Paraneoplastic glomerular diseases and malignancies

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Abstract

Paraneoplastic glomerulopathies are rare manifestations of neoplastic disease to be distinguished from iatrogenic renal damage. Solid tumors are preferentially associated with membranous nephropathy, whereas Hodgkin's lymphomas are associated with minimal change disease. The most common neoplasia associated with paraneoplastic glomerular disease are carcinomas of the lung and of the gastrointestinal tract. Nephrotic syndrome is the most frequent presentation of paraneoplastic glomerulopathy and the most critical glomerular disease regarding prognosis and patient care.

Renal biopsy is recommended in patients with glomerular proteinuria or nephrotic syndrome and cancer, depending on life expectancy and therapeutic options. The primary treatment must be directed at the cancer in all cases. Symptomatic treatment of the nephrotic syndrome with diuretics and ACE inhibitors is justified. Prevention of nephrotic syndrome complications, i.e. thromboses and infections, should also be addressed and systematic regular renal follow-up is warranted. All treatments should be regularly reviewed to avoid toxicity, associated renal function loss or low albumin levels for patients receiving albumin-binding drugs.

Epidemiologic studies have low evidence-based value. There is no widely accepted experimental model of the association of glomerulopathy and cancer. Thus, epidemiologic and mechanistic studies are needed to determine the true prevalence of paraneoplastic glomerulopathies and investigate new pathophysiologic approaches.

Introduction

Paraneoplastic syndromes are manifestations of neoplastic disease. The term ‘paraneoplastic syndrome’ refers to clinical manifestations not directly related to tumor burden, invasion or metastasis, but caused by the secretion of tumor cell products (such as hormones, cytokines, growth factors and tumor antigens) [1]. Among paraneoplastic syndromes, the concept of paraneoplastic glomerulopathy was first suggested by Galloway in 1922, with the description of a nephrotic syndrome associated with Hodgkin's disease [2]. After Galloway, many authors have also reported cases of patients with both cancer and glomerular disease, but the causal link remains unclear.

‘Glomerulopathy’ is a general term for glomerular damage. A nephrotic syndrome is a massive urinary protein loss resulting in hypoalbuminemia and edema. It is one of the most common clinical presentations of glomerulopathy. Since the most frequent glomerular disease associated with solid tumors is membranous nephropathy, and since it is usually manifested by a nephrotic syndrome, we will particularly focus on these two issues [1], [3], [4], [5].

The diagnosis of paraneoplastic syndrome may be suspected in the presence of the following criteria: (i) no obvious alternative etiology for the associated syndrome; (ii) existence of a time relationship between the diagnosis of the syndrome and cancer; (iii) clinical (and histological) remission after complete surgical removal of the tumor or full remission achieved by chemotherapy; (iv) recurrence of the tumor associated with an increase of associated symptoms [1], [6].

Different glomerular diseases are associated with different neoplasms: whereas the nephrotic syndrome is generally due to membranous nephropathy (MN) in patients with solid tumors, cases of minimal change disease (MCD), IgA nephropathy (IgA-N), focal and segmental glomerulosclerosis (FSGS), mesangiocapillary glomerulonephritis, crescentic glomerulonephritis, amyloidosis and thrombotic microangiopathies have also been reported. The most common neoplasias associated with paraneoplastic glomerular disease are carcinomas of the lung and of the gastrointestinal tract [5]; MCD is strongly associated with Hodgkin's lymphoma [7].

The purpose of this review is to analyze the characteristics and occurrence of both the glomerular disease and cancer, and to identify their major interactions. The following description is the result of a systematic search of the Pubmed database using the following items: ‘cancer AND glomerulopathy’, ‘cancer AND glomerular disease’, ‘cancer AND membranous nephropathy’, ‘cancer AND minimal change disease’, ‘cancer AND IgA nephropathy’, ‘cancer AND focal segmental glomerulosclerosis’, ‘cancer AND mesangiocapillary glomerulonephritis’, ‘cancer AND crescentic glomerulonephritis’, ‘cancer AND amyloidosis’, ‘cancer AND thrombotic microangiopathy’, ‘cancer AND glomerular disease AND children’ and ‘cancer AND glomerular disease AND treatment’.

The value of the different studies was classified according to the French Evidence-Based Medicine Scores defined by the ANAES (National Agency for Habilitation and Evaluation In Public Health) in 2000 [8]: level 1 studies correspond to systematic reviews and randomized controlled trials; level 2 studies correspond to low-power randomized controlled trials, non-randomized controlled trials and cohort studies; level 3 studies correspond to case/control studies; and level 4 studies correspond to retrospective studies, case series, and descriptive epidemiological studies.

Section snippets

Cancer in the presence of glomerular disease

In 1966, a first study found that 11% of nephrotic syndromes in adults were associated with malignant tumors [9]. This prevalence depends on the age of the patients and the type of glomerular lesion: 69% of the patients who had both nephrotic syndrome and cancer had membranous nephropathy [4]. Three recent contributions to the epidemiology of cancer in the presence of glomerular disease can be highlighted. A French study of 240 patients with membranous nephropathy undergoing renal biopsy

Different types of glomerular diseases associated with cancer

All cases reported below cannot be considered as true paraneoplastic glomerulopathies since some determining criteria are sometimes missing.

Paraneoplastic glomerulopathies in children

Association of malignancy with nephrotic syndrome is rare in children. Of 66 children with nephrotic syndrome studied in 1975, seven had a neoplasia [32]. As far as we know, only six cases of membranous nephropathy associated with a solid malignant tumor have been reported in the literature. These data are summarized in Table 10[6], [24], [32], [243], [244]. A membranoproliferative glomerulonephritis has been described in association with a desmoplatic round cell tumor in a 11-year-old girl

Definitions

Paraneoplastic renal lesions are mainly glomerular. Other renal lesions consist in tubulo-interstitial damage and/or vascular lesions. Predominant glomerular lesions may be suspected in the presence of proteinuria (especially over 1 g/day) or nephrotic syndrome, microscopic or painless gross hematuria without blood clots, arterial hypertension, and/or decreased glomerular filtration rate and progressive renal disease [247].

A nephrotic syndrome is defined by biological criteria: proteinuria

Other renal complications of cancer

Paraneoplastic glomerulopathy is a rare type of renal complication of neoplasia. Other renal complications of cancer have been described: either mechanical complications (ureteral compression, vascular compression or invasion, obstructive uropathy by retroperitoneal fibrosis, infiltration of renal parenchyma), or iatrogenic complications (electrolyte disorders, acute renal failure, tumor lysis syndrome, radiation nephropathy, chemotherapy complications with drug-induced tubulointerstitial

Conclusion

The link between malignancies and nephrotic glomerulopathies is difficult to prove; however, it is suggested by clinical features such as close temporal relationship and parallel evolution (improvement, resolution, relapse) [5].

Table 11 summarizes all the results of different types of glomerulopathies and different main neoplasia. As described by other authors, gastro-intestinal and respiratory tract neoplasia are frequent etiologies of paraneoplastic glomerulopathies; however thymoma and renal

Reviewers

Sven Arvid Birkeland, M.D., D.M.Sc., Odense University Hospital, Department of Nephrology, DK-5000 Odense C, DENMARK.

Conflicts of interests

None.

Acknowledgements

The authors thank Mrs. Marie-Dominique Reynaud for skillful help in the edition of the manuscript and Dr Brigitte Mac Gregor (Hôpital Edouard Herriot, Lyon) for providing pictures of renal biopsies.

Justine Bacchetta is currently resident in Pediatric Nephrology in Lyon, France. Her interests include clinical and basic research on calcium phosphate metabolism in pediatric chronic kidney disease.

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    Justine Bacchetta is currently resident in Pediatric Nephrology in Lyon, France. Her interests include clinical and basic research on calcium phosphate metabolism in pediatric chronic kidney disease.

    Laurent Juillard has obtained his MD degree and was board certified in Nephrology in 1998 at the School of Medicine of the University of Lyon. He received his PhD degree in 2000 at the University of Lyon and performed his post-doctoral fellowship at the Mayo Clinic School of Medicine. He is currently consultant in nephrology, head of the dialysis unit of the University Hospital Edouard Herriot, in Lyon. His research activity is focused on the exploration of ischemic nephropathy by innovative functional imaging modalities.

    Pierre Cochat has obtained his MD degree and was board certified in Pediatrics and Nephrology in 1985 at the School of Medicine at the University of Lyon. He is Professor of Pediatrics and Dean of Laennec School of Medicine. He is coordinator of the Pediatric Renal Transplantation Programme and of the Reference Centre for Rare Renal Diseases in Lyon. He is President of the European Society of Paediatric Nephrology and council member of the International Pediatric Nephrology Association. He has managed and/or participated at 26 clinical trials. He has published more than 150 papers in international peer-reviewed journals and contributed to 70 book chapters. His interests include inherited renal diseases, urolithiasis, pediatric renal transplantation and nephrotoxicity.

    Jean-Pierre Droz obtained his MD degree in 1975 at the Paris-VI University School of Medicine, his PhD at the University of Lyon (Claude-Bernard Lyon-I University). He was formerly Chairman of the Department of Medicine at the Institute Gustave-Roussy in Villejuif. He is Professor of Medical Oncology at the University of Lyon (RTH Laënnec School of Medicine), Chairman of the Department of Medical Oncology and Director of Teaching Programs at the Léon-Bérard Cancer Center in Lyon. His major clinical research interests are: Genito-Urinary tumors, mainly Germ-Cell Tumors and Prostate Cancer, new drug development, Geriatric Oncology and Endocrine Tumors. He chaired the Genito-Urinary Tumor Group (GETUG) of the French Comprehensive Cancer Center Network from 1994 to 1999. He is the President of the SIOG (International Society of Geriatric Oncology) and serves as President of the Geriatric Oncology Clinical Trials Group; he is also a member of the Geriatric Oncology Board of the French National Cancer Institute. He has managed and/or participated to more than 80 clinical trials. He has published more than 200 articles in international peer-reviewed journals. He has participated to more than 30 chapters in books and is editing a textbook on uncommon cancers. His interest also includes basic research on the biology of germ cell tumors, principally the mechanisms of carcinogenesis possibly related to hormone disruptors.

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