In the case of RA patients’ hematuria the urological cause of the finding should be primarily excluded.
Since no clinical association has been established between isolated microhematuria and use of DMARD (White et al. 1984; Leonard et al. 1987; Korpela et al. 1995; Koseki et al. 2001) or NSAID therapies (Richards et al. 1988; Korpela et al. 1995; Koseki et al. 2001), there is no basis for discontinuation of this therapy. The most frequent renal histological diagnosis related to microhematuria is MesGN, and the favorable long-term prognosis of the condition was here confirmed.
Furthermore, isolated hematuria, even glomerular, is not usually an indication for renal biopsy at present, and after urological investigations the finding can be followed up at longish intervals.
In the case of proteinuria a positive screening test must first be confirmed by diurnal urine collection. Protein excretion exceeding 500 mg/day warrants the discontinuation of nephrotoxic DMARDs (gold salts and DPA) and avoidance of NSAIDs. If proteinuria continues for several months, showing no response to cessation of nephrotoxic DMARDs, referral to a nephrologist and renal biopsy is to be considered. The possibility of AA-amyloidosis should be borne in mind, especially in advanced
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RA patients with prolonged high disease activity, proteinuria and/or renal insufficiency. To retard the progression of AA-amyloidosis the underlying inflammation should be controlled with intensified anti- rheumatic treatment (Ahlmen et al. 1987; Berglund et al. 1993; Elkayam et al. 2002).
On the basis of the present findings, the GFR of RA patients is recommended to be estimated using the CG formula or creatinine clearance. The sensivities of serum creatinine or cystatin C measurements are not satisfactory in patients with RA. It is of vital importance to adjust the dosage of medications excreted by the kidneys (e.g. methotrexate, hydroxychloroquine) and avoid NSAIDs and nephrotoxic DMARDS such as cyclosporine, gold salts and DPA in RA patients with estimated GFR <60ml/min/1.73m2.
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SUMMARY AND CONCLUSIONS
1. In patients with long-lasting RA and clinical nephropathy findings in the cross-sectional population-based study in 1988, isolated proteinuria and proteinuria combined with hematuria and/or CRF very frequently continued over the 13-year follow-up. RA patients with these findings had poor clinical long-term prognosis, mostly by reason of underlying renal amyloidosis. Isolated hematuria and isolated CRF were associated with evidently better prognosis with good preservation of renal function and infrequent need for dialysis therapy.
New abnormal renal findings were recorded in almost one third of RA patients, but these findings were mostly mild in character.
2. Mesangial glomerulonephritis had a favorable clinical prognosis in the 15-year follow-up, whereas renal AA-amyloidosis was associated with evidently poorer prognosis with frequent appearance of serious impairment of renal function and frequent need for dialysis therapy.
3. Creatinine clearance and the CG formula had the best diagnostic ability to identify RA patients with reduced GFR. Sole use of the measurement of plasma creatinine, cystatin C or urea to estimate the GRF of RA patients cannot be recommended in clinical practice.
4. The cumulative incidence of repeated hematuria findings in the 11-year follow-up of early RA patients was high, the incidence of repeated proteinuria and raised serum creatinine being evidently more infrequent. The repeated finding of eGFRCG<60ml/min/1.73m2 was made in
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over 10 % of patients. Single nephrotoxic DMARDs were in only few cases associated with the occurrence of proteinuria or CRF. The initial remission-targeted therapy with the FIN-RACo combination DMARD therapy in early RA was safe for the kidneys and induced no more short- or long-term renal complications compared to therapy with a single DMARD.
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ACKNOWLEDGEMENTS
This study was carried out at the Department of Internal Medicine, Tampere University Hospital, and at the Medical School, University of Tampere, Finland.
I am truly grateful to my supervisors Professor Jukka Mustonen, M.D. and Docent Markku Korpela, M.D. for their patience and support during this work. They introduced me to the scientific field of rheumatology and nephrology and their help and guidance were prerequisite to the completion of this study.
I wish to express my warmest gratitude to Docent Heikki Saha, M.D. for his contribution to the planning and implementation of the study of measures of renal function. His patient guidance and encouraging attitude towards the whole undertaking has been invaluable.
I wish express my sincere thanks to my co-authors Professor Pekka Hannonen, Docent Aimo Harmoinen, PhD, Professor Marjatta Leirisalo-Repo, Professor Timo Möttönen, and Vappu Rantalaiho, M.D. for their invaluable contribution to the study. I am greatly indebted to Docent Heikki Helin, M.D. for the histological diagnostics and Hannu Kautiainen, B.A. and Professor Terho Lehtimäki, M.D. for their invaluable part in the statistical analysis of my findings. I also warmly thank all the members of the FIN-RACo Trial group for their tireless work with the trial and also for letting me utilize their accomplishments in my study.
I am deeply indebted to my co-author and dear colleague Susanna Sihvonen, M.D. for her significant contribution to the study, for her heartening words in my melancholy moments, and for her endless optimism over the outcome. I also owe thanks to my close workmate nurse Heidi Marika Mäkinen for her invaluable assistance with the study patients and materials and for her always so encouraging attitude towards the study. Her professional skills and humane sensitivity have brought pleasure to my everyday work during the past years. I extend my warmest thanks to the entire personnel of the Department of Rheumatology for encouraging me in my efforts.
I warmly thank Docent Kari Pietilä, M.D. and Docent Jaakko Antonen, M.D. Heads of the Department of Internal Medicine, for providing me the facilities to carry out this study and for a positive and understanding attitude towards my study.
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I sincerely thank the official reviewers, Docent Agneta Ekstrand, M.D. and Docent Jorma Viitanen, M.D., for their valuable comments and constructive criticism, which greatly improved the quality of this thesis.
I am most thankful to Mr Robert Mc Gilleon, MA for careful and swift revision of the English language of this thesis.
My warmest thanks belong to my fellow-student Johanna Palmio for our weekly squash matches and our lively conversations about everything from the academic issues to gardening during breaks. Those moments greatly helped me to maintain a proper perspective on everyday life during these years. I am also grateful to Sinikka Forsberg, M.D. for introducing me to the interesting world of rheumatology, setting a good example of clinical expertise and human approach.
I warmly thank my parents Mervi and Keijo Vidqvist for their never-ending support and encouragement and being so proud of everything I have done.
I dedicate this book to my family, who have supported me throughout these years. To my older daughter Eerika, whose growth into a young lady I have proudly followed, and to my younger daughter Annika, whose sparkling girl-power brings laughter to my life. And finally to my beloved husband Tuomas, the light of my life, who has unselfishly made it possible for me to concentrate on this work.
Life with him has been filled with love, companionship and new adventures and I am privileged to have shared all these years with him.
This work was financially supported by grants from the Competitive Research Funding of the Pirkanmaa Hospital District, the Finnish Kidney Foundation, the Scandinavian Rheumatology Research Foundation, Tampereen Reumayhdistys, the Local Branch of the Finnish Rheumatism Association, and the Finnish Society for Rheumatology.
Tampere, March 2009
Krista Karstila
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