A male nephrotic patient with rapid decline of renal function

Douglas A. Charney1, Ashutosh Singh2 and Narcis Aron2

1 Department of Pathology and 2 Department of Internal Medicine, Nephrology Division, St Luke's-Roosevelt Hospital Center, New York, NY, USA

Correspondence and offprint requests to: Douglas A. Charney, MD, St Luke's Hospital, Department of Pathology, Clark 4, 1111 Amsterdam Avenue, New York, NY 10025, USA. Email: dcharney{at}chpnet.org

Keywords: crescent; fibrin crescent; membranous nephropathy



   Case
 Top
 Case
 Discussion
 Teaching points
 References
 
A 56-year-old African American male presented to the emergency room after 2 weeks of gradually worsening dyspnoea, cough, periorbital and lower extremity oedema, a 20 lb weight gain and dark coloured urine. The patient had a history of hypertension and hypercholesterolaemia, and had been treated with hydrochlorothiazide, lisinopril and atorvastatin.

Three months previously, his blood urea nitrogen (BUN) was 22 mg/dl (7.8 mmol/l), serum creatinine was 1.3 mg/dl (115 µmol/l) and urinalysis showed 3+ proteinuria by dipstick.

Currently, his physical examination revealed a blood pressure of 177/125 mmHg and periorbital and 3+ lower extremity oedema. Initial abnormal laboratory data included BUN of 47 mg/dl, serum creatinine of 3.5 mg/dl, albumin of 1.2 gm/dl, cholesterol of 348 mg/dl, triglycerides of 252 mg/dl and serum creatine kinase of 783 U/l. Blood cell counts and coagulation parameters were within normal limits. Urinalysis showed a pH of 5.5, specific gravity of 1.025, 3+ protein and 2+ blood by dipstick, with a urine sediment notable for 0–4 white blood cells (WBCs) per high power field, 10–15 red blood cells (RBCs) per high power field, some dysmorphic, one RBC cast, few granular casts, occasional epithelial cells and no crystals. No urine eosinophils were identified. Chest radiograph was normal. A 24 h urine collection revealed 11.5 g of protein. Nephrosonogram showed a right kidney 12.5 cm in length, left kidney 12.6 cm in length, no hydronephrosis, but bilaterally increased echogenicity. Additional laboratory work-up revealed normal complement fraction (C3 and C4) levels and negative anti-nuclear antibody, anti-streptolysin-O antibody, anti-neutrophil cytoplasmic antibodies (ANCAs), anti-glomerular basement membrane (GBM) antibody, human immunodeficiency virus-1 antibodies, serum hepatitis B surface antigen, hepatitis C antibodies and cryoglobulins. Serum and urine protein immunofixation electrophoreses revealed no monoclonal gammopathy.

Table 1 summarizes the pertinent clinical course, therapy and renal function parameters, both before and after percutaneous renal biopsy was performed on day 3. Treatment with steroids, followed by mycophenolate mofetil (MMF), resulted in normal renal function and trace proteinuria within 1 year (see Table 1).


View this table:
[in this window]
[in a new window]
 
Table 1. Renal function parameters, clinical course and therapy

 
Renal biopsy revealed focal (present in 20% of glomeruli) extracapillary cellular crescents, each surrounding a conglomerate of fibrin within Bowman's space (Fig. 1). No intracapillary fibrinoid necrotizing lesions were identified. Moderate interstitial fibrosis and tubular atrophy were present.



View larger version (152K):
[in this window]
[in a new window]
 
Fig. 1. A pair of glomeruli, each containing a crescent-shaped conglomerate of fibrin within Bowman's space, itself flanked by reactive proliferating epithelial cells. A mitotic figure can be seen within an epithelial cell at the 9 o’clock position of the figure (periodic acid–methenamine silver, original magnification x200).

 
Immunofluorescence microscopy showed diffuse, global finely granular glomerular capillary loop staining for IgG (3+) (Fig. 2), C3 (2–3+), {kappa} (3+), {lambda} (2–3+) and IgA (1+), with no mesangial staining. The extracapillary epithelial cell proliferation showed bright streaks when stained for fibrinogen (3+).



View larger version (110K):
[in this window]
[in a new window]
 
Fig. 2. Immunofluorescence microscopic image of a glomerulus stained for IgG. Typical of membranous nephropathy, there is diffuse and finely granular glomerular capillary loop staining (fluorescein isothyocyanate-labelled rabbit anti-human IgG x400).

 
Electron microscopy showed numerous small epimembranous and partially intramembranous electron-dense immune-type deposits with no mesangial deposits. No endothelial cell tubuloreticular inclusions were identified (Fig. 3).



View larger version (156K):
[in this window]
[in a new window]
 
Fig. 3. Electron microscopic image of several glomerular capillary loops showing multiple relatively small epimembranous electron-dense immune-type deposits, some with thin electron lucent rims or halos (arrows) (electron microscopy, original magnification x8.5 x 103).

 
A diagnosis of membranous nephropathy with epithelial crescents was rendered.



   Discussion
 Top
 Case
 Discussion
 Teaching points
 References
 
Idiopathic membranous nephropathy, although histologically characterized by diffusely thickened glomerular capillary loops, is seldom if ever accompanied by extracapillary epithelial cell proliferation, i.e. crescents. Certain secondary forms, such as those associated with systemic lupus erythematosus, may show intracapillary proliferative features. However, unless accompanied by an active glomerulonephritis, such as class III or IV lupus nephritis, anti-GBM disease or ANCA-associated pauci-immune glomerulonephritis, glomerular crescents are rare.

There have been fairly numerous reports of membranous nephropathy with epithelial crescents, the earliest of which appeared in the literature in the 1970s [1–4], and which included cases of membranous nephropathy both with [2,3] and without [1] superimposed anti-GBM disease. These early reports were followed by additional such cases throughout the 1980s [5–11], which also included cases both with [9] and without [5–8,10] superimposed anti-GBM disease. In some case reports, testing for anti-GBM was either not mentioned [4] or not done [11].

However, with the discovery of ANCAs in 1982 [12] and subsequent routine testing for ANCA beginning in the 1990s, all cases of membranous nephropathy with crescents demanded ANCA testing in order to rule out concurrent pauci-immune vasculitic glomerulonephritis. Thus, reports of primary or secondary membranous nephropathy with crescents in the 1990s and beyond stressed the negativity of their cases for ANCA [13–16] unless superimposed ANCA-associated glomerulonephritis was the main focus of their studies [17,18].

Biopsy-proven pauci-immune crescentic glomerulonephritis is not necessarily accompanied by a positive serological test for either c- or p-ANCA. In fact, up to 35% of Wegener's granulomatosus patients and 42% of microscopic polyangiitis patients test negative for ANCA [12].

Thus, the true incidence of membranous nephropathy with crescents, but without associated vasculitic glomerulonephritis or anti-GBM disease, remains nebulous. Experimental animal models and clinical experience, however, do support its existence.

Okuda et al. studied experimentally induced membranous nephropathy (i.e. ‘Heymann nephritis’) in partially nephrectomized rats. They noted that rats with Heymann nephritis and 5/6 nephrectomy experienced global or segmental glomerulosclerosis in ~70% of glomeruli, and some glomeruli displayed cellular crescents or extracapillary fibrinous exudates. These rats also suffered rapidly progressive renal functional deterioration and increase in proteinuria. They attribute these dire consequences to enhanced glomerular damage by circulating immune complexes and mechanical stress to the few remaining nephrons [19]. Van Damme et al. described 63 clinical cases of membranous nephropathy with ‘capsular lesions’. These lesions consisted of adhesions, focal sclerosis and/or ‘protein crescents’, all of which most probably arose from segmental podocyte detachment. Such detachment may result in injection of ‘plasma-like’ material between the epithelium of Bowman's capsule and its basement membrane. All cases of membranous nephropathy with such capsular lesions experienced a lower incidence of remission and higher levels of proteinuria and serum creatinine at their last follow-up [20]. Injection of serum into Bowman's space may cause significant injury, as fibrin deposition within Bowman's space has been shown to be the essential step in cellular crescent formation [21,22].

Our patient had nephrotic syndrome with nephritic sediment and rapidly progressive renal insufficiency, but negative serological work-up for autoimmune conditions, including ANCA-associated glomerulonephritis, lupus or other connective tissue disease, and anti-GBM disease. Considering the absence of a ‘full house’ immunofluorescence pattern, mesangial deposits, tubuloreticular inclusions and intracapillary necrotizing lesions, this case convincingly appears to be one of membranous nephropathy with crescents and without a separate superimposed glomerulonephritis.

The persistence of nephrotic range proteinuria with rapid renal functional deterioration, in the presence of crescents on renal biopsy, places this patient in the category of high-risk membranous nephropathy. Potent immunosuppressive regimens, such as cyclophosphamide, in addition to steroids, are usually used in such cases in an attempt to halt progression to end-stage renal failure [23]. Recently, however, MMF has emerged as an efficient immunosuppressive drug with a lower risk profile compared with other steroid-sparing agents, such as cyclophosphamide [24,25]. Thus, MMF was utilized with success in this patient, while prednisone was gradually tapered and, ultimately, discontinued.



   Teaching points
 Top
 Case
 Discussion
 Teaching points
 References
 

  1. When a nephrotic syndrome of unclear origin displays accelerated decline of renal function, with nephritic sediment, a full serological work-up, followed by kidney biopsy, should be performed.
  2. In such a case, membranous nephropathy with crescents, unassociated with a separate superimposed glomerulonephritis, is rare but can occur.
  3. Prompt identification of this entity followed by aggressive immunosuppressive treatment may rescue renal function.

Conflict of interest statement. None declared.



   References
 Top
 Case
 Discussion
 Teaching points
 References
 

  1. Hill GS, Roberson J, Grossman R et al. An unusual variant of membranous nephropathy with abundant crescent formation and recurrence in the transplanted kidney. Clin Nephrol 1978; 10: 114–120[ISI][Medline]
  2. Klassen J, Elwood C. Grossberg AL et al. Evolution of membranous nephropathy into anti-glomerular basement membrane glomerulonephritis. N Engl J Med 1974; 290: 1340–1344[ISI][Medline]
  3. Moorthy AV, Zimmerman SW, Burkholder PM et al. Association of crescentic glomerulonephritis with membranous nephropathy: a report of three cases. Clin Nephrol 1976; 6: 319–325[Medline]
  4. Taylor KT, Senekjian HO, Knight TF et al. Membranous nephropathy with epithelial crescents in a patient with pulmonary sarcoidosis. Arch Intern Med 1979; 139: 1183–1185[Abstract]
  5. Abreo K, Abreo F, Mitchell B et al. Idiopathic crescentic membranous glomerulonephritis. Am J Kidney Dis 1986; 4: 257–261
  6. Gerhardt RE, Peskoe ST, Rao RN et al. Spontaneous remission in idiopathic membranous glomerulonephritis with crescents. South Med J 1982; 75: 356–359[ISI][Medline]
  7. Koethe JD, Gerig JS, Glickman JL et al. Progression of membranous nephropathy to acute crescentic rapidly progressive glomerulonephritis and response to methylprednisolone. Am J Nephrol 1986; 6: 224–228[ISI][Medline]
  8. Mitas JA II, Frank LR, Swerdlin AR et al. Crescentic glomerulonephritis complicating idiopathic membranous glomerulopathy. South Med J 1983; 76: 664–667[ISI][Medline]
  9. Savige JA, Dowling J, Kincaid-Smith P. Superimposed glomerular immune complexes in anti-glomerular basement membrane disease. Am J Kidney Dis 1989; 2: 145–153
  10. Tateno S, Sakai T, Kobayashi Y et al. Idiopathic membranous glomerulonephritis with crescents. Acta Pathol Jpn 1981; 31: 211–219[Medline]
  11. Williams WW, Shah DJ, Morgan AG et al. Membranous glomerulonephritis with crescents in systemic lupus erythematosus. Am J Nephrol 1985; 5: 158–162[ISI][Medline]
  12. McLaren JS, Stimson RH, McRorie ER et al. The diagnostic value of anti-neutrophil cytoplasmic antibody testing in a routine clinical setting. Q J Med 2001; 94: 615–621
  13. Arrizabalaga P, Boix AS, Rabassa AT et al. Monoclonal antibody analysis of crescentic membranous glomerulopathy. Am J Nephrol 1998; 18: 77–82[CrossRef][ISI][Medline]
  14. James SH, Lien YHH, Ruffenach SJ et al. Acute renal failure in membranous glomerulopathy: a result of superimposed crescentic glomerulonephritis. J Am Soc Nephrol 1995; 6: 1541–1546[Abstract/Free Full Text]
  15. Kwan JTC, Moore RH, Dodd SM et al. Crescentic transformation in primary membranous glomerulonephritis. Postgrad Med J 1991; 67: 574–576[Abstract]
  16. Taskapan H, Oymak O, Dogukan A et al. Transformation of hepatitis B virus-related membranous glomerulonephritis into crescentic form. Clin Nephrol 2000; 54: 161–163[ISI][Medline]
  17. Tse WY, Howie AJ, Adu D et al. Association of vasculitic glomerulonephritis with membranous nephropathy: a report of 10 cases. Nephrol Dial Transplant 1997; 12: 1017–1027[Abstract]
  18. Marshall S, Dressler R, D’Agati V. Membranous lupus nephritis with antineutrophil cytoplasmic antibody-associated segmental necrotizing and crescentic glomerulonephritis. Am J Kidney Dis 1997; 29: 119–124[ISI][Medline]
  19. Okuda S, Oh Y, Tsuruda H et al. Rapidly progressive renal deterioration in partially nephrectomized rats with experimental membranous nephropathy. Nephron 1985; 41: 359–364[ISI][Medline]
  20. Van Damme B, Tardanico R, Vanrenterghem Y et al. Adhesions, focal sclerosis, protein crescents and capsular lesions in membranous nepropathy. J Pathol 1990; 161: 47–56[ISI][Medline]
  21. Holzman, LB and Wiggins RC. Glomerular crescent formation. Semin Nephrol 1991; 11: 346–353[ISI][Medline]
  22. Mathieson PW. The ins and outs of glomerular crescent formation. Clin Exp Immunol 1997; 110: 155–157[ISI][Medline]
  23. Jindal K, West M, Bear R et al. Long-term benefits of therapy with cyclophosphamide and prednisone in patients with membranous glomeulonephritis and impaired renal function. Am J Kidney Dis 1992; 19: 61–67[ISI][Medline]
  24. Briggs WA, Choi MJ, Scheel PJ Jr. Successful mycophenolate mofetil treatment of glomerular disease. Am J Kidney Dis 1998; 31: 213–217[ISI][Medline]
  25. Miller G, Zimmerman R, Radhakrishnan J, Appel G. Use of mycophenolate mofetil in resistant membranous nephropathy. Am J Kidney Dis 2000; 36: 250–256[ISI][Medline]




This Article
Extract
Full Text (PDF)
All Versions of this Article:
20/6/1263    most recent
gfh724v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Charney, D. A.
Articles by Aron, N.
PubMed
PubMed Citation
Articles by Charney, D. A.
Articles by Aron, N.