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Background: Renal function at diagnosis is a strong predictor not only of renal survival but also of patient survival of those with anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis (ASVV). Apart from the renal function at diagnosis, there are no other established risk factors for renal outcome in ASVV. We have previously reported that in other forms of glomerular diseases, an increased urine excretion of IgM is an early marker of poor renal outcome., Methods: In this single-centre observational study, the prognostic significance of urine IgM excretion and other selected prognostic markers was studied in 83 consecutive patients (49 males, 34 females) with ASVV with renal involvement., Results: Patient survival at 1 and 5 years was 93 and 77%, respectively, and the corresponding figures for renal survival censored for death were 84 and 76%. Univariate analysis indicated that patient survival was inversely associated with age, male sex, serum creatinine, low serum albumin and high urine IgM excretion. Renal survival was inversely associated with serum creatinine, albuminuria and urine IgM. Multivariate analysis determined that only old age and high urine IgM excretion were independent predictors of patient survival [odds ratio (OR) = 11.2 and 4.4, respectively, P<0.01]. Urine excretion of IgM was the only independent predictor of end-stage renal disease (OR = 19.8, P = 0.004). Overall, 35% of the patients reached the composite end-point of either death or renal replacement therapy. Urine IgM excretion was the most potent single predictor of such an outcome (OR = 7.7, P = 0.000)., Conclusion: The occurrence of an increased amount of IgM in urine at presentation is a strong marker of poor prognosis for patients with ANCA-associated renal vasculitis.

Background: Severe long-standing hypertension is associated with an increased urinary protein excretion., Methods: To investigate the mechanisms of this proteinuria, we measured the glomerular clearances and calculated the glomerular sieving coefficients (theta) for neutral albumin (theta(o-alb)) and for native albumin (theta(alb)) in spontaneously hypertensive rats (SHR) at the ages of 3, 9 and 14 months, in comparison with age-matched normal control Wistar rats (NCR). The hypothesis was that increases in the glomerular permeability of both negatively charged and neutral albumin would indicate a preferential size-selective dysfunction of the glomerular capillary wall (GCW), while an increased permeability to negatively charged albumin, as compared with neutral albumin, predominantly would indicate a charge-selectivity dysfunction of the GCW. A tissue (renal) uptake technique together with urinary sampling was used to assess theta. The glomerular filtration rate was assessed using the plasma to urine clearance of (51)Cr-EDTA., Results: The theta(alb) in SHR increased 2.6 times at 14 months of age as compared with at 3 months, while there was no significant change of theta(alb) in NCR with age. Furthermore, the increased theta(alb) in old SHR correlated significantly with an increase in theta(o-alb) (r = 0.86, P<0.001), suggesting that albuminuria in old SHR primarily results from an increased number of rather unselective ('large') pores in the glomerular filter., Conclusions: In old age, but not at a young age, hypertensive rats develop proteinuria as a result of dysfunction of the glomerular capillary filter, affecting primarily its size-selectivity. The changes are functionally compatible with the appearance in the glomerular barrier of an increased number of more unselective pores.

Background: The transport of large proteins across the glomerular capillary wall (GCW) may increase several fold in glomerular diseases. The occurrence of IgM in urine is a consequence of the presence of large defects or shunts in the GCW, whereas albuminuria is probably a result of an altered charge- and size-selectivity of the GCW. In order to examine whether patho-morphological differences influence the renal outcome in proteinuric glomerulopathies, we examined urinary excretion of IgM and albumin as prognostic markers of glomerular disease., Methods: An observational study over a median of 41 (+/-3) months was conducted in 84 patients with biopsy-verified glomerular disease. The patients were subdivided into groups with low (< or =0.002) and high (>0.002) proteinuria selectivity index based upon IgM (IgM-SI), and into groups with low (< or =200 mg/mmol) and high (>200 mg/mmol) albumin creatinine index (ACI)., Results: In the high IgM-SI group, the median creatinine clearance (Ccr) decreased by 26%, and 62% of the patients decreased in Ccr by >5 ml/ min/year during the follow-up time. In comparison, the median Ccr decreased by 8% in the low IgM-SI group (P<0.001) and only 18% of the patients in this group deteriorated by >5 ml/min/year in the Ccr. Eleven (21%) of the 51 patients in the high IgM-SI group developed end-stage renal failure compared with none of the 33 patients in the low IgM-SI group. All the patients that progressed to uraemia had decreased Ccr (<60 ml/min) at entry into the study. However, among all these patients, only those with high IgM-SI, and none with low IgM-SI, developed end stage renal failure. The fall in Ccr did not differ significantly between the patients in high (12%) and low (16%) ACI groups., Conclusion: The results of this study indicate that an increased IgM-SI value is a stronger predictor of clinical outcome in proteinuric glomerulopathies than baseline albuminuria. This finding may reflect different patho-histological mechanisms influencing renal survival in glomerular diseases.

Background: Alterations of the charge-selective properties of the glomerular capillary wall are important constituents of the pathogenesis of many glomerular diseases. Thus, differences in the degree of such changes could be of help in understanding the mechanisms governing the transport of macromolecules across the glomerular capillary wall., Methods: The ratio between urine concentrations of neutral IgG2 and negatively charged IgG4 (IgG2/IgG4-ratio) was measured in 150 proteinuric patients and 21 healthy controls. The patients were subdivided into seven biopsy verified diagnostic groups., Results: The study revealed decreased IgG2/ IgG4-ratio in membranous glomerulonephritis (0.57) compared to healthy controls (2.09) and to all other diagnosis groups; crescentic necrotizing glomerulonephritis (1.28), diffuse proliferative glomerulonephritis (1.10), IgA nephropathy (1.11), mesangial proliferative glomerulonephritis (1.55), minimal change nephropathy (1.00), and nephrosclerosis secondary to hypertension (1.06). Although not statistically significant, there was a tendency towards lower IgG2/IgG4-ratio values in all the studied glomerular diseases compared to healthy controls., Conclusions: Since IgG is transported entirely through the large pores of the glomerular basement membrane decreased IgG2/IgG4-ratio implies that this pathway is strongly influenced by the charge-selective properties of the glomerular capillary wall. The conclusion that could be drawn from that is that the large pore radius must be discrete, in the order of 80-90 A, and thus not non-discriminatory to macromolecules as previously thought.

Background: The diagnosis of renal amyloidosis is normally established by kidney biopsy. In order to advance the determination of the diagnosis and the initiation of the therapy, fast and cheap, non-invasive diagnostic techniques are required., Methods: Urine excretion of glycosaminoglycans (GAG) was measured in 10 patients with AA amyloidosis and 5 patients with AL amyloidosis and compared to 25 controls with primary glomerular diseases and 22 healthy controls. The subjects with primary glomerular disease were matched with regard to their renal function and the degree of albuminuria., Results: The median urine GAG to creatinine ratio and the median fractional GAG excretion were significantly decreased (P < 0.05) in both AA amyloidosis (0.21 mg/mmol and 0.053 respectively) and AL amyloidosis (0.33 mg/mmol and 0.077 respectively) compared to control patients with primary glomerular disease (1.73 mg/mmol and 0.336 respectively) and healthy controls (2.67 mg/mmol and 0.226 respectively). The urine GAG to creatinine ratio did not correlate to age, sex, serum creatinine, urine albumin, or to the plasma levels of acute phase proteins., Conclusions: The decreased GAG excretion in renal amyloidosis is probably caused both by diminished number of functioning nephrons, decreased GAG synthesis in functioning glomeruli, and the trapping of GAG by amyloid fibrils. Urinary GAG excretion may serve as an independent marker of renal amyloidosis. It may be used in diagnostic work-up of renal amyloidosis in patients with glomerular diseases and in screening of amyloidosis in patients with chronic inflammatory disorders, with or without signs of renal disease.