Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the least studied of the causes of idiopathic nephrotic syndrome, and there are few specific guidelines for treatment. AIM: To review data from five UK renal units to investigate whether adult patients with FSGS were treated uniformly, and to examine the effect of treatment on proteinuria and survival. DESIGN: Retrospective record review. METHODS: We examined electronic records of patients with idiopathic FSGS for information on baseline clinical parameters, treatment regimens and outcomes. RESULTS: Of 136 patients with primary FSGS and nephrotic range proteinuria, 76 (56%) were treated with prednisolone and of this group, 59% were treated with additional immunosuppression. Among the treated patients, the total remission rate (complete and partial) was 67%, and one hospital achieved a remission rate of 80%. Treated patients had a significantly higher remission rate than those who were not treated. Remission was associated with a 5-year survival off dialysis of 94%, compared with 53% if remission was not achieved. Baseline serum creatinine and remission were independently associated with survival off dialysis in a multivariate Cox proportional hazards model. DISCUSSION: Patients with primary FSGS and nephrotic range proteinuria, who are treated with corticosteroids, are more likely to enter remission than those who are not treated. Remission rates of up to 80% can be achieved with prolonged treatment, and remission is an independent predictor of survival off dialysis. Patients who do not achieve remission have a poor prognosis. Further clarification of optimal treatment regimens requires additional, prospective studies.

The link between circulating markers of endothelial function and proteinuria in patients with primary glomerulonephritis.

INTRODUCTION: It is well established that there is an increase in the incidence of cardiovascular mortality in patients with proteinuric renal disease. The magnitude of the increase in risk is unlikely to be explained by traditional risk factors for cardiovascular disease alone. Proteinuria itself may constitute an additional risk factor, and proteinuric patients are known to have a degree of endothelial dysfunction. The nature of this relationship between proteinuria and endothelial function is the subject of intense investigation. AIM: The aim of this study was to examine the relationship between proteinuria and endothelial dysfunction, as reflected by serum von Willebrand factor (vWF), and the soluble cell adhesion molecules VCAM and ICAM, in patients with primary glomerulonephritis (GN). A secondary aim was to discern whether any relationship could be explained by renal function, lipid profile, inflammation or blood pressure. METHODS: A cross-sectional study was undertaken in consecutive patients attending a general nephrology clinic with biopsy-proven primary GN. Patients with end-stage renal disease (ESRD), those on immunosuppressive drugs, or with intercurrent infective illnesses were excluded. Blood pressure and body mass index were recorded. Routine lab assays were undertaken for serum creatinine, lipid profile, and 24-hour urinary protein (U(Prot)). Additional serum samples were stored at -80 degrees C for subsequent measurement of vWF, VCAM, ICAM and sensitive C reactive protein (sCRP). RESULTS: Data were collected from 129 (86 male) patients. Mean (standard deviation) estimated creatinine clearance was 64 (32) ml/min, and median (interquartile range) 24-hour proteinuria was 1.1 (0.22-2.9) g. Mean vWF was 173 (68) IU/dl, median VCAM, ICAM and sCRP were 594 (410-708) ng/ml, 235 (208-286) ng/ml, and 2.33 (0.83-5.68) mg/l, respectively. There was a significant positive correlation between vWF and U(Prot) (Spearman rank correlation, r = 0.41, p < 0.001). When split into tertiles, according to U(Prot) (0-500 mg, 500-2000 mg, and > 2000 mg), there was a significant, stepwise increase in mean vWF (p < 0.001), log VCAM (p < 0.001), and log ICAM (p = 0.002). On multivariate analysis with vWF as the continuous dependent variable, U(Prot), age, total cholesterol and sCRP were the only significantly independent correlates (model-adjusted R2 = 33%). CONCLUSION: In patients with primary GN, there is a significant association between endothelial activation as reflected by vWF, VCAM, or ICAM and increasing proteinuria. Elevations in vWF, as well as being related to classical risk factors, are associated with increases in total proteinuria and low-grade inflammation. Thus, future prospective studies should examine the extent to which vWF and other circulating markers of endothelial activation predict coronary heart disease risk in patients with proteinuric renal disease.

Intensified treatment of patients with type 2 diabetes mellitus and overt nephropathy.

BACKGROUND: Diabetic nephropathy is the single most common cause of chronic renal failure requiring dialysis. Effective treatment exists, but no clinical audit or large trial has reduced the rate of loss of renal function as effectively as in small groups of intensively managed patients. AIM: To determine the effect of intensive vs. standard medical management on the rate of progression of renal failure in patients with diabetic nephropathy. DESIGN: Prospective randomized controlled study. METHODS: Patients with type 2 diabetes and nephropathy were randomly allocated to an intensive group (n = 47) or control group (n = 43). Treatment targets were the same for both groups, but the intensive group were seen as often as required to meet the targets; controls were seen at their normal clinics. The primary end-point was the rate of progression of renal disease in the second year. RESULTS: The groups were well matched at baseline. During follow-up, the intensive group had lower mean SBP, DBP and cholesterol. Median rate of progression of renal failure in the intensive group fell from 0.44 ml/min/month in the first year to 0.14 ml/min/month in the second year, compared to 0.49 ml/min/month and 0.53 ml/min/month in the control group (p = 0.04 for second year). Patients in the intensive group spent significantly less time in hospital. DISCUSSION: Intensive treatment slowed progression of renal disease within 2 years in patients with established diabetic nephropathy. Mean creatinine clearance at the start of the trial was 55 ml/min, so assuming that the rates of progression achieved at the end of the second year persisted, onset of dialysis would be delayed by 20 years in the intensive group compared with the control group.

Diabetic nephropathy: how effective is treatment in clinical practice?

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal failure in patients starting dialysis in the developed world. In clinical trials, interventions, particularly blood pressure control, have achieved major reductions in the rate of decline in renal function. AIM: To investigate whether results from clinical trials can be achieved in routine clinical practice. DESIGN: Observational study of 170 consecutive patients referred to a combined diabetic-renal clinic over a 10 year period. METHODS: We collected demographic and laboratory data from the electronic patient record. RESULTS: Median serum creatinine at referral was 170 micromol/l and was >350 micromol/l in 26% of patients. Mean blood pressure (BP) was 159/85. The publication of guidelines by the Scottish Intercollegiate Guidelines Network in 1997, recommending more active intervention and earlier referral, had no impact on referral BP and creatinine. In the 125 patients with at least 1 year follow-up, significant improvements in BP, albuminuria, HbA(1c) and serum cholesterol were seen. In the 63 patients followed up for 3 years (median creatinine 120 micromol/l), the median rate of decline in renal function slowed from 0.52 ml/min/month (first year) to 0.27 ml/min/month (third year) (p=0.003), nearly doubling the time to end-stage renal failure. DISCUSSION: Patients referred early to a combined diabetic-renal clinic benefited by slowing in the rate of decline of renal function. A challenging but achievable standard for audit would be to reduce the rate of progression to <0.25 ml/min/month in 70% of patients with diabetic nephropathy presenting with a serum creatinine <150 micromol/l.

The atherogenic lipoprotein phenotype: small dense LDL and lipoprotein remnants in nephrotic range proteinuria.

The dyslipidaemia in nephrotic-range proteinuria is believed to contribute to the increased atherogenesis associated with the condition. Excess small dense low density lipoprotein (LDLIII) contributes to this risk. Lipoprotein remnants (RLP) may also be implicated but have not been studied in this population. We measured the plasma concentration of low density lipoprotein (LDL) subfractions (by density gradient ultracentrifugation), RLP (by immunoaffinity gel), very low density lipoprotein (VLDL) subfractions, post heparin lipases and cholesteryl ester transfer protein (CETP) activity in 27 patients with glomerular disease and albuminuria >2.0g. These were compared with 27 age and sex matched controls. Proteinuric patients had increased LDLIII concentration (patients 182 (84:267) vs. controls 31 (27:62); P<0.0001) with reduced lighter LDLI (36 (24:43) vs 69 (46:101); P<0.0005) and LDLII (124 (79:220) vs 178 (129:236); P<0.04, all mg/dl, median+interquartile range). RLP-cholesterol (RLP-C) and triglyceride (RLP-TG) were increased in proteinuric patients (RLP-C 18.9 (11.0:26.9) vs 7.7 (6.0:8.8); P<0.0001, RLP-TG 35.8 (11.8:54.7) vs. 7.2 (4.3:10.0); P<0.0001, all mg/dl). Increased LDLIII and RLP were independent of renal function. VLDL(1) and VLDL(2) concentrations were increased by 258 and 260% (both P<0.0001). CETP activity was increased by 46% (P<0.005). Lipoprotein and hepatic lipase activities did not differ from control values. LDLIII concentration (r(2)=45.7%, P<0.001), RLP-C (r(2)=85.2%, P<0.001) and RLP-TG (r(2)=87.5%, P<0.001) all correlated positively with plasma triglyceride. Moreover, increased LDLIII was associated with both RLP-C (r(2)=31.3%, P<0.002) and RLP-TG (r(2)=33.6%, P<0.002). Excess LDLIII and RLP are present in nephrotic-range proteinuria and add to the spectrum of cardiovascular risk factors present in proteinuric patients. Increases in LDLIII and RLP are closely related to plasma triglyceride. The association between excess RLP and LDLIII suggests that RLP contribute to the increased atherogenicity attributed to the atherogenic lipoprotein phenotype.

Patients with nephrotic-range proteinuria have apolipoprotein C and E deficient VLDL1.

BACKGROUND: Impaired very low-density lipoprotein (VLDL) clearance contributes to dyslipidemia in nephrotic-range proteinuria. VLDL can be subdivided into large light VLDL1 (Sf 60 to 400) and smaller, denser VLDL2 (Sf 20 to 60). In nephrotic-range proteinuria, the clearance of VLDL1 is delayed. VLDL1 lipolysis is influenced by apolipoprotein CII (apoCII) and apoCIII, whereas apoE regulates receptor-mediated clearance. METHODS: To ascertain whether impaired VLDL1 clearance was related to a deficiency in apolipoproteins on VLDL1, we measured VLDL subfraction concentrations and VLDL1 apolipoprotein and lipid compositions in 27 patients with glomerular disease and urinary albumin> 2 g/24 h along with 27 age- and sex-matched controls. RESULTS: Proteinuric patients had increased plasma VLDL1, VLDL2, apoCII, apoCIII (all P < 0.001), and apoE concentration (P < 0.002). Patients appeared to have smaller VLDL1 particles, as assessed by triglyceride per particle (median + interquartile range, moles per VLDL1 particle): patients, 4.9 (3.0 to 7.9) x103; controls, 7.0 (4.6 to 15.7) x103, P < 0.05, with reduced apoCII, 4.2 (3.1 to 8.2) versus 9.9 (7.4 to 23.2), P < 0.0004; apoCIII, 16.6 (9.1 to 27.2) versus 29.3 (18.5 to 69.4), P < 0.02; and apoE content, 0.17 (0.08 to 0.44) versus 0.48 (0.31 to 1. 31), P < 0.006. The VLDL1 surface free cholesterol to phospholipid results were increased in proteinuric patients (0.55 +/- 0.17 vs. 0. 40 +/- 0.18, P < 0.002, all mean +/- SD). For all patients, VLDL1 apoCII, apoCIII, and apoE contents per particle were related to particle size (apoCII, r2 = 61.5%, P < 0.001; apoCIII, r2 = 75.8%, P < 0.001; apoE, r2 = 58.2%, P < 0.001) and inversely to the free cholesterol to phospholipid ratio (apoCII, r2 = 41.6%, P < 0.001; apoCIII, r2 = 38.8%, P < 0.001; apoE, r2 = 11.7%, P < 0.05). Multivariate analysis suggested that the relative lack of apoCII and apoCIII on patients VLDL1 was related to smaller particle size and increased free cholesterol:phospholipid (FC:PL) ratio. Particle size but not free cholesterol determined the apoE content of VLDL1. CONCLUSIONS: We postulate that impaired VLDL1 clearance in nephrotic-range proteinuria results from the appearance of particles deficient in apoCII, apoCIII, and apoE. VLDL1 apoC deficiency is associated with the formation of smaller particles with a high FC:PL ratio, and is likely to cause inefficient lipolysis. VLDL1 apoE deficiency is associated with smaller VLDL1 particles but not altered VLDL1 surface lipid content, and may reduce receptor-mediated clearance of this lipoprotein.

Presentation, survival and prognostic markers in AA amyloidosis.

We reviewed 43 patients with AA amyloidosis who presented to our unit between 1985-1999: 70% had an underlying chronic rheumatological diagnosis. Median (95% CI) patient survival from time of diagnosis was 52.9 months (9.4-96.6) and median renal survival was 18 months (3.2-32.8) Twenty-four patients have died; 42% of deaths were due to infection, while renal failure accounted for 12.5%. Presenting factors which adversely influenced outcome were a low serum albumin and a high 24-h urinary albumin excretion (p=0.007 and p=0.003, respectively). Stepwise multivariate regression analysis identified albuminuria and presenting creatinine clearance as significant predictors. (p=0.005 and p=0.035, respectively). Mean C-reactive protein (CRP) throughout follow-up correlated weakly but not significantly with survival off dialysis (p=0.06). Change in creatinine clearance correlated with albuminuria. (r(2)=40%, p=0.001)

Atherogenic lipoprotein phenotype in end-stage renal failure: origin and extent of small dense low-density lipoprotein formation.

End-stage renal failure (ESRF) is associated with dyslipidemia and accelerated atherosclerosis. Triglyceride-rich lipoproteins accumulate and qualitative changes take place in low-density lipoprotein (LDL), with a predominance of the small dense LDL phenotype. Increased small dense LDL (LDLIII) is a known risk factor for cardiovascular disease. To assess the extent of LDLIII formation in ESRF and identify factors contributing to LDLIII production, we analyzed LDL subfractions by density-gradient ultracentrifugation, very low-density lipoprotein subfractions, and lipase activity in 75 patients with ESRF (25 hemodialysis [HD], 25 peritoneal dialysis [PD], and 25 predialysis patients) and 40 age- and sex-matched controls. The percentage of LDLIII was increased in all three patient groups compared with controls (PD, 33% +/- 29% [mean +/- SD]; P < 0.005; HD, 30% +/- 22%; P < 0.01; predialysis, 26% +/- 26%; P < 0.01; all versus controls, 14% +/- 10%). Plasma LDLIII concentration was increased only in PD patients (median, 84 mg/dL; interquartile range [IQR], 29 to 160 mg/dL versus controls; median, 31 mg/dL; IQR, 26 to 54 mg/dL). In other patient groups, total LDL level was less, with heterogeneity in LDLIII concentrations. Forty percent of PD patients and 28% of HD and predialysis patients had LDLIII concentrations greater than 100 mg/dL compared with 2.5% of controls (P = 0.002). Plasma triglyceride levels (r(2) = 38.4%; P < 0.001) and hepatic lipase activity (r(2) = 6.7%; P < 0.03) were independent predictors of LDLIII concentration. The strong association between LDLIII concentration and triglyceride level was present in all three patient groups (HD, r(2) = 47.9%; PD, r(2) = 45. 2%; predialysis, r(2) = 25.8%); plasma triglyceride levels greater than 177 mg/dL (2.0 mmol/L) had an 86% specificity and 79% sensitivity for predicting an LDLIII concentration greater than 100 mg/dL. We conclude that the atherogenic lipoprotein phenotype predominates in ESRF, with excess LDLIII particularly prominent in PD patients. Atherogenic levels of LDLIII are found in patients with triglyceride levels greater than 177 mg/dL. This is likely to represent a further cardiovascular risk factor in this population.

Has the prognosis for patients with pauci-immune necrotizing glomerulonephritis improved?

BACKGROUND: Over the past 14 years, important advances have been made in diagnosis and treatment of patients with pauci-immune necrotizing glomerulonephritis (PINGN). The present study set out to evaluate the impact of these advances on prognosis by comparing patient survival during the period 1985-1995 with previously reported results for such patients between 1975 and 1982. METHOD: A retrospective analysis was carried out at two affiliated inner-city renal units on all patients considered to have PINGN during the period 1985 1995. Details of renal and extra-renal disease at presentation and during follow-up, along with treatment regimes, were noted. Figures for renal and patient survival were compared with those previously reported from one of these units. RESULTS: A total of 47 patients were diagnosed over the period 1985 1995, with a median age of 57 years. The overall patient survival (+/- standard error) at 1 and 5 years was 72.3 (+/- 0.06) and 51.2% (+/- 0.12) respectively, with corresponding renal survival (alive and independent of renal replacement therapy) at these times of 61.7 (+/- 0.07) and 49.9% (+/- 0.09) respectively. We identified increased age at presentation and advanced renal failure (requiring dialysis or serum creatinine > 300 micromol/l) as predictors of reduced patient and renal survival. When comparing our results with those previously reported (1975-1982), we found no improvement in prognosis for patients with PINGN during the latter period. CONCLUSIONS: These results suggest that the prognosis for patients with PINGN has not improved despite diagnostic and therapeutic advances. Delay in diagnosis and treatment may compromise the therapeutic potential in PINGN.

Increased atherogenicity of low-density lipoprotein in heavy proteinuria.

BACKGROUND: Heavy proteinuria is associated with marked abnormalities of lipoprotein metabolism and increased risk of atherogenesis. It is possible that qualitative as well as quantitative changes occur in lipoproteins to contribute to increased cardiovascular risk; for example, it is known that LDL exhibits heterogeneity, with small, dense LDL III particles being more atherogenic. METHODS: We investigated LDL subfractions (measured by density gradient ultracentrifugation), VLDL subfractions, and post-heparin lipases in 12 patients with primary glomerular disease and 24-h albuminuria >2.5 g. These were compared to 23 age- and sex-matched controls. RESULTS: Total LDL concentrations were similar in proteinuric patients and controls; however, there was a shift in subfraction distribution. The larger LDL I and LDL II particles were lower in the proteinuric group (29 +/- 24 vs 62 +/- 26 mg/dl P=0.011 and 121 +/- 80 vs 197 +/- 74 mg/dl P=0.028), whereas the concentration of atherogenic LDL III (small dense) was higher (135 +/- 64 vs 75 +/- 71 mg/dl P=0.0016). The concentration of total VLDL and both its subfractions were increased in the patients with proteinuria. Post-heparin hepatic and lipoprotein lipase levels were similar to normal. CONCLUSIONS: These findings suggest that the atherogenicity of LDL is increased in patients with heavy proteinuria because of the redistribution towards smaller denser particles. Since small, dense LDL has a lower affinity for the LDL receptor, the altered nature of the lipoprotein in proteinuria may decrease its clearance by the receptor-mediated pathway and contribute to the reduced clearance of LDL observed in this population. This may contribute to progression of renal failure or the accelerated vascular disease found in patients with heavy proteinuria.

Immunosuppression and outcome in idiopathic membranous nephropathy.

From 1986 to 1996, 53 patients with idiopathic membranous nephropathy (IMN) presented to the Glasgow Royal Infirmary renal unit: 19 (36%) were treated because of progressive disease. We compared outcomes of treated and untreated patients with 37 historical and untreated controls. Five- and 10-year survival rates off dialysis were 83.5 and 53.5%, respectively. At the end of a mean observation period of 5.9 years, 47% of patients were in remission, 13% had reached end-stage renal failure, 15% had died, 13% had persistent proteinuria but stable renal function, and 11% had declining renal function. These results are better than those in historical controls, with a reduction in the number of patients reaching ESRF (13% vs. 22%), a larger proportion of patients achieving remission (47% vs. 30%) and smaller numbers of patients with declining renal function (11% vs. 19%) at the end of a similar follow-up period. These data suggest that the use of immunosuppression in selected patients with IMN improves prognosis, although the results did not achieve statistical significance.

An artificial neural network can select patients at high risk of developing progressive IgA nephropathy more accurately than experienced nephrologists.

BACKGROUND: The object of the study was to develop an artificial neural network (ANN) to identify patients with IgA nephropathy (IgAN) with a poor prognosis and to compare the predictions of the ANN with the predictions of six experienced nephrologists. METHODS: The following data from the time of renal biopsy were retrieved from the records of 54 patients with IgAN: age, sex, systolic and diastolic blood pressure, number of prescribed antihypertensive drugs, 24-h urine protein excretion, and serum creatinine. Patients aged less than 14 years, or who had serum creatinine > 350 mumol/l at presentation, liver disease or concomitant kidney disease were excluded. Outcome was assigned as 'stable' if serum creatinine was < 150 mumol/l after 7 years and 'non-stable' if serum creatinine was > or = 150 mumol/l. The ANN was trained and tested using a 'jack-knife' sampling technique and performance evaluated in terms of number of correct predictions, sensitivity and specificity. The six nephrologists were asked to predict outcome at 7 years for each patient using the same data as the ANN and their performance was assessed in the same manner. RESULTS: The ANN assigned the correct outcome to 47/54 (87.0%) patients: sensitivity 19/22 (86.4%), specificity 28/32 (87.5%). The mean score for nephrologists was 37.5/54 (69.4%, range 35-40), mean sensitivity 72% and mean specificity 66%. CONCLUSIONS: An ANN trained using routine clinical information obtained at the time of diagnosis can potentially predict 7-year outcome for renal function in IgAN more accurately than experienced nephrologists, and can therefore identify a group of high-risk patients requiring close follow-up.

The influence of familial factors on the progression of IgA nephropathy.

BACKGROUND: Vascular risk factors in first degree relatives of patients with insulin dependent diabetes mellitus are known to increase the risk of that patient developing diabetic nephropathy. We explored the influence of vascular risk factors in first degree relatives on patients with stable (serum creatinine < 150 mumol/l for > 5 years) and progressive (serum creatinine > 200 mumol/l, and > 150% serum creatinine at presentation, after minimum follow-up at 2 years) IgA nephropathy (IgAN). METHODS: We compared sodium-lithium countertransport activity (SLC Vmax), plasma lipoprotein(a) and von Willebrand factor (vWf) concentrations, incidence of vascular disease, and incidence of hypertension in 37 first degree relatives of 23 patients with stable IgAN and 33 first degree relatives of 17 patients with progressive IgAN. The two groups of relatives were comparable with respect to other risk factors: age, smoking, blood pressure, and plasma glucose, creatinine, cholesterol and triglyceride concentrations. RESULTS: SLC Vmax was higher in relatives of stable patients (mean 0.37 mmol/h/l RBC [S.D. 0.18] vs 0.30 [S.D. 0.09]; P = 0.034 two-sample t-test). There was no difference between the relatives of stable and progressive patients in plasma lipoprotein(a) concentration (median 11.5 mg/l vs 13.0: P = 0.45; 95% C.I. -12 to 3; Mann-Whitney test), plasma vWf concentration (149.4 IU/dl [S.D. 55.6] vs. 163.2 IU/dl [S.D. 57.3]; P = 0.31 two-sample t-test), or incidence of hypertension (13/37 [35.1%] vs 10/33 [30.3%]; chi 2 = 0.185; P = 0.667). Relatives of patients with progressive IgAN had a slightly higher incidence of vascular disease (10/33 [30.3%] vs 8/37 [21.6%]; chi 2 = 0.688; P = 0.407). CONCLUSIONS: Familial vascular risk may increase the likelihood of progressive renal failure in patients with IgAN but the influence is likely to be small and unrelated to the factors we measured. SLC Vmax was significantly higher in relatives of patients with stable disease which contrasts with data from other studies and is unexplained.

Diabetic nephropathy: an observational study on patients attending a joint diabetes renal clinic.

Diabetic nephropathy is a major cause of renal failure, accounting for 20% of patients starting dialysis. In clinical trials, effective blood-pressure control, especially by angiotensin-converting-enzyme inhibitors (ACEIs), retards the rate of progression of renal failure substantially. We examined these effects in clinical practice by surveying patients at a joint diabetes renal clinic at Glasgow Royal Infirmary from 1989 to 1995. We examined the relationship between progression of diabetic nephropathy, mean arterial pressure (MAP), and the use of ACEIs. The average MAP of the whole group of patients fell by 7%, the urine albumin:creatinine ratio fell by 29%, and the rate of progression as measured by the slope of reciprocal of serum creatinine with time (l/mumol/day) was slowed, from -4.59 to -2.76. This is equal to delaying the necessity for dialysis by about 2 years. The joint clinic met its aim and was cost-effective.

Meloxicam pharmacokinetics in renal impairment.

AIMS: The aim of the present study was to determine how the pharmacokinetics of meloxicam are affected by kidney dysfunction and consequently to define the appropriate dose for the use of meloxicam in patients with mild or moderate renal impairment. METHODS: Meloxicam was administered to subjects with mild (creatinine clearance 41-60 ml min-1) to moderate (20-40 ml min-1) renal impairment compared with normal renal function (> 60 ml min-1). Thirty-eight subjects received meloxicam 15 mg once daily over 9 days. Meloxicam plasma concentrations were determined from blood samples taken during the study and pharmacokinetic parameters calculated according to noncompartmental methods. RESULTS: Subjects with no or mild renal impairment showed similar pharmacokinetic profiles (geometric mean AUCSS (%gCV) 55 (33%) vs 55 (38%) micrograms ml-1 h). Subjects with moderate renal impairment demonstrated lower total plasma meloxicam concentrations (AUCSS 35 (50%) micrograms ml-1 h, with corresponding higher plasma clearance (P = 0.013) compared with subjects with no renal impairment. However, this was combined with higher meloxicam free fractions in moderately impaired subjects such that free meloxicam concentrations were similar in all three groups. Meloxicam was well tolerated with few adverse events occurring and no difference in incidence observable between groups. CONCLUSIONS: On the basis of these results there is no necessity for a dosage adjustment when administering meloxicam to patients with mild to moderate renal impairment.