Clinical Investigation

Kidney International (1984) 25, 689–695; doi:10.1038/ki.1984.75

Diffuse proliferative lupus nephritis: Identification of specific pathologic features affecting renal outcome

Howard A Austin III, Larry R Muenz, Kathleen M Joyce, Tatiana T Antonovych and James E Balow

Clinical Nephrology Service and Arthritis and Rheumatism Branch, National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases; Clinical and Diagnostic Trials Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and the Nephropathology Section, Armed Forces Institute of Pathology, Washington, D.C.

Correspondence: Dr H A Austin III, Department of Health and Human Services, National Institutes of Health, Building 10, Room 3N-116, Bethesda, Maryland 20205, USA

Received 13 May 1983; Revised 29 September 1983.

Top

Abstract

Diffuse proliferative lupus nephritis: Identification of specific pathologic features affecting renal outcome. Prerandomization renal biopsy specimens were examined in 102 patients upon entry into prospective therapeutic trials of lupus nephritis in an attempt to identify early predictors of renal failure outcome. All 11 renal failures occurred among the 72 individuals with diffuse proliferative or membranoproliferative glomerulonephritis (DPGN/MPGN); thus, these patients were at modestly, but significantly, increased risk of endstage renal disease compared to those with focal proliferative, membranous, or mesangial glomerulonephritis. Considering the low incidence of endstage renal disease among patients with DPGN/MPGN, we sought to refine the prognostic information obtained from renal morphology by semiquantitative scoring of individual histologic features and by derivation of composite histologic scores specified by Activity (AI) and Chronicity (CI) Indices. Among the 72 patients with DPGN/MPGN, the composite AI was more strongly predictive of renal failure than were the individual active histologic features; cellular crescents and extensive fibrinoid necrosis yielded positive associations, while endocapillary proliferation, leucocytic exudation, and hyaline thrombi in glomeruli and interstitial inflammation by themselves did not emerge as useful prognostic indicators. However, chronicity items (glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis) considered individually, as well as in the composite CI, were highly predictive of renal failure outcome. Particularly striking was the prognostic value of tubular atrophy; all 11 renal failures were among the 43 patients with tubular atrophy on prerandomization renal biopsy. While no single pathologic variable improved outcome predictions among those with tubular atrophy, examination for interactions among variables revealed that glomerular sclerosis and cellular crescents had a synergistic effect which augmented the prognostic information derived from analysis of tubular atrophy alone. Thus, the simultaneous occurrence of tubular atrophy, glomerular sclerosis, and cellular crescents identified a very high-risk group; six of nine patients progressed to endstage renal disease within 4 years of study entry. In conclusion, semiquantitative scoring of individual histologic features can refine estimates of the risk of renal failure in lupus patients with DPGN or MPGN.

Néphrite lupique proliférative diffuse: Identification de caractéristiques pathologiques spécifiques affectant l'évolution rénale. Les spécimens biopsies rénales de 102 malades avant randomisation ont été examinées à l'entrée dans des essais thérapeutiques prospectifs de la néphrite lupique, destinés à identifier les facteurs prédictifs précoces de survenue d'une insuffisance rénale. La totalité des 11 insuffisances rénales est survenue parmi les 72 sujets atteints d'une glomérulonéphrite diffuse proliferative ou membrano-proliférative (DPGN/MPGN); ainsi, ces malades avaient un risque modérément, mais significativement, accru de néphropathie terminale, par rapport à ceux atteints d'une glomérulonéphrite proliférative focale, extramembraneuse ou mésangiale. En considérant la faible incidence d'une néphropathie terminale parmi les patients atteints de DPGN/MPGN, nous avons cherché à affiner l'information pronostique obtenue à partir de la morphologie rénale par un score semiquantitatif des caractéristiques histologiques individuelles et par des scores histologiques composites dérivés spécifiés par des Index d'Activité (AI) et de Chronicité (CI). Parmi les 72 malades atteints de DPGN/MPGN, G AI composite était plus fortement prédictif d'une insuffisance rénale que les caractéristiques histologiques actives individuelles; les croissants cellulaires et une nécrose fibrinoïde étendue donnaient des associations positives, alors que la prolifération endocapillaire, l'exsudation leucocytaire et des thrombus hyalins dans les glomérules, ainsi que l'inflammation interstitielle en eux-mêmes, n'apparaîssaient pas comme des indicateurs utiles de pronostic. Cependant, les items de chronicité (sclérose glomérulaire, croissants fibreux, atrophie tubulaire, et fibrose interstitielle) considáerés individuellement, ainsi que dans le CI composite, étaient hautement prédictifs de la survenue d'une insuffisance rénale. Particulièrement frappante était la valeur pronostique de l'atrophie tubulaire; les 11 insuffisances rénales étaient parmi les 43 malades ayant une atrophie tubulaire à la biopsie ráenale prérandomisation. Alors qu'aucune variable pathologique isolée n'améliorait les prédictions sur le devenir parmi ceux atteints d'atrophie tubulaire, l'examen des interactions entre variables a révélé que la sclérose glomérulaire et les croissants cellulaires avaient un effet synergistique qui augmentait l'information pronostique obtenue à partir de l'analyse de l'atrophie tubulaire seule. Ainsi, l'apparition simultanée d'une atrophie tubulaire, d'une sclérose glomérulaire et de croissants cellulaires identifiait à un groupe à très haut risque; six de neuf malades ont progressé vers une néphropathie terminale dans les quatre ans suivant l'entrée dans l'étude. En conclusion, un score semiquantitatif des caractéristiques histologiques individuelles peut raffiner les estimations du risque d'insuffisance rénale chez des malades lupiques atteints de DPGN ou de MPGN.

Top

References

  1. Pollak VE, Pirani CL, Kark RM: Effect of large doses of prednisone on the renal lesions and life span of patients with lupus glomerulonephritis. J Lab Clin Med 57:495–511, 1961
  2. Pollak VE, Pirani CL, Schwartz FD: The natural history of the renal manifestations of systemic lupus erythematosus. J Lab Clin Med 63:537–550, 1964 | PubMed | ISI | ChemPort |
  3. Baldwin DS, Lowenstein J, Rothfield NF, Gallo G, McCluskey RT: The clinical course of the proliferative and membranous forms of lupus nephritis. Ann Intern Med 73:929–942, 1970 | PubMed | ISI | ChemPort |
  4. Zweiman B, Kornblum J, Cornog J, Hildreth EA: The prognosis of lupus nephritis. Role of clinical-pathologic correlations. Ann Intern Med 69:441–453, 1968
  5. Estes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine 50:85–95, 1971 | PubMed | ChemPort |
  6. Cheatum DE, Hurd ER, Strunk SW, Ziff M: Renal histology and clinical course of systemic lupus erythematosus: a prospective study. Arthritis Rheum 16:670–676, 1973 | PubMed |
  7. Baldwin DS, Gluck MC, Lowenstein J, Gallo G: Lupus nephritis: clinical course as related to morphologic forms and their transitions. Am J Med 62:12–30, 1977 | Article | PubMed | ISI | ChemPort |
  8. Appel GB, Silva FG, Pirani CL, Meltzer JI, Estes D: Renal involvement in systemic lupus erythematosus (SLE): a study of 56 patients emphasizing histologic classification. Medicine 57:371–410, 1978 | PubMed | ISI | ChemPort |
  9. Hecht B, Siegel N, Adler M, Kashgarian M, Hayslett JP: Prognostic indices in lupus nephritis. Medicine 55:163–181, 1976
  10. Fish AJ, Blau EB, Westberg NG, Burke BA, Vernier RL, Michael AF: Systemic lupus erythematosus within the first two decades of life. Am J Med 62:99–117, 1977
  11. Fries JF, Porta J, Liang MH: Marginal benefit of renal biopsy in systemic lupus erythematosus. Arch Intern Med 138:1386–1389, 1978
  12. Cameron JS, Turner DR, Ogg CS, Williams DG, Lessof MH, Chantler C, Leibowitz S: Systemic lupus with nephritis: a longterm study. Q J Med 48:1–24, 1979 | PubMed | ChemPort |
  13. Ballou S, Chung-Park M, Waggoner DM, Kushner I: Prognostic value of clinical and renal biopsy findings in lupus nephritis (abstract). Clin Res 28:339A, 1980
  14. Wallace DJ, Podell TE, Weiner JM, Cox MB, Klinenberg JR, Forouzesh S, DuBois EL: Lupus nephritis: experience with 230 patients in a private practice from 1950 to 1980. Am J Med 72:209–220, 1982
  15. Whiting-O'Keefe Q, Henke JE, Shearn MA, Hopper J, Biava CG, Epstein WV: The information content from renal biopsy in systemic lupus erythematosus: step-wise linear regression analysis. Ann Intern Med 96:718–723, 1982 | PubMed | ChemPort |
  16. Decker JL, Steinberg AD, Reinertsen JL, Plotz PH, Balow JE, Klippel JH: Systemic lupus erythematosus: evolving concepts. Ann Intern Med 91:587–604, 1979
  17. Balow JE: Therapeutic trials in lupus nephritis: problems related to renal histology, monitoring of therapy and measures of outcome. Nephron 27:171–176, 1981
  18. Steinberg AD, Kaltreider HB, Staples PJ, Goetzl EJ, Talal N, Decker JL: Cyclophosphamide in lupus nephritis: a controlled trial. Ann Intern Med 75:165–171, 1971 | PubMed | ISI | ChemPort |
  19. Steinberg AD, Decker JL: A double-blind controlled trial comparing cyclophosphamide, azathioprine and placebo in treatment of lupus glomerulonephritis. Arthritis Rheum 17:923–937, 1974
  20. Decker JL, Klippel JH, Plotz PH, Steinberg AD: Cyclophosphamide or azathioprine in lupus glomerulonephritis: a controlled trial: results at 28 months. Ann Intern Med 83:606–615, 1975
  21. Dinant HJ, Decker JL, Klippel JH, Balow JE, Plotz PH, Steinberg AD: Alternative modes of cyclophosphamide and azathioprine therapy in lupus nephritis. Ann Intern Med 96:728–736, 1982
  22. Carette S, Klippel JH, Decker JL, Austin HA, Plotz PH, Steinberg AD, Balow JE: Controlled studies of oral immunosuppressive drugs in lupus nephritis: a long-term follow-up. Ann Intern Med 99:1–8, 1983 | PubMed | ChemPort |
  23. Austin HA, Muenz LR, Joyce KM, Antonovych TT, Kullick ME, Klippel JH, Decker JL, Balow JE: Prognostic factors in lupus nephritis: contribution of renal histology. Am J Med 75:382–391, 1983 | Article | PubMed | ISI |
  24. Cohen AS, Reynolds WE, Franklin EC, Kulka JP, Ropes MW, Shulman LE, Wallace SL: Preliminary criteria for the classification of systemic lupus erythematosus. Bull Rheum Dis 21:643–648, 1971
  25. McCluskey RT: Lupus nephritis, in Pathology Decennial, edited by Sommers SC, New York, Appleton-Century-Crofts, 1975, pp 435–460
  26. Pirani CL, Salinas-Madrigal L: Evaluation of percutaneous renal biopsy. Pathol Annu 3:249–296, 1968
  27. Pirani CL, Pollak VE, Schwartz FD: The reproducibility of semiquantitative analyses of renal histology. Nephron 1:230–237, 1964
  28. Donadio JV, Holley KE, Wagoner RD, Ferguson RH, McDuffie FC: Treatment of lupus nephritis with prednisone and combined prednisone and azathioprine. Ann Intern Med 77:829–835, 1972
  29. Morel-Maroger L, Mery JP, Droz D, Godin M, Verroust P, Kourilsky O, Richet G: The course of lupus nephritis: contribution of serial renal biopsies. Adv Nephrol 6:79–118, 1976
  30. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 34:585–612, 1976 | PubMed | ISI | ChemPort |
  31. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35:1–39, 1977 | PubMed | ISI | ChemPort |
  32. Lee EL: Statistical Methods for Survival Data Analysis. Belmont, California, Wadsworth, 1980, pp 75–154
  33. Cox DR, Hinkley DV: Theoretical Statistics. London, Chapman and Hall, 1974, p 315
  34. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958 | Article | ISI |
  35. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52:203–223, 1965 | PubMed | ISI | ChemPort |
  36. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170, 1966 | PubMed | ChemPort |
  37. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, John Wiley and Sons, 1980, p 15
  38. Cox DR: Regression models and life tables (with discussion). Royal Stat Soc, Series B 34:187–220, 1972
  39. Muehrcke RC, Kark RM, Pirani CL, Pollak VE: Lupus nephritis: a clinical and pathological study based on renal biopsies. Medicine 35:1–145, 1957
  40. Striker GE, Kelly MR, Quadracci LJ, Scribner BH: The course of lupus nephritis: a clinical-pathological correlation of fifty patients, in Glomerulonephritis, edited by Kincaid-Smith P, Mathew T, Becker EL, New York, John Wiley and Sons, 1973, pp 1141–1166
  41. Mahajan SK, Ordonez NG, Spargo BH, Katz AI: Changing histopathology patterns in lupus nephropathy. Clin Nephrol 10:1–8, 1978
  42. Comerford RF, Cohen AS: The nephropathy of systemic lupus erythematosus: an assessment by clinical, light and electron microscopic criteria. Medicine 46:425–473, 1967
  43. Nanra RS, Kincaid-Smith P: Lupus nephritis: clinical course in relation to treatment, in Glomerulonephritis edited by Kincaid-Smith P, Mathew TH, Becker EL, New York, John Wiley and Sons, 1973, pp 1193–1210
  44. Hill GS, Hinglais N, Tron F, Bach J-F: Systemic lupus erythematosus: morphologic correlations with immunologic and clinical data at the time of biopsy. Am J Med 64:61–79, 1978
  45. Ehrenreich J, Churg J: Pathology of membranous nephropathy. Pathol Ann 3:145–186, 1968

Extra navigation

.
ADVERTISEMENT