View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 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 Plasmodium 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 malaria 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 antigen 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 mosquito-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 Hendrickseand Adeniyi sponse in which antigen-antibody complexes dam- gross pathologic features. The essential lesion age the glomerular basement membrane. The le- noted was thickening of the capillary walls in the sion, once initiated,