50, 3^

Editorials^ 351

The Immunological Basis of Glomerular Diseasein Leprosy—A Brief Review'

Amyloidosis and glomerulonephritis arethe important glomerular lesions occurringin leprosy. Amyloidosis has only an indi-rect immune basis, but glomerulonephritisis a direct result of immunological mecha-nisms.

AMYLOIDOSISThe prevalence of renal amyloidosis in

biopsy and autopsy studies on unselectedhospitalized patients with leprosy is shownin Table I. A high prevalence of more than3(Y has been reported from the U.S.A. andArgentina, but it is much less common inPanama, India, Japan, and Turkey. Thisgeographical difference in prevalence is notmerely due to observer variation, and maybe related to diet or racial factors-. Eventhough the mean reported prevalence ofamyloidosis in leprosy in tropical areas isonly 5%, leprosy is still the most frequentcause of amyloidosis in areas endemic forleprosy".

Unlike the immunoglobulin derived amy-loid of immunocyte dyscrasias 5 , the amy-loid deposits in leprosy are composed of anon-immunoglobulin protein designated AAand derived from a circulating serum pre-cursor SAN'. There is, therefore, no directlink between immunoglobulins and amyloidin leprosy. However, an indirect immuno-logical basis does exist in that it is frequent-ly associated with recurrent erythema no-

' Presented at the seminar on The Immunopathol-ogy of Leprosy, organized by the Indian Associationof Pathologists and Microbiologists on I December1981, at Trivandrum, Kerala, India.

Williams, R. C., Cathcart, E. C., Calkins, E., Fite,G. L., Rubio. J. 13. and Cohen, A. S. Secondary amy-loidosis in I epromatous leprosy. Possible relationshipsof diet and environment. Ann. Intern. Med. 62 (196.511000-1007.

Date, A. and Job, C. K. The prevalence of amy-loidosis in autopsy material. J. Indian NIed. Assoc. 62(1974) 287-288.

' McAdam, K. I'. W. J., Anders. R. F., Smith, S.R., Russel, D. A. and Price, NI. A. Association ofamyloidosis with erythema nodosum leprosum reac-tions and recurrent neutrophil leukocytosis in leprosy.Lancet 2 ( 1975) 572-576.

Glenner, G. C. Amyloid deposits and amyloidosis(the /3-fibrilloses). N. Engl. J. Med. 302 (1980) 1283-1292 and 1333-1343.

dosum leprosum (ENL), which is animmune complex disease". McAdam, el al.'have shown that SAA levels rise sharplyduring ENL reactions, and they suggest thatthis is secondary to the neutrophil leuko-cytosis which is also a feature of ENL. TheSAA levels are also raised in leprosy pa-tients with amyloidosis due to chronictrophic

GLOMERULONEPHRITISPrevalence. The prevalence of glomeru-

lonephritis in unselected renal biopsy andautopsy material from hospitalized patientswith leprosy is given in Table I. This tabledoes not include the earlier postmortemstudies summarized by Shwe 7 which con-tain references to "nephritis — without fur-ther specification of the type. The meanprevalence in biopsy studies is 37%. This ismuch higher than the 7% reported in autop-sy studies, and the reasons for this differ-ence undoubtedly include: a) the difficultyin identifying minor degrees of glomerularhypercellularity in autopsy material: b) anunconscious observer bias when examiningbiopsies, resulting in an over diagnosis ofglomerular abnormalities, and accountingfor the poor correlation with abnormal lab-oratory findings, and c) the fact that mostbiopsy studies were published after 1971 andreflect a greater awareness of this entity af-ter the first renal biopsy study was pre-sented'. The patients in these studies werenot selected to match the prevalence of thedifferent immunopathologic types of lep-rosy in the population from which they weretaken. Most of the patients biopsied hadlepromatous leprosy but non-lepromatousdisease is much more common in theseareas. Statistical analysis of such data tocompare the prevalence of glomerulone-

" Waters, M. F. R., Turk, J. L. and Wemambu, S.N. C. Mechanisms of reactions in leprosy. Int. J. Lepr.39 (19711 417-428.

' Shwe, T. Immune complexes in glomeruli of pa-tients with leprosy. Lepr. Rev. 42 (1972) 282-289.

Johny, K. V. and Karat, A. 13. A. Renal biopsystudies in leprosy. J. Assoc. Physicians India 19 (1971)117-118.

352^ International Journal of Leprosy^ 1982

TABLE 1. Prevalence of renal anzyloidosis and glomerulonephritis in leprosy.

Authors and year Country No.studied

Amyloidosisno. (%)

Glomerulo-nephritisno. (%)

AutopsiesKean and Childress, 1941' 2 Panama 103 4^(4%) 12 (12%)Powell and Swan, 1955 3" U.S.A. 50 19 (38%) not givenShuttleworth and Ross, 1956 34 U.S.A. 18 10 (55%) not givenJunnarkar, 1957 3 ' India (Poona) 20 I^(5%) not givenDesikan and Job, 1968 3"•" India (Vellore) 37 3^(8%) 2^(5%)Bernard and Vazquez, 1973 37 Argentina 60 19 (32%) 2^(3%)Ozaki and Furtita, 1975 30^Japan

Renal biopsies on patients unselected for renal disease

160 25 (15%) not given

Shwe, 1972' U.K.') 7 1 (14%) 2 (28%)Mittal, et al.^1972" India (Delhi) 30 0 8 (27%)eSainani and Rao, 1974 -1 " India (Nagpur) 60 1^(2%) 8 (13%)Johny, et a/.^1975• India (Vellore) 35 2^(6%) 13 (37%)Gupta, et al.^1977 32 India (Jabalpur) 50 0 3^(6%)Cologlu, 1979' 0 Turkey 20 1^(5%) 10 (50%)Peter, et al.^1981 1 " India (Calicut) 21 0 15(71%)Gupta, et al.^1981" India (Allahabad) 21 3 (14%) 13 (62%)

" Includes the cases reported by Krishnamurthy and Job'''.1) Patients mainly of Asian origin.

Glomerular hypercellularity described.'' A preliminary report on this study was presented in 1971".

phritis in different types of leprosy" istherefore not worthwhile. Glomerulone-phritis has been reported in all types of lep-rosy except for the polar tuberculoid, pureneuritic, and indeterminate types.

Light microscopy. Using standardterminology"), Table 2 lists the differenthistological types of glomerulonephritis re-ported in the studies given in Table 1 andin other studies of leprosy patients biopsiedfor clinical renal disease".^' 2 . I". 14• IS ' I" ' II .

" Ng, W. L., Scollard, D. M. and Hutt, A. Glomer-ulonephritis in leprosy. Am. J. Clin. Pathol. 76 (1981)321-329.

1 " Turner, D. R. Gionientionephriti.^). Recent Ad -

vances in Histopathology, Number 10. Anthony, P. P.and Woolf, N., eds. London: Churchill Livingstone,1978. pp. 235-257.

" Bedi, '1'. R., Kaur, S., Singhal, P. C., Kumar, B.and Banerjee, C. K. Fatal proliferative glomerulo-nephritis in lepromatous leprosy. Lepr. India 49 (1977)500-503.

Bullock, W. E., Callerame, M. L. and Partner, B.J. Immunohistologic alteration of skin and ultrastruc-tural changes of glomerular basement membranes inleprosy. Am. J. Trop. Med. Hyg. 23 (1974) 81-86.

' 3 Date, A., Neela, P. and Shastry, J. C. M. Mem-branoproliferative glomerulonephritis in a tropical en-vironment. Ann. Trop. Med. Parasitol. 77 (1983) (inpress).

I 1 Date, A., Thomas, A., Mathai, R. and Johny, K.V. Glomerular pathology in leprosy. An electron mi-

It is seen that all morphological types ofglomerulonephritis, except focal sclerosis,have been reported in leprosy. Most of thesetypes of glomerulonephritis are known orsuspected to have an immune complexetiology"'. This variety of morphological le-sions suggests a heterogenous pathogen-esis, but not necessarily different etiolo-gies, since it is well known that a singledisease like systemic lupus erythematosuscan involve the glomeruli to produce eitherdiffuse or focal, membranous or prolifera-tive, glomerulonephritis. This variety pre-sumably reflects differences in the amountand type of immune complexes present".

croscopic study. Am. J. Trop. Med. Hyg. 26 (1977)266-272.

Drutz, D. J. and Gutman, R. A. Renal manifes-tations of leprosy. Glomerulonephritis—a complica-tion of erythema nodosum leprosum. Am. J. Trop.Med. Hyg. 22 (1973) 496-502.

'" Iveson, J. M. I., McDougall, A. C., Leathern, A.J. and Harris, IL J. Lepromatous leprosy presentingwith poly arthritis, myositis and immune-complex glo-merulonephritis. Br. Med. J. 3 (1975) 619-621.

Singhal, P. C., Shush, K. S., Kaur, S. and Malik,A. K. Acute renal failure in leprosy. Int. J. I,epr. 45(1977) 171-174.

's Germuth, F. G., Jr. and Rodriguez, E. Minium,-patho/ogy of the Renal Glomerulmv. Immune ComplexDeposit and Anfibasement Membrane Disease. Bos-ton: Little, Brown and Company, 1973, pp. 209-210.

50, 3^ Editorials^ 353

TABLE 2. Morphological types of glomerulonephritis in leprosy.

I)iffuse endocapillary proliferative 7.". 1.1 • 15 •" 2." 7."" .1 " .." .." ."Diffuse mesangial proliferative"• 15 . 1 ".".."." ."Diffuse crescentic"• 17 •'sDiffuse membranous . "Diffuse mesangiocapillary"Focal proliferative'" - "Diffuse sclerosing 7 .32 .."..12.1 "Minimal change disease"•"•"

Normal histology on light microscopy, but unsampled focal proliferative lesions may have been present.

Ninth nohistochemist ry . I m mu nohi sto-chemical studies of' kidney tissue in leprosyhave shown granular deposits of IgG andC3, and less frequently IgM, IgA and fibrin,located in the glomerular mesangium and/or, along the capillary walls 7 '"' H• '`• I". Thispattern of staining is typical of an immunecomplex glomerulonephritisu'.

Ultrastructure. Electron microscopicstudies also confirm the immune complexorigin of this disease. Glomerular densedeposits have been reported in the mes-angial-subendothelial region' 2 • '4' IS orsubepithelially"' ' 4 ' 2", corresponding to theexperimental localization of small, relative-ly soluble, and large, poorly soluble com-plexes, respectively'''. This again indicatesthat different types of immune complexesare involved in the production of this con-dition. Other ultrastructural findings, suchas neutrophil leukocyte infiltration, footprocess fusion, mesangial proliferation,expansion and interposition, and base-ment membrane duplication and thick-enin_Q9.12,11,19, are secondary effects of im-mune complex deposition.

Etiological considerations. The morpho-logical evidence summarized above showsthat the glomerulonephritis occurring inleprosy is of the immune complex type. Thesource of these immune complexes is, asyet, unknown since the antigens responsi-ble have not been demonstrated in the glo-merular deposits. However, indirect evi-dence is available indicating certain possibleetiological relationships.

ENL is an immune complex disease in-volving mycobacterial antigens released by

1"Cologlu, A. S. Immune complex glomerulone-phritis in leprosy. Lepr. Rev. 50 (1979) 213-222.

2" Date, A. and Johny, K. V. Glomerular subepithe-lial deposits in lepromatous leprosy. Am. J. Trop. Med.Hyg. 24 (1975) 853-856.

breakdown of Mycobacterium leprae". ENLreactions are also accompanied by abnor-malities of renal function''• 21.22 . It wouldthus seem likely that glomerulonephritis insome patients could he a manifestation ofENL caused by deposition of mycobacte-rial antigen-antibody complexes. Such cir-culating mycobacterial antigen-antibodycomplexes have been demonstrated in manypatients with leprosy-'.

ENL is, however, not the sole cause ofglomerulonephritis in leprosy, since glo-merulonephritis often occurs in patientswithout ENL". In addition to ENL, pa-tients in the lepromatous halt' of the diseasespectrum have depressed cell-mediated im-munity (anergy) with exaggerated and un-controlled humoral immune responses''' 25 ,

resulting from loss of T cell control. Sucha situation is known to promote the devel-opment of immune complex glomerulone-phritis 2 "• 27 . Given this predisposing situa-tion, a variety of antigens may triggerimmune complex formation. Anergy would

21 Bajaj, A. K., Gupta, S. C., Sinha, S. N., Govil,D. C., Gaur, U. C. and Kumar, R. Renal functionalstatus in lepromatous leprosy. Int. J. Lepr. 49 ( 1981)37-41.

22 Thomas, G., Karat, A. B. A., Rao, P. S. S. andPrathapkumar, C. Changes in renal function duringreactive phases of lepromatous leprosy. Int. J. Lepr.38 (1970) 170-176.

2" Reed, W. P. and Williams, R. C. Immune com-plexes in infectious diseases. Adv. Intern. Med. 22(1977) 49-72.

21 Bryceson, A. D. M. Immunology of leprosy. Lepr.Rev. 47 ( 1976) 235-244.

2 ' Bullock, W. E. Anergy and infection. Adv. In-tern. Med. 21 ( 1976) 149-173.

2 " Bhat, J. G., Gombos, E. A. and Baldwin, D. S.Depressed cellular immune response to streptococcalantigens in poststreptococcal glomerulonephritis. Clin.Immunol. Immunopathol. 7 (1977) 230-239.

Hoffsten, P. E., Villalbos, R., Hill, C. and Klahr,S. T cell deficiency in immune complex glomerulo-nephritis. Kidney Int. 11 (1977) 318-326.

354^ International Journal of Leprosy^ 1982

also delay elimination of bacteria such asstreptococci and staphylococci and viralagents, such as hepatitis B virus, which arecommonly present and also well knowncauses of glomerulonephritis''' 28 ' 2" . The listof potential antigens extends even to ther-apeutic agents since dapsone-antidapsoneantibodies in circulating immune com-plexes have been reported".

Also significant are the many autoanti-bodies found in leprosy-a. 24 . Of these thebest documented are the IgG-IgM cry-()globulins which are frequently present inthe circulations and which can cause glo-merulonephritis in these patients'". Whilethe above factors are more commonly rec-ognized in patients with disease in the lep-romatous half of the immunopathologicspectrum, circulating immune complexesand a variety of autoantibodies are also fre-quent in patients with tuberculoid leprosy'.

Eknoyan, G. and Dillman, R. 0. Renal compli-cations of infectious diseases. Med. Clin. North Am.62 ( 1978) 979-1003.

2" Thyagarajan, S. P., Subramaniarn, S., Solomon,S., Panchanadam, M. and Madanagopalan, N. Inci-dence of hepatitis 13 surface antigen and antibody inpatients with liver diseases, blood donors and leprosypatients—a preliminary report. Indian J. Med. Res. 67(1978) 528-534.

"" Das, P. K., Klatser, P. R., 1 40[1(1m:in, K. W., Ilui-keshoven, H., Landheer, J. E., Leiker, D. L. and Rees,R. J. Dapsone and anti-dapsone antibody in circulatingimmune complexes in leprosy patients. Lancet I ( 1980)131)9-131 I .

"' Nuti, NI., D'Amelio, R., Seminara. R.. Milano,C. F., Palmisano, L. and Aiuti, F. Circulating immunecomplexes detected by Clq solid phase assay in lep-rosy. Int. J. Lepr. 49 (1981) 27-3(l.

" 2 Kean, 13. H. and Childress, M. E. A summary of1(13 autopsies on leprosy patients on the Isthmus ofPanama. Int. J. Lepr. 111 11942) 51-59.

"" Powell, C. S. and Swan, L. L. Leprosy: Patho-logical changes observed in fifty consecutive necrop-sies. Am. J. Pathol. 31 )1955) 1131-1147.

Shuttleworth, J. S. and Ross, Sister Hilary. Sec-ondary amyloidosis in leprosy. Ann. Intern. Med. 45(1956) 23-28.

"' Junnarkar, R. V. Late lesions in leprosy. Lepr.India 29 (1957) 148-154.

Immune complex glomerulonephritis inleprosy may therefore have a multifactorialorigin. The antigens involved could eitherbe mycobacterial and specific to leprosy, ornon-mycobacterial, exogenous antigens andautoantigens which also cause glomerulo-nephritis in patients without leprosy. De-pressed T cell function with exaggerated Bcell activity present in some patients wouldalso favor development of immune complexglomerulonephritis. This multifactorial ori-gin is reflected in the variety of morpholog-ical expressions of this condition.

—Anand Date, M.B., B.S., M.D.Pr(lessor, Department of PathologyChristian Medical College HospitalVellore 632 00-1, Tamil NaduIndia

Desikan, V. K. and Job, C. K. A review of post-mortem findings in 37 cases of leprosy. Int. J. Lepr.36 (1968) 32-44.

"' Bernard, J. C. and Vazquez, C. A. J. Viscerallesions in lepromatous leprosy. Study of sixty necrop-sies. Int. J. Lepr. 41 (1973) 94-101.

"" Ozaki, NI. and Furuta, M. Amyloidosis in leprosy.Int. J. Lepr. 43 (1975) 116-124.

"" NIittal, M. NI., Agarwal, S. C., Maheswari, H. B.and Kumar, S. Renal lesions in leprosy. Arch. Pathol.93 (1972) 8-12.

'" Sainani. G. S. and Rao, K. V. N. Renal changesin leprosy. J. Assoc. Physicians India 22 (1974) 659-664.

" Johny, K. V.. Karat, A. B. A., Rao, P. S. S. andDate, A. Glomerulonephritis in leprosy—a percuta-neous renal biopsy study. Lepr. Rev. 46 (1975) 29-37.

'' Gupta, J. C., Diwakar, R., Singh, S.. Gupta, 0.K. and Panda. P. K. A histopathological study of renalbiopsies in fifty cases of leprosy. Int. J. Lepr. 45 (1977)167-170.

4" Peter, K. S., Vijayakumar, T., Vasudevan, D. M.,Leena Devi, K. R., Mathew, M. T. and Gopinath,Renal involvement in leprosy. Lepr. India 53 (1981)163-178.

11 Gupta, S. C., Bajaj, A. K., Govil, D. C., Sinha.S. N. and Kumar, R. A study of percutaneous renalbiopsy in leprommons leprosy. Lepr. India 53 (1981)179-184.

Krishnamurthy, S. and Job, C. K. Secondaryamyloidosis in leprosy. Int. J. Lepr. 34 (1966) 1.55-158.