased risk of developing contrast-induced nephropathy if undergoing angiography. The appropriate prophylactic measures to reduce the risk of radiocontrast induced nephropathy include: \200 Atheroembolism There is no speci \201 c therapy for renal atheroembolism, but there are a number of general measures that can be considered. ACEIs need to be stopped if implicated i n the etiology. If not implicated they may be effective in managing the hypertension trigge red by the atheroembolism. Corticosteroids have been used in patients with an acute inflamm atory response or those with gastrointestinal assessment to confirm that the investigation is appropriate; avoidance of nephrotoxic drugs , e.g. NSAIDs; adequate volume expansion prior to and following the procedure with 0.9% sod ium chloride 1 mL/kg/h (volume administered will be dependent upon volume status); minimiza tion of the volume of contrast media used; use of iso-osmolar contrast media. \200 \200 CHAPTER 10.8 Ischemic acute kidney injury 359 involvement. Their use is controversial and is based on small series and case reports. Nutr itional support should be considered as patients are often malnourished prior to the event. Statins should be started or continued due to their anti- in \202 ammatory properties and ability to stabilize plaques. Hemodialysis is the preferred form of renal replacement ther apy but should be performed with minimal anticoagu- lation if atherosclerotic disease is wi despread. Peritoneal dialysis is usually not practical due to previous abdominal surgery, g astrointestinal ischemia and nutritional compromise. Table 10.8.2 Causes of renal vein thrombosis Nephrotic syndrome Membranous nephropathy Lupus nephritis Amyloidosis Malignancy Renal cell carcinoma Retroperitoneal tumor Hypercoagulable states Oral contraceptive Pregnancy Antiph ospholipid syndrome Protein S and C de \201 ciency Antithrombin III de \201 ciency Factor V Leiden mutation Trauma Surgical Blunt Renal transplantation Acute pancreatitis Prognosis The overall prognosis of atheroembolic AKI is dif \201 cult to quantify and is d ependent upon the associated comorbidi- ties and extrarenal organ involvement. Patients who develop cardiac failure and AKI following atheroembolism have a 1 year mortality of 50%. P atients developing ESRD following atheroembolism have a 5 year mortality rate of 40%. Indic ators of a poor prognosis include: \200 \200 Thrombosis of inferior vena cava recurrent atheroembolism; gastrointestinal involvement. Urine Urinalysis, expect: \200 \200 One-third of patients with AKI due to atheroembolism remain dialysis dependent. hematuria; proteinuria. Renal vein thrombosis Renal vein thrombosis (RVT) is a rare and often undiag- nosed cause o f AKI. Radiology Ultrasound and Doppler: \200 \200 \200 may demonstrate increased renal size and echogenicity; \201 lling defect in renal vein; \206\221 resistive indices. Epidemiology This is poorly de \201 ned. There is a reported incidence of 22% in patients with nephrotic syndrome. MRA: Can be used to make the diagnosis but is rarely necessary. Etiology RVT may occur in patients who have a hypercoagulable state including: \200 \200 \200 Renal biopsy Not indicated. nephrotic syndrome; malignancy; pregnancy. Management Management is dependent upon the underlying disease process. Systemic anticoagul ation to prevent thrombus extension and embolization. Anticoagulation must be continued ind e \201 nitely if there is a hypercoagulable state. Nephrectomy may be required for tumor-r elated RVT, capsular rupture or longer-term consequences of a non- functioning kidney such as hypertension or infection. Catheter-directed thrombolysis with percutaneous thrombectomy has been reported to be successful in some cases. Conservative therapy may be favored in t he case of a left RVT because its extensive collateral venous supply may allow venous drain age and partial recovery of renal function. Patients with nephrotic syndrome secondary to membra- nous nephropathy and lupus nephritis are particularly at risk. Extrinsic compression of the renal vein can occur secondary to re troperitoneal \201 brosis and tumor. Clinical features \200 \200 \200 \200 \200 \200 loin, testicular or \202 ank pain; low grade fever; AKI with oliguria/anuria (bilateral o r single functioning kidney); hematuria (microscopic); pulmonary embolus (as a consequence) . Investigations Blood tests Clotting screen if thrombophilia suspected. A.J.P. LEWINGTON 360 Further reading Harris R, Ismail N. Extrarenal complications of nephrotic syndrome. Acute Kidney Injury Network: http://akinet.org/index.php Renovascular Forum: Am J Kidney Dis 1994; 23: 477 \200\223497. Modi KS, Rao VK. Atheroembolic renal disease. J Am Soc Nephrol 2001; 12: 1781. http://www.renovascularforum.org Journal of Renovascular Disease: Paris B, Bobrie G, Rossignol P, et al. Blood pressure and renal out- comes in patients with kidney infarction and hypertension. J Hypertens 2006; 24: 1649. http://www.journalrenovasculardisease.com/ Scolari F, Tardanico R, Zani R, et al. Cholesterol crystal embolisa- tion: a recognizable c ause of renal disease. Am J Kidney Dis 2000; 36: 1089. See also Clinical approach to acute kidney injury, p. 318 Renovascular disease, p. 292 Scolari F, Ravani P, Pola A, et al. Predictors of renal and patient outcomes in atheroembol ic renal disease: a prospective study. J Am Soc Nephrol 2003; 14: 1584 \200\2231590. Internet resources Acute Dialysis Quality Initiative: http://www.ADQI.net This page intentionally left blank A.J.P. LEWINGTON 362 Pigment-induced acute kidney injury An important distinguishing characteristic is that in the case of hemoglobinuria the plasma is dark (heme pigment), but it remains clear in rhabdomyolysis. Introduction AKI can occur secondary to the release of intracellular heme pigments. Muscle cell breakdown (rhabdomyolysis) results in the release of myoglobin and myoglobinuria where as red blood cell breakdown (hemolysis) leads to the release of heme pigments and hemoglobi nuria. Investigations Blood tests Full blood count, expect: \200 anemia (hemolysis); \200 redu ced platelet count (rhabdomyolysis); \200 elevated reticulocyte count (hemolysis). Epidemiology There are wide variations in the reported incidence of AKI secondary to hemoly sis and rhabdomyolysis, in many cases the discrepancy is due to the varying de \201 nition s of AKI used by investigators. Rhabdomyolysis-related AKI is responsible for up to half of all cases of AKI requiring renal replacement therapy following earthquakes. Blood \201 lm, expect: \200 \200 fragmented red blood cells (schistocytes); parasites (e.g. malaria), spherocytes (hemolysis ). Coagulation screen, expect: \200 \200 elevated D-dimers (rhabdomyolysis); reduced haptoglobin (hemolysis). Red cell autoimmune sc reen, expect: \200 Etiology Rhabdomyolysis There are a number of causes of rhabdomyolysis (Table 10.9.1). The \201 nal common pathway involves striated muscle injury with the release of cellular cont ents includ- ing myoglobin. In rhabdomyolysis there is sequestration of large volumes of \202 uid in damaged muscle (up to 15 \200\22320 L) which can result in volume depletion. My oglobin (17 kDa) is freely \201 ltered by the glomerulus and in the setting of volume dep letion and acidosis myoglobin binds more avidly to Tamm \200\223Horsfall protein and slough ed tubular epithelial cells promoting the formation of casts. Tubular degradation of reabso rbed myoglobin generates a highly toxic hydroxyl radical with subsequent free-radical- medi ated cellular injury. positive direct Coombs test (some causes of hemolysis). Serum biochemistry, expect: \200 \200 \200 \200 \200 \200 elevated urea and creatinine; elevated K+ (rhabdomyolysis and hemolysis); 2-, urate, lactat e (rhabdomyolysis); elevated PO4 reduced Ca2+ (rhabdomyolysis); elevated CK (usually >10 00 0 U/L in rhabdomyolysis); elevated LDH (rhabdomyolysis and hemolysis). Liver function tests, expect: \200 \200 elevated bilirubin (hemolysis); elevated ALT/AST (rhabdomyolysis). Thyroid function tests: \200 elevated TSH (if hypothyroidism is the cause of rhabdomyolysis). Hemolysis Hemoglobinuria can occur following massive intravascular hemolysis (Table 10.9.2) . In this setting haptoglobin binding of free hemoglobin is overwhelmed. Unbound hemoglobin dissociates into dimers (34 kDa) which are \201 ltered by the glomerulus. The \201 lte red hemoglobin may cause tubular obstruction through cast formation or may be taken up by t ubular epithelial cells and exert a toxic effect. Autoantibodies: \200 Anti-aminoacyl-tRNA synthetase antibodies, e.g. anti- Jo-1 (if polymyositis is the cause of rhabdomyolysis). Toxicology screen: \200 for evidence of causative drug ingestion (Tables 10.9.1 and 10.9.2). Urine Urinalysis, expect: \200 strong positivity for blood (both myoglobinuria and hemoglobinuria); myoglobin (rhabdomyoly sis). Clinical features The clinical features of rhabdomyolysis can vary dependent upon the speci \201 c cause, but it should be suspected if oliguric AKI is associated with: \200 \200 \200 \200 \200 Urine microscopy, expect: \200 \200 no red blood cells on microscopy; pigmented casts. fever; myalgia (50%); muscle weakness; compartment syndrome; crush injury. Microbiology \200 \200 Blood cultures. Serology (Tables 10.9.1 and 10.9.2). Virology \200 Where the cause of AKI is hemolysis there will be features of anemia along with features of the precipitating cause (Table 10.9.2). If a viral infection is suspected screen for suspected pathogens (Table 10.9.1). Differential diagnosis The differential diagnosis will include other causes of oliguric AKI but the diagnosis is often readily apparent from a careful clinical evaluation and simple investigations. CHAPTER 10.9 Pigment-induced acute kidney injury 363 Table 10.9.1 Causes of rhabdomyolysis and myoglobinuria Table 10.9.2 Causes of hemolysis and hemoglobinuria Transfusion reactions Falciparum malaria Mycoplasma infection Toxins Snake bite Insect bite s Muscle injury Trauma Compartment syndrome Prolonged immobilization Burns Electric shock Acu te vascular occlusion Seizures Excessive exertion Sickle cell disease Polymyositis/dermatom yositis Drugs Statins Fibrates Antimalarials Zidovudine Heroin Cocaine Alcohol Ecstasy Amph etamines Electrolyte abnormalities Hypokalemia Hypocalcemia Hypophosphatemia Hyponatremia H ypernatremia Toxins Snake venom Insect venom Poisoning copper sulfate Autoimmune hemolytic anemia Drug-induced hemolytic anemia aspirin \200 chloroquine Mechanical hemolysis Bacterial endocarditis Dysfunctional prosthetic heart valves Renal biopsy A renal biopsy may be performed when a clinical diagnosis of AKI is not clearly secondary t o rhabdomyolysis or hemoglobinuria. Characteristic histopathological changes include featur es of acute tubular necrosis with granular tubular casts, which may stain positively for my oglobin in rhabdomyolysis (Fig. 10.9.1). Muscle biopsy This may be indicated if: \200 \200 there is no obvious precipitant for rhabdomyolysis; there is a history of myoglobinuria pro voked by exer- cise; an underlying in \202 ammatory disorder is suspected. Infections Bacterial Legionella spp. \200 Streptococcus pneumoniae \200 Salmonella spp. \200 Staphylococcu s aureus Electromyography Polymyositis is associated with short polyphasic motor potentials, occasional spontaneous \201 brillation and high frequency repetitive discharges. Viral in \202 uenza \200 HIV \200 EBV \200 coxsackievirus Management Prompt diagnosis and appropriate treatment may prevent the development of AKI following rha bdomyolysis. Identi \201 cation of the cause is important to allow more speci \201 c ther apy. Prophylactic fasciotomy in cases of rhabdomyolysis compli- cating a compartment syndro me may be required to save tissue/organ function. Vigorous \202 uid resuscitation is esse ntial. Management should include: \200 \200 \200 \200 Familial Malignant hyperthermia Neuroleptic malignant syndrome McArdle \200\231s disease Ca rnitine palmitoyltransferase de \201 ciency Endocrine Hypothyroidism Diabetic ketoacidosis careful assessment of the volume status; central venous pressure monitoring; measurement of the urine output; IV 0.9% sodium chloride 10 \200\22315 mL/kg/h to achieve euvolemia; main tain urine output >200 mL/h. Radiology Ultrasound, expect: \200 \200 normal renal tract; no speci \201 c abnormalities. Urinary alkalinization is controversial and is not routinely recommended. There is a risk o f precipitating volume overload, hypernatremia and symptomatic hypocalcemia due to a fall i n the ionized calcium concentration. Intracompartment pressure measurement If a compartment syndrome is suspected, measure intra - compartment pressure by tonometry. A.J.P. LEWINGTON 364 Rebound hypercalcemia can occur during the recovery phase. If attempts to prevent AKI are u nsuccessful then renal replacement therapy will be necessary. The management of hemoglobinu ria involves treatment of the underlying disorder and vigorous \202 uid resuscitation. Prognosis Renal function generally returns to normal if the underly- ing cause is treated. Further reading Brown CV. Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a differ- ence? J Trauma 2004; 56: 1191 \200\2231196. Holt S, Moore K. Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin. Exp Nephrol 2000; 8: 72 \200\22376. Fig. 10.9.1 AKI secondary to rhabdomyolysis. Immunoperoxidase staining demonstrates myoglob in within acutely injured dilated tubules with \202 attened epithelium. (Courtesy of Dr D . Leitch, St James \200\231s University Hospital, Leeds, UK.) Sever MS, Vanholder R, Lameire R. Medical progress; management of crush-related injuries af ter disasters. New Engl J Med 2006; 354: 1052 \200\2231063. Internet resources Acute Dialysis Quality Initiative: If urinary alkalinization is attempted, 1.26 \200\2231.4% sodium bicarbonate can be added t o the IV \202 uid regimen to achieve a urinary pH >6.5. There is little evidence to suppo rt a role for mannitol, which may precipitate a hyperosmolar state and worsen the degree of AKI. Treat speci \201 c electrolyte abnormalities as required. Hypocalcemia associated wi th rhabdomyolysis should not be routinely corrected unless there are complications such as tetany or arrhythmias. Aggressive correction of hypocalcemia may cause meta- static calci \201 cation in the injured muscle. http://www.ADQI.net Acute Kidney Injury Network: http://www.akinet.org See also Clinical approach to acute kidney injury, p. 318 Renal replacement therapies in AKI 328 This page intentionally left blank S. BAVANANDAN 366 Acute kidney injury in tropical countries Development of infection-related AKI is usually multifacto- rial (Table 10.10.2). General m anagement of infection-related AKI is supportive with close attendance to \202 uid balanc e and management of acute electrolyte disturbances and longer-term nutritional support. Spe ci \201 c treatment recommendations will be discussed below. Introduction The causes and presentation of AKI in the tropics vary con- siderably from tha t seen in Western countries. There is also a varied spectrum of AKI even among tropical cou n- tries due to regional differences in bioecology, social behavior and socioeconomic devel opment. In the larger cities, causes of AKI resemble those in the developed world, e.g. nep hrotoxic drugs, prerenal AKI due to func- tional hypovolemia (cardiac failure) and AKI as a postop- erative complication following complex cardiothoracic surgery. Diarrhea-associated AKI Diarrhea most commonly leads to prerenal AKI secondary to volume de pletion with the development of ATN. Acute cortical necrosis may occasionally occur in pedi atric cases with severe volume depletion. Epidemiology Reliable statistics regarding the true incidence of AKI in tropical countries are not available but it is estimated at an average annual incidence of 150 cases pmp. Comm unity-acquired AKI is more common, and patients are generally younger than in Western count ries. Epidemiology Children are more susceptible to the development of AKI following diarrhea tha n adults. In India, diarrheal diseases account for 35 \200\22350% of pediatric AKI requirin g dialysis. The incidence is greatest in summer and peaks during the rainy season. AKI associated with internal medicine practice Medical causes of AKI predominate. The overall incidence has remained unchanged for the las t four decades (Table 10.10.1) but diarrheal disease, intravas- cular hemolysis due to gluc ose 6-phosphate dehydroge- nase (G6PD) de \201 ciency and self-poisoning have largely been replaced by sepsis, drugs and toxins as the main med- ical causes of AKI. Common causative organisms Viral: \200 rotavirus and Norwalk agent. Bacterial: \200 \200 \200 \200 \200 \200 \200 Escherichia coli; Campylobacter jejuni; Klebsiella pneumoniae; Shigella spp.; Salmonella en teritides; Vibrio cholerae; Pseudomonas aeruginosa. AKI associated with obstetric practice AKI complicating childbirth is declining with improv ements in prenatal care and obstetric practice. Legalization of abortion in several develop ing countries has been followed by a substantial decline in the rate of AKI related to sept ic abortion. AKI associated with surgical practice Surgical AKI incidence is increasing. This probably r e \202 ects the increasing complexity of surgery in addition to increasing age and comorbi dity of patients in whom surgery is undertaken. Clinical presentation Dehydration, oliguric AKI severe metabolic acidosis and hypokalemi a. Investigations Stool cultures stool hanging drop examination. Infection-related AKI There is a high prevalence of infection in the tropics due to bioecol ogical factors: \200 warm climate; \200 abundant animal and insect vectors; \200 pove rty; \200 overcrowding; \200 poor hygiene; \200 malnutrition. Treatment Fluid replacement. Correction of electrolyte abnormalities. Antibiotics for speci \201 c infections. Malaria-associated AKI Malarial AKI results from a variable combination of ATN, interstitia l nephritis and development of a mesangial prolif- erative glomerulonephritis. Late/inadequate medical attention, particularly in remote areas, predisposes to complicatio ns such as AKI. Infective causes of AKI include: \200 \200 \200 \200 \200 Epidemiology Malaria affects 300 \200\223500 million people annually, with 1 \200\2233 mill ion deaths. The overall prevalence of AKI in falciparum malaria is <1% but may reach 60% wi th severe infection. Residents in endemic areas acquire various degrees of immunity to infe ction: their incidence of AKI is 2 \200\2235%. Nonimmune visitors develop a more severe inf ection and are at higher risk of AKI (25 \200\22330%). diarrheal diseases; malaria; leptospirosis; hemolytic uremic syndrome; melioidosis. CHAPTER 10.10 Acute kidney injury in tropical countries 367 Table 10.10.1 Patterns and trends in AKI among tropical countries Country Time period Authors No. of cases Proportion (%) of AKI cases associated with: Internal medicine Surgery Obstetrics Singapore Thailand Ghana Nepal India 1964 \200\22373 1960 \200\22370s 1972 \200\22375 1998 \200\22399 1965 \200\22374 1975 \200 \22380 1981 \200\22386 1976 \200\22380 1994 2004 Ku et al., 1975 Sitprija et al., 1975 Adu et al., 1976 Khakurel et al., 2005 Chugh et al., 1989 Chugh et al., 1989 Chugh et al., 1989 Suleiman, 1982 Chow et al., 2007 Chow et al., 20 07 143 162 50 45 325 510 1027 184 78 211 60 61 62 84 67 55 61 41 69 73 24 24 4 4 11 24 30 32 31 26 16 15 24 11 22 21 9 27 0 1 Malaysia Quinine or quinidine dosage should be reduced by one-third after 48 h if there is no clinic al improvement, if AKI persists or there is hepatic dysfunction. No dose adjustment is nece ssary if the patient is on hemo- dialysis (HD) or hemo \201 ltration (HF). A switch to ora l treatment can be made once the patient is able to tolerate oral medications. A 7 day trea tment regimen should be completed. In nonpregnant patients, doxycycline should be added for 7 days. Indications for renal replacement therapy (RRT): Initiate HD or HF early in establ ished AKI or severe metabolic acidosis unresponsive to rehydration. There are no comparativ e trials of HD versus HF. HF is associated with more rapid correction of biochemical abnorm alities and lower mortality compared with perito- neal dialysis. Hyperparasitemia (>300 000 / L) may also be an indication for early RRT; this may reduce the number of organs failing by removing cytokines and toxic metabolites generated by the parasite and treatment. Causative organism AKI is associated mainly with Plasmodium falciparum. Very occasionally i t complicates Plasmodium vivax. Clinical presentation AKI is usually oliguric, hypercatabolic and associated with other com plications: \200 jaundice (>75%); \200 anemia (70%); \200 thrombocytopenia (70%); \200 hepatitis (20%); \200 hypotension (20%); \200 septic in \202 ammatory response s yndrome (5%). Cerebral malaria is rarely associated with malarial AKI. Investigations Thin and thick blood \201 lm microscopy to diagnose and type the malarial parasite. Proteinuria occurs in 60% but is usually <1 g/24 h. Hyponatremia occurs in up to 55% due to internal dilution salt wasting. Hyperkalemia may be striking due to hemolysis , rhabdomy- olysis, acidosis and AKI. Prognosis Dialysis is required in up to 78% of cases. Oliguria may last for a few days to s everal weeks. The mortality ranges from 15 to 45%. The prognosis depends on severity of AKI , associated extra-renal complications, early institution of antimalarial treatment and ava ilability of RRT. Treatment Once the diagnosis is suspected a rapid clinical assessment is required with tran sfer of the patient to the highest level of care available as soon as possible. Supportive measures: \200 intensive invasive/noninvasive monitoring of tissue oxy- genation, \202 uid balance and c onscious level; care is required with IV \202 uids, particularly in adults, due to the ri sk of noncardiogenic pulmonary edema. If CVP is available, target 0 \200\2235 cm water; if not, \202 uid therapy should be guided by physical \201 ndings/urine indices; regular a ssessment of FBC, clotting studies, serum bio- chemistry (U&Es, LFTs glucose and lactate le vels), arte- rial blood gasses and parasite counts are required. Leptospira-associated AKI (Weil \200\231s disease) Renal failure may develop as a consequen ce of prerenal AKI and ATN due to hemodynamic instability or acute interstitial nephritis ( AIN). There may also be a direct nephrotoxic contribution from tubular hemoglobin and myogl obin casts. Epidemiology The peak incidence is between 11 and 40 years of age. There is a male preponde rance. The incidence rises during or soon after the rainy season, especially post \202 oo ds. Speci \201 c antimalarial chemotherapy: In severe falciparum malaria, the drug of choice i s either a parenteral cinchona alkaloid (quinine and quinidine) or artemisinin derivatives (artesunate, artemether and artemotil). S. BAVANANDAN 368 Table 10.10.2 Pathogenetic mechanisms of AKI in tropical infections. Direct invasion of renal parenchyma Bacteria Microabcesses (systemic melioidosis) or solitary abscesses (typhoid). Acute inters titial nephritis (leptospirosis, diphtheria, scrub typhus, tuberculosis and leprosy). Viruses Dengue fever. Hanta virus infection (hemorrhagic fever \200\223renal failure syndro me). Protozoa Visceral leishmaniasis/kala-azar (acute interstitial nephritis). Immune complex-me diated glomerulonephritis Mesangial proliferative GN (acute typhoid fever, acute malaria). Diffuse proliferative GN (post-streptococcal GN, and GN associated with endocarditis or pne umococcal pneumonia). Induction of an immune response leading to glomerular or tubulointerstitial damage Vasculitis Severe streptococcal or falciparum malaria infection. Acute interstitial nephritis Postdysenteric hemolytic uremic syndrome Intravascular volume depletion Dehydration from hy perpyrexia, excess sweating, vomiting and/or diarrhea. Hemodynamic disturbances other insults leading to acute tubular necrosis (ATN) Compromise of renal microcirculation By sludging of red blood cells and platelets due to he moconcentration. \200\230Sticky \200\231 parasitized erythrocytes in falciparum malaria, w hich adhere to adjacent healthy erythrocytes, platelets and capillary endothelium to form rosettes and clumps, impede the m icrocirculation. Systemic in \202 ammatory response syndrome Peripheral blood pooling and capillary leakage mediated by nitric oxide, TNF-A, prostaglandins, kinins and free oxygen radicals results in a reduced effective circulatory volume, renal ischemia and ATN. Pigment-related ATN Heme pigment, bilirubin, myoglobin. Increased mechanical fragility of p arasitized erythrocytes in malaria causes intravascular hemolysis. Rhabdomyolysis may occur as a nonspeci \201 c effect of hyperpyrexia or due to speci \201 c viruses (in \202 uen za, HIV, coxsackie, Epstein \200\223Barr virus) and bacteria (Legionella spp., Francisella spp., Streptococcus pneumoniae, Salmonella spp., Staphylococcus aureus). Nephrotoxic drugs For ex ample, aminoglycosides, amphotericin, NSAIDs. Iatrogenic renal injury associated with treatment or prophylaxis against tropical infection s G6PD de \201 ciency Hemolysis induced by certain drugs, e.g. sulfur-based agents, primaqui ne. Based on Barsoum (2004). Leptospira serology: a single titer >1:400 or a four-fold rise is considered signi \201 ca nt. Causative organism \200 Leptospira interrogans (a spirochaete which infects a wide range of mammals, and is shed in the urine). Treatment IV crystalline penicillin (1.5 million units every 6 h) or oral doxycycline (100 mg bd) for 7 days. Aggressive nutritional support and daily dialysis may be required. Clinical presentation The severity of illness ranges from mild constitutional symptoms to f ulminant liver and renal failure (when known as Weil \200\231s disease). Classically the cl inical course is biphasic: Initial phase: \200 Prognosis A poor prognosis is associated with: \200 \200 \200 \200 \200 \200 advanced age; pulmonary complications; hyperbilirubinemia; diarrhea; hyperkalemia; associat ed infection/underlying disease. abrupt onset fever, myalgia, arthralgia, headache and conjunctival injection. Second phase: \200 jaundice with mild transaminitis, conjugated hyperbiliru- binemia and subsequent developmen t of AKI. Investigations Blood cultures (in \201 rst 10 days). Urine cultures (up to 30 days). AKI usually recovers within 2 months. CHAPTER 10.10 Acute kidney injury in tropical countries 369 Hemolytic uremic syndrome This has been reported as one of the commonest causes of pediatri c AKI in certain tropical countries, e.g. India. Unlike Western countries where HUS is asso ciated with verotoxin-producing E. coli (0157:H7), HUS in the tropics is linked with: \200 \200 \200 \200 \200 \200 \200 Typhoid Intravascular hemolysis in G6PD-deficient patients, myoglobinuria, AIN from ciprofl oxacin treatment and HUS. Lepromatous leprosy ATN, intravascular hemolysis, glomerulonephritis, and AIN secondary to rifampicin treatment. Shigella dysenteriae serotype 1 (most commonly); Salmonella spp.; Klebsiella spp.; nonverot oxin producing strains of E.coli; Shigella \202 exneri; Proteus spp.; Pseudomonas spp. AKI due to toxins and chemicals Ingestion of traditional medicines/foods or accidental expo sure to noxious local plants and animals contribute to toxin-related AKI. Chemical poisonin g (e.g. copper sulfate, paraquat, etc.) is now relatively uncommon. Snakebite nephropathy Snake venom can lead to marked hemodynamic changes induced by release of cytokines and vasoactive mediators ( blood loss in severe hemorrhage). Prerenal AKI i s therefore a potential complication of various snakebites. The development of prerenal AKI may be compounded by other contributory factors such as: \200 \200 \200 \200 Melioidosis AKI commonly complicates acute septicemic melioidosis which may result in marke d hemodynamic changes and prerenal AKI but also an acute interstitial nephritis and formati on of multiple renal microabscesses. Epidemiology It is endemic in South East Asia and northern Australia. Predisposing factors: \200 \200 \200 \200 \200 hemolysis; rhabdomyolysis; intravascular coagulation; direct snake venom nephrotoxicity thr ough metallopro- teases and phospholipase. diabetes; thalassemia; chronic kidney disease; alcoholic liver disease; occupation (rice pa ddy farmers). The commonest \201 ndings in renal biopsy series are: \200 \200 \200 \200 \200 \200 ATN (70 \200\22380%); acute interstitial nephritis; acute cortical necrosis; mesangiolysis; glomerulonephritis; vasculitis. Causative organism Burkholderia pseudomallei (Gram-negative bacteria found in soil and wate r). Clinical presentation Fever, signs and symptoms of pneumonia, multiple cutaneous/ visceral abscesses. The infection exists in acute and chronic forms. AKI occurs in up to 61% in acut e septicemic melioidosis where mortality is >90% if untreated. Epidemiology AKI following snakebites constitutes 1.2% of AKI in Thailand, 3% in India and up to 70% in Myanmar. AKI is usually caused by snakebites from the Viperidae, Colubridae an d Hydrophidae families, i.e. those with hemotoxic or myotoxic venom. Investigations A complete septic screen is required including cultures of blood, urine, spu tum, throat swab, aspirated pus. Serological tests may be of limited value in endemic areas . Clinical presentation Pain, swelling tissue necrosis at the bite site Systemic involveme nt: \200 \200 \200 \200 \200 Treatment Intravenous antibiotics for 10 \200\22314 days: \200 \200 hypotension; disseminated intravascular coagulation; hemorrhage; intravascular hemolysis; r habdomyolysis. drug of choice: ceftazidime; alternatives: carbapenem/amoxycillin-clavulanate. Maintenance treatment with oral cotrimoxazole and doxycycline is required for 12 \200\22320 weeks. Other infections Rarer causes of tropical infection-associated AKI: AKI is usually hypercatabolic and oligoanuric. Apart from AKI, proteinuria and hematuria ar e commonly seen following snakebites. Mucormycosis Renal vascular invasion with renal infarction and necrosis. Treatment Early administration of antivenom, preferably monovalent. Repeated doses may be r equired due to delayed absorption of venom from the bite. Coagulation indices need to be te sted for up to 3 days. Replacement of blood loss with fresh blood. Tetanus immune globulin administration. Aspergillosis Renal abscesses, infarcts, papillary necrosis and obstructive uropathy from f ungal bezoars. Kala-azar Acute interstitial nephritis. S. BAVANANDAN 370 Antibiotics may be required for pyogenic infection at site of bite wound. Early institution of good \202 uid balance with maintenance of good urine \202 ow and urinary alkaliniza tion may reduce risk of AKI. Dialysis should be instituted early if available. Further reading Adu D, Anim-Addo Y, Foli AK, Yeboah ED, Quartey JK, Ribeiro BF. Acute renal failure in tropical Africa. Br Med J 1976; 1: 890. Barsoum RS. Malarial acute renal failur e. J Am Soc Nephrol 2000; 11: 2147 \200\2232154. Barsoum RS. Tropical acute renal failure. In: Ronco C, Bellomo R, Brendolan A (eds): Sepsis , kidney and multiple organ dysfunction. Contrib Nephrol 2004; 144: 44 \200\22352. Prognosis AKI typically lasts 2 \200\2233 weeks. With cortical necrosis there may be no rec overy/delayed recovery with residual renal impairment. Other animal toxins: Scorpion and je lly \201 sh stings, spider and centipede bites lead to AKI in 6 \200\22310% of incidents. Oral ingestion of raw carp bile may be associated with gastrointestinal toxicity and lead t o hematuria (77%), jaundice (62%) and AKI in up to 54% of cases. Chow YW, Lim BB, Hooi LS. Acute renal failure in the same hospital ten years apart. Med J Malaysia 2007; 62: 27 \200\22332. Chugh KS, Sakhuja V, Malhotra HS, Pereira BJ. Changing trends in acute renal failure in thi rd-world countries \200\223 Chandigarh study. Q J Med 1989; 73: 1117 \200\2231123. Chugh KS, Sitprija V, Jha V. Acute renal failure in the tropical coun- tries. In: Davison A M, Cameron JS, Grunfeld J-P, et al. (eds), Oxford Textbook of Clinical Nephrology, 3rd edn. Oxford: Oxford University Press; 2005. Vol. 2, pp. 1614 \200\2231630. Khakurel S, Satyal PR l, Agrawal RK, Chhetri PK, Hada R. Acute re- nal failure in a tertiar y care center in Nepal. J Nepal Med Assoc 2005; 44: 32 \200\22335. Plant toxins and AKI Mushrooms of the genera Amanita, Galerina and Cortinarius may produce gastrointestinal and hepatic toxicity, and AKI. Mortality can be >50% in severe cases. Attr actyloside, an alkaloid from tubers of Callilepsis laure- ola (commonly used in Southern an d Central Africa as a traditional remedy) can cause AKI, hypoglycemia and liver dysfunction . The mortality rate is >50%. Djenkolic acid in the djengkol bean from the Pithecellobium j iringa/lobatum tree in South East Asia can cause dysuria, hematuria, proteinuria, urolithia sis and AKI. The diagnosis can be con \201 rmed by \201 nding characteristic needle-shap ed crystals of djenkolic acid on urine microscopy. Other plant toxins: \200 Ku G, Lim CH, Pwee HS, Khoo OT. Review of acute renal failure in Singapore. Ann Acad Med Si ngapore 1975; 4 (Suppl):115 \200\223120. Sitprija V. Snakebite nephropathy. Nephrology 2006 ; 11: 442 \200\223448. Sitprija V, Kashemsant U, Arthachinta S, Poshyachinda V. Pathogenesi s of renal failure in tropical diseases. Nippon Jinzo Gakkai Shi 1975; 17: 707 \200\223709. Suleiman AB. Clinical review of acute renal failure: a 5-year experience at Kuala Lumpur. Ann Acad Med 1982; 11: 32 \200\22335. Vetter RS, Visscher PK. Bites and Stings of medically important venomous arthropods. Int J Derm 1998; 37: 481 \200\223496. Internet resources WHO Global Malaria Program: http://www.who.int/malaria Melioidosis Research Center: phenolic compounds (via skin exposure) in the sap of the marking-nut tree of India (Semecar pus anacardium); gaultherin in Securidaca longipe dunculata; divicine and isouramil in Vici s favus (broad bean) in G6PD de \201 cient individuals. http://www.melioid.org/ G6PD De \201 ciency Association: \200 http://www.g6pd.org/favism/english/index.mv Snake bites, a useful introduction to the subje ct: For all the plant poisonings described above, treatment is mainly supportive. With djenkol and Vicis favus, increasing \202 uid intake and alkalinizing urine may be helpful. http://www.usyd.edu.au/su/anaes/venom/snake- bite.html See also Clinical approach to acute kidney injury, p. 318 Renal replacement therapies in ac ute kidney injury, p. XXX Dialysis and hemoperfusion treatment of acute poisoning, p. 336 A cute kidney injury in infants and children, p. 372 Acute tubulointerstitial nephritis, p. 3 44 Hemolytic uremic syndrome and thrombotic thrombocyt- penic purpura, p. 348 Pigment-induc ed acute kidney injury, p. 362 Glucose 6-phosphate dehydrogenase (G6PD) de \201 ciency This affects >400 million people w orldwide, mainly in Africa, the Mediterranean, Middle and Far East. It may confer a surviva l advantage in regions with malaria because infected erythrocytes are cleared more rapidly by the spleen. It is associated with intravascular hemolysis on exposure to oxidative stres s from infection, medication and certain foods. AKI may occur after severe hemolysis due to heme pigment nephropathy. Preventive measures include maintenance of a high urine output a nd urinary alkalinization. This page intentionally left blank K. TULLUS 372 Acute kidney injury in infants and children Many children have edema and respiratory symptoms due to pulmonary edema. Fever, rashes and other symptoms of infection or an in \202 am- matory disease are common. It is important to ask about urine output and whether there is hematuria. It is also important to ask about symptoms such as polyuria and polydipsia which can help in distinguishing between an acute disease and a more longstanding cause for the renal failure. Measurement of blood pressure : high blood pressure must be interpreted in conjunction with other clinical \201 ndings; with cool peripheries it suggests intravascular depletion and with warm peripheries it sug gests volume overload.