Evolution of antibody titre against the M-type phospholipase A2 receptor and clinical response in idiopathic membranous nephropathy patients treated with tacrolimus.

INTRODUCTION AND OBJECTIVES: The level of circulating antibodies against M-type phospolipase A2 receptor has been reported as having a significant correlation with clinical activity in idiopathic membranous nephropathy. However, the usefulness of monitoring antibody titre as a predictor of clinical response following the onset of treatment has not been formally analysed. The predictive value of the evolution of anti-PLA2R antibody titre on the clinical response of idiopathic membranous nephropathy patients treated with tacrolimus is analysed in the following study. PATIENTS AND METHOD: 36 patients with nephrotic syndrome secondary to idiopathic membranous nephropathy with immunosuppressive treatment indication criteria were treated with tacrolimus in monotherapy. The level of anti-PLA2R antibodies was determined before treatment and at 3, 6, 9 and 12 months after the onset of treatment. The study analysed the predictive value of the reduction in antibody titre and the relative and absolute reduction in antibody titre at 3 and 6 months over the period until remission and on the probability of remission at 6, 9 and 12 months. RESULTS: The relative reduction in the anti-PLA2R antibody titre was significantly greater in those patients with remission and it preceded the clinical response. No association was observed between the antibody titre prior to treatment and the mean response time or the response at 12 months. Reduction in antibody titre is significantly associated with the time until signs of remission. Relative reduction in anti-PLA2R antibody titre at 3 months had a high sensitivity and specificity to predict the response at 6 and 9 months, but not at 12 months; however the relative reduction in the antibody titre at 6 months had a high sensitivity and specificity for predicting the response at 12 months. CONCLUSION: In patients with IMN associated with anti-PLA2R antibodies, the monitoring of antibody titre following the onset of treatment is useful for estimating the time period until remission and predicting the probability of remission at 12 months.

[Diagnostic value of soluble urokinase-type plasminogen activator receptor serum levels in adults with idiopathic nephrotic syndrome]. / Valor diagnóstico de los niveles séricos del receptor soluble de la uroquinasa en adultos con síndrome nefrótico idiopático.

INTRODUCTION: Recent studies suggest that soluble urokinase-type plasminogen activator receptor (suPAR) levels could be useful for distinguishing idiopathic focal segmental glomerulosclerosis (FSGS) from other glomerulopathies that cause nephrotic syndrome, but these data have not been confirmed in independent studies. The objective of our study is to analyse whether circulating levels of suPAR are useful for identifying primary kidney disease in patients with nephrotic syndrome secondary to FSGS, minimal change disease or idiopathic membranous nephropathy (MN). METHODS: We measured circulating suPAR at diagnosis in 60 patients with nephrotic syndrome secondary to FSGS, minimal change disease (MCD) and membranous nephropathy (MN). The correlations between suPAR levels and demographic, clinical and biochemical variables were analysed. The sensitivity and specificity of suPAR in distinguishing FSGS patients were analysed by ROC curves. RESULTS: After adjusting for age and renal function, suPAR levels were significantly higher in patients with FSGS than in those with MCD (p<.001), but there were no differences between FSGS and MN (P=.12). A suPAR value ≥3452 pg/ml had a sensitivity of 73.7% and a specificity of 72.5%, with an area under the curve (AUC) of 0.782 ± 0.124, p=.001, for identifying patients with FSGS. After excluding patients with MN, a value ≥3531 pg/ml had a specificity of 99.93% for distinguishing between MCD and FSGS. CONCLUSIONS: suPAR values alone do not distinguish between the three types of glomerulopathy. Nevertheless, after excluding the diagnosis of MN, a suPAR level >3531 pg/ml could have a high specificity (but a low sensitivity) in the diagnosis of FSGS.

[Value of soluble urokinase receptor serum levels in the differential diagnosis between idiopathic and secondary focal segmental glomerulosclerosis]. / Valor de los niveles séricos del receptor soluble de la uroquinasa en el diagnóstico diferencial entre glomeruloesclerosis focal y segmentaria idiopática y secundaria.

BACKGROUND: It has been reported that the circulating level of the soluble urokinase receptor (suPAR) could be useful for distinguishing idiopathic from secondary focal segmental glomerulosclerosis, but the results published are conflicting. In this study, we analyse the intraindividual variability and clinical and anatomopathological variables associated with the suPAR levels and if circulating suPAR levels allow the different forms of focal segmental glomerulosclerosis (FSGS) to be distinguished, i.e., idiopathic forms from secondary FSGS, regardless of the presence of nephrotic syndrome and the activity phase. METHOD: We studied 35 patients affected by idiopathic FSGS and 48 with secondary FSGS (83 in total). We carried out measurements of circulating suPAR at the time of diagnosis and/or after remission and we analysed correlations between suPAR levels and demographic, clinical and biochemical variables. The ability of suPAR to distinguish between both forms of FSGS was analysed by ROC curves and logistic regression analysis. RESULTS: In both forms of FSGS, suPAR levels were independent of proteinuria and the histopathological subtype of FSGS and they were significantly associated with age and renal function. After adjusting for both variables, suPAR levels were significantly higher in patients with idiopathic FSGS, both in the nephrotic syndrome phase and in partial or complete remission. The most sensitive suPAR level (80%) and the most specific (73%) for discriminating between idiopathic and secondary forms was 3443.6 pg/ml (area below curve [ABC] 0.78 ± 0.083, P<.001). In the logistic regression analysis, after adjusting for age, renal function and presence of nephrotic syndrome, suPAR levels were independently associated with the diagnosis of idiopathic FSGS, but the model was poorly adjusted for low risk categories in which it tended to classify primary forms as secondary forms (χ(2) = 11.2 p=.027). CONCLUSIONS: SuPAR levels lack sensitivity for differentiating between idiopathic and secondary FSGS. However, suPAR values greater than 4000 ng/ml are highly specific to primary FSGS, and as such, with a morphological FSGS pattern associated with non-nephrotic proteinuria, they would indicate a low probability of secondary FSGS.

Prevalence, diagnostic value and clinical characteristics associated with the presence of circulating levels and renal deposits of antibodies against the M-type phospholipase A2 receptor in idiopathic membranous nephropathy.

UNLABELLED: The M-type phospholipase A2 receptor (PLA2R) has been identified as one of the target antigens of the autoimmune response in idiopathic membranous nephropathy (MN). The prevalence of anti-PLA2R antibodies in patients with idiopathic MN is around 70% but this varies in accordance with geographic region, and until present, anti-PLA2R has not been shown to be associated with any particular clinical profile of the disease. METHODS: We studied 64 adults with nephrotic syndrome who were diagnosed with MN, confirmed by renal biopsy. Forty-seven patients had idiopathic MN and 17 had secondary MN. We determined the presence of circulating anti-PLA2R antibodies by indirect immunofluorescence (IIF) and their titre by ELISA, and we analysed the presence of anti-PLA2R antibody renal deposits by immunohistochemical techniques. We calculated the sensitivity and specificity of the IIF and ELISA techniques for the identification of patients with renal deposits and for the identification of those with idiopathic MN and we tested whether there were differences in the clinical profile of the disease at the time of diagnosis according to the presence or absence of anti-PLA2R antibodies. RESULTS: We did not observe significant differences in the clinical-demographic variables between patients with idiopathic and secondary MN. The prevalence of anti-PLA2R glomerular deposits by IHC was 76.6%. The IIF and ELISA techniques had a similar sensitivity (IIF 94.4% and ELISA 97.2%) and specificity (100%) for the identification of patients with anti-PLA2R renal deposits and the detection of circulating anti-PLA2R antibodies. The determination of anti-PLA2R by IIF identified patients with idiopathic MN with a sensitivity of 72.3% and a specificity of 94.2%. A titre of antibodies >15RU/ml measured by ELISA had a sensitivity of 74.45% and a specificity of 94.2% for the identification of patients with idiopathic MN. Patients with idiopathic MN and anti-PLA2R had significantly higher proteinuria figures (13.25 [P25-P75: 9.05-15.87] compared to 9.43 [P25-P75: 6.30-15] g/day, P:.018). No statistical correlation was observed between the antibody titre measured by ELISA and age, glomerular filtration rate or 24-hour proteinuria or albuminaemia. CONCLUSIONS: The techniques employed to determine anti-PLA2R in patients with MN are highly specific for the diagnosis of idiopathic forms of the glomerular disease. The frequency with which patients with MN and anti-PLA2R were identified is similar to that reported in previous studies. Staining by immunohistochemistry is the most sensitive method for detecting cases of MN associated with the presence of anti-PLA2R antibodies. The IIF and ELISA techniques allow circulating anti-PLA2R antibodies to be detected in most patients with renal deposits, but they may very infrequently have false negative results. The concordance of these tests is high. Patients with idiopathic MN and anti-PLA2R antibody renal deposits have higher proteinuria than patients that are anti-PLA2R negative, but the differences have little clinical importance.

KAP degradation by calpain is associated with CK2 phosphorylation and provides a novel mechanism for cyclosporine A-induced proximal tubule injury.

The use of cyclosporine A (CsA) is limited by its severe nephrotoxicity that includes reversible vasoconstrictor effects and proximal tubule cell injury, the latter associated whith chronic kidney disease progression. The mechanisms of CsA-induced tubular injury, mainly on the S3 segment, have not been completely elucidated. Kidney androgen-regulated protein (KAP) is exclusively expressed in kidney proximal tubule cells, interacts with the CsA-binding protein cyclophilin B and its expression diminishes in kidneys of CsA-treated mice. Since we reported that KAP protects against CsA toxicity in cultured proximal tubule cells, we hypothesized that low KAP levels found in kidneys of CsA-treated mice might correlate with proximal tubule cell injury. To test this hypothesis, we used KAP Tg mice developed in our laboratory and showed that these mice are more resistant to CsA-induced tubular injury than control littermates. Furthermore, we found that calpain, which was activated by CsA in cell cultures and kidney, is involved in KAP degradation and observed that phosphorylation of serine and threonine residues found in KAP PEST sequences by protein kinase CK2 enhances KAP degradation by calpain. Moreover, we also observed that CK2 inhibition protected against CsA-induced cytotoxicity. These findings point to a novel mechanism for CsA-induced kidney toxicity that might be useful in developing therapeutic strategies aimed at preventing tubular cell damage while maintaining the immunosuppressive effects of CsA.

Pathological findings in the complete trisomy 9 syndrome: three case reports and review of the literature.

The term "complete trisomy 9" is used to indicate trisomy of the entire chromosome 9 without evidence of mosaicisms. It is a relatively rare chromosomal abnormality because the vast majority of affected pregnancies result in 1st trimester spontaneous abortions. The purpose of this paper is to delineate the complete trisomy 9 syndrome, based on autopsy findings. We performed an exhaustive review of the literature of complete forms of this trisomy with autopsy examination and added 3 new cases from our center with new findings not previously described.