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Kidney International, Vol. 16 (1979), pp. 64-74

Quartan malarial nephrotic syndrome in children

R. G. HENDRICKSE and ADEOYE ADENIYI

Department of Tropical Paediatrics, School of Tropical Medicine, Liverpool, England, and Department of Child Health, Faculty of Health Sciences, University of Ilorin, Ilorin, Nigeria

The nephrotic syndrome is characterized by pro- presumed to be rare [5-7]. In contrast to European fuse albuminuria, hypoalbuminemia, generalized and American experience, that an etiologic agent is edema, and usually hyperlipidemia [1]. The syn- seldom identified in the nephrotic syndrome, expe- drome occurs world wide and may occur at any age, rience in tropical Africa has revealed a very definite but it has a predeliction for the early years of life [2, etiologic association between the nephrotic syn- 3]. Many etiologic factors have been incriminated, drome and infection with malariae [5- and the renal pathology is extremely variable, but in 8]. While acknowledging the pitfalls of extrapolat- most cases seen in childhood, in temperate cli- ing from experience in specialized institutions to mates, no specific cause can be identified, and renal communities at large, we find it difficult to avoid the histology by light microscopy is unremarkable. conclusion, based on all evidence currently avail- Such cases are referred to as "idiopathic" or "mini- able, that the nephrotic syndrome associated with mal change" nephrotic syndrome and are represen- quartan is a prevalent and serious disorder tative of the vast majority of patients who constitute in tropical countries, and in a global context, quar- the basis for the considerable world literature on the tan malaria probably represents the single most im- nephrotic syndrome in childhood [4]. portant etiologic factor identified to date in the In developing countries in the tropics, the pattern nephrotic syndrome in childhood. and prevalence of childhood diseases in general and This account is an attempt to synthesize available of renal disease in particular remains poorly de- information about the clinical features and clini- fined. Clinical recognition of renal disease is ren- copathologic correlations in the quartan malarial dered difficult because endemic diseases such as, nephrotic syndrome in children and draws largely for example, nutritional edema and urinary schis- on experience acquired over the past 20 years by us tosomiasis may simulate, distort, or obscure renal in the Nephrosis Clinic of the Department of Pae- pathology, and conditions of practice usually pre- diatrics of the University of Ibadan, Nigeria. clude the use of sophisticated radiologic, biochemi- Historical note. Reference to an association be- cal, pathologic, and immunologic investigations re- tween P. malariae and renal disease can be found in quired to identify and characterize renal disorders. the tropical medicine literature dating back to the The advent of medical schools in tropical Africa last century [9]. in recent times, with their associated teaching hos- Watson in 1905, reviewing the clinical features of pitals, facilitated investigation of renal disease and P. malariae infections, remarked on the presence of disclosed an unusually high prevalence of the ne- edema and albuminuria in several of his patients phrotic syndrome in childhood in areas where the [10], and Clarke in 1912 felt strongly enough about condition previously was recognized seldom and was the association to write, "I believe that the occur- rence of edema in the tropics, of such a nature as to make one think of parenchymatous nephritis is a Received for publication November 10, 1978 reason for making a search for quartan malaria 0085-2538/79/0016-0064 $02.20 parasites imperative" [11]. In 1917, MeFie and In- © 1979 by the International Society of Nephrology gram reported nine cases of the nephrotic syndrome

64 Quartan malarial nephrotic syndrome in children 65 in children under 10 years of age in the Gold Coast, more frequently associated with the earlier than it is all of whom had P. malariae in the peripheral blood the later stages of the disease [24]. The reverse [12]. In 1930, Giglioli made a major contribution to would be anticipated if the nephrotic syndrome pre- the subject when he reported on his survey of renal disposed to infection with P. malariae. disease and its relationship to P. malariae carried (2) P. malariae has been demonstrated in out in British Guiana between 1923 and 1929 [13]. renal lesions in about one third of patients with the He noted a close relationship between P. malariae nephrotic syndrome [24-27]. infection, albuminuria, and the nephrotic syndrome (3) In a prospective study of nephrotic and non- and postulated a causal association. Subsequently, nephrotic children in a hyperendemic malarious reports from Sumatra [14], Suriname [15], Kenya area, the subjects were initially cleared of malarial [16], Solomon Islands and New Guinea [17], and In- parasitemia and then monitored without any ma- dia [18] all supported Giglioli's observations. In laria chemoprophylaxis for evidence of reinfection. 1948 Maegraith [19], after critically reviewing the There was no discernible difference in susceptibility literature, accepted the association between P. ma- to malaria in the two groups of children [28]. lariae and the nephrotic syndrome, but his view Direct evidence of the etiologic role of quartan gained little support, and in general the suggestion malaria in the nephrotic syndrome is provided by of a relationship between quartan malaria and the observations made in circumstances which exclude nephrotic syndrome was ignored or treated with in- any possibility than quartan malarial infection fol- credulity in publications on medicine in the tropics lowed rather than caused the nephrotic syndrome. [20]. As recently as 1958, not only was the relation- Keital et al [29] described a case of congenital quar- ship generally regarded as unproven, but it was also tan malaria which presented with the nephrotic syn- popularly believed that the nephrotic syndrome is a drome at 21 months of age. The drug-addicted rare entity in pediatric practice in the tropics [21]. mother had acquired her infection by syringe in- In 1963 Gilles and Hendrickse [6] published their oculation in a nonmalarious area. Complete remis- findings of a comparative study of P. malariae prev- sion of the nephrotic syndrome occurred following alence in 113 nephrotic children, 920 ill non- antimalarial treatment. Boyd [30], observing the nephrotic children, and 340 "healthy" village chil- long-term effects of -transmitted and blood dren in Western Nigeria. Their results showed a inoculated quartan malaria in 38 adults, noted pro- highly significant selective increase in P. malariae teinuria in all subjects, which was gross in 14, and parasitemia in the nephrotic children (P <0.001 associated with edema in 6. Recent experimental for both sets of controls), confirming beyond any work on Aotus monkeys has confirmed that infec- reasonable doubt a relationship between P. ma- tion with quartan malaria to which these animals are lariae and the nephrotic syndrome. Comparison of susceptible causes the nephrotic syndrome [31, the age distribution of the nephrotic patients with 32]. the age-specific prevalence of P. malariae in the The satisfactory response to antimalarial treat- community provided additional epidemiologic evi- ment recorded by Keital et al [29], in their child dence of a specific relationship [6]. with congenital malaria, is in keeping with claims in These findings were interpreted as evidence of a earlier publications [17, 30, 33] that antimalarial causal relationship between P. malariae infection treatment is effective in inducing remission of the and the nephrotic syndrome. The alternative that nephrotic syndrome of quartan malaria. The thera- children with the nephrotic syndrome have an in- peutic value of antimalarials in this condition has creased susceptibility toP. malariae infection could not been substantiated in more recent reports [6, 7]. not be completely disproved, but seemed unlikely The earliest studies on the pathology of quartan in view of Giglioli's observations in British Guiana, malarial nephrosis (QMN) included a careful search that following malaria eradication there, the ne- for P. malariae or malarial pigment in renal tissues. phrotic syndrome, which had previously been com- These studies failed to demonstrate P. malariae or mon, had become a rare condition [22, 23]. Sub- malarial pigment in the renal lesions, and it seemed sequent clinical studies have put the causal relation- highly improbable, therefore, that renal changes re- ship between P. malariae and the nephrotic flected direct injury by the P. malariae parasite [6, syndrome beyond any reasonable doubt. 7, 34, 35]. Hendrickse and Gilles [7] in 1963 sug- (I) P. malariae is significantly more prevalent gested that a possible explanation for the renal pa- among younger children than it is among older chil- thology was that in some individuals infection with dren presenting with the nephrotic syndrome, and is P. malariae provokes an abnormal immunologic re- 66 renal biopsyspecimensshoweddefiniteandfairly in childhoodelsewherewasararefinding.Most change" histologythatcharacterizesthecondition in Africa,itbecameapparentthattheminimal gation ofthecondition. potent stimulustosubsequentimmunologicinvesti- immunologically mediateddisorderandproveda (Fig. 1).Itprovidedsupportforthehypothesisofan with thenephroticsyndromeofquartanmalaria tion ofimmunecomplexesinthekidneyspatients mens examined[36].Thiswasthefirstdemonstra- copy. Hefoundcoarse,granular,immunofluores- from theirpatientsbyimmunofluorescencemicros- demonstrated inthekidneysofthesepatients. techniques, antigen-antibodycomplexesshouldbe hypothesis wascorrect,then,withappropriate influenced byantimalarialtreatment.Ifthis age theglomerularbasementmembrane.Thele- cent depositscontainingIgGandC3inallthespeci- sequently examinedsomerenalbiopsyspecimens sion, onceinitiated,tendstobeprogressiveandun- sponse inwhichantigen-antibodycomplexesdam- Very earlyinthestudyofnephroticsyndrome This provedtobethecasewhenDixonsub- positive fluorescenceforIgG. Fig. 1.Firstdemonstrationofimmune complexesinthequartanmalarialnephroticsyndrome(QMN), showing Renal pathology

a Hendrickse p4 and Adeniyi Their differentiationfromthelesionsfoundinpost- these lesionswillmostprobablybethoseofalocal- the stateofknowledgequartanmalarialnephrotic tempts tofitthehistologicchangesobservedinto gross pathologicfeatures.Theessentiallesion scribed inthisdiscussionasseverelipoidnephrosis. ized focalglomerulitiswithtubularchanges,de- must stillbeelucidated,butitisconsideredthat may causeinthekidneyeitherdirectlyorindirectly syndrome asfollows:thelesionsthatP.malariae nephritis andotheretiologicentities. tients withvariantsofpoststreptococcalglomerular cribed toquartanmalariaincludedmaterialfrompa- topathologic featuresofthenephroticsyndromeas- accepted thatsomeoftheearlierdescriptionshis- clinicopathologic correlation[35].Itnowmustbe data inmanycasesconfoundedattemptsataccurate difficult, andincompleteclinicalbiochemical pean andAmericanexperience[4,37,38]proved classifications ofrenalpathologybasedonEuro- sions, andfeaturesofpyelonephritis[6—8,35].At- able endocapillarycellproliferation,capsularadhe- rosis. Associatedfeaturesdescribedincludedvari- glomerular tuftleadingtoeventualscle- noted wasthickeningofthecapillarywallsin Edington andMainwaringin1966summarized '1 4$ Quartan malarial nephrotic syndrome in children 67

4

w

Fig. 2. Typical histologic appearance in QMN. Note plexiform thickening of capillary walls, little mes- angial expansion and lack of cellular proliferation. (PAS; x290) streptococcal nephritis will always be difficult and essential lesion is thickening of the glomerular cap- require careful clinicopathologic studies in indi- illary walls, which in early cases affects only a few vidual patients" [35]. glomeruli in a segmental manner. The thickening in- Subsequentcollaborative clinicopathologic-im- volves the subendothelial aspects of the basement munologic studies [24] have done much to clarify membrane and gives rise to a double contour or the pathology of the quartan malarial nephrotic syn- plexiform arrangement of PAS positive, argyrophil- drome, which can be summarized as follows: The ic fibrils (Figs. 2 and 3). As the disease progresses,

p• efl.a. V - I, •1' •' rc.-a-.-- & ,

Fig. 3. Part of glomerulus, showing capillary wall thickening with plexiform arrangement of agyrophilic fibrils in subendothelial region. Note variability of extent of capillary lesion. (PASM; x680) 68 Hendrickse and Adeniyi

Fig. 4. End-stage QMN. Note complete hyalinization of glomeruli, tubular atrophy, and interstitial round cell infiltration. (PAS; x 34) more capillaries become affected, and the lesions walls were diffuse, resulting in narrowed or even extend to cause progressive narrowing and even- completely obliterated lumens. Total glomerular tually complete obliteration of capillary lumens. sclerosis, tubular atrophy, and interstitial infil- The mesangium shares in this sclerosing process, tration were also prominent. This grading has some which is initially segmental but ultimately becomes predictive value in relation to response to therapy. diffuse, leading to total glomerular sclerosis (Fig. 4). All cases who have responded to prednisolone or Cellular proliferation is typically absent although immunosuppressive drugs like cyclophosphamide occasional foci of hypercellularity may be seen and azathioprine have fallen into grade I, and all sometimes. The capsular space is usually present, cases in grades II and III have been nonresponsive but in a few cases small fibroepithelial crescents, to any form of treatment. It must be acknowledged, locally adherent to the glomerular tuft, may occur. however, that the majority of patients in grade I Hyaline droplets in the proximal tubules are com- show no essential differences in their clinical behav- mon. The extent of tubular atrophy and interstitial ior and response to treatment from those graded II round cell infiltration reflects the degree of glomeru- and III. This finding indicates the need to refine the lar damage to which they are apparently secondary. criteria for grading the pathology of QMN. Biopsy specimens designated QMN were graded The ultramicroscopic findings in QMN are based for severity by the pathologists in a collaborative on more limited study than light microscopic find- study of children presenting in Ibadan, Nigeria, as ings are. The description that follows reflects expe- follows [24]: Grade 1. Up to 30%ofglomeruli rience of 22 specimens from Ibadan that were exam- showed definite evidence of glomerular lesions, ined in Birmingham, by Glasgow and White [24]. consisting mainly of localized capillary wall thick- These findings have some support from more limit- ening and segmental sclerosis. Grade II. Thirty to ed observations elsewhere [39]. seventy-five percent of glomeruli were affected, The essential abnormality is thickening of the with segmental or diffuse capillary-wall thickening capillary basement membrane. This is variable in and sclerosis, often producing a honeycomb" ap- amount and consists of an increase in the sub- pearance. Occasional adhesions and areas of tubu- endothelial basement membrane-like material of lar atrophy were also seen. Grade III. More than varying density in the subendothelial zone, as well 75% of glomeruli were affected. Extensive mesangi- as occasional aggregations of electron-dense and al sclerosis and plexiform thickening of the capillary cytoplasmic material within the basement mem- Quartan malarial nephrotic syndrome in children 69

tributed than is immunoglobulin fluorescence. Pa- tients with diffuse fluorescence are rarely com- plement-positive and tend to have IgG fluorescence only. Detection of IgA is exceptional. In about one third of subjects P. malariae antigen is detected. A more detailed description of these immunologic findings is given elsewhere. There appears to be no specific relationship be- tween histologic grading on light microscopy and pattern of immunofluorescence observed. All three patterns of immunofluorescence have been seen in association with the three histologic grades [24]. There appears to be a relationship between the pat- 1-., Cr' tern of immunoglobulin fluorescence and response .1-3 - .-..l,, '-F- to treatment. Most responders have granular fluo- 1,1 *. rescence, and the remainder fall into the mixed I pattern. No patient showing diffuse immunofluo- rescence has shown a satisfactory response to treat- ,c :i.A ment. Irrespective of the pattern of immunofluo- Fig. 5. Electron microscopy of QMN. The basement membrane rescence, no patient graded II or III on histology is irregularly thickened and contains lacunae, many of which has shown a response to treatment [24]. Immuno- contain electron-dense material. (x 23,100) fluorescent deposits disappear or become much less evident in repeat renal biopsy specimens of patients who respond to treatment. Immunofluorescence brane itself. Small lacunae scattered throughout the persists, may intensify, or may change its character basement membrane, often containing an island of from granular to diffuse in repeat biopsy specimens material similar in density to the basement mem- on nonresponders to treatment [42]. brane, were present in every specimen designated Table 1 correlates immunofluorescent findings QMN on light microscopy in the Ibadan study with histology, selectivity of proteinuria, and re- (Fig. 5). The characteristic subepithelial deposits sponse to treatment in a series of 41 children with ("humps") classically described in poststreptococ- the nephrotic syndrome studied in Ibadan and Bir- cal mesangial proliferative nephritis and which were mingham [24]. Whereas the majority of patients reported in an earlier description of electron micro- with non-QMN histology respond to treatment, on- scopic appearance in the nephrotic syndrome of ly a small minority of QMN cases, all in grade I and African children [40], were not seen in any of these showing a granular or mixed pattern of fluores- QMN biopsy specimens. cence, respond to treatment. Immunofluorescent microscopy. With occasion- al exceptions only, immunoglobulin deposits have Clinicalfindings been regularly detected in renal biopsy specimens Mode of presentation. Patients almost invariably of QMN [24-27, 40, 41]. Three patterns of fluores- present with generalized edema. The onset may be cence have been observed. (1) Coarse, medium- insidious starting initially as periorbital swelling on sized, granular deposits distributed along the capil- waking, which disperses during the day, later be- lary walls is the most common finding, (2) a diffuse coming persistent and progressive over a period of pattern of very fine deposits homogeneously distrib- months. Alternatively, edema may be very rapid in uted along the vessel walls occurs in a minority of onset and reach gross proportions within a week. patients, (3) a mixture of granular and diffuse depos- The majority of patients have been edematous for 2 its in different proportions is observed often but oc- to 4 weeks at the time of presentation. Duration and curs less frequently than does the coarse granular severity of edema show no specific correlation with pattern. IgG and 1gM usually are detected together, the severity of renal pathology. but either may occur alone in the granular and Most patients complain of fever in the early mixed patterns, usually in association with the C3 stages of their illness, and this may occasionally be component of complement, but fluorescence of C3 of the characteristic quartan type with spikes every is always granular and tends to be less widely dis- 72 hours (Fig. 6). As the disease progresses, fever 70 Hendrickse and Adeniyi

Table!. Correlation of immunofluorescent findings with histology, selectivity of proteinuria, and response to treatments Renal morphology: Selectivity of proteinuria QMN I QMN II QMN III MC and others ______— ______Totalgood High Mod. Poor High Mod. Poor High Mod. Poor High Mod. Poorresponses Immunofluorescent pattern Granular OOX OOX OXX X XX X X X — 000 — 0 7/19 Mixed 0 — OXXXX — X XX — — XXXX 0 0 — 3/15 Diffuse — XX XX X — X — — X — — — 0/7 Total good responses 2/4 1/5 2/10 0/2 0/3 0/4 0/1 0/1 0/5 3/4 1/1 1/I 5/19 0/9 0/7 5/6 10/41 This figure is reprinted with the permission of Lancet [24]. hQdenotesgood response; 0, fair response; X, poor response. MC is minimal change nephropathy; QMN is quartan malarial nephro- sis. diminishes. There are no other characteristic com- ease occurs, but it is our distinct impression that plaints. In particular, it must be stressed that hema- within the prevailing local nutritional spectrum, it is tuna, dysuria, and oliguria are admitted rarely, the least well nourished who most frequently ac- even on direct questioning, although 24-hour urine quire the disease. collection usually shows a significant reduction in Investigations of the correlations between malnu- output. trition and malarial infection in areas where both P. Age and sex. The sexes appear to be equally af- falciparum and P. malariae occur have shown that fected. The disease is rare during the first 2 years of whereas the prevalence of P. falciparu,n infection is life, but thereafter increases in incidence to a peak largely uninfluenced by nutritional status and the at about 5 years, after which prevalence gradually disease may indeed be more severe in well-nour- declines but does not disappear, cases occurring in ished than poorly nourished subjects [431, P. ma- adolescence and adult life. The age incidence con- lariae infections tend to be more frequent among trasts with experience in Europe and America malnourished than they are among well-nourished where peak prevalence of the nephrotic syndrome children [44]. is between 2 and 3 years of age, after which it falls Main physical findings. Edema is obvious in all sharply (Fig. 7). cases and is usually associated with ascites. In addi- Nutritional condition and social status. The vast tion, some patients may have pleural effusions. The majority of patients are poor, badly nourished, illit- detection of ascites is clinically important, as it dif- erate peasants. This, in the main, reflects the eco- ferentiates the nephrotic syndrome from Kwashior- nomic and social background against which this dis- kor, in which ascites is a rare clinical finding. A large, persistent, submental collection of edema is another finding which is characteristic of the ne- phrotic syndrome. The liver and the spleen are both enlarged in about 50% of patients, and in a further 25% either the liver or the spleen may be enlarged. C) The degree of enlargement of these organs is usual- E F- ly moderate and frequently masked by ascites, but hepatosplenomegaly is sometimes gross and obvi- ous. Most patients show some degree of anemia. Associated findings and complications which are C) not infrequently observed include respiratory infec- 0S tions, primary , severe anemia, gross malnutrition, and specific childhood infections, such as measles, whooping cough, and so forth. The blood pressure is usually normal in the early stages of this disease, but moderate hypertension Fig. 6. Temperature chart of a patient showing typical P. Ma- (BP> 120/80 mm Hg) does occasionally occur. The lariae pattern of 72 hourly peaks. detection of significant hypertension in a patient Quartan ,nalarial nephrotic syndrome in children 71

— American children, 425 = 100% be very low, and values well below 1.0 gIlOO ml are 30 — Nigerian children, 156 = 100% the rule rather than they are the exception. Serum globulin concentrations are higher than they are in 25 Europe but show little difference from those record- ed in normal children in the same environment, ex- 20 cv cept for the elevation of the a2 fraction. Cholesterol

15 concentrations reflect the low dietary lipid intake and tend to be much lower than are those observed a10 C) in European children with the nephrotic syndrome, 00) // but they are significantly elevated by local stan- 5 / dards. Blood urea concentrations are well within I—— I the normal range in the early stages of the disease 1 2 3 4 5 6 7 8 9 10 [6, 7]. Serum complement (C3) is usually within the Age of onset of disease, yr normal range but occasionally may be depressed in Fig.7.Comparisonof age prevalence of nephrotic syndrome in patients with recent onset of disease [46]. American and Nigerian children, Immunoelectrophoretic studies of the com- plement component C3 (/3-1-C) provide evidence to with a short history of illness should cause the phy- support the concept of an immunologically mediat- sician to query the accuracy of the history or to re- ed disease. C3 has been detected in the first peak of vise the diagnosis of quartan malarial nephrotic syn- "G-200 Sephadex" gel filtration of the serum of drorne. In the later stages of the disease, many pa- some patients, as well as in the middle peak as nor- tients develop hypertension. Administration of mal, showing that it is incorporated into a macro- prednisolone tends to precipitate or exacerbate hy- molecular form, as would be expected if it were pertension. It is exceptional to find evidence of re- bound to antigen excess soluble antigen- nal failure in the absence of hypertension. complexes [46]. Spontaneous remission in established cases of quartan malarial nephrotic syndrome is very rare, Management, course, and prognosis but significant reduction in edema and proteinuria Management of these patients presents many may occur following antimalarial chemotherapy and problems which are magnified under conditions of other measures (see below). practice in the tropics. Apart from short admissions Urinalysis. Proteinuria is heavy and persistent. for special investigation or to treat serious compli- Spun urinary deposit typically shows a few leuko- cations, most patients have been managed as out- cytes, some granular and hyaline casts, and only oc- patients. That control of edema is regarded as casional red cells. Macroscopic hematuria does not "cure" by many leads to a high default rate with all occur, and significant microscopic hematuria is un- its attendant problems [7]. usual. The atypical patient who shows significant Most patients improve and lose edema in re- hematuria tends to progress rapidly toward renal in- sponse to initial management on a high-protein, sufficiency. low-sodium diet, combined with the use of diuretics Differential protein clearance studies show that, and treatment of complications such as intercurrent in contrast to experience with the idiopathic (mini- infections and anemia, but proteinuria is largely mal change) nephrotic syndrome, the majority of unaffected by these measures. Spontaneous tempo- these patients have poorly selective proteinuria [24, rary remission of albuminuria has on occasion been 42, 45,46]. Highly selective proteinuria occurs in observed in association with measles, and stable re- 20% or less of patients, among whom are to be mission has been observed in a patient successfully found most of the small minority with this disease treated for purulent meningitis which complicated who are responsive to prednisolone [24,42, 45,46]. his illness, but such events are exceedingly rare. The natural history of this disease is one of per- Biochemicalfindings sistent albuminuria associated with slowly progres- The salient biochemical findings in the quartan sive renal damage leading to hypertension and renal malarial nephrotic syndrome do not show any es- insufficiency within a period of 3 to 5 years. Death sential differences from those classically described, when it occurs is usually caused by hypertension, but they tend to be modified by environmental fac- renal failure, or intercurrent infection [7, 24, 42, 45— tors. Thus, plasma albumin concentrations tend to 48]. 72 Hendrickse and Adenivi

The serious prognosis associated with this dis- 20% of the patients with highly selective protein- ease has prompted a search for specific therapy uria, less than half show a good response to pre- which has included trials of antimalarial drugs, dnisolone [42, 45]. This is a lower percentage of re- prednisolone, and cytotoxic drugs. It is both inter- sponders than would be expected in similar age esting and instructive to briefly review the sequen- groups with similar selectivity index in Europe and tial development of therapeutic trials in this dis- America, and it indicates that in QMN selectivity order. index of proteinuria is less accurate as a means of Antimalarial drug therapy. Having confirmed a identifying prednisolone responders than it is in the definite relationship between P. malariae and the idiopathic nephrotic syndrome. It remains, how- nephrotic syndrome early in the course of our stud- ever, the simplest means of picking out some ste- ies [5—7], we thought it logical to try the effect of roid responders from the large group of non- antimalarial treatment on these patients. Contrary responders. A trial of prednisolone would seem jus- to earlier reports, we were unable to confirm any tified, therefore, in patients who have highly lasting benefits of such treatment. In a controlled selective proteinuria, provided that these patients trial in which 44 patients received chloroquin fol- can be closely observed for early detection of any lowed by weekly pyrimethamine (group A), 45 pa- untoward effects of prednisolone administration. tients received no antimalarials (group B), and 24 Whenever possible, selectivity of proteinuria patients received chloroquin plus primaquine for 14 should be combined with renal biopsy, which will days, to ensure tissue eradication of P. ,nalariae permit identification of likely nonresponders (QMN (group C), the results assessed 6 months from the histology grade II or III) among patients with highly start of therapy showed no difference between the selective proteinuria, or possible responders (QMN three groups. Three patients only in groups A and B histology grade I) among patients with poor selec- and two in group C showed cessation of albumi- tivity [24]. nuria, whereas the remainder in all three groups Cytotoxic drugs. The poor response to anti- showed no improvement or had deteriorated [6]. malarial drugs and prednisolone in the vast majority Predn iso/one. The therapeutic effects of prednis- of patients with the QMN syndrome prompted olone, which in western countries induces a remis- study of the therapeutic effects of cyclophospha- sion in most childhood nephrotics, was next investi- mide and azathioprine in this disease. In 1966, gated either alone or in combination with anti- Kibukamusoke reported an impression of striking malarial treatment [49]. The results of this and benefit from azathioprine therapy in patients ob- subsequent studies have demonstrated conclusively served in East Africa [50]. Subsequent studies in that prednisolone is ineffective in inducing a remis- West Africa have demonstrated conclusively that sion of symptoms in most patients, and its use is azathioprine does not control proteinuria in most associated with a very high rate of serious compli- cases and that its use is associated with a signifi- cations, including sudden unexpected death, severe cantly increased risk of infection and a significant infections and, most frequent of all, steroid-induced reduction in the 2-year survival rate when com- hypertension with its attendant risks of cerebrovas- pared with controls [47] (See Fig. 8). On the avail- cular accidents and cardiac failure [7, 24, 42, 45, 47— able evidence, azathioprine must be regarded as 49]. The risks of prednisolone administration in the contraindicated in the treatment of the QMN syn- quartan malarial nephrotic syndrome so far out- drome. The increased mortality observed in pa- weigh the possible benefits to the small minority of tients treated with azathiaprine is interesting and steroid responders, that its general use is con- could be an example of the postulated system in traindicated in the management of this condition. which a drug may accelerate renal pathology by The circumstances in which a trial of prednisolone causing more damage to mechanisms concerned is justified are discussed below. with antigen clearance than it does to the mecha- Most children with the nephrotic syndrome in nisms causing the renal damage [51, 52]. Europe and America respond well to prednisolone, Cyclophosphamide treatment has sometimes and most of these have a highly selective index of been associated with complete remission of albu- proteinuria: nonresponders tend to have a non- minuria, [42, 45, 47], and some reduction in protein- selective type of proteinuria [37]. uria has been observed in many patients given this Most children with QMN have a poorly selective drug, but this apparent benefit has not been associ- type of proteinuria, and a poor response to prednis- ated with improved survival, and the use of cyclo- olone is thus to be expected. Of the approximately phosphamide is attended by serious side effects, no- Quartan malarial nephrotic syndrome in children 73

12 chemical findings of the quartan malarial nephrotic syndrome are similar to those classically described 11 for the nephrotic syndrome in childhood, but the renal pathology seen on light, electron, and immu- nofluorescent microscopy show strikingdif- 10 ferences and distinctive features. The disease tends to pursue a chronic course and in most patients is nonresponsive to treatment with antimalarial drugs, 9 prednisolone, and immunosuppresive drugs. The overall prognosis is poor, with most patients devel- 8 oping hypertension and evidence of renal failure within 3 to 5 years of onset.

Acknowledgments Figures 2 through 5 are from our Ibadan cases 0 > and were prepared by Eric Glasgow, who sent them > 6 0 U, Cyclophosphamide to us on request. To the best of our knowledge, these photographs have not been published pre- 5 viously. Reprint requests to Dr. R. G. Hendrickse, Department of 4 Tropical Paediatrics, School of Tropical Medicine, Liverpool, England.

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