Kidney International, Vol. 34 (1988), pp. 867—877 NEPHROLOGY FORUM

Nephropathy in falciparum

Principal discussant: VIsITH SITPRIJA

Chulalongkorn University Hospital, Bangkok, Thailand

phosphatase, 63 IU; serum albumin, 3.8 g/dl; and globulin, 3.2 g/dl. Serum C3 was 80 mg/dl and plasma fibrinogen was 612 mgldl. The urine Editors was strongly positive for bilirubin and showed a specific gravity of JORDAN J. COHEN 1.020, 1 + protein, a pH of 5.8, a few red blood cells, granular casts, and JOHN T. HARRINGTON bilirubin-stained casts. The 24-hour urine volume was 310 ml; urine osmolality was 301 mOsm/kg H20; urine sodium, 57 mEq/liter; urine JEROME P. KASSIRER creatinine, 98 mgldl; urine protein, 0.2 g/24 hr; urine uric acid, 120 NICOLAOS E. MADIAS mg/dl; fractional sodium excretion, 2.6%; and renal failure index, 3.3. was given intravenously at a dosage of 1200 mg initially Managing Editor followed by 600 mg every 8 hours for 24 hours and then at 12-hour CHERYL J. ZUSMAN intervals. The degree of parasitemia decreased to 5% the next day, but the blood chemistry values worsened and the patient became confused. The BUN rose to 180 mg/dl, the serum creatinine to 7.5 mgldl, and the serum potassium to 6.2 mEq/liter. deepened and oliguria State University of New York at Stony Brook continued. Hemodialysis was followed by improvement of clinical and and laboratory data; interdialytic increases in BUN and serum creatinine were always rapid. With quinine administration, the parasitemia disap- Tufts University School of Medicine peared on the seventh day of hospitalization. The patient was dialyzed 3 times; diuresis began 15 days after admission. The remaining hospital course was uneventful, and the patient was discharged 32 days after admission with a serum creatinine of 1.1 mg/dl.

Case presentation Discussion A 33-year-old man entered the Chulalongkorn University Hospital DR. VISITH SITPRIJA (Professor of Medicine, and Chief, because of and over 5 days. He had been treated symptom- Division of Nephrology, Department of Medicine, Chulalong- atically by a local physician without improvement. During the previous korn University Hospital, Bangkok, Thailand): This patient had 3 days, the patient noticed that his urine was scanty and dark. Twoacute renal failure during the course of severe falciparum weeks before the onset of this illness, he had traveled to a rural area where malaria is endemic. malaria. He had heavy parasitemia, cholestatic jaundice, and, Physical examination revealed a muscular, acutely ill man withas is characteristic of malaria-induced acute renal failure, jaundice. The blood pressure was 124/78 mm Hg; temperature, 39°C; hypercatabolism with rapid rises of blood urea nitrogen and pulse rate, regular at 112 beats/mm; and respirations, 28/mm. Theserum creatinine. The urine uric acid-urine creatinine ratio patient was somewhat lethargic but communicable; no significant neurologic signs were present. The sclerae were markedly icteric.exceeded unity, a finding not unexpected in hypercatabolic Auscultation revealed a clear chest. The liver was 4 cm below the costal acute renal failure with severe jaundice [1]. No evidence of margin, and the spleen was slightly enlarged. A complete blood count intravascular was present, but low-grade intravascu- showed a of 8.7 g/dl; count, 3.0 x 106/mm3; lar coagulation was noted. The clinical data and the clinical and white blood cell count, 9500/mm3 with 78% neutrophils and 22%course were consistent with acute tubular necrosis. lymphocytes. A peripheral blood smear revealed ring forms of Plasmo- diumfalciparum in 7% of the erythrocytes. Platelets were 100,000/mm3, Falciparum malaria is one of the common parasitic diseases serum haptoglobin was 142 mg/dl, and serum fibrin degradation prod- causing morbidity and mortality in the tropics. Renal involve- ucts were 4.8 mg/dl. Blood chemistry revealed: blood urea nitrogen, 131 ment varies widely, from mild proteinuria in the company of mg/dl; serum creatinine, 5.7 mg/dl; uric acid, 10.6 mg/dl; serum sodium, urinary sediment changes to acute renal failure. Electrolyte 128 mEq/liter; potassium, 5.2 mEq/liter; bicarbonate, 12 mEq/liter; abnormalities are often observed as well. I will discuss the chloride, 89 mEq/liter; calcium, 7.2 mg/dl; and phosphorus, 3.8 mgldl. Liver function tests showed a total bilirubin of 19 mg/dl; direct bilirubin, clinical spectrum of renal involvement, renal pathologic 13 mg/dl; prothrombin time, 82% of control; serum glutamic oxaloacetic changes, and pathogenesis with an emphasis on acute renal transaminase, 98 U; glutamic pyruvic transaminase, 80 U; alkalinefailure.

Spectrum of renal and electrolyte abnormalities Presentation of the Forum is made possible by the support of B.L.H. Urinary abnormalities. Mild proteinuria and an abnormal Trading Co., Ltd., Bangkok, Thailand. This Forum was presented at urinary sediment occur commonly in patients with falciparum the 4th Annual Conference of the Royal College of Physicians ofmalaria without renal failure [2]. Proteinuria is usually less than Thailand, Cha-am, Thailand, April 1988 1 g/24 hours; abnormal urine findings include a few red blood © 1988 by the International Society of Nephrology cells or white blood cells with occasional granular casts. The

867 868 NephrologyForum: Nephropathy in falciparum malaria

Table 1. Clinicalspectrum of renal and electrolyte abnormalities in laria and has been attributed to decreased potassium intake and falciparum malaria respiratory alkalosis. Hyperventilation, which often occurs Proteinuria with mild urinary sediment changes when high fever is present, results in low plasma pCO2 and respiratory alkalosis [11]. Hyperkalemia occurs in patients with Methemoglobinuria intravascular hemolysis or acute renal failure. This complica- Abnormal serum electrolytes Hyponatremia Hyperkalemia tion can be alarming and requires the same emergency treat- Hypernatremia Hypocalcemia ment as in any patient with hyperkalemia and acute renal Hypokalemia Hypophosphatemia failure. Acute renal failure Hypocalcemia, independent of renal failure, can be manifest Hypercatabolism in severe infection. The cause is not clear, but it might be Cholestatic jaundice related to an intracellular calcium shift [18, 19] and to a low serum albumin level [20]. Calcium levels in infected erythro- cytes are elevated; most calcium within the red blood cell is urinary protein consists of albumin and both macro- and micro-localized within the parasites [18]. Calmodulin, necessary for molecular proteins. Proteinuria is therefore both glomerular andthe activation of the calcium pump, is significantly reduced in tubular in origin [3]. Urinary changes usually disappear quicklyschizont-infected erythrocytes. Although such a reduction in when the disease is controlled. This transient proteinuria iscalcium-magnesium ATPase might not be sufficient in the noted in 20% to 70% of patients [4—6]. Renal function usually isnormal condition to account for the elevation of intracellular normal in patients with mild proteinuria and minor sedimentcalcium, this reduction of calcium-magnesium ATPase can have changes. Occasionally, moderate proteinuria can be present,considerable biologic effects in circulating erythrocytes under- but it resolves during recovery. A nephritic syndrome has beengoing shear stress [21]. Severe malaria is associated with tissue described, but it is rare [7, 8]. Although persistent nephroticanoxia and anaerobic glycolysis; lactic acid production there- syndrome has been reported [91, a cause-and-effect relationshipfore is increased [22]. The decreased intracellular pH that between malarial infection and the syndrome has not beenoccurs because of lactic acid accumulation can activate the substantiated. Interestingly, a strong positive correlation existscalcium/hydrogen antiporter and can result in calcium entry between urinary N-acetyl beta glucosaminidase and the degreeinto the cell with hydrogen ion extrusion [23]. of parasitemia [10]. This relationship indicates subclinical tubu- Hypophosphatemia can occur in the absence of acute renal lar injury due to renal ischemia that may be related to thefailure, perhaps because of a shift of phosphate into cells from number of parasitized erythrocytes. Hemoglobinuria and met-the accompanying respiratory alkalosis [24]. The urinary phos- hemoglobinuria can be present in association with intravascularphate is decreased. Insulin secretion, induced by quinine ad- hemolysis (Table 1). ministration [25], also shifts phosphate into cells [26]. Nuclear Serum electrolyte alterations. Hyponatremia, usually asymp-magnetic resonance spectroscopy has revealed that the inor- tomatic, is noted in 67% of patients without renal failure andganic phosphate content in the parasitized erythrocytes is often is associated with severe infection [11]. This abnormalityincreased [27]. is due to multiple factors. Secretion of antidiuretic hormone can Acute renal failure. Acute renal failure, one of the dread increase [11], perhaps in response to the high fever. In uncom-complications of falciparum malaria, is observed, as a rule, only plicated malaria, hypervolemia has been observed [12]; Malloy,in patients with heavy parasitemia or intravascular hemolysis Brook, and Barry suggested that the observed increase inwith or without glucose-6-phosphate dehydrogenase deficiency plasma volume was a compensatory response to a decreased[2]. The diagnosis of blackwater fever should be made only after effective circulating blood volume consequent to vasodilation.glucose-6-phosphate dehydrogenase deficiency has been ex- The findings are similar to those observed in heat acclimatiza-cluded. So defined, blackwater fever is no longer common. tion. Secretion of antidiuretic hormone could result from vaso-Indeed, most of the patients diagnosed as having blackwater dilation and relative hypovolemia. In some patients, the labo-fever in the old days probably had undetected glucose-6- ratory findings suggest a "reset" of the osmoreceptor [11].phosphate dehydrogenase deficiency. Sodium accumulates in parasitized as well as nonparasitized Renal failure can be nonoliguric; its duration ranges from a erythrocytes because of decreased sodium-potassium ATPasefew days to several weeks. The overall prevalence of acute activity; the increased accumulation in the erythrocytes mayrenal failure is less than 1% in falciparum malaria [28], but it further contribute to the development of hyponatremia, al-occurs in 60% of patients with severe infection [29]. In our own though quantitatively this factor plays a very minor role [13,experience in an area where malaria is endemic, the prevalence 14]. Finally, true sodium depletion rarely is observed. Fluidis 4%; the renal failure usually is seen within 4 to 7 days after administration in malaria should proceed with caution in thethe onset of fever. As noted earlier, patients with malaria- setting of inappropriate secretion of ADH, because fluid over-induced renal failure are hypercatabolic, and blood urea nitro- load and pulmonary edema can ensue. This can be particularlygen and serum creatinine levels rise rapidly. Hyperuricemia and problematic in the severely infected patient because of in-hyperkalemia frequently are present. Hemoglobinuria and met- creased vascular permeability in the lung [15, 16]. As antici-hemoglobinuria can occur in the presence of intravascular pated, diuretics such as furosemide are useful in this clinicalhemolysis. Today's patient illustrates the associated hyperca- setting [17]. Hypernatremia is rare, but it has been observed intabolism as evidenced by the swift increase in BUN and cerebral malaria with severe water depletion due to bluntedcreatinine between dialyses. Cholestatic jaundice usually ac- thirst and inadequate provision of water [6]. companies the acute renal failure, and alkaline phosphatase Hypokalemia occasionally is observed in uncomplicated ma-levels rise out of proportion to the elevation of transaminases, Nephrology Forum: Nephropathy in falciparum malaria 869 as in this patient. Disseminated intravascular coagulation alsoSitprija V. Lumlertgul D). In patients with severe renal failure can occur [30—32]. (serum creatinine greater than 5 mg/dl), the regimen of dopa- Quinine remains the drug of choice for falciparum malaria. Inmine and furosemide had no effect on the course of the renal severe malaria, quinine should be given intravenously. Thefailure. loading dose is 16.7 mg/kg followed by 8.4 mg/kg every 8 hours for 7 days. The dose need not be reduced when renal failure is Renal pathology mild, that is, if the serum creatinine approximates 3 mg/dl [331. The glomerular histology usually is not remarkable, no matter In patients with more severe renal failure, we use a standardwhat the clinical pattern of malaria. Glomerular hypercellularity dose during the first 24 to 48 hours to decrease the parasitemia.can occur, however. The hypercellularity, often mild, is due to After parasitemia is decreased, the dosage can be reduced to 8.4mononuclear cell infiltration, mesangial hyperplasia, and an mg/kg every 12 to 24 hours for 7 days. The dosage of quinineincreased mesangial matrix [41]. The glomerular capillaries can needed in severe renal failure requires further study. ,be normal, bloodless, or engorged with erythrocytes. Renal when needed, must be performed frequently because of thespecimens obtained from patients early in the course of the hypercatabolism. We prefer hemodialysis; peritoneal dialysis isdisease reveal parasitized erythrocytes and malarial pigment- less effective than under most other circumstances because ofladen macrophages in the glomerular capillary loop. Thickening the impaired peritoneal microcirculation due to parasitizedof the basement membrane is sometimes present. These erythrocytes and vasoconstriction, which result in reducedchanges probably are responsible for the development of mild solute transport. The efficiency of peritoneal dialysis returns toproteinuria and urinary sediment changes, but they are not normal as parasitemia declines [34, 35]. In developing coun-associated with renal failure; these alterations are mild and tries, peritoneal dialysis continues to be used because of itstransient and resolve within 4 to 6 weeks, and they do not differ technical simplicity and also because of its low cost. Continu-from changes observed in other acute infections. More severe ous peritoneal dialysis has been performed with good results inglomerular hypercellularity with polymorphonuclear cell infil- lowering blood urea nitrogen and serum creatinine concentra-tration can occur occasionally, but it resolves quickly when the tions [36]. malaria is treated [8]. Exchange blood transfusion has been used with good results Immunofluorescent examination discloses granular deposi- in patients with sustained heavy parasitemia or severe hyper-tion of 1gM and C3 in the mesangial areas and along the luminal bilirubinemia (total serum bilirubin greater than 25 mg/dl). Thisside of the glomerular capillaries. In some cases, IgG and IgA technique reduces parasitemia, chemical mediators (such asmay be detectable. Granular deposition of falci- catecholamine, histamine, and serotonin), and jaundice. Ex-parum antigens is demonstrable in the mesangial areas and change blood transfusion thus is an effective adjunctive treat-along the capillary wall [2]. ment to dialysis for severe falciparum malaria [31, 37, 38]. Electron microscopy reveals electron-dense deposits in the Because of the presence of intravascular coagulation and vaso-paramesangial and subendothelial areas. Deformed erythro- constriction in malaria, the use of prostacyclin has been sug-cytes are seen in the space formed by endothelial cytofolds. gested but requires confirmation [39]. Infusion of monoclonalCollagen fibrils occasionally are observed in the mesangial antibody against a parasite receptor in the vascular endotheliumareas. Granular and amorphous materials can be seen in the might have clinical implications in the future treatment ofinner layer of the basement membrane and subendothelial area malaria, but this is speculative at present. without thickening of the lamina densa or lamina externa [2]. In The prognosis of acute renal failure generally is favorable inone of our studies, we noted that firbin deposition occasionally patients who have early and frequent dialysis. In our experi-occurs in the paramesangial areas [42]. ence, 60% of patients with malarial renal failure require dialy- In patients with uncomplicated falciparum malaria who have sis, and the mortality has decreased from 30% in the past to lessmild proteinuria, renal biopsy usually reveals no tubulointersti- than 10% at present. The figures are comparable with thosetial changes. In patients with renal failure, tubular changes vary from Stone et al [40]. The prognosis is grave, however, whenfrom unremarkable, mild cloudy swelling and vacuolation [43] multiple organs are involved, especially when acute respiratoryto marked tubular degeneration and necrosis involving most of failure is present. the distal tubules, some proximal tubules, and the collecting Based on the present understanding of renal pathophysiol-ducts [40, 44, 45]. Fine and coarse hemoglobin granules some- ogy, prompt antimalarial treatment as well as maintenance oftimes are present in the proximal tubular cells. Hemoglobin good urine flow and fluid and electrolyte balance are importantcasts and granular casts often are observed in the lumen of the in the prevention of renal failure. The urine should be rendereddistal and collecting tubules. These changes are more striking in alkaline when hemoglobinuria occurs. Since this regimen hasthe unusual patient with blackwater fever and in the patient been instituted, the occurrence of renal failure in rural hospitalswith intravascular hemolysis. Edema and mononuclear cell in Thailand has decreased. Dopamine and furosemide appearinfiltration occur in the interstitium. During the recovery phase, beneficial in maintaining the renal blood flow and urinarymitotic activity signifying epithelial regeneration can be prom- output. In mild renal failure (serum creatinine less than 5inent in the cells lining the macula densa [2]. mg/dl), dopamine and furosemide (given on admission along In falciparum malaria, the vessels usually are not remarkable. with conventional treatment with quinine) prevent further de-Deposition of C3 may be visible in the wall of the glomerular terioration of renal function, shorten the clinical course of renalafferent arterioles, but this is a nonspecific finding shared by a failure when compared with a control group receiving onlyvariety of infectious diseases. Renal specimens obtained early quinine (with a comparable degree of renal functional impair-in the course of the disease in patients with heavy parasitemia ment), and obviate the need for dialysis (unpublished data,demonstrate crowding of peritubular capillaries with parasitized 870 Nephrology Forum; Nephropathy in falciparum malaria

tissue. Glomerulonephritis theoretically can be due to in-situ immune-complex formation, but this phenomenon has not been /(_. shown in humans with falciparum malaria. E M EARlY CONTACTBETWEEN Pat ho genesis of acute renal failure ) ThEMEROZOITE (M AND HOSTERYThROCYTE CE) Two mechanisms are involved in the pathogenesis of renal failure in falciparum malaria: effects of parasitized erythrocytes and nonspecific inflammatory effects. Parasitized erythrocytes and hemorrheologic changes. Entry of merozoites into erythrocytes requires formation of a junction between the erythrocyte membrane and the apical end of the

THICKENEDERYTHROCYTE merozoite (Fig. 1). Migration of the junction parallel to the long MEMaANE( ARROW)AT THE axis of the merozoite brings the merozoite into an invagination POINTOF AITACHISIT of the erythrocyte. The erythrocyte receptors recognized by the malarial parasites are believed to be glycoproteins [50, 51]. Alterations in the membrane of the infected erythrocytes form electron-dense protrusions, or knobs [52, 53]. A few knobs occur in the membrane of the erythrocyte infected with the ring form; the number of knobs increases as the parasite matures. These knobs can adhere to the vascular endothelial cells or to MEROZOITE IN 11* INVAGINATED PORTION the knobs of other erythrocytes [54, 55]. The precise mecha- OF ERYTHROCYTE nism of endothelial cytoadherence is not clear. The endothelial WITH POINT OF ATTACHMENT (ARROWS) cytofolds may enhance erythrocyte trapping. The receptor of this binding protein is thought to be thrombospondin, a 450—500 kDa glycoprotein. Of interest is the fact that only P. falciparum- infected erythrocytes bind to the endothelial cells of the capil- laries and venules (Fig. 2). P. malariae- and P. vivax-infected erythrocytes do not have this property [56]. Therefore, inter- ference with the microcirculation is an important pathophysio- logic change in falciparum malaria. When these knobs appear ERYTHROCY 'IC CIJOLL CONTAINING A MEROZOITE on the erythrocyte membrane, the trophozoite-infected cells WFTH POINT Of ATIACHMENT C ARROW retreat from the peripheral circulation and are sequestered in the venules and capillaries of various organs. Impedance of the Fig. 1.Varioussteps of erythrocyte entry by a merozoite. microcirculation by endothelial cytoadherence and the rapid multiplication of parasites in falcipartim malaria make renal failure common in falciparum malaria, as opposed to its rare erythrocytes. Malarial pigment-laden macrophages, lympho-occurrence in the other . cytes, plasma cells, and fibrin thrombi also are seen [291. Parasitized erythrocytes have decreased deformability. Adherence of parasitized erythrocytes to the endothelial cellsRheoscopy of parasitized erythrocytes reveals impaired deform- has been revealed by electron microscopy [46]; this could be anability at physiologic shear stresses and shows that the eryth- important cause of renal ischemia and renal failure. rocytes recover their normal shape slowly [57]. Erythrocytes containing more mature parasites exhibit no deformability at Patho genesis all. Loss of deformability increases with maturity of parasites in Patho genesis of glomerular lesions the erythrocytes, causing the sluggish flow in the microcircula- Mild glomerular changes in falciparum malaria clearly aretion. Acute-phase proteins, especially fibrinogen, are increased caused by immunologic mechanisms. The soluble antigens of P.(as in this patient), and account for the increased plasma falciparum are detectable in circulating immune complexes andviscosity. Erythrocyte viscosity also is increased because of in the glomeruli [8, 41, 47]. Serum C3 and C4 may be decreasedrigidity of the infected erythrocytes; the whole-blood viscosity during the acute phase of the disease. In our unpublishedthus is increased and contributes further to the slow flow in the experience, this is observed in approximately 50% of cases.microcirculation. Glomerulonephritis in falciparum malaria therefore appears to Nonspecific effects of infection. Several pathophysiologic be immune-complex in type. It is transient and, like many otheralterations that occur in falcipanim malaria can lead to renal acute postinfectious glomerulonephritides, it is associated withischemia and tubular injury. These alterations are the nonspe- rapid clearing of immune-complex deposition. In Plasmodiumcific consequences of infection, but they are important factors berghei infection in mice, which corresponds to falciparumin the pathogenesis of renal failure. malaria in humans, free plasmodium antigens can be detected in (a) Hypovolemia. Blood volume determination in falciparum the glomeruli without immunoglobulin deposition [48, 491.malaria has yielded conflicting results depending on the stage of Antigen deposition is related in this model to the degree ofinfection and on fluid administration. Hypervolemia attributed parasitemia; this finding raises the possibility of primary phys-to systemic vasodilation with fluid retention has been described ical interaction or adherence of malarial antigens to the renalin uncomplicated falciparum malaria [12, 58]. Patients with Nephrology Forum: Nephropathy in falciparum malaria 871

Fig.2. Knobs on the parasitized erythrocyte membrane (arrows)adhereto the glomerular endothelium (EN). (Courtesy of Dr. V. Boonpucknavig; magnified x 30,500.) renal failure have been reported to be normovolemic [43], butlana contributes to water retention and hyponatremia. In severe these patients received fluid prior to blood volume determina-infection, vascular permeability is increased by chemical medi- tion. In induced malaria in humans, hypovolemia occurredators including kinins, prostaglandins, leukotrienes, histamine, initially and was followed by hypervolemia and normovolemiaserotonin, adenosine, and probably other unidentified sub- [59]. Hypovolemia developed in a group of patients with renalstances [61—63]. Fluid leaks from the intravascular compart- failure who received no fluid prior to the study [601. ment and leads to hypovolemia. Vascular endothelial damage— What do these data mean? I believe that in uncomplicatedinduced by anoxia, complement activation, and oxygen radicals malaria, hypervolemia occurs due to vasodilation and fluid shiftreleased during the inflammatory process [64] and circulatory from cells; this change is similar to what is seen in heatreflow [651—further increases fluid leakage from the intravas- exposure. Antidiuretic hormone release in uncomplicated ma-cular space. Blood volume thus decreases in severe infection, 872 Nephrology Forum: Nephropathy in falciparum malaria and this decline in volume is further compounded by decreased Table 2. Multiregression analysis of risk factors in the development fluid intake and increased fluid loss through the skin and of acute renal failure in falciparum malariaa respiration. Factor Coefficient P Value (b) Intravascular coagulation. Alterations in coagulation Hypovolemia 2.44 <0.025 factors, prolonged prothrombin time, thrombocytopenia, andHeavy parasitemia 4.21 <0.01 the presence of fibrin degradation products are common inBlood hyperviscosity 4.21 <0.01 severe falciparum malaria [66—69]. The fibrinogen half-life isJaundice 4.17 <0.01 diminished [67], and fibrin can be deposited in the vascular bed Intravascular hemolysis 1.38 >0.05 [69]. Occasionally, disseminated intravascular coagulation oc- Intravascular 1.04 >0.05 curs in severe cases and is associated with cerebral, pulmonary, coagulation and renal complications [30—32]. Cerebral malaria, acute respi- a Theanalysis is based on our data from 20 malarial patients with ratory failure, and renal failure are well known in severerenal failure and 20 malarial patients without renal failure. (Unpublished malaria. In most patients, however, the classic picture ofobservations.) disseminated intravascular coagulation is not present, and fibrin deposition in the glomeruli is infrequent. Generally only re- gional or low-grade intravascular coagulation is present, and itstubules has not been described, endotoxin increases the isch- contribution to the development of renal failure is probablyemic renal injury [83]. Recently, cytokines have been impli- minimal. cated in various mechanisms in the inflammatory process [84]. (c) Intravascular hemolysis. Several factors including mem-Cytokines can activate polymorphonuclear cells (thus promot- brane changes [70, 71], immunologic reactions [72, 73], altera-ing adhesion of neutrophils to the endothelial cells), exert tion of charges on the erythrocyte surface 123, 74], and inter-procoagulant activity, increase expression of thrombomodulin, ference with erythrocyte ATP and sodium-potassium ATPasecause fever, and increase protein catabolism and depression of [13, 75] have been incriminated in causing hemolysis. Yet,membrane potential in the muscle fiber. Injection of the cyto- except for patients with glucose-6-phosphate dehydrogenasekine cachectin in rats induces hemoconcentration, shock, and deficiency or those receiving multiple drug treatment (which isacute tubular necrosis [85]. Clark has suggested that cytokines common in the tropics), hemolysis is often mild and usuallyare important in the production of endotoxin-like effects in extravascular. Blackwater fever therefore is rare if one rigidlymalaria [86, 87]. excludes patients with glucose-6-phosphate dehydrogenase de- (f)Jaundice.Although mild jaundice does not have an ficiency. In the majority of cases, hemoglobin cannot be de-injurious effect on the kidney, severe jaundice can adversely tected in the plasma, and serum haptoglobin, as in today'saffect renal function. The mechanism is not clear. Jaundice patient, is normal. increases the vascular response to catecholamine [88], in- (d) Catecholamine effects. There is good evidence for cate-creases plasma renin activity [89], and induces hyperuricosuria cholamine release both in animal and human malarias. Constric-[90]. It therefore is not surprising to see the urine uric acid-to- tion of the splanchnic blood vessels has been demonstrated inurine creatinine ratio above one in hypercatabolic and hyper- the animal model; dilation of these vessels was achieved withbilirubinemic acute renal failure [1], as in the patient we are the administration of phenoxybenzamine [761. During the earlydiscussing. Natriuresis with failure to conserve sodium in phase of acute renal failure in human malaria, decreased urineresponse to sodium restriction has been observed in patients flow, a low urine sodium concentration, low creatinine clear-with obstructive jaundice when the total serum bilirubin ex- ance, and high urine osmolality have been observed. In 2ceeds 25 mg/dl [91]. Hemodynamic studies have demonstrated patients, phenoxybenzamine injection increased urine flow,decreased left-ventricular function in severe jaundice, which in urine sodium, and creatinine clearance [77]. These findingsturn might play a role in the decline in renal function [92, 93]. indicate increased catecholamine activity. Catecholamine re-Jaundice is invariably present in severe falciparum malaria with lease is attributed to sympathetic stimulation arid stimulation ofrenal failure, so it could contribute to compromised renal the adrenal gland by kinin [78]. Catecholamines, along withfunction. The improvement of renal function following ex- renin-angiotensin activation by hypovolemia, contribute to thechange blood transfusion supports the adverse renal effects of decreased renal blood flow [60] and also participate, by leu-severe jaundice. kocyte-mediated activation of the kallikrein-kinin system, in All these nonspecific factors are shared by various infections increasing vascular permeability [79]. Catecholamines also can[941 and are known to play a role in the pathogenesis of acute directly increase vascular permeability [80]. In infected mice,renal failure in malaria. Statistical analysis of the data compar- catecholamines probably play a role in the development ofing patients with and without renal failure discloses that heavy pulmonary edema because phenoxybenzamine administrationparasitemia, blood hyperviscosity, jaundice, and hypovolemia can prevent pulmonary edema [811. are the critical predisposing factors (Table 2). Renal failure in (e) Endoloxemia. The clinical manifestation of malaria resem-malaria therefore is due to multiple factors, as shown in Figure bles septicemia and endotoxemia. Although malarial toxins3. Oxygen radicals and complement activation, either by clas- could not be identified, bacterial endotoxin has been detected insical or alternative pathway [95, 96], can contribute further to some patients [82]. Gram-negative bacteria have been isolatedthe cellular injury. In the animal model, renal tubular injury also from the blood of patients with severe malaria. Vascular stasiscan be induced by hyperpyrexia [971, and oxygen radicals as in the gut and failure of hepatic clearance of the absorbedwell as complement activation may be incriminated [98]. Alter- endotoxin from the gastrointestinal tract are the possible causesations in T-cell function in severe malarial infection [99], of endotoxemia. Although a direct toxic effect on the renalespecially natural killer cells through decreased interleukin-2 Nephrology Forum: Nephropathy in falciparum malaria 873

effective are the current epidemiologic and mea- Vascular permeability f Fluid loss Fluid intake sures in reducing the frequency of malaria? DR. SITPRIJA: According to the recent report of the Thailand Ministry of Health, the incidence of malaria in Thailand has Hypovolemia/ decreased from 1,000 per 100,000 population in 1981 to 550 per 100,000 in 1986, and the mortality rate has dropped from 9 per 100,000 to 3 per 100,000. The incidence of renal failure also has Renin-angiotensin/ Catecholamines declined in provincial hospitals. DR. COHEN: Given the adequacy of current supportive mea- Intravascular coagulation Intravascular hemolysis RBF sures for acute renal failure, why do some patients with falciparum malaria die? DR. SITPRIJA: They die of multiple organ involvement, espe- Cytoadherence Endotoxemia Hemorrheologic changes Cytokines cially acute respiratory failure, cerebral malaria, and superim- posed bacterial infection. DR. HARRINGTON: I am interested in your observation that a Tubular necrosis combination of dopamine and furosemide seems to abort the development of full-blown acute renal failure, at least in pa- tients treated early in the course of the disease. Could you Hyperthermia Oxygen radicals provide us with more details regarding the design of the study Jaundice Complement activation and the numbers of patients involved? Specifically, were the Fig.3. Renal failure in malaria. patients randomly allocated to a control group, to treatment with furosemide alone, or to treatment with furosemide and dopamine? DR. SITPRuA: The patients under study had serum creatinine production [100], could impair eradication of malarial parasites,levels ranging from 2.6 mg/dl to 4.5 mg/dl with urinary indices favor secondary infection, and lead to further renal compro-compatible with acute tubular necrosis. The patients were mise. randomly allocated into 3 groups with 4 patients in each group. The control group received only quinine, the second group Questions and answers received quinine and furosemide (200 mg intravenously at DR. JOHN T. HARRINGTON (Chief of Medicine, Newton-6-hour intervals), and the third group received quinine and Wellesley Hospital, Newton, Massachusetts): Thank you veryfurosemide (200 mg intravenously at 6-hour intervals) with much, Dr. Sitpnja, for your comprehensive review of renaldopamine (1 tgIkg/min intravenously). All groups were dysfunction in falciparum malaria. Could you comment furthermatched with respect to age, duration of onset of fever, degree on the interrelationship among glucose-6-phosphate dehydroge-of parasitemia, serum creatinine, and clinical features. The nase deficiency, malarial infection, and drug treatment? I amstudy was performed in a controlled and prospective fashion. especially interested in knowing whether the glucose-6-phos-Furosemide and dopamine were given on the second hospital phate-dehydrogenase-deficient erythrocyte is more or less sus-day, which was 6 to 8 days after the onset of fever. The serum ceptible to malarial infection than is a normal erythrocyte.creatinine continued to rise in controls and in the second group, Second, is the red cell deficient in glucose-6-phosphate dehy-but it remained stable in the third group, who received furose- drogenase more susceptible than a normal red cell to hemolysismide and dopamine. after being infected by malaria? DR. NICOLAOS E. MADIAS (Chief, Division of Nephrology, DR. SITPRIJA: Glucose-6-phosphate-dehydrogenase-deficientNew England Medical Center, Boston, Massachusetts): I was erythrocytes are more resistant to malarial infection. Theyparticularly intrigued by the information you provided on the generally are invaded by the parasites, but maturation ofparasitic invasion of erythrocytes by binding to specific recep- intracellular parasites is delayed and impaired by metabolictors on the erythrocytic surface. I have several questions about changes [101]. Yet, glucose-6-phosphate-dehydrogenase-de-this. Does the virulence of various strains of P. falciparum ficient erythrocytes are more susceptible to hemolysis. Inrelate to specific receptor requirements for invasion of erythro- glucose-6-phosphate-dehydrogenase deficiency, reduced gluta-cytes? Does nature employ the strategy of depleting erythro- thione cannot be formed because the ability of NADH in thecytes of those receptors, thus conferring resistance against hexose monophosphate shunt to be reduced is impaired. He-parasitization? What is the basis of resistance against malaria molysis is not noticeable until the individual is exposed to anassociated with various hemoglobinopathies, such as sickle-cell oxidant stress induced by infections or drugs. The hemolysis isanemia and ? attributed to oxidant damage of erythrocyte membrane and DR. SITPRIJA: Certainly the severity of infection is related to hemoglobin, the process that is usually protected by the pres-the number of receptors on erythrocytes. However, the viru- ence of reduced glutathione. Glucose-6-phosphate-dehydroge-lence of the parasite should be viewed in light of the intrinsic nase-deficient erythrocytes therefore are more susceptible toproperty of the parasite itself with respect to the surface charge hemolysis when infected by malaria than are infected erythro-and the receptor in the parasitic membrane. It is speculated that cytes with normal glucose-6-phosphate dehydrogenase. decreased negative charges could bring the parasite close to the DR. JORDAN J. COHEN (Dean of Medicine, State Universityreceptor on the erythrocyte and could enhance penetration of New York at Stony Brook, Stony Brook, New York): How[102]. 874 Nephrology Forum: Nephropathy in falciparum malaria

Depletion of receptors on the erythrocyte by trypsin de- DR. SITPRIJA: Your question is quite relevant. Hypovolemia creases parasitic invasion [103]. Monoclonal antibody againstshould be corrected by normal saline. Because there is evidence the trypsin-sensitive portion of the receptor has resulted inof inappropriate secretion of ADH in malaria, however, fluid marked inhibition of invasion [103]. It is, however, not knownadministration must be handled with caution to avoid fluid whether nature employs this mechanism to induce parasiticoverload and pulmonary edema. Adult respiratory distress resistance. syndrome is one of the dread complications in severe malaria. In sickle-cell hemoglobinopathy, low oxygen tension duringWith adequate urine flow, fluid can be administered at ease. If sequestration of infected erythrocytes in the venous environ-there is no urinary response to fluid load within 6 hours, I use a ment and the decreased pH of infected erythrocytes cause thecombination of furosemide and fluid administration. hemoglobin S-containing host cells to sickle. The host cell DR. COHEN: If one could block the adherence of the parasite plasma membrane thus becomes leaky to potassium and causesto endothelia, how might the clinical manifestation of the potassium loss and death of parasites [104]. In thalassemia, thedisease be altered? Is such blockage feasible? erythrocytes also are unfavorable to the growth of parasites. DR. SITPRIJA: Adherence of the parasite to the endothelial The erythrocytes are sensitive to oxidant stress, which causescells can be blocked by the use of thrombospondin antibody. membrane damage, potassium leakage, and death of the para-Although this has been tried in animals [54], it has not yet been sites [105]. Phagocytosis of these cells is also increased. used in humans. Conceivably blockade of cytoadherence could DR. DUSTT LUMLERTGUL (Assistant Professor of Medicine,be of great benefit if both cachectin and thrombospondin could Chiang Mai Hospital, Chiang Mai, Thailand): Do you thinkbe blocked. that cachectin plays a role in the pathogenesis of malarial DR. COHEN: As you noted, thrombospondin is the endothelial infection? receptor for the "knob" on erythrocytes infected with P. DR. SITPRIJA: Recent evidence indicates that it does. Endo-falciparum. Does thrombospondin have any known physiologic toxemic symptoms and pathologic changes seen in malaria—function or pathophysiologic significance in any other diseases? including hypotension, hypoglycemia, hypertriglyceridemia, DR. SITPRIJA: Thrombospondin is secreted in the alpha hepatic necrosis, renal tubular necrosis and pulmonary accu-granules of platelets, by several mesenchymal cells, and by mulation of neutrophils—can be induced by cachectin injection.mesangial cells. It binds many constituents of plasma as well as Mice with experimental malaria are more susceptible than arecellular and extracellular matrix elements. Heparin, type-V normal mice to injected cachectin; this finding implies thecollagen, fibrinogen, laminin, fibronectin, von Willebrand fac- functional significance of cachectin in malaria [871. tor, histidine-rich glycoprotein, and plasminogen also show Da. HARRINGTON: Are blockers of cachectin available? If so,specific affinities for thrombospondin. Thrombospondin secre- do they protect against the development of acute tubulartion by smooth muscle cells can be stimulated by platelet- necrosis in the rat? derived growth factor. Thrombospondin plays a role in regulat- DR. SrrpauA: That is an interesting question in view of theing the proliferative response of smooth muscle cells to injury, finding that passive immunization against cachectin in miceand it might be significant in the pathogenesis of glomerular protects animals from the lethal effect of endotoxin [106]. I dodisease with mesangial proliferation and matrix expansion not know of any data on malarial renal failure. However, in a[105]. recent study in mice with malaria induced by P. berghei, prior DR. HARRINGTON: Could you quantitate the immunofluores- injection of cachectin antibody protected against cerebral ma-cent deposition of P. falciparum antigens in renal tissue and lana without modifying the parasitemia. Cerebral vesselscorrelate that observation with the severity of renal failure? showed no lesions, as opposed to the control animals with focal DR. SITPRIJA: On theoretical grounds, more malarial antigens accumulation of packed mononuclear cells containing infectedshould be found ih the kidneys of patients with severe renal erythrocytes [107]. Theoretically, because renal failure in ma-failure. But because renal biopsy usually is performed late in laria is due to multiple mechanisms, cachectin antibody wouldthe course of the disease, no correlation between the amount of offer only partial protection. antigen deposition and the severity of renal failure has been DR. COHEN: Can P. falciparum invade any cells other thanobserved. erythrocytes? DR. COHEN: Does respiratory alkalosis occur any more DR. SITPRLJA: I don't believe so, except for liver cell invasioncommonly in falciparum malaria than in other illnesses with by sporozoites during the initial stage of infection. comparable degrees of fever, or is the alkalosis simply a DR. KRIANG TUNGSANGA (Assistant Professor of Medicine, nonspecific consequence of fever? Chulalongkorn Hospital): Malarial parasites have been found in DR. SITPRIJA: The occurrence is the same in malaria as in platelets. The mechanism of penetration is not clear [108]. other febrile diseases. I believe that it is a nonspecific effect of DR. MADIAS: Are chioroquine-resistant strains of P. falcipa-fever. rum different from those sensitive to chloroquine in terms of DR. SAUWALUCK CHUSIL (Assistant Professor of Medicine, inducing acute renal failure? Chulalongkorn Hospital, Bangkok): The duration between the DR. SITPRIJA: I am not aware of any data demonstrating aonset of malarial infection and the development of glomerulo- difference in inducing renal ischemia between the two strains. nephritis is short, and glomerulonephritis seems similar to acute DR. SUCHATI INDRAPRASIT (Professor of Medicine, Rama-serum sickness. Have you ever seen severe glomerulonephritis thibodi Hospital, Bangkok): Dr. Sitprija, you proposed thatin acute malaria? Have you studied the glomerular pathology of hypovolemia due to increased vascular permeability is one ofchronic malarial infection? the causes of renal failure in malaria. I would like to know about Da. SITPRIJA: We have not seen severe glomerulonephritis in fluid administration in this setting. falciparum malaria, and I doubt its existence. In previous Nephrology Forum: Nephropathy in falciparum malaria 875 reports of persistent nephritis, a cause-and-effect relationship 11. MILLER LH, MAKARANOND P, SITPRIJA V. SUEBSANGUAN C, was not shown. We have not studied the glomerular change in CANFIELDCJ:Hyponatremia in malaria. AnnTrop Med Parasitol 61:265—279,1967 repeated malarial infection. On clinical grounds, there is no 12. MALLOY JP, BROOK NH, BARRY KG: Pathophysiology of acute evidence of glomerulonephritis in those patients. falciparum malaria II. Fluid compartmentalization. Am J Med DR. COHEN: Given that patients who contract falciparum 43:745—750, 1967 malaria are likely at risk for re-exposure to the parasite, how 13. DUNN MJ: Alterations of red blood cell sodium transport during common is recurrent disease? Do patients develop effective malarial infection. J Cliii Invest 48:674—684, 1969 14. OVERMAN RR: Reversible cellular permeability alterations in immunity? disease. In vivo studies on sodium, potassium and chloride DR. SITPRuA: Immunity to malaria is of short duration, concentrations in erythrocytes of the malarious monkey. Am J lasting from 3 to 6 months. However, subsequent infections Physiol 152:113—121, 1948 usually do not produce as high a degree of parasitemia as that in 15. MARTEL RW, KALLENBACK J, Zwi S: Pulmonary edema in the original infection. falciparum malaria. BrMed J 1:1763—1764,1979 DR. ANUCHIT CHUTAPUTTI (Medical Resident, Pramong- 16. JAMES MFM: Pulmonary damage associated with falciparum malaria: A report of ten cases. 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