Renal safety of initial combination versus single DMARD therapy in patients with early rheumatoid arthritis: an 11-year experience from the FIN-RACo Trial.

OBJECTIVE: To evaluate the renal safety of traditional disease-modifying antirheumatic drugs (DMARDs) in early rheumatoid arthritis (RA). METHODS: One hundred and ninety-five DMARD-naïve patients with recent-onset RA were randomised to receive combination DMARD therapy (n=97) starting with sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone (COMBI) or monotherapy (n=98), initially with sulfasalazine, with or without prednisolone (SINGLE). After two years, the choice and dosing of DMARDs and prednisolone were not restricted, but the treatment was still targeted to achieve or maintain remission. Urinalysis, serum creatinine and glomerular filtration rate (GFR; estimated according to the Cockcroft-Gault formula [eGFRCG]) were analysed at baseline and at months 6, 9, 12, 18, 24 and thereafter yearly up to 11 years. RESULTS: The cumulative incidence of repeated (>or=3 times) abnormal renal findings during the 11-year follow-up period were as follows (COMBI versus SINGLE; p-values adjusted for age and sex): proteinuria (dipstick positive) 4.8% (95%CI 1.8-12.2) vs. 5.3% (95%CI 2.0-13.7, p=0.93), haematuria (dipstick positive) 14.1% (95%CI 8.0-24.2) vs. 22.1 % (95%CI 14.5-33.0, p=0.14), raised serum creatinine (>or=100 micromol/l in females and >or=115 micromol/l in males) 4.4% (95%CI 1.7-11.4) vs. 6.7% (3.0-14.3, p=0.87) and eGFRGC<60 ml/min/1.73 m2 11.9% (95%CI 6.8-20.5) vs. 10.5% (95%CI 5.8-18.7, p=0.85). CONCLUSION: Initial remission targeted therapy with the FIN-RACo DMARD combination in early RA is safe for kidneys and does not induce more short- or long-term renal complications compared to traditional therapy with a single DMARD.

Paricalcitol aggravates perivascular fibrosis in rats with renal insufficiency and low calcitriol.

Cardiovascular complications are a major problem in chronic renal failure. We examined the effects of plasma calcium, phosphate, parathyroid hormone (PTH), and calcitriol on cardiac morphology in 5/6 nephrectomized rats. Fifteen weeks after nephrectomy rats were given a control diet, high-calcium or -phosphorus diet, or given paricalcitol treatment for 12 weeks. Sham-operated rats were on a control diet. Blood pressure, plasma phosphate, and PTH were increased, while the creatinine clearance was reduced in remnant kidney rats. Phosphate and PTH were further elevated by the high-phosphate diet but suppressed by the high-calcium diet, while paricalcitol reduced PTH without influencing phosphate or calcium. The high-calcium diet increased, while the high-phosphate diet reduced plasma calcium. Plasma calcitriol was significantly reduced in other remnant kidney groups, but further decreased after paricalcitol. Cardiac perivascular fibrosis and connective tissue growth factor were significantly increased in the remnant kidney groups, and further increased in paricalcitol-treated rats. Hence, regardless of the calcium, phosphate, or PTH levels, cardiac perivascular fibrosis and connective tissue growth factor increase in rats with renal insufficiency in association with low calcitriol. Possible explanations are that aggravated perivascular fibrosis after paricalcitol in renal insufficiency may be due to further suppression of calcitriol, or to a direct effect of the vitamin D analog.

Severity of tubulointerstitial inflammation and prognosis in immunoglobulin A nephropathy.

Many risk factors for progression in immunoglobulin A nephropathy (IgAN) have been found. We focused on renal leukocyte infiltrations and cytokines in IgAN. The subjects were 204 IgAN patients. Renal histopathological changes were semiquantitatively graded. Expression of tubulointerstitial Leukocyte common antigen (LCA), CD3, CD68, interleukin (IL)-1beta, and IL-10 was evaluated by immunohistochemistry. These parameters were correlated with progression of IgAN. The significance of these correlations was tested by a multivariate analysis. Glomerulosclerosis, tubular atrophy, interstitial inflammation, and hyaline arteriolosclerosis correlated with progression in all patients and also in patients with initially normal serum creatinine. Tubulointerstitial LCA, CD3, CD68, and IL-1beta expression correlated with progression. CD3 had the strongest correlation. In the multivariate analysis, tubulointerstitial CD3, hypertriglyceridemia, elevated serum creatinine concentration, and interstitial fibrosis were independently associated with progressive disease in all patients, and tubulointerstitial CD3 expression and hyaline arteriolosclerosis in patients with initially normal serum creatinine. We found parameters reflecting tubulointerstitial inflammation to predict deterioration of renal function in IgAN. This was also seen in patients whose serum creatinine was normal at the time of renal biopsy. Our findings show that, an immunohistochemical evaluation of tubulointerstitial inflammation seems to be a useful tool in determining the prognosis in IgAN.

Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis.

Nephropathia epidemica (NE) is a hemorrhagic fever with renal syndrome caused by Puumala hantavirus. Its long-term prognosis is considered favorable. There are, however, some reports about subsequent hypertension, glomerular hyperfiltration, and proteinuria after previous hantavirus infection. Therefore, we studied 36 patients 5 and 10 years after acute NE, with 29 seronegative controls. Office blood pressure, ambulatory 24-h blood pressure (ABP), glomerular filtration rate (GFR), and proteinuria were examined. Hypertensive subjects were defined as those patients having increased ambulatory or office blood pressure, or receiving antihypertensive therapy. Office blood pressure was used to define hypertension only if ABP was not determined. At 5 years, the prevalence of hypertension was higher among NE patients than in controls (50 vs 21%, P=0.020). At 10 years, the difference between the groups was no more significant (39 vs 17%, P=0.098). Five years after NE, patients showed higher GFR (121+/-19 vs 109+/-16 ml/min/1.73 m(2), P=0.012) and urinary protein excretion (0.19 g/day, range 0.12-0.38 vs 0.14 g/day, range 0.09-0.24, P=<0.001) than controls. At 10 years, there were no more differences in GFR or protein excretion between the groups (GFR: 113+/-20 vs 108+/-17 ml/min/1.73 m(2), P=0.370; proteinuria: 0.14 g/day, range 0.07-0.24 vs 0.13 g/day, range 0.06-0.31, P=0.610). In conclusion, the 10-year prognosis of NE is favorable, as glomerular hyperfiltration and slight proteinuria detected at 5 years disappeared during the longer follow-up. However, the possibility exists that NE may predispose some patients to the development of hypertension.

QTc dispersion increases during hemodialysis with low-calcium dialysate.

BACKGROUND: The risk of ventricular arrhythmias is known to increase during hemodialysis (HD) treatment, but the cause of this phenomenon has remained unidentified. QT dispersion (= QTmax - QTmin) reflects heterogeneity of cardiac repolarization, and increased dispersion is known to predispose the heart to ventricular arrhythmias and sudden cardiac death. METHODS: We studied the effect of dialysate calcium concentration on cardiac electrical stability during HD treatment in 23 end-stage renal disease patients. Three HD treatments were applied with dialysate Ca++ concentrations of 1.25 mmol/L (dCa++1.25), 1.5 mmol/L (dCa++1.5), and 1.75 mmol/L (dCa++1.75). The QTc interval and QTc dispersion were measured before and after the three sessions. RESULTS: With the dCa++1.5 and dCa++1.75 dialyses, serum Ca++ increased and the QTc interval remained stable (dCa++1.5) or decreased (dCa++1.75), but no significant change was noted in QTc dispersion. With dCa++1.25 HD, serum Ca++ decreased (1.24 +/- 0.11 vs. 1.20 +/- 0.09 mmol/L, P < 0. 05), and both the QTc interval (403 +/- 27 vs. 419 +/- 33 ms, P < 0. 05) and QTc dispersion increased (38 +/- 19 vs. 49 +/- 18 ms, P < 0. 05). The change in the QTc interval correlated inversely with the change in serum Ca++ (r = -0.68, P < 0.0001). Except for serum Ca++ and plasma intact parathyroid hormone, predialysis and postdialysis values in other blood chemistry, blood pressure, heart rate, body weight, and total ultrafiltration were equal in the three dialysis sessions. CONCLUSION: This study is the first, to our knowledge, to demonstrate that HD increases QTc dispersion if a low-calcium (dCa++1.25) dialysate is used. This indicates that the use of low-calcium dialysate may predispose HD patients to ventricular arrhythmias and that perhaps it should be avoided, at least when treating patients with pre-existing cardiac disease.

Urinary albumin excretion rate is independently related to autonomic neuropathy in type 2 diabetes mellitus.

OBJECTIVE: To evaluate if urinary albumin excretion rate (UAER) is independently related to subclinical autonomic neuropathy in type 2 diabetes. DESIGN: A controlled cross-sectional study. SETTING: Primary health care centre. SUBJECTS: Consecutive recently diagnosed (< 1 year) type 2 diabetic patients (group A, n = 150) and patients with long-standing (median 11 years) type 2 diabetes (group B, n = 146) chosen at random. A nondiabetic control group (group C, n = 150) matched for age and gender to group A. MAIN OUTCOME MEASURES: Neuropathy by cardiovascular reflex tests and UAER by nephelometry. METHODS: Univariate statistics in group A + B (t-test chi 2- or McNemars test) with Valsalva and breathing ratios as categorical grouping variables and the independent variables gender, smoking, systolic and diastolic blood pressure, fasting serum cholesterol, HDL cholesterol, triglycerides, haemoglobin A1c, glucagon stimulated C-peptide, fasting and postload 1 and 2 h blood glucose and serum insulin, UAER, coronary heart disease and congestive heart failure. Logistic regression analyses in group A + B with Valsalva and breathing ratios as dependent categorical variables and age, systolic blood pressure, congestive heart failure, coronary heart disease, fasting blood glucose, serum triglycerides and UAER as independent variables. RESULTS: Compared to nondiabetic subjects the diabetic patients of both groups were at increased risk of neuropathy as judged by the Valsalva ratio (P < 0.01). In known diabetic patients with a UAER > or = 30 mg 24-1 h neuropathy was more common than amongst their normoalbuminuric counterparts (Valsalva test P = 0.007, breathing test P = 0.02). In logistic regression analysis UAER independently explained abnormal Valsalva (P = 0.015) and breathing tests (P = 0.04) in the group A + B. CONCLUSIONS: UAER is independently related to subclinical autonomic neuropathy in type 2 diabetes.

Hemodialysis with high-calcium dialysate impairs cardiac relaxation.

BACKGROUND: During hemodialysis (HD), serum ionized calcium is directly related to the dialysate calcium concentration. We have recently shown an acute induction of hypercalcemia to impair left ventricular (LV) relaxation. In the current study we sought to establish whether changes in serum Ca++ also affect LV function during HD. METHODS: We echocardiographically examined the LV relaxation and systolic function of 12 patients with end-stage renal disease before and after three HD treatments with dialysate Ca++ concentrations of 1.25 mmol/liter (dCa++1.25), 1.5 mmol/liter (dCa++1.50), and 1.75 mmol/liter (dCa++1.75), respectively. Age- and sex-matched healthy controls were also examined echocardiographically. RESULTS: The LV posterior wall thickness and the interventricular septum thickness, and the LV end-diastolic dimension and the end-systolic dimensions were significantly greater in the patients when compared with the controls, and the LV fractional shortening, the ratio of peak early to peak late diastolic velocities (E/Amax), and the isovolumic relaxation time (IVRT) showed impairment of LV relaxation and systolic function in the patients. Serum ionized calcium increased significantly during the dCa++1.5 HD (1.24 +/- 0.10 vs. 1.34 +/- 0.06 mmol/liter, P = 0. 004) and dCa++1.75 HD (1.19 +/- 0.10 vs. 1.47 +/- 0.06 mmol/liter, P = 0.002), and plasma intact parathyroid hormone decreased significantly during the dCa++1.75 HD (medians 8.2 vs. 2.7 pmol/liter, P = 0.002). LV systolic function was not altered during any of the treatments. The changes in E/Amax and IVRT suggested impairment of relaxation during all sessions, but only during the dCa++1.75 HD was the impairment statistically significant (E/Amax 1. 153 +/- 0.437 vs. 0.943 +/- 0.352, P < 0.05; IVRT 147 +/- 29 vs. 175 +/- 50 msecond, P < 0.05). CONCLUSION: HD with high-calcium (dCa++1. 75 mmol/liter) dialysate impairs LV relaxation when compared with lower calcium dialysate (dCa++1.25 and dCa++1.5 mmol/liter) treatments.

Age-related appearance of amyloid P component in human renal glomeruli.

Amyloid P component (AP) is a matrix glycoprotein of adult renal glomeruli. To establish whether the deposition of AP in glomeruli is an age-related phenomenon, this study used indirect immunofluorescence (IF) to investigate 34 renal biopsy specimens and 11 renal autopsy specimens. The biopsy specimens were taken from 9 patients (age range from 2 to 38 years) with normal glomerular morphology and from 25 patients (age range from 4 to 56 years) with various renal diseases. All autopsy specimens (age range form 2 months to 28 years) showed normal glomerular morphology. AP was not detected in glomeruli before age 6. By age 14, the IF intensity reached the level of the adult specimens, in which a strong fluorescence was seen along the basement membranes and within the mesangial matrix. In renal diseases, glomerular AP also appeared after age 6, although varying in its location and intensity. In conclusion, our results indicate that the appearance of AP in glomeruli is an age-related phenomenon, the pattern of which varies in renal diseases.

Urinary albumin excretion rate and its determinants after 6 years in non-insulin-dependent diabetic patients.

BACKGROUND: The present study was undertaken to clarify the progression of urinary albumin excretion rate (UAER) in non-insulin-dependent diabetic (NIDD) patients 6 years after diagnosis, and to elucidate the risk factors of nephropathy. METHODS: This is a population-based controlled (baseline) cohort study. The prospective evaluation utilized the diabetic patients as internal controls. The setting was an urban primary health care centre. Main outcome measures were the UAER-24 h and fractional urinary albumin excretion rate (FAC) and their relation to mean blood pressure, haemoglobin Alc, fasting serum insulin and cholesterol and renal size. RESULTS: UAER (mg/24 h) was increased (geometric mean, quartile 1 and 3) in the diabetic patients at baseline, compared to the non-diabetic control subjects; 21 (10 and 33) versus 12 (8 and 15), P = 0.0001 (Wilcoxon's rank test). The UAER-24 h was not increased in diabetic subjects at follow-up; 24 (7 and 49) P = 0.3791 versus diabetic subjects at baseline. Eighteen per cent of normoalbuminuric (UAER < 30mg/24 h) patients developed microalbuminuria (UAER = 30-300 mg/24 h) and 3% clinical nephropathy (UAER > 300 mg/24 h). Of the microalbuminuric subjects 19% progressed to clinical nephropathy, 46% remained microalbuminuric and 35% remitted to normoalbuminuria. Serum insulin concentration, after assessment of confounding factors, measured at the baseline predicted the UAER for all diabetic subjects at follow-up in multiple linear regression analysis in an independent and significant way (P = 0.01). Serum insulin concentration (P = 0.034) and diuretic therapy (P = 0.050) at baseline independently predicted the outcome of the categorical variable progressor/nonprogressor (n = 22/86) based on the UAER-24 h at baseline and at follow-up. CONCLUSIONS: Progression of the UAER during the first 6 years is found among approximately every fifth NIDD subject who develops either microalbuminuria (from normoalbuminuria) or clinical nephropathy (from microalbuminuria). The role of serum insulin (insulin resistance) or some factor associated with it, is suggestive in the genesis of kidney disease.

HLA-DQ gene polymorphism in primary IgA nephropathy in three European populations.

MHC Class II genes may contribute to susceptibility to IgA nephropathy (IgAN). We have previously identified a restriction fragment length polymorphism (RFLP) of the DQB1 region that associated with IgAN in British Caucasoids. However, another group, while demonstrating a DQB1 association, was unable to confirm our finding. MHC molecules are heterodimers consisting of an alpha and beta chain, and thus polymorphism of the DQA1 alpha chain may also be important to disease pathogenesis in IgAN. Therefore, we have determined DQA1 alleles and re-examined DQB1 alleles in British Caucasoids with IgAN using an approach that can differentiate between the common DQ alleles; we have also extended our studies to Caucasoid populations from Northern and Southern Europe, thereby addressing the possibility of variation in genetic susceptibility between populations. DNA was prepared from IgAN patients (British, N = 105; Italian, N = 71; Finnish, N = 48) and healthy controls (British, N = 111; Italian, N = 63; Finnish, N = 41). DQA1 alleles were identified by TaqI RFLP and Southern blotting; alleles that could not be fully resolved by Taq Southern blotting were identified by PCR-RFLP. DQB1 alleles were identified by polymerase chain reaction (PCR) based technique (PCR-RFLP). No consistent association of DQ alleles were found between the populations studied. In British patients a decreased frequency of DQB1*0201 was observed (P = 0.008), in Finnish patients a decreased frequency of DQB1*0602 was observed (P = 0.01), and in Italian patients no association between DQ markers and IgAn was found. These data demonstrate population variation in disease association, but no strong or consistent association in the DQ region.

Occurrence of late specific complications in type II (non-insulin-dependent) diabetes mellitus.

The objective of the present study was to determine the occurrence of late specific complications, i.e., nephropathy, retinopathy, and autonomic neuropathy, in type II (non-insulin-dependent) diabetic subjects with a recent onset and with a disease duration of at least 5 years. The study design comprised of a population-based controlled cross-sectional survey of middle-aged type II diabetic subjects in the City of Tampere, Southwest Finland. The mean (SD) albumin excretion rate per 24 h was found to have increased in recently diagnosed diabetic subjects, i.e., 54 (111) mg (p < 0.0001), and in long-term diabetic subjects, 134 (479) mg (p < 0.0001), compared to nondiabetic controls, 16 (19) mg. Microalbuminuria (30 mg/24 h < or = albumin excretion rate < or = 300 mg/24 h) was detected in 8% of nondiabetic subjects and in 29% of recently diagnosed subjects and 27% of long-term diabetic subjects. The prevalence of clinical nephropathy (albumin excretion rate > 300 mg/24 h) was 7% in long-term and 4% in recently diagnosed diabetic subjects and zero in nondiabetic subjects. The differences between diabetic and nondiabetic subjects tested for microalbuminuria and clinical nephropathy were significant (p = 0.02-0.0001) exempting the difference between recently diagnosed female diabetic subjects and nondiabetic female subjects tested for clinical nephropathy. Seventy-five percent of biopsied diabetic subjects with an albumin excretion rate exceeding 100 mg/24 h were found to have diabetic glomerulosclerosis, while the rest had a normal finding. In long-term diabetic subjects the prevalence of nonspecific, background and proliferative retinopathies were present in 40%, 31%, and 8%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis.

OBJECTIVE: To evaluate renal biopsy findings and clinicopathologic correlations in patients with rheumatoid arthritis (RA). METHODS: Retrospective study of renal biopsy specimens from 110 RA patients in whom the clinical renal disease was probably due to RA itself and/or to antirheumatic therapy. RESULTS: The most common histopathologic finding was mesangial glomerulonephritis (GN) (n = 40), followed by amyloidosis (n = 33), membranous GN (n = 19), focal proliferative GN (n = 4), minimal-change nephropathy (n = 3), and acute interstitial nephritis (n = 1). Amyloidosis was the most common finding in patients with the nephrotic syndrome. In patients with isolated proteinuria, amyloidosis, membranous GN, and mesangial GN were almost equally common. Although mesangial GN was found in almost two-thirds of the RA patients with hematuria (with or without proteinuria), there still remained a 1 in 5 chance that the biopsy would reveal membranous GN or amyloidosis. Membranous GN was closely related to gold or D-penicillamine therapies, whereas mesangial GN probably related to RA itself. CONCLUSION: The renal morphologic lesion in RA patients with isolated proteinuria and those with hematuria cannot be accurately predicted on the basis of clinical symptoms and signs. Biopsy is thus useful in differential diagnosis, assessment of prognosis, and decision-making with regard to treatment.

Sequential changes in vitamin D and calcium metabolism after successful renal transplantation.

A prospective study was made of sequential changes in the metabolism of vitamin D and calcium in 19 allograft recipient during the first year after successful renal transplantation. All but one of the patients received cyclosporine A combined with corticosteroids and azathioprine as immunosuppressive therapy. Shortly after transplantation most patients showed transient hypocalcemia and hypophosphatemia. At the time of transplantation 17 of 19 patients had an elevated plasma intact parathyroid hormone (PTH) level, and at the close of follow-up one in four patients. In six other patients intact PTH was within the reference range, but high in relation to simultaneously measured serum ionized calcium. According, one year after transplantation less than half of the patients showed complete resolution of hyperparathyroidism. The change towards normal in the metabolism of vitamin D began within the first post-transplantation week irrespective of the onset of diuresis. One to two weeks after transplantation 1,25(OH)2D3 and 24,25(OH)2D3 reached the lower limit of normal range. In these renal allograft recipients who received cyclosporine A the long-term values of serum 1,25(OH)2D3 did not differ from those of normal subjects.

IgA-IgM nephropathy. A subgroup of primary mesangial glomerulonephritis.

The renal biopsy material of Tampere University Central Hospital comprises 1992 renal biopsy specimens, accessioned during the years 1978-1989. Among these, there were three cases of mesangial glomerulonephritis with a peculiar type of immunofluorescent reactivity. Striking mesangial deposits of both IgA and IgM were found in glomeruli, whereas C3 deposits were absent or present in slight amounts. The light microscopic findings ranged from mild mesangial glomerulonephritis to more advanced forms of sclerosing glomerulopathy. Electron microscopic examination disclosed an increase of mesangial matrix, together with mesangial and paramesangial electron-dense deposits. Two of the patients had microscopic hematuria associated with proteinuria, and one had isolated proteinuria. The authors propose that this group of cases may represent a new subgroup of primary mesangial glomerulonephritis that has not been described previously. They differ immunohistologically from both IgA nephropathy and IgM nephropathy, and therefore could be designated as IgA-IgM nephropathy.