Skip Navigation


NDT Advance Access originally published online on August 5, 2006
Nephrology Dialysis Transplantation 2006 21(11):3324-3326; doi:10.1093/ndt/gfl456
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
21/11/3324    most recent
gfl456v3
gfl456v2
gfl456v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by von Vietinghoff, S.
Right arrow Articles by Kettritz, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by von Vietinghoff, S.
Right arrow Articles by Kettritz, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
(Section Editor: A. Meyrier)

Crescentic glomerulonephritis and malignancy—guilty or guilt by association?

Sibylle von Vietinghoff, Wolfgang Schneider, Friedrich C. Luft and Ralph Kettritz

Medical Faculty of the Charité, Franz Volhard Clinic and Department of Pathology, HELIOS Klinikum-Berlin, Germany

Correspondence and offprint requests to: Ralph Kettritz, MD, Franz Volhard Clinic, Wiltbergstrasse 50, 13122 Berlin, FRG. Email: kettritz{at}charite.de

Keywords: ANCA; crescentic glomerulonephritis; malignancy



   Introduction
Top
 Introduction
Crescentic glomerulonephritis in...
 Could dysregulated epithelial...
 References
 
Rapidly progressive glomerulonephritis (GN) is one of the harrowing challenges in nephrology. The condition is histologically characterized by extracapillary proliferation with crescent formation. Most crescentic glomerulonephritides occur in systemic autoimmune diseases and require prompt immunosuppressive treatment. Occasionally, patients with crescentic GN may be diagnosed with an additional life-threatening disease, namely malignant neoplasms. Immunosuppressive drugs may promote such malignancies. However, some patients are initially diagnosed with both diseases, suggesting a more intimate relationship between crescentic glomerulonephritis and malignancies.

We recently encountered a 68-year-old man, referred to us from the urology department because of an increasing serum creatinine. He had initially presented with intermittent haematuria a month earlier. Cystoscopy revealed an exophytic bladder tumour that was resected. Histological examination (Figure 1) disclosed papillary carcinoma. When the patient returned for follow-up 4 weeks after tumour resection, his creatinine had increased from slightly above normal values to 307 µmol/l. The patient denied fever, weight loss, night sweats, cough, sputum production, skin or joint abnormalities. He had coronary artery disease with prior myocardial infarction, and had undergone coronary bypass surgery 8 years earlier. His blood pressure was 140/80 mmHg and his lungs were clear. He had a functional systolic ejection murmur and no oedema. The laboratory urine testing revealed blood in the urine, no evidence of infection, but 3.7 g of protein per 24 h. An initial urinary sediment shortly after cystoscopy showed many eumorphic erythrocytes. Serum potassium concentration was 5.41 mmol/l, albumin was 3.9 g/dl, total protein was 7.1 g/dl, the haemoglobin 12.7 g/dl. Diagnostic ultrasound revealed two normal-sized kidneys. Renal blood flow in arteries and veins showed no abnormalities. However, a repeated urinary sediment after cessation of macrohaematuria showed occasional granular casts and numerous erythrocytes, some of which were dysmorphic. Serological testing was positive for perinuclear anti-cytoplasmic antibodies with specificity for myeloperoxidase (MPO–ANCA) at 520 U/ml. A computerized tomogram of the lungs revealed a left lower lobe infiltrative process that had been hidden by the cardiac silhouette in an earlier chest X-ray. A renal biopsy showed a diffuse proliferative extracapillary GN (Figure 2). Immunofluorescence was scant to absent (pauci-immune). The diagnosis of an MPO–ANCA positive necrotizing crescentic GN was made. Cyclophosphamide and prednisone were begun and the serum creatinine, that had peaked at 450 µmol/l, decreased to 180 µmol/l. The patient was spared dialysis.


Figure 1
View larger version (116K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1. Bladder histology showing non-invasive papillary carcinoma of the bladder.

 

Figure 2
View larger version (146K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2. Crescentic extracapillary GN.

 
Causes of acute renal failure in cancer patients are diverse. Impaired renal function, even if the decrease in glomerular filtration rate is small, has substantial effects on morbidity and mortality. Nephrotoxicity is associated with chemotherapy, supportive drugs and contrast agents. More recently, new protocols that include bone marrow transplantation were shown to be associated with additional, rather specific renal insults, including marrow-infusion toxicity and hepato-renal syndrome after veno-occlusive disease [1]. Furthermore, the malignant disease itself can lead to acute renal failure for several reasons. In patients with this aetiology, post-renal obstruction is frequently observed, whereas direct infiltration of the kidneys, for example by lymphomas occurs, but is rarely the cause of acute renal failure.



   Crescentic glomerulonephritis in patients with malignancies
Top
 Introduction
 Crescentic glomerulonephritis in...
Could dysregulated epithelial...
 References
 
An increased rate of malignancy in patients with membranous GN was the first association between cancer and glomerular disease to be reported [2]. Since then, GN of virtually all types has been described in conjunction with either solid or haematological neoplasms [3,4]. Severe forms of crescentic GN affecting more than 50% of the glomeruli were also found in biopsies from cancer patients. This rapidly progressive type of GN was most commonly characterized by paucity of immunoglobuline deposition. However, crescentic GN in cancer patients may also occur with anti-GBM antibody [5,6] or immune complex deposition [7–9]. Underlying malignancies found in patients with pauci-immune crescentic GN include solid tumours, such as prostate cancer, transitional cancer of the bladder, adenocarcinoma of the lung and occult gastric carcinoma [10–12], as well as haematological neoplasms, such as myelodysplastic [13] and myeloproliferative syndromes [14] and lymphatic leukaemia [15]. After tests for anti-neutrophil cytoplasmic antibodies (ANCA) became available, most cases of pauci-immune crescentic GN were found to be ANCA associated [14], and this also applies in cancer patients.

In addition to these case reports, Biava et al. [16]. systematically studied a series of 80 patients with crescentic GN. The authors identified an underlying cancer in seven cases, compared with only one in 80 patients with minimal change disease and focal segmental sclerosing glomerulonephritis (FSGS). These data suggest an increased incidence of solid tumours in patients with crescentic GN. All crescentic glomerulonephritides reported by Biava had a pauci-immune immunofluorescence pattern as found in ANCA patients. However, this study was performed before ANCA testing was available.

Tatsis et al. [17] studied 477 patients with Wegener's granulomatosis and an age-matched group of rheumatoid arthritis patients. Cancer diagnoses at or before diagnosis of the autoimmune disease were more common in the former cohort. This finding was most marked for renal cell carcinoma with seven cases in patients with Wegener's granulomatosis vs one case in the rheumatoid arthritis group. The observation of an increased risk of malignancy has been confirmed in a cohort of 200 patients with Wegener's granulomatosis and microscopic polyangitis from England [18]. However, as cancers occurred up to 512 months after the diagnosis of vasculitis, the effect of cytotoxic treatment cannot be excluded. Aggressive immunosuppression exposes patients to an increased risk of cancer. For example, the incidence of bladder cancer after 12 months of cyclophosphamide treatment was 11-fold elevated in patients with Wegener's granulomatosis and microscopic polyangiitis [19]. The risk doubled for every 10 g of the drug in a Swedish cohort that also showed an increase in other types of malignancies, including squamous-cell skin cancer and haematological neoplasms [20].



   Could dysregulated epithelial proliferation be the link between crescentic GN and cancer?
Top
 Introduction
 Crescentic glomerulonephritis in...
 Could dysregulated epithelial...
References
 
A number of candidate mechanisms that could link malignancy and GN have been postulated, including dysregulated T-cell response and elaboration of various cytokines. An interesting molecule in this regard is uteroglobin, a small, 17 kDa, homodimeric secreted protein that is expressed by most epithelia such as lung, prostate and endometrium [21]. Uteroglobin is markedly reduced in several carcinomas and was found to be chiefly responsible for invasive growth of epithelial tumours cells [22]. When uteroglobin was deleted in mice, the animals were more susceptible to lung cancer [23]. Interestingly, uteroglobin-deleted mice and uteroglobin-antisense-RNA expressing mice also develop glomerular lesions with the deposition of fibrin and IgA [24]. Moreover, Lee et al. [25] were able to prevent experimental crescentic GN by intraveneously administered recombinant uteroglobin.

We do not know if our patient's bladder cancer was in any way related to his crescentic GN. There were alternative explanations for acute renal failure in our patient and we rather believe that most physicians would not have pursued the possiblity of glomerular disease in this patient. The fact that the diagnosis of ANCA-associated crescentic GN was established and prompt treatment was initiated improved his outcome. There should be a high index of suspicion in the initial evaluation and follow-up of patients with crescentic GN. Furthermore, patients with cancer and haematuria deserve several careful urinary sediment evaluations.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Crescentic glomerulonephritis in...
 Could dysregulated epithelial...
 References
 

  1. Lameire NH, Flombaum CD, Moreau D, Ronco C. (2005) Acute renal failure in cancer patients. Ann Med 37:13–25.[CrossRef][Web of Science][Medline]
  2. Lee JC, Yamauchi H, Hopper J Jr. (1966) The association of cancer and the nephrotic syndrome. Ann Intern Med 64:41–51.[CrossRef][Web of Science][Medline]
  3. Da'as N, Polliack A, Cohen Y, et al. (2001) Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients. Eur J Haematol 67:158–164.[CrossRef][Web of Science][Medline]
  4. Keur I, Krediet RT, Arisz L. (1989) Glomerulopathy as a paraneoplastic phenomenon. Neth J Med 34:270–284.[Web of Science][Medline]
  5. Hatakeyama S, Kawano M, Konosita T, et al. (1990) A case of renal cell carcinoma associated with rapidly progressive glomerulonephritis. Nippon Jinzo Gakkai Shi 32:1125–1132.[Medline]
  6. Maes B, Vanwalleghem J, Kuypers D, et al. (1999) IgA antiglomerular basement membrane disease associated with bronchial carcinoma and monoclonal gammopathy. Am J Kidney Dis 33:E3.[Medline]
  7. Mak SK, Wong PN, Lo KY, Wong AK. (1998) Successful treatment of IgA nephropathy in association with low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue type. Am J Kidney Dis 31:713–718.[Web of Science][Medline]
  8. Meyrier A, Simon P, Mignon F, Striker L, Ramee MP. (1984) Rapidly progressive (‘crescentic’) glomerulonephritis and monoclonal gammapathies. Nephron 38:156–162.[Web of Science][Medline]
  9. Petzel RA, Brown DC, Staley NA, et al. (1979) Crescentic glomerulonephritis and renal failure associated with malignant lymphoma. Am J Clin Pathol 71:728–732.[Web of Science][Medline]
  10. Baschinsky DY, Baker PB, Niemann TH, Wilmer WA. (2000) Pauci-immune ANCA-positive crescentic glomerulonephritis associated with metastatic adenocarcinoma of the lung. Am J Kidney Dis 36:E24.[Medline]
  11. Edgar JD, Rooney DP, McNamee P, McNeill TA. (1993) An association between ANCA positive renal disease and malignancy. Clin Nephrol 40:22–25.[Web of Science][Medline]
  12. Hruby Z, Bronowicz A, Rabczynski J, Kopec W, Szewczyk Z. (1994) A case of severe anti-neutrophil cytoplasmic antibody (ANCA)-positive crescentic glomerulonephritis and asymptomatic gastric cancer. Int Urol Nephrol 26:579–586.[Medline]
  13. Komatsuda A, Miura I, Ohtani H, et al. (1998) Crescentic glomerulonephritis accompanied by myeloperoxidase-antineutrophil cytoplasmic antibodies in a patient having myelodysplastic syndrome with trisomy 7. Am J Kidney Dis 31:336–340.[Web of Science][Medline]
  14. Jennette JC. (2003) Rapidly progressive crescentic glomerulonephritis. Kidney Int 63:1164–1177.[CrossRef][Web of Science][Medline]
  15. Tisler A, Pierratos A, Lipton JH. (1996) Crescentic glomerulonephritis associated with p-ANCA positivity in fludarabine-treated chronic lymphocytic leukaemia. Nephrol Dial Transplant 11:2306–2308.[Free Full Text]
  16. Biava CG, Gonwa TA, Naughton JL, Hopper J Jr. (1984) Crescentic glomerulonephritis associated with nonrenal malignancies. Am J Nephrol 4:208–214.[Web of Science][Medline]
  17. Tatsis E, Reinhold-Keller E, Steindorf K, Feller AC, Gross WL. (1999) Wegener's granulomatosis associated with renal cell carcinoma. Arthritis Rheum 42:751–756.[CrossRef][Web of Science][Medline]
  18. Pankhurst T, Savage CO, Gordon C, Harper L. (2004) Malignancy is increased in ANCA-associated vasculitis. Rheumatology 43:1532–1535.[Abstract/Free Full Text]
  19. Westman KW, Bygren PG, Olsson H, Ranstam J, Wieslander J. (1998) Relapse rate, renal survival, and cancer morbidity in patients with Wegener's granulomatosis or microscopic polyangiitis with renal involvement. J Am Soc Nephrol 9:842–852.[Abstract]
  20. Knight A, Askling J, Ekbom A. (2002) Cancer incidence in a population-based cohort of patients with Wegener's granulomatosis. Int J Cancer 100:82–85.[CrossRef][Web of Science][Medline]
  21. Peri A, Cordella-Miele E, Miele L, Mukherjee AB. (1993) Tissue-specific expression of the gene coding for human Clara cell 10-kD protein, a phospholipase A2-inhibitory protein. J Clin Invest 92:2099–2109.[Web of Science][Medline]
  22. Zhang Z, Kundu GC, Panda D, et al. (1999) Loss of transformed phenotype in cancer cells by overexpression of the uteroglobin gene. Proc Natl Acad Sci USA 96:3963–3968.[Abstract/Free Full Text]
  23. Yang Y, Zhang Z, Mukherjee AB, Linnoila RI. (2004) Increased susceptibility of mice lacking Clara cell 10-kDa protein to lung tumourigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen in cigarette smoke. J Biol Chem 279:29336–29340.[Abstract/Free Full Text]
  24. Zheng F, Kundu GC, Zhang Z, et al. (1999) Uteroglobin is essential in preventing immunoglobulin A nephropathy in mice. Nat Med 5:1018–1025.[CrossRef][Web of Science][Medline]
  25. Lee DS, Yang SH, Kim HL, et al. (2004) Recombinant uteroglobin prevents the experimental crescentic glomerulonephritis. Kidney Int 66:1061–1067.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
21/11/3324    most recent
gfl456v3
gfl456v2
gfl456v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by von Vietinghoff, S.
Right arrow Articles by Kettritz, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by von Vietinghoff, S.
Right arrow Articles by Kettritz, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?