Rituximab for the treatment of membranous nephropathy: a single-center experience.

BACKGROUND: Treatment of idiopathic membranous nephropathy with rituximab was introduced more than a decade ago following experimental data that suggested involvement of B-cell-mediated reactions in its pathogenesis. It was a logical step towards a more selective therapy with less severe side effects as compared to the recommended first-line immunosuppressive therapy with corticosteroids and different immunosuppressant drugs. METHODS: We retrospectively analyzed the anonymous data of patients who were treated with rituximab for idiopathic membranous nephropathy at our institution from January 2006 to July 2016. Daily proteinuria and serum creatinine were analyzed 3, 6, 9, and 12 months after rituximab application. The patients were divided into 4 groups according to proteinuria. We separately analyzed remission rates in the whole group and in groups with different quantity of daily proteinuria. Other history data and laboratory parameters were also compared within different groups of patients. RESULTS: The study involved 29 rituximab treatments in 26 patients: 7 (26.9%) female and 19 (73.1%) male patients. In 16 out of 29 treatment cases (55.1%), patients had been previously treated with cyclophosphamide and steroids, or cyclosporine with low dose of steroids, or both. In 72.4% of patients, antiphospholipase A2 receptor antibodies were present. In 2 cases of treatment (6.9%), patients received rituximab 375 mg/m2 of body surface area in 3 and 4 weekly doses, respectively. In all other cases, repeated rituximab applications were given as needed according to the levels of circulating CD-20 B-cells. The total remission rate in our cohort of patients was 37.9% (11 out of 29 cases). The average serum creatinine in the group of patients who achieved remission was significantly lower than in the group without remission (86.5 vs. 155.5 µmol/L, p = 0.003). There was no difference in the duration of the disease prior to treatment with rituximab between the groups (53.6 and 56.4 months, respectively). The remission rate was highest in the group with daily proteinuria less than 4 g per day (83.3%). There were no remissions in the group of patients with daily proteinuria more than 12 g per day. CONCLUSION: The remission rate after rituximab treatment in our cohort of patients with idiopathic membranous nephropathy was lower than in other studies. The reason for this is possibly the application of a single dose of rituximab in the majority of patients, which might have been insufficient in patients with higher proteinuria.
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Treatment of antibody-mediated rejection of kidney grafts with bortezomib and/or rituximab compared to standard regimen: experience of Slovene National Center.

BACKGROUND: The aim of our study was to determine outcomes of standard treatment of antibody-mediated rejection (ABMR) of kidney grafts as compared to the addition of bortezomib or rituximab. METHODS: The cohort of this retrospective study included patients treated for ABMR of kidney grafts at our national center in the period of 2005 - 2017, divided into two groups: standard (ST) group treated standardly with plasmapheresis or immunoadsorption, intravenous immunoglobulins, and corticosteroids, and BR group treated with the addition of bortezomib and/or rituximab. Patient and graft survival at 2 years was analyzed by Kaplan-Meier method, and predictors of graft survival were analyzed by Cox regression. RESULTS: There were 78 patients with ABMR (48 in the ST group, 30 in the BR group), 41 (53%) were men, mean age 49.5 ± 13.8 years. In ST and BR, respectively, mean serum creatinine was 267 ± 164 and 208 ± 112 µmol/L (p = 0.088), donor-specific antibodies (DSA) were positive in 75% and 97% (p = 0.022), and ABMR was acute in 50% and 33% (p = 0.149). Patient survival at 2 years was 89% in the ST and 100% in the BR group (p = 0.125). Cumulative proportion of kidney graft survival at 1 and 2 years was 67% and 53% in the ST group and 73% and 48% in the BR group, respectively, (p = 0.641). Chronic ABMR (HR 5.22, p = 0.004) was significant, while dialysis dependency at biopsy (HR 3.28, p = 0.072), serum creatinine at kidney biopsy (HR 1.003, p = 0.082), and presence of DQ-DSA (HR 3.37, p = 0.062) were borderline significant predictors of worse graft outcome. Infections were relatively common in both groups, with a trend towards more rehospitalizations due to infections in the first 6 months after treatment in the BR group (p = 0.066). In 5 patients (17%), treatment with bortezomib was discontinued prematurely due to cytopenia. CONCLUSIONS: Bortezomib or rituximab, added to standard treatment, did not significantly improve kidney graft survival and was also not associated with significant side effects, except cytopenia in some cases. Treatment of acute ABMR resulted in better graft survival than chronic ABMR.
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Tubular urinary indexes reliably distinguish between primary tubulointerstitial and primary glomerular diseases in patients referred for kidney biopsy.

AIMS: Kidney biopsy remains the gold standard for accurately diagnosing renal diseases. Urinalysis and assessment of renal function are the cornerstones for assessment of patients prior to biopsy. There is significant overlap in the results of routine urine parameters (proteinuria, erythrocyturia, leukocyturia) among different kidney diseases, which hinders the possibility of adequately estimating disease etiology prior to the biopsy. The aim of our study was to assess whether diverse markers of glomerular and tubular proteinuria - urinary albumin, IgG, α-1-microglobulin (α-1-m) and N-acetyl-ß-D-glucosaminidase (NAG) - are capable of distinguishing between patients with primary tubulointerstitial (TID) and primary glomerular disease (GLOM). METHODS: Our study is a retrospective, single-center, consecutive case series of patients referred for kidney biopsy. We analyzed routine urinalysis results performed on a second morning urine sample immediately prior to the biopsy. RESULTS: Patients with TID had significantly higher values of α-1-m and NAG, with lower values of albumin and IgG in the urine compared to patients with GLOM. Three tubular urinary indexes had high sensitivity and specificity for distinguishing TID from GLOM: NAG/albumin, α-1-m/proteinuria, and α-1-m/albumin, with the highest values in the latter index (96.6% and 98.2%, respectively, cut-off point ≥ 0.33). CONCLUSIONS: Prior to kidney biopsy, tubular urinary indexes may present a valuable tool in distinguishing patients with TID from patients with GLOM.
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Determination of red blood cells in urinary sediment: Do pH and specific gravity of urine matter?

INTRODUCTION: It has been postulated that erythrocyte cell lysis in urine is common in the case of low urine specific gravity and high urine pH. We aimed to verify the influence of urine dipstick pH and specific gravity on erythrocyturia in the urine sediment in the case of positive dipstick hemoglobinuria. METHODS: We retrospectively collected data on dipstick specific gravity, pH, and urine sediment analysis done by nephrologists in the clinical and research urine laboratory at the Department of Nephrology, University Medical Center Ljubljana. RESULTS: During the 6-year observation period, we analyzed 843 second morning midstream urine samples with positive dipstick hemoglobinuria. Erythrocyturia in urinary sediment was detected significantly less often in urine samples with concomitant hemoglobinuria 1+ and pH < 6.0, (odds ratio (OR) 0.40; 95% confidence interval (CI) 0.21 - 0.76, p = 0.005). The difference was maintained in multivariate analysis including patient age, gender, and specific gravity (OR 0.32; 95% CI 0.15 - 0.65, p = 0.002). In samples with higher grade of hemoglobinuria (≥ 2+), the impact of cell lysis in the case of low pH was negligible. Specific gravity did not have any influence on erythrocyte detection in urinary sediment. CONCLUSIONS: Urinary pH < 6.0 impaired the detection of erythrocytes in urinary sediment, while the dipstick measured urine specific gravity did not have any impact on it. Urine samples with low-grade hemoglobinuria and low pH without erythrocyte detection in urinary sediment should be evaluated again to avoid false-negative results.
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The predictive value of urinary vascular endothelial growth factor (VEGF) on worsening kidney function in proteinuric chronic kidney disease.

OBJECTIVES: To evaluate the role of urinary vascular endothelial growth factor (VEGF) as an early predictor of chronic kidney disease (CKD) progression in patients with glomerular diseases. METHODS: We prospectively included patients with proteinuria and CKD grade 1 - 5 due to glomerular disease at the time of kidney biopsy. At baseline, we collected demographics, comorbidities, smoking history, serum creatinine (sCr), proteinuria, and urinary VEGF in collected 24-hour urine. The primary outcome was a 50% increase in sCr at last follow-up. Binary regression was used to explore the impact of urinary biomarkers adjusted for baseline patient characteristics on the outcome. RESULTS: From July 2011 to September 2012 we included 49 patients aged 45.2 ± 14.8 years, 43% female, with different glomerular diseases. We followed them for 29 ± 11 months. Twelve out of 49 (22%) patients met the primary outcome. The patients with a 50% increase in sCr at last follow-up had a significantly higher baseline sCr (193 ± 101 vs. 127 ± 84; p = 0.014) and higher urinary VEGF/creatinine in 24-hour urine (7.7 ± 6.4 vs. 3.0 ± 4.0; p = 0.005). When we added both sCr and urinary VEGF/creatinine to the binary regression model, the correlation with baseline sCr was not significant (OR 1.01; 95% CI 1.00 - 1.01; p = 0.184), while urinary VEGF/creatinine remained significant (OR 1.18; 95% CI 1.04 - 1.35; p = 0.008). Baseline patient characteristics, such as age, gender, body mass index, sCr, proteinuria, smoking status, histopathologic diagnosis, concomitant arterial hypertension, and time to last follow-up did not influence the primary outcome. CONCLUSIONS: The urinary VEGF/creatinine ratio in 24-hour urine seems to independently predict worsening of chronic kidney disease in patients with glomerular diseases.
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Acute granulomatous interstitial nephritis and acute rejection in a kidney transplant recipient after zoledronic acid therapy - a case report and review of the literature.

BACKGROUND: Acute granulomatous interstitial nephritis (AGIN) in native kidneys is most commonly linked to drugs. In allografts, it is a rare complication, and it occurs mostly with infections. CASE PRESENTATION: Our case report presents AGIN with simultaneous acute cellular rejections and acute tubular necrosis in a kidney transplant patient 2 weeks after intravenous application of zoledronic acid. A kidney biopsy showed signs of destructive AGIN with acute cellular rejection. After treatment with methylprednisolone pulses and immunosuppressive therapy modification, rebiopsy confirmed complete regression of AGIN with less intense persistent acute cellular rejection and acute tubular necrosis. Kidney function improved after glucocorticoid and intravenous immunoglobulin G therapy. CONCLUSION: To our knowledge, this is the first case of AGIN related to bisphosphonate zoledronate in a kidney transplant patient with consequent acute cellular rejection. In using intravenous zoledronate infusion in a kidney transplant recipient, we should be aware that it could potentially induce acute granulomatous tubulointerstitial nephritis and acute rejection.
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