Renal involvement in SLE and systemic sclerosis is well

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1 Update Article Rheumatoid Arthritis and The Kidney E Pathan, VR Joshi* Abstract It is clear that kidney is involved in rheumatoid arthritis (RA) with both glomerular and tubular damage. Renal disease in RA however is usually asymptomatic and is detected only on laboratory investigations. It is often difficult to differentiate between damage due to disease activity and that due to drugs used to treat RA. Although there are a number of parameters to study renal function, these cannot be applied to day to day practice and still remain research tools. In such a scenario, it is important to periodically monitor serum creatinine and carry out urine examination so as to pick up the earliest signs of renal dysfunction. INTRODUCTION Renal involvement in SLE and systemic sclerosis is well known. Clinically manifest renal involvement in RA has been commonly attributed to (secondary) amyloidosis and renal vasculitis. Patients of RA receive NSAIDs at some time or the other during the course of their illness. Disease modifying anti-rheumatic drugs (DMARDs) like gold and d- penicillamine are also nephrotoxic. It is therefore difficult to ascertain the true incidence of renal involvement due to RA itself. There is evidence that both functional abnormalities and histopathological lesions that cannot be attributed to concomitant drug intake or to vasculitis or amyloidosis do occur in RA patients. Boers 1 in his review classified renal disorders into three categories- those due to RA and its complications, those related to drug therapy and a third category, RA nephropathy. In this article, we review relevant literature on renal affection due to RA. A med-line search (using index words: rheumatoid arthritis, acute renal failure, chronic renal failure, nephropathy, glomerulonephritis, interstital nephritis) was done from 1990 to Of these selected major relevant communications have been reviewed. Additionally, a few important communications prior to this period have also been included. METHODS Both clinical and laboratory parameters have been used to study renal involvement in RA. Earlier reports were based on necropsy and biopsy studies. Although these provided anatomical evidence of kidney involvement, patients *Consultant Physician and Rheumatologist, Director Research Centre, PD Hinduja National Hospital and Medical Research Centre, Mahim, Mumbai Received : ; Accepted : underwent biopsies only in the presence of urine abnormalities (like haematuria, proteinuria or both) or renal insufficiency/ failure (in terms of rise in creatinine or fall in creatinine clearance). More recent studies have used selective markers of glomerular and tubular involvement as means of identifying early renal involvement. To date, no clear consensus has emerged as to which parameter(s) should be monitored in a case of rheumatoid arthritis as also the frequency of such an evaluation. HISTOPATHOLOGY Salomon et al 2 reported a minimal increase in mesangial cells and matrix of glomeruli with thickening of the Bowman s capsule in seven of 18 patients who underwent kidney biopsies for urinary abnormalities. Subsequently, an autopsy study by Ramirez et al 3 looked at renal pathology in a group of 76 RA patients with a mean disease duration of 14.3 years as against an age and sex matched population. They found evidence of interstitial fibrosis in 43% and increased mesangial matrix in 38% of RA patients as against none in controls. There was marked intimal proliferation of arterioles in the RA group (30%) without clinically significant hypertension, leading the authors to believe that when renal failure does occur in patients of RA, it is on the basis of interstitial nephritis and nephroarteriosclerosis. The incidence of both amyloidosis and azotaemia was low (7% and 9% respectively) in this study. Boers et al 4 published a study based on renal histology (light microscopy) in 132 necropsied RA cases with a mean disease duration of 14.5 years. No specific pattern of renal affection was observed by these workers. Glomerular lesions included proliferative glomerulonephritis (GN) in 11 (six of which had systemic vasculitis), membranous GN in nine, focal glomerulosclerosis in five and membranoproliferative GN (MPGN) in one case. The study included a higher proportion JAPI VOL. 52 JUNE 2004

2 of patients with systemic vasculitis (18 cases). Renal vasculitis was present in eight cases. Damage in cases with vasculitis was extensive and was associated with severe exudative and proliferative glomerulonephritis leading to uraemia. The high incidence of benign nephrosclerosis seen (91%) was attributed to concomitant hypertension. A clear relation between the severity of nephrosclerosis and duration of RA was noted, suggesting that RA itself could be an additional aetiological factor for the development of nephrosclerosis. In a retrospective Japanese study by Yoshida et al 5 of 31 patients of RA [17-nephrotic syndrome, 5-isolated proteinuria, 2-proteinuria with haematuria and 7-renal failure], 16 patients had membranous nephropathy, 2-proliferative glomerulonephritis, 2-minor glomerular abnormalities, 6- amyloidosis and 2-tubulointerstitial nephritis. Eleven of the 16 patients with membranous GN had been on gold or d- penicillamine. Two cases of MGN were associated with nephrotic syndrome. ARF was related to NSAIDs. There were 2 cases of non-iga DPGN, which was regarded as native nephropathy of RA. The study concluded that the histology findings varied in RA and biopsy examination was useful. In a more recent retrospective study by Helin et al 6, 110 cases of RA with clinical renal disease due to RA itself and/or antirheumatic therapy underwent renal biopsy (between ). Findings were suggestive of mesangial glomerulonephritis in 40 cases, amyloidosis in 33, membranous glomerulonephritis in 19, focal proliferative GN in four, minimal change nephropathy in three and acute interstitial nephritis in one case. Mesangial GN as against membranous GN was found to be associated with long standing RA and was thought to be probably related to the disease itself. Necrotizing vasculitis associated with rapidly progressive glomerulonephritis (RPGN) and extra-capillary proliferation was found to be a rare complication of RA. Another retrospective study of cases seen between 1979 and 1996 by Nakano et al 7 looked at renal biopsy findings in 158 Japanese RA patients with urine abnormalities and/or renal dysfunction. They found mesangial proliferative GN in 54 patients, membranous GN in 49 and secondary amyloidosis in 30 patients. One half of the 54 mesangial GN patients demonstrated IgA glomerulonephritis by immunofluorescence(if). The diffuse thinning of the glomerular basement membrane (GBM) observed in 30 of the 81 patients on electron microscopy was suspected to be due to RA itself. Korpela et al 8 (1997) studied mesangial IF findings in 37 RA patients presenting with haematuria and /or proteinuria and tried to co-relate the nature of the glomerular immunedeposits with clinical data, levels of serum immunoglobulin and the titers of serum rheumatoid factors (RF). Two main patterns of IF- IgM and IgA were found. The intensity of granular IgM deposits neither correlated with the duration or severity of RA nor with the levels of serum immunoglobulins. However a significant correlation was found between the intensity of IgM deposits and levels of serum IgM class RF. Table 1: Histopathology of the kidney in rheumatoid arthritis in various studies Study (year) No. of patients Histopathology findings Salomon et al 2 7/18 Increased mesangial cells and (1973) matrix of glomeruli in 7/18 patients Ramirez et al 3 76 Interstitial fibrosis(33) (1981) Increased mesangial matrix(27) Lymphocytic infiltration(26) Intimal proliferation (39) Hyalinized glomeruli (34) Periglomerular fibrosis (9) Amyloidosis (5) Vasculitis (7) Proliferative glomerulonephritis (3) Papillary necrosis (1) Boers et al Proliferative GN (1) (1987) Membranous GN (9) Focal glomerulosclerosis(5) MPGN (1) Renal vasculitis (8) Benign nephrosclerosis (120) Yoshida et al 5 31 Membranous nephropathy (16) (1991) Proliferative GN(2) Minor glomerular abnormality (2) Amyloidosis (6) Tubulointerstitial nephritis(2) Helin et al Mesangial GN(40) (1995) Amyloidosis (33) Membranous GN(19) Focal proliferative GN (4) Minimal change nephropathy (3) Acute interstitial nephritis(1) Korpela et al 8 37 Granular IgM (25) and IgA(9) (1997) glomerular immunodeposits on IF in mesangial GN Nokano et al Mesangial proliferative GN (54) (1998) Membranous GN (49) Secondary amyloidosis (30) IgA glomerulonephritis (26) GBM diffuse thinning (30) Korpela et al Glomerular IgA, IgM and C3 (1990) deposits were the most prominent findings on IF in mesangial GN (23/56). Table 2 : Clinical features and urine abnormalities in patients of RA with renal involvement Study (year) No. of patients Clinical presentation Boers et al Urine abnormalities with normal (1987) renal function (26) Normal urine with loss of renal function (27) Uraemia (30) Proteinuria with uraemia in 11/14 patients with amyloidosis Yoshida et al 5 31 Nephrotic syndrome (17) (1991) Isolated proteinuria (5) Proteinuria with haematuria(2) Renal failure (7) Harper et al Renal impairment (9) (1997) Haematuria (8) (Patients with focal Proteinuria (10) segmental necrotising GN) Extra-renal vasculitis (5) JAPI VOL. 52 JUNE

3 Table 3 : Various laboratory markers used to study renal function Study No. of patients Parameters used Neiderstadt et al Immunoluminometric assay for quantification of individual urinary marker proteins (glomerular & tubular) Pederson et al Microalbuminuria Nordin et al Microalbuminuria Salli et al Microproteinuria on multifractional cellogel RS electrophoresis of urinary proteins Dieppe et al Urinary N-acetyl-glucosaminidase Iqbal et al Urinary N-acetyl-glucosaminidase and its isoforms Lewandowski et al Beta 2 microglobulin in serum and urine Viergever et al Serum and 24 hours urinary beta 2 microglobulin Mannge et all Cystatin C by automated nephelometric assay Boers et al Glomerular function: GFR, ERPF, creatinine clearance, 24 hours urinary protein and urine sediment Tubular function: urine and serum beta 2 microglobulin, urinary NAG, urinary glucose and maximum urinary concentrating capacity and acid excretory capacity The intensity of mesangial IgA deposits correlated significantly with the duration and severity of RA and especially with serum IgA levels. The authors concluded that mesangial glomerulonephritis is related to the basic rheumatoid disease and should be regarded as an extraarticular manifestation of RA. Pollen et al 9 described three cases of RA who had a mesangiopathy characterized by increased quantities of mesangial matrix and deposition of IgM without other lesions. They postulated that removal of circulating RF-IgG complexes is a function of the mesangium and might produce this renal lesion. Korpela et al 10 studied the immunological profile of patients with RA with and without nephropathy. Serum IgG, IgM, IgA, C3, C4, circulating immune complexes (CIC), rheumatoid factor (RF) and antinuclear antibodies (ANA) were measured in 56 RA patients with nephropathy (23 with mesangial, 13 with membranous and 20 with amyloidosis) and 35 RA patients without nephropathy. There were no differences in occurrence of RF, ANA, CIC, C3 and C4 between the two groups. Serum IgM and IgA were higher in patients with mesangial glomerulopathy and amyloidosis. In patients with mesangial glomerulopathy, glomerular IgA, IgM and C3 were the most prominent findings on IF. Circulating immune complexes were not found to have a major role in nephropathy unlike in other extra-articular manifestations of RA. INFLUENCE OF NSAIDs AND DMARDs ON RENAL HISTOPATHOLOGY NSAIDs and DMARDs have been shown to produce a variety of histopathological lesions. Interstitial nephritis with long term NSAID usage and gold or d-pencillamine induced membranous glomerulonephritis are the most commonly detected abnormalities in various studies. In the study by Boers et al 4, membranous nephropathy was found only in patients who had received gold and/or d- penicillamine ( 79% and 11% cases had received gold and d- penicillamine respectively). Nakano et al 6 have reported membranous nephropathy in 40 of the 49 patients on DMARD therapy. This study found no co-relation between DMARDS and renal disorders except membranous nephropathy. Although DMARDs were found to contribute to mesangial GN in the study by Helin et al, 6 isolated haematuria in RA patients was found to be unrelated to DMARD therapy. Renal function was normal or slightly reduced in patients with gold and penicillamine related nephropathies. Membranous glomerulonephritis is not always found to be a consequence of DMARD therapy. It has been noted in patients of RA who had not received drugs known to cause membranous glomerulonephritis. Zarzara et al 11 reported a case of membranous glomerulonephritis in a case of RA who had never been treated with gold or d-penicillamine. Freidman et al 12 reported a case of RA who developed focal segmental glomerulonephritis with nephrotic range proteinuria within a year of clinical diagnosis and in the absence of therapy with either gold or d-penicillamine. Adu et al 13 studied 10 patients who developed glomerulonephritis not related to gold or d- penicillamine. Renal histology showed membranous glomerlonephritis in five, mesangial IgA nephropathy in two, focal segmental necrotizing glomerulonephritis in two and focal segmental glomerulosclerosis in one case. This suggests that progressive glomerular disease can occur with RA in the absence of any treatment known to produce nephrotic syndrome and that it is not associated either with long standing or particularly aggressive joint disease. Saito et al 14 compared thickness of glomerular basement membrane in 48 RA patients as against 10 controls after ruling out secondary glomerular diseases and hereditary thin basement membrane disease. They found that the mean GBM thickness was significantly thinner in RA patients as against the control group. However, the mean GBM thickness of RA patients without gold sodium thiomalate treatment (GST) was not statistically different from the control group, while RA patients with GST had significantly thinner GBM as compared to controls. This led the authors to conclude that the thinning of GBM in RA may be related to GST treatment. Nakano et al 15 retrospectively analysed renal biopsies from 158 RA patients with urinary abnormalities and/or renal dysfunction in order to clarify characteristics of renal pathology and its relation to DMARDs. Mesangial proliferative GN was diagnosed in 54 cases, membranous GN in 49 and secondary amyloidosis in thirty. Renal dysfunction JAPI VOL. 52 JUNE 2004

4 was more common in those with amyloidosis (22/30) than in those without (40/128). Forty of the 49 patients with membranous GN developed it while on DMARDs. Two thirds of the patients with mesangial GN developed renal disease when no DMARDs were used and half of them demonstrated IgA GN by IF. Diffuse thinning of the GBM was seen in 30 of the 81 specimens subjected to electron microscopy The study found no co-relation between DMARDs and renal disorders excepting membranous GN. In the study by Helin et al, 6 chronic interstitial nephritis was not found in any of the patients. The authors concluded that RA patients are not at special risk of developing analgesic nephropathy as drug intake is intermittent and under medical supervision. In a more recent study by Tsybul ko et al, of the 94 patients of RA examined were on NSAIDs continuously, eighteen patients for a year, 32 for 5 years, 14 for 6 to 10 years and 17 for over 10 years. Glomerular and tubular dysfunction was found in 69 patients and signs of early renal failure in 20 patients, but no cases of acute renal failure were reported. There was no relationship between both 5 and 10 year use of NSAID to the symptoms of renal disease, but use for over 10 years was concurrent with signs of chronic renal failure and hypertension. CLINICAL MANIFESTATIONS AND URINE ABNORMALITIES Overt clinical presentation due to renal involvement in RA is rare except in the presence of vascuilits or amyloidosis. Most patients present with urine abnormalities like haematuria, proteinuria or both. Renal impairment with rise in creatinine is not common if vasculitis and amyloidosis are excluded. Korpela et al 17 evaluated the presence and causes of isolated haematuria in an unselected RA population of 1018 patients as against an age and sex matched control population (n=457). The prevalence of isolated microscopic haematuria was not significantly more frequent in patients with RA than in age and sex matched controls. Mesangial glomerulopathy was the most common renal biopsy finding in RA patients with isolated haematuria. In a study by Boers et al 4 involving132 necropsies of RA patients with a mean duration of illness of 14.5 years studied during their final year of illness, 20% had urine abnormalities with normal renal function, 21% had urine abnormalities with loss of renal function (as defined by serum creatinine >100mmol/l), 11% had loss of renal function with normal urine findings and 23% were uraemic (defined as serum creatinine >200mmol/l) at death. Patients with amyloidosis had a longer duration of RA. Amyloidosis was accompanied by proteinuria and uraemia (both occurred in 11 of the 14 patients with amyloidosis). In the study by Yoshida et al, 5 of the 31 patients of RA, with renal disease 17 were found to have nephrotic syndrome, five had isolated proteinuria, two had proteinuria and haematuria and seven had renal failure. Harper et al 18 reported 10 patients of RA who developed focal segmental necrotizing glomerulonephritis (FSNGN) and extracapillary proliferation typical of vasculitic glomerulonephritis. Renal presentation was with renal impairment in nine (median creatinine 726 mmol/ l), microscopic haematuria in eight and proteinuria in ten patients. Five patients had extrarenal vasculitis. Four out of the five patients were p-anca positive. Nine patients were seropositive and had bony erosions suggesting that FSNGN should be considered in RA patients who are seropositive, have extra-renal vasculitis and renal dysfunction. However, Qarni et al 19 reported two cases of RA with deteriorating renal function due to p-anca positive pauci-immune necrotizing crescentic GN with minimal systemic vasculitic signs or symptoms. They suggest that one should suspect necrotizing GN in patients of RA who present with acute renal insufficiency even in the absence of frank vasculitis. Yoshihara et al 20 have similarly reported three cases of RA complicated by myeloperoxidase specific-anca associated glomerulonephritis which presented as RPGN. All three patients developed rapid deterioration in renal function and developed residual chronic renal insufficiency. Kuznetsky et al 21 reported four cases of RA who underwent renal biopsy for declining renal function, proteinuria and active urine sediment. Pathology revealed segmental necrotizing glomerulonephritis without significant glomerular deposition in three and segmental necrosis with diffuse membranous glomerulonephritis in the fourth case. Matsubara et al 22 have described a patient with RA who developed nephrotic syndrome with normal renal function while on d-penicillamine. Biopsy revealed minimal change glomerulopathy(mcns). The patient responded over 6 weeks to steroids and stoppage of all drugs except for NSAID. In view of the low incidence of minimal change disease associated with either d-penicillamine or NSAID, the authors postulated that MCNS may be associated with RA. NATURAL HISTORY/PROGNOSIS: Korpela et al 23 followed up 23 patients with RA and renal biopsy proven mesangial glomerulopathy for 4 to 117 months in order to evaluate the course of renal disease. At the time of renal biopsy, isolated haematuria was seen in 10 patients, isolated proteinuria in five and haematuria combined with proteinuria in seven cases. Haematuria persisted and renal function remained normal in all patients with isolated haematuria. No correlation was found between haematuria and the use of antirheumatic drugs, but proteinuria was associated with the use of anti-rheumatic drugs in nine out of 13 cases. Renal function remained stable in all but one patient with IgA glomerulonephritis who developed nephrotic syndrome. In a study by Kelly et al, patients with seropositive RA and previously documented haematuria were recalled at a median 7.7 years (range 3-12) after initial investigation. Of the 18 patients who had undergone biopsy, mesangial GN was found in all but four cases. Renal function was found to have remained normal in all patients with previous mesangial changes despite the presence of persistent haematuria in JAPI VOL. 52 JUNE

5 most cases. Koseki et al 25 prospectively studied proteinuria, haematuria and renal dysfunction in 235 patients of early RA who presented within a year of onset of RA as against a group of 100 controls. This study found that drug induced renal dysfunction and proteinuria occurred in only 1.7% and 1.5% patients respectively. The outcome of DMARD induced nephropathy was generally good and raised CRP, increased ESR and age > 50 years were the risk factors for persistent drug induced proteinuria. NSAIDs were found to play a role in renal dysfunction in those on diuretics or with dehydration. However, haematuria had no co-relation with drug therapy and was related to disease activity supporting the notion that mesangioproliferative glomerulonephritis can be caused by RA itself. MARKERS OF RENAL INVOLVEMENT Although renal biopsy is the gold standard, recent reports have looked at glomerular and tubular proteinuria as markers of nephropathy in RA. These were preferred over serum creatinine 26 and creatinine clearance 27 which have been shown to lack sensitivity to detect renal dysfunction in RA.This is attributed to loss of muscle mass and hence creatinine production as also to altered renal handling of creatinine due to either intrinsic renal disease or drug therapy (NSAID). Neiderstadt et al 28 studied 44 RA patients (none of whom were cases of amyloidosis) against 46 controls (osteoarthritis) by applying a highly sensitive immunoluminometric assay for quantification of individual urinary marker proteins. None of the patients were subjected to renal biopsy. NSAID, gold and penicillamine consumption was recorded in all patients. Twenty four of 44 RA patients had pathological proteinuria (defined as urine albumin > 25mg/l and α1-microlgobulin > 14mg/l) while impaired renal function as detected by elevated serum creatinine or reduced creatinine clearance was seen in only two RA patients. The median serum creatinine as also creatinine clearance when corrected for age was similar in the two groups. The patients with RA showed a broad range of urinary protein excretion. In six of the 24 cases, a possible cause like vasculitis, gold or penicillamine consumption was present. All the six patients had non-selective glomerular proteinuria. Patients taking gold or d-penicillamine had a proteinuria below nephrotic range although the creatinine clearance was equal to that of the control group. Also a pathological mixed glomerular-tubular proteinuria and a decreased creatinine clearance was detected in four of five patients with vasculitis. Of the remaining 18 patients with pathological proteinuria and no obvious cause, three had selective glomerular proteinuria, 10 had tubular proteinuria and five had non-selective glomerular-tubular proteinuria. They concluded that proteinuria is frequent in RA (nephropathy) and screening for renal disease should not only include creatinine measurement but also more sensitive methods to detect glomerular and tubular proteinuria. Pederson et al 29 studied the prevalence of microalbuminuria in 65 patients with RA and the association between urinary albumin excretion and disease activity (estimated by ESR and CRP) as also with antirheumatic drugs. Patients with previous renal disease, hypertension, diabetes were excluded and urinary albumin was assayed by immunoturbidimetry in random urine samples on two occasions within 7 months. Urinary albumin to creatinine ratio in patients was significantly greater than in controls. Microalbuminuria was present in 27.7% of patients with RA and 2.8% of controls. Treatment with gold or d-penicillamine increased the risk of developing microalbuminuria. Urinary albumin excretion was found to be significantly correlated with CRP and may be a sensitive indicator of disease activity. Hence microalbuminuria may be used as a simple and sensitive test to detect early subclinical renal dysfunction as also drug induced renal damage in RA. Similar results were reported by Nordin et al 30 who studied 65 RA patients as against 51 age and sex matched controls. Microalbuminuria was significantly increased in RA patients (27.7%) as compared to 7.8% controls. Patients with microalbuminuria had a significantly greater median duration of disease. Similarly a significant correlation was found with CRP as a marker of disease activity and treatment with gold and d-penicillamine. This reconfirmed its use as a simple and sensitive test to detect early subclinical renal dysfunction as also drug induced renal damage in RA. Salli et al 31 studied microproteinuria as an index of initial renal lesion in patients with rheumatoid arthritis. Twenty patients of RA with a negative routine proteinuria test and 20 healthy controls were screened for microproteinuria using multifractional Cellogel RS electrophoresis of urinary proteins. 11 RA patients showed glomerular type proteinuria (five selective and six non-selective type) as against no microproteinuria in controls. The authors suggested that in view of the high sensitivity, easy handling and low cost of multifractionated electrophoresis, it should be introduced as a routine test for all RA patients. Urinary N-acetyl glycosaminidase (NAG) is another marker that has been studied. Measurement of NAG is a simple and sensitive test of renal damage that is used as an early warning sign of renal graft rejection. Dieppe et al 32 have reported a significant positive co-relation between urinary NAG excretion and disease activity. An abnormally raised urinary NAG level was detected in eight of 20 previously untreated RA patients suggesting that the rheumatoid process affects renal function. A more recent study by Iqbal et al 33 looked at excretion of NAG and its isoenzyme patterns in two groups of patients with RA (20 seropositive and 19 seronegative) and in 15 normal control subjects. The mean urinary NAG value in RA patients was found to be significantly higher in seropositive RA compared to the mean NAG value in normal healthy subjects and patients with seronegative RA. NAG exists in two isoforms A and B. The mean proportion of isoenzyme form B to A in seropositive RA patients was found to be significantly different from the proportion of these forms in normal healthy subjects and seronegative RA patients. A correlation JAPI VOL. 52 JUNE 2004

6 between concentration of urinary NAG and severity of disease in seropositive RA was also observed. Boers et al 34 looked at vasculitis and hypergammaglobulinaemia as risk factors for renal disease. They studied GFR, effective renal plasma flow, creatinine clearance, 24 hour urinary proteins and urine sediment for assessing glomerular function. Tubular function was assessed by urine and serum beta-2 microglobulin, urinary NAG, urinary glucose and maximum urinary concentrating capacity and acid excretory capacity. No single pathological process emerged as a cause of renal dysfunction. Glomerular damage was implied by the finding of reduced GFR and microproteinuria. GFR co-related negatively with age and duration of RA and positively with creatinine clearance. Tubulointerstitial damage was reflected by an increased excretion of NAG and beta-2 microglobulin and defective urinary concentrating capacity. Although both vasculitis and hypergammaglobulinaemia did not come out as definite risk factors, the study concluded that the disease and the drugs administered in RA cause a mild chronic nephropathy which remains unnoticed till subsequent trauma either related to RA (e.g. amyloidosis) or unrelated to RA (e.g. urinary tract infection) produces an overt renal insufficiency. Lewandowski et al 35 studied beta -2-microglobulin concentration in serum and urine of 50 RA patients. A significant increase of beta-2 microglobulin concentration in serum of patients without rheumatoid factor and in patients with proteinuria was seen. The concentration of beta-2 microglobulin in urine was significantly higher than in controls but did not change the treatment. They concluded that beta- 2 microglobulin may be a marker of early renal damage in RA. A larger study by Viergever et al 36 which looked at serum and 24- hour urinary beta-2 microglobulin in a group of 101 RA patients without any signs of renal disease in the past or present as against controls, found an elevated 24- hour urinary beta-2 micoglobulin due to renal proximal tubular dysfunction in 19% of patients but not in controls. There was a significant correlation with clinical signs of extra-articular RA. Elevated serum beta-2 microglobulin levels were observed in 44% of RA patients and only in 3% of controls. This also correlated with clinical signs of a more severe RA as well as with increased 24-hour urinary beta-2 microglobulin excretion. Recently cystatin C has been used as a new parameter of renal function. Cystatin C is a proteinase inhibitor with a low molecular weight. It is produced at a constant rate in all nucleated cells, freely filtered in the renal glomeruli and reabsorbed and catabolised in the proximal tubules. The concentration of serum cystatin C is mainly determined by glomerular filtration, which makes it an endogenous marker of GFR. 37 Serum cystatin C is independent of age, sex and muscle mass. It has been shown to be useful in detecting mild reduction in GFR and may be therefore important in detection of early renal insufficiency 38 and subclinical renal dysfunction. 39 However, it is still premature to suppose that cystatin C can replace creatinine in routine tests but can be useful in cases in which it is not possible to determine creatinine clearance. 40 Mannge et al 41 studied the renal status of patients suffering from prolonged RA by measuring plasma cystatin C levels. Fifty six patients with RA of more than 5 years duration and treated with NSAIDs for more than 50 months were included. Besides plasma creatinine, estimated GFR, creatinine clearance, plasma cystatin C was analysed by an automated nephelometric immunoassay. Sixty percent of RA patients exhibited elevated levels of plasma cystatin C as against only three of the 56 patients who showed elevated plasma creatinine, even though creatinine clearance was decreased in 57% of patients. Elevated cystatin C indicated incipient renal disease and can be recommended for screening purposes as it is a simple and reproducible technique unlike the tedious clearance determinations. REFERENCES 1. Boers M Renal disorders in rheumatoid arthritis. Semin Arthritis Rhem 1990;20: Salomon MI, Gallo G, Poon TP, Goldbalt MV, Tchertkoff V. The kidney in rheumatoid arthritis. Nephron 1974; 12: Ramirez G, Lambert R, Bloomer A. Renal pathology in patients with rheumatoid arthritis. Nephron 1981;29: Boers M, Croonen AM, Dijkmans BA, Breedveld FC, et al. Renal findings in rheumatoid arthritis: clinical aspects of 132 necropsies. Ann Rheum Dis 1987;46: Yoshida K,Morozumi K, Sunganuma T, Aoki J, et al. 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Microproteinuria as an index of initial renal lesion in patients with rheumatoid arthritis. Clin Exp Rheumatol 1990;8: Dieppe PA, Doyle DV, Burry HC, Tucker SM. Renal disease in rheumatoid arthritis. Br Med J 1976;1: Iqbal MP, Ali MM, Waqar MA, Mehboobali N. Urinary N- acetyl-d-glucosaminidase in rheumatoid arthritis. Exp Mol Med 1998;30: Boers M, Dijkmans BAC, Breedveld FC, Camps JA, et al. Subclinical renal dysfunction in rheumatoid arthritis. Arthritis Rheum 1990;33: Lewandowski B, Bernaka K, Kucharewicz B, Szimitkowski M, Klimiuk PA. Assessment of beta-2-microglobulin concentration in serum and urine in rheumatoid arthritis. Rocz Akad Med Bialymst 1996;41: [Abstract] 36. Viergever PP, Swaak AJ. Urine and serum beta-2- microglobulin in patients with rheumatoid arthritis: a study of 101 patients without signs of kidney disease. Clin Rheumatol 1989;8: Randers E, Erlandsen EJ. Serum Cystatin C as an endogenous marker of the renal function- a review. 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Clin Chim Acta 2000; 300: Announcement API Tripura Branch is going to organize Joint Conference of IV Annual Conferene of API - Tripura (TAPICON ) alongwith VI Annual Conference of CSI - NE Chapter (NE - CARDICON) at Agartala on 10th-12th September, For further details please contact : Dr. Pradip Bhaumik, General Secretary, API - Tripura Branch and Organising Secretary (TAPICON and NE - CARDICON) Dhaleswar, Road No - 1, Agartala , Tripura. Ph. (0381) (Resi), (Clinic), Mobile : Fax : (0381) pradeepagt@yahoo.com JAPI VOL. 52 JUNE 2004