| Abstract|| |
A significant proportion of individuals with systemic lupus erythematosus (SLE) will have clinical or laboratory evidence of renal involvement at some point in the course of their disease. Lupus nephritis (LN) is one of the more important systemic manifestations of SLE and although progression to end-stage renal disease (ESRD) is not usually the norm, a significant minority of patients will do so, some in a rather dramatic fashion. It is in such instances that LN constitutes a true nephrologic emergency. Gratifyingly, it is rarely a silent emergency and heightened awareness amongst clinicians about its unpredictable course should lead to earlier recognition and intervention. For this reason, a case of LN presenting with historical and histologic evidence of chronic kidney disease and superimposed, acute acceleration of renal function decline, leading rapidly to ESRD is reported here. A brief review of the literature surrounding the pathophysiologic mechanisms, clinicopathologic characteristics and current therapeutic approaches to LN is subsequently explored.
|How to cite this article:|
Komolafe OO. Rapidly progressive glomerulonephritis: A wild card manifestation of lupus nephritis. Saudi J Kidney Dis Transpl 2018;29:443-51
|How to cite this URL:|
Komolafe OO. Rapidly progressive glomerulonephritis: A wild card manifestation of lupus nephritis. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2020 Sep 28];29:443-51. Available from: http://www.sjkdt.org/text.asp?2018/29/2/443/229293
| Case Report|| |
A 24-year-old African female presented to the medical outpatient department with complaints of persistent, worsening fatigue, and recurrent episodes of diurnal facial and leg swelling over the previous year. Within this time frame, she had been admitted on four separate occasions into various other hospitals due to the aforementioned symptoms. During one of the admissions, she received a unit of whole blood for unexplained anemia. She had not observed any reduction in her daily urine volume although her urine had become frothy in recent months. There were no nocturia and no visible hematuria. She volunteered a history of nausea and occasional vomiting in recent weeks. The episodes of vomiting were often times, unrelated to meals. Review of systems was negative for symptoms referable to hepatic or cardiac disease; however, she was noted to have a three-month history of amenorrhea. She had no history of joint pains, skin rash, or hair loss. There was no history of fever or photosensitive skin lesions. She had not been on any routine prescription or over-the-counter medication. She did not report taking herbal remedies or supplements. In the past four days, her symptoms appeared to be getting worse, necessitating her presentation to hospital. At her initial evaluation, significant findings were mild facial puffiness, conjunctival pallor, bilateral ankle edema, and sacral edema. Apart from evidence of early hair thinning, examination of the skin and integuments was unremarkable. Her pulse rate and blood pressure were 88 beats per minute and 130/90 mm Hg, respectively. Baseline laboratory investigations were requested and she was asked to return for a follow-up visit in a week's time. At her second visit, her hitherto requested investigations revealed marked azotemia and severe anemia [Table 1]. On account of these findings, she was admitted into hospital with a working diagnosis of complicated nephrotic syndrome for further management and supportive blood transfusions. During the course of admission, she had several sessions of hemodialysis due to persistently rising urea and creatinine. She had a stormy clinical course characterized by severe refractory hypertension and worsening oligoanuria. Ultrasound findings were nonspecific indicating bilaterally normal renal sizes, position, and outline with reduction in corticomedullary distinction. A moderate amount of echo-free intraperitoneal fluid was noted. There were no features of urinary tract obstruction, and the uterus was empty. Based on renal biopsy findings, it was suspected that her primary renal pathology could be proliferative lupus nephritis (LN) [Figure 1] and [Table 2] in view of light microscopy findings which showed three of 12 sampled glomeruli with global sclerosis, one of which had a partial cellular crescent. The remaining nine glomeruli had segmental sclerosis. Visible glomerular capillary loops showed a moderate increase in mesangial matrix and cells with occasional wire loop-like lesions. Tubules had evidence of mild focal inflammation and patchy tubular atrophy. Mild-to- moderate edema of the interstitium was seen, with patchy cell infiltrate and patchy fibrosis. Blood vessels were unremarkable. All of the six glomeruli processed for immunofluore- scence microscopy showed IgA, IgG, IgM, C3, C1q, kappa, and lambda staining in a coarse, granular mesangial pattern as well as along capillary walls. Autoimmune serology results were confirmatory of systemic lupus erythematosus (SLE). Medications received during admission include antihypertensive therapy, pulsed intravenous (IV) methylpredni- solone, and oral prednisolone. Consent could not be secured for cyclophosphamide induction therapy; furthermore, financial constraints made mycophenolate mofetil inaccessible to the patient. About two months after presentation, she was determined to be dialysis dependent and went on to have a successful renal transplant at another center.
|Figure 1: Renal histopathology slides - Findings correspond to lupus nephritis Class IV(S) A/C. (ISN/RPS 2004)*|
(a) Low-power view showing three glomeruli with segmental sclerosis and mild leukocyte infiltration
(b) High-power view showing glomerulus with partial crescent formation
(c) High-power view showing glomerulus with partial crescent formation between 5 and 7 o'clock
(d) High-power view of a glomerulus showing several wire loop lesions representing extensive subendothelial deposits of immune complexes
(e) and (f) “full-house” immunofluorescence staining in a coarse, granular pattern within mesangium and along capillary walls.
‡International Society of Nephrology (ISN)/Renal pathology Society (RPS) criteria.
*Weening JJ, D'Agati VD, Appel GB et al. The classification of glomerulonephritis in systemic lupus nephritis. Kidney Int 2004;65:521-30.
Click here to view
|Table 2: Activity-chronicity index*. Each of the above histological appearances is scored using integer values on an incremental scale from 0 to +3, (i.e., 0, +1, +2, or +3) depending on the degree to which it is present. The findings of fibrinoid necrosis/karyorrhexis and/or cellular crescents are, however, given weighted double scores (i.e., assigned score is multiplied by 2) because of their more ominous prognostic importance.|
Click here to view
| Discussion|| |
Incrementally detailed descriptions of the clinical condition that would later become known as SLE began since the times of Hippocrates of Cos., SLE is diagnosed in the presence of greater than 3 American College of Rheumatology criteria.
A role for genetic factors in the etiopathogenesis of lupus is suggested by the observance of racial predilection (most common among individuals of Afro-Caribbean and Asian extraction), familial clustering, and high concordance rates in monozygotic twins. Its disproportionate gender bias for females between the second and fourth decades highlights the potential influence of sex hormones in its occurrence.
LN refers to involvement of the kidneys in a patient with SLE. The first reference to renal involvement in lupus was made by Sequira and Balean in the early 20th century. LN could be the initial clinical presentation of SLE, although much of the time this is not so. Conversely, however, evidence of renal involvement can be found in up to 50% of individuals within three years of being diagnosed with SLE.
As with SLE, the natural history of LN is characterized by periods of overt exacerbations referred to as “flares” that are interspersed with stretches of relative disease quiescence. Not uncommonly, however, even in those periods of apparent clinical remission, or in patients without detectable symptoms or laboratory abnormalities, underlying subclinical, smoldering biologic disease activity can be ongoing which itself can be quite destructive in the long term.
The primary driver for SLE is a failure of recognition and consequent loss of tolerance to self-antigens, resulting in an antibody response toward them and formation of immune complexes. Defects in apoptosis are thought to play a major role in the pathogenesis of SLE such that failure of effective clearance of apoptotic debris leads to nucleosomal and other cellular proteins being engulfed by circulating B-cells, these proteins are processed, and the resultant peptides are presented to histone-specific CD4+ cells which in conjunction with appropriate co-stimulatory signals lead to cytokine-dependent autoreactive B-cell activation with autoantibody production.,
The main targets of these autoantibodies are intracellular nucleic acids, nucleosomes including DNA histone as well as nuclear and cytoplasmic ribonucleoproteins. It is the presence of these antibodies that form the basis of serologic testing for antinuclear antibodies (ANA), anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies, and antiribo-nucleoprotein (anti-RNP) antibodies among others.
Other explanations that have been adduced for the pathogenesis of SLE include persistence into adulthood of autoreactive T-cells that escape embryonic thymic deletion, antigenic mimicry by viral or bacterial peptides with subsequent cross-reactivity involving self-antigens, and unrestricted polyclonal B-cell stimulation from superantigens leading to the proliferation of pathogenic autoantibodies among others.
Specifically, LN results from deposition of circulating or locally formed immune complexes within the glomeruli (commonly its subendothelial region) and mesangium. The presence of these immune deposits triggers a response characterized by recruitment of inflammatory cells, generation of cytokines, neutrophil-induced oxidant injury, and consumption of complement. Ongoing chemokine-mediated inflammation within the tubulo-interstitial space further induces activation and proliferation of fibroblasts alongside increased synthesis of extracellular matrix and other changes associated with chronicity the net result of which is varying degrees of renal damage.
The clinical presentation of LN is often heterogeneous and could include in any combination, asymptomatic urine abnormalities, an acute nephritic syndrome, nephrotic syndrome or chronic kidney disease. Indeed, in certain individuals (as in the index case), LN runs a rampaging course, typified by rapidly progressive glomerulonephritis (RPGN) and leading quickly to end-stage renal disease (ESRD). It has been estimated that up to 30% of cases of active LN result in RPGN.
RPGN is a clinical syndrome, the hallmark of which is a rapid loss of renal function and potentially leading to ESRD, within weeks to months. RPGN often portends a poor renal prognosis, particularly if it is not recognized and treated early. Very often, however, even when it is identified and treated expeditiously, no ironclad guarantees exist for reversal of the disease process or restoration of glomerular filtration rate (GFR) to normal values.
Crescentic glomerulonephritis is the usual histologic correlate of RPGN. While the term, crescentic glomerulonephritis, is an elegant description of this pattern of glomerular inflammation, the clinical implications of the finding are far less flattering. In 1914, Volhard and Fahr recognized the association between severe renal failure and the microscopic finding of glomerular crescents. Ellis in 1942 provided pictorial insight and further characterization of this aggressive kind of glomerulonephritis. Crescents are defined by the presence of two or more layers in the Bowman's space and they are a reflection of severe glomerular injury. Scanning electron microscopy images provide clear evidence to show that perforation of the glomerular basement membrane (GBM) is the initiating event that is central to the process of crescent formation. The structural disruption of the GBM barrier permits spillage of glomerular contents into Bowman's space with consequent activation of coagulation factors including fibrin, generation of a cytokine response, and recruitment of inflammatory cells culminating in the proliferation of glomerular epithelial cells within Bowman's space. Continued cellular proliferation tends to occlude the Bowman's space with dramatic and often dire consequences on renal function. Crescentic glomerulonephritis may not be an uncommon occurrence in LN. In Thailand, Sumethkul et al found that LN was implicated in 51.6% of specimens with biopsy-proven rapidly progressive crescentic glomerulonephritis over a six-year period. The propensity to discount the contribution of lupus nephritis to cases of RPGN probably stems both from the inherently arbitrary natural history of LN as well as the widely held age-old paradigm that lupus nephritis may be an infrequent cause of RPGN. The latter likely reinforced by findings of Jennette and colleagues’ seminal study in which histologic patterns from over 6000 renal biopsies analyzed at the University of North Carolina nephropathology laboratory were reviewed. Their results showed that crescent formation was a finding in 95% of patients with anti-GBM, 90% of those with anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis and in only 40% of patients with Class III and IV lupus nephritis. While the finding of anti-GBM disease and ANCA associated glomerulonephritis accounting for the overwhelming proportion of cases of crescentic glomerulonephritis in this study may hold true for their study population which was comprised largely of Caucasians (whom are well- known to have a higher prevalence of these two conditions), it could be misleading to extrapolate this trend to other populations, particularly in Africa and Asia who in contrast may have a relatively higher prevalence of SLE. Furthermore, Jennette acknowledges that there may have been an underrepresentation of LN as a cause of crescentic glomerulonephritis in his series because SLE patients with clinically benign-appearing renal disease were more likely not to have been subjected to renal biopsy. In this patient, although the renal pathologist reported “early crescent formation in one glomerulus,” a follow-up biopsy (which was not done) would likely have demonstrated more extensive glomerular involvement in keeping with her clinical course.
Clinically, LN patients could present with peripheral edema, elevated systemic blood pressure, or other standard features of renal failure, depending on the stage of kidney disease. Proteinuria is almost invariably present in patients with LN, and in active cases, the urine sediment has been described as “telescopic” implying the presence of the full range of cells and casts. Varying degrees of elevation in creatinine may also be seen. Anemia and/or pancytopenia may be evident from hematologic workup, and serology will confirm the presence of autoantibodies, mainly ANA, anti-dsDNA, anti-RNP, and anti-Smith. In particular, rising anti-ds DNA titers and hypocomplementemia (C3 and C4) have long been noted to be useful indicators of a LN flare. Antiphospholipid antibodies may be found in a proportion of patients with LN/SLE and their presence confers an increased risk of vascular thrombosis which could also involve both small and large renal vessels. Renal sonographic findings in LN are relatively nonspecific. Although an invasive procedure, renal biopsy is a nearly indispensable requirement in SLE patients with laboratory evidence of LN because it has important therapeutic and prognostic implications. The erstwhile WHO classification of LN has been superseded by the International Society of Nephrology (ISN)/Renal Pathology Society (RPS) criteria due to greater utility of the later. The histologic appearances in LN are highly pleomorphic; nevertheless, the presence of “full- house” IgG, IgA, IgM, C1q, and C3 staining on immunofluorescence is highly suggestive of LN. Electron microscopy, where available, will also confirm the presence of electron-dense deposits mainly in subendothelial and mesangial locations. Intramembranous or sub-epithelial deposits may also be visible. Histologic class transformation is a common occurrence that may mandate follow-up biopsies.
Traditionally, patients with ISN/RPS Class III or IV lesions required initial induction therapy consisting of pulsed IV methylpredni-solone and IV cyclophosphamide to forestall their high risk of progression to ESRD. This is then followed with a maintenance phase during which oral immunosuppressants are administered. This regimen, due to its employment of cytotoxic agents, has for decades posed a therapeutic dilemma to clinicians because of the well-known immediate and long-term effects of their use particularly in younger patients. More recent reports support the use of newer agents such as mycophegnolate mofetil and azathioprine which have comparable efficacy and kinder safety profiles. In like manner, a convincing case can be made for the use of calcineurin inhibitors.
Insights garnered from ongoing research into the pathophysiologic origins of SLE will likely lead to the development of safer, more effective “bespoke” agents as against the more “broad-spectrum” ones in the current use. Toward this end, various molecular therapeutic targets are being identified. Experimental work has focused on B-cell depletion therapy, B-cell tolerization, anti-B-cell survival factor molecules (belimumab and blisibimod), modulation of costimulatory molecules (abatacept), anticytokine agents, anti-C5 monoclonal antibodies, synthetic endocannabinoids (resunab), nonimmunosuppressant immunomodulatory peptides (dalazatide and rigerimod), interferon blockers (anifrolumab), IV immunoglobulin, immunoablation, and peripheral blood stem cell transplantation.
Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown some promise in the treatment of refractory proliferative LN. Consideration also has to be given to the accessibility and affordability of newer agents.
Standard approaches to the management of glomerulopathies, in general, must not be overlooked; these include dietary protein restriction, use of angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers, optimal glycemic control and blood pressure control as well as avoidance of potential nephrotoxins. Cardiovascular risk reduction strategies must be judiciously implemented. Osteoporosis prophylaxis with calcium and Vitamin D should be instituted bearing in mind that the majority of patients will require long-term, albeit low-dose oral glucocorticoid therapy. There is good evidence that with appropriate monitoring, daily hydroxychloro-quine is beneficial in maintaining disease quiescence.
Adverse prognostic indices that have been identified in patients with LN include Afro-Caribbean descent, high disease activity on biopsy specimens, presence of crescents, higher baseline creatinine, greater baseline protei- nuria, younger age (<24 years), elevated blood pressure, delay in therapy, and low-socio-economic status.
The patient in this case report was classified as ISN/RPS Class IV (s) A/C signifying a diffuse segmental proliferative nephritis with presence of active and chronic lesions. Her NIH activity and chronicity index scores were 7/24 and 6/12, respectively.
Arguably, all of the aforementioned adverse prognostic factors were present in our patient. Notably, limitations within an under-resourced practice environment led to delays in making a definitive diagnosis of her primary renal disease as samples for autoimmune serology as well as renal biopsy specimens had to be outsourced to reference laboratories in South Africa and India, respectively.
Individuals with LN who progress to ESRD have similar survival with both dialysis modalities and comparable postrenal transplant outcomes as ESRD patients from other causes.
| Conclusion|| |
Sometimes, unpredictable course of LN mandates prompt and thorough evaluation of all known patients with LN who present in the acute setting. In individuals with clinicopathologic evidence of severe, proliferative LN, an active approach to treatment balancing the risks of side effects using conventional agents with tangible cost concerns attributable to application of newer immunosuppressants is required to prevent irreversible loss of renal function. In all patients with SLE, periodic surveillance for evidence of LN is required as early detection of renal involvement and institution of renoprotective strategies will likely improve renal prognosis. In this regard, a strong therapeutic alliance together with patient education on the importance of adherence to therapy and follow-up visits will yield significant benefits. Hopefully, in the near future, novel therapies for SLE/LN will be available that can achieve disease suppression with minimal side effects.
| Acknowledgement|| |
My gratitude goes to Consultant Pathologist, Dr. Shailesh Soni (MD, PDCC, MBA, IFCAP) and his team at the pathology department of Muljibhai Patel Urological Hospital (MPUH), Nadiad, India for their kind assistance in processing and interpreting the renal biopsy specimens. Thanks also to Consultant Pathologist, Dr. Ikechukwu Nweke (FMCPath), for his help in annotating the images.
Conflict of interest: None declared.
| References|| |
Smith CD, Cyr M. The history of lupus erythematosus. From Hippocrates to Osler. Rheum Dis Clin North Am 1988;14:1-4.
Fatovic-Ferencic S, Holubar K. Early history and iconography of lupus erythematosus. Clin Dermatol 2004;22:100-4.
American College of Rheumatology 1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematosus. Available from: http://www.tinyurl.com/1997SLEcriteria
. [Last accessed on 2017 Jan 02]
Lim SS, Drenkard C. The epidemiology of lupus. In: Wallace DJ, Hahn BH, editors. Dubois’ Lupus Erythematosus and Related Syndromes. 8th ed. Philadelphia, PA: Elsevier Saunders; 2013. p. 438-54.
Cameron JS. Lupus nephritis. J Am Soc Nephrol 1999;10:413-24.
Grimaldi CM. Sex and systemic lupus erythematosus: The role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells. Curr Opin Rheumatol 2006;18:456-61.
Sequira JH, Balean H. Lupus erythematosus: A clinical study of seventy one cases. Br J Dermatol 1902;14:367-9.
Feldman CH, Hiraki LT, Liu J, et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with medicaid coverage, 2000-2004. Arthritis Rheum 2013;65:753-63.
Vargas-Arenas RE, Tapanes F, Daboin I, et al. Silent lupus nephritis. Immunologia 2004;23: 278-83.
Stuart L, Hughes J. Apoptosis and autoimmunity. Nephrol Dial Transplant 2002;17:697-700.
Jacobi AM, Diamond B. Balancing diversity and tolerance: Lessons from patients with systemic lupus erythematosus. J Exp Med 2005;202:341-4.
Waldman M, Madaio MP. Pathogenic autoantibodies in lupus nephritis. Lupus 2005;14: 19-24.
Appel GB, Cameron JS. Lupus nephritis. In: Feehally J, Floege J, Johnson RJ, editors. Comprehensive Clinical Nephrology. 3rd ed. Philadelphia, PA: Mosby Elsevier; 2007. p. 291-303.
Volhard F, Fahr T. Die brightschenierenkrankheit: Klink, pathologic und atlas. Berlin: Springer; 1914. p. 300.
Ellis A. Natural history of Bright's disease: Clinical, histological and experimental observations. Lancet 1942;1:1-7.
Bonsib SM. Glomerular basement membrane necrosis and crescent organization. Kidney Int 1988;33:966-74.
Tipping PG, Kitching AR, Cunningham MA, Holdsworth SR. Immunopathogenesis of crescentic glomerulonephritis. Curr Opin Nephrol Hypertens 1999;8:281-6.
Sumethkul V, Chalermsanyakorn P, Changsirikulchai S, Radinahamed P. Lupus nephritis: A challenging cause of rapidly progressive cre- scentic glomerulonephritis. Lupus 2000;9:424-8.
Couser WG. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms and therapy. Am J Kidney Dis 1988; 11:449-64.
Jennette JC. Crescentic glomerulonephritis. In: Jennette JC, Olson JL, Schwatrtz MM, Silva FG, eds. Hepinstall's Pathology of the Kidney, 5th
edn, Chapter 14. Lipincott-Raven, Philadelphia, 1998; 625-656.
Swaak AJ, Groenwold J, Bronsveld W. Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus. Ann Rheum Dis 1986;45:359-66.
Grande JP, Balow JE. Renal biopsy in lupus nephritis. Lupus 1998;7:611-7.
Weening JJ, D’Agati VD, Appel GB, et al. The classification of glomerulonephritis in systemic lupus nephritis. Kidney Int 2004;65:521- 30.
Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolatemofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219-28.
Karim MY, Pisoni CN, Khamashta MA. Update on immunotherapy for systemic lupus erythematosus – what's hot and what's not! Rheumatology (Oxford) 2009;48:332-41.
Gunnarson I, Jonsdottir T. Rituximab treatment in lupus nephritis-where do we stand? Lupus 2013;22:381-9.
Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: A systematic review. Ann Rheum Dis 2010;69:20-8.
Korbet SM, Lewis EJ, Schwartz MM, et al. Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 2000;35:904-14.
Austin HA 3rd, Boumpas DT, Vaughan EM, Balow JE. Predicting renal outcomes in severe lupus nephritis: Contributions of clinical and histologic data. Kidney Int 1994;45:544-50.
Ponticelli C, Moroni G. Renal transplantation in lupus nephritis. Lupus 2005;14:95-8.
Hahn BH, McMahon MA, Wilkinson A, et al. American college of rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) 2012;64:797-808.
Dr. Opeyemi O Komolafe
Renal Unit, Abuja Clinics, Maitama, Abuja
[Table 1], [Table 2]