Nephrology Education
Goodpasture’s syndrome with concomitant immune complex mixed membranous and proliferative glomerulonephritis
Vesna Jurčić, Alenka Vizjak, Andreja Aleš Rigler, Jera Jeruc, Jörgen Wieslander and Dušan Ferluga
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Volume 81 (2014) p. 216 - 223
Abstract
Clinical Nephrology, Vol. 81 – No. 3/2014 (216-223)
Goodpasture’s syndrome with concomitant immune complex mixed membranous and proliferative glomerulonephritis
Vesna Jurčić1, Alenka Vizjak1, Andreja Aleš Rigler2, Jera Jeruc1, Jörgen Wieslander3, and Dušan Ferluga1
1Institute of Pathology, Faculty of Medicine, University of Ljubljana, 2Clinical Department of Nephrology, University Clinical Center, Ljubljana, Slovenia, and 3Department of Nephrology, Lund University Hospital, Lund, Sweden
Classical Goodpasture’s (GP) syndrome is a monophasic illness characterized by pulmonary hemorrhage and rapidly progressive glomerulonephritis with linear IgG deposition along the glomerular and distal tubular basement membrane and estructive necrotizing diffuse extracapillary crescentic glomerulonephritis. The majority of patients have circulating anti-glomerular basement membrane (GBM) antibodies, detectable with standard anti-GBM ELISA. Concurrence of GP syndrome with proliferative glomerulonephritis has only rarely been described. In this report, for the first time we describe in a 21-year-old woman GP syndrome with 50% crescentic sclerosing glomerulonephritis with linear immunofluorescence characteristic of anti-GBM pathogenesis, combined with mixed membranous and membranoproliferative glomerulonephritis with granular immunofluorescence and subepithelial, mesangial and subendothelial deposits characterizing immune complex pathogenesis. The clinical picture was also unusual for GP syndrome, manifesting a recurrent but non-progressive course, nephrotic syndrome, normal renal function and low values of anti-GBM antibodies, identified only by novel more sensitive techniques.Correspondence to:
Dr. Vesna Jurčić, MD, PhD
Institute of Pathology, Faculty of Medicine
University of Ljubljana
Korytkova 2, 1105 Ljubljana, Slovenia
Email: [email protected]
Clinical Nephrology
Tubular urinary indexes reliably distinguish between primary tubulointerstitial and primary glomerular diseases in patients referred for kidney biopsy
Andrej Škoberne, Špela Borštnar, Nuša Avguštin, Damjan Kovač, Andreja Aleš Rigler, Željka Večerić-Haler, Jernej Pajek, Mladen Krsnik, Nika Kojc, Dušan Ferluga, and Jelka Lindič
Volume 88 (2017) p. 1 - 6
Abstract
Clinical Nephrology, Vol. 88 – Suppl. 1/2017 (S1-S6)
Tubular urinary indexes reliably distinguish between primary tubulointerstitial and primary glomerular diseases in patients referred for kidney biopsy
Andrej Škoberne1, Špela Borštnar1, Nuša Avguštin1, Damjan Kovač1, Andreja Aleš Rigler1, Željka Večerić-Haler1, Jernej Pajek1, Mladen Krsnik2, Nika Kojc3, Dušan Ferluga3, and Jelka Lindič1
1Department of Nephrology and 2Institute of Clinical Chemistry and Biochemistry, University Medical Center Ljubljana, and 3Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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-β-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.
Correspondence to:
Andrej Škoberne, MD, PhD
Department of Nephrology
University Medical Centre Ljubljana
Zaloška 7, 1000 Ljubljana, Slovenia
Email: andrej.skoberne@
gmx.net
Kidney Transplantation
Outcome of polyomavirus nephropathy in renal transplant patients: a single-center experience
Nika Kojc, Andreja Aleš Rigler, Gregor Mlinšek, Damjan Kovač, Dušan Ferluga, and Miha Arnol
Volume 88 (2017) p. 109 - 114
Abstract
Clinical Nephrology, Vol. 88 – Suppl. 1/2017 (S109-S114)
Outcome of polyomavirus nephropathy in renal transplant patients: a single-center experience
Nika Kojc1#2, Andreja Aleš Rigler3, Gregor Mlinšek3, Damjan Kovač3, Dušan Ferluga1, and Miha Arnol2#3
1Institute of Pathology, 2Medical Faculty, University of Ljubljana, and 3Department of Nephrology, University Medical Center Ljubljana, Ljubljana, Slovenia
Background: Reduction of immunosuppression is a common therapeutic strategy in patients with polyomavirus nephropathy (PVN) but may be associated with acute rejection. This study aimed to evaluate the morphology of PVN in renal biopsies after reduction of immunosuppression. Methods: Eight of 241 patients who received a kidney transplant between January 2012 and December 2015 presented with BK viremia and biopsy-proven PVN. Morphological evaluation according to Banff criteria and correlation with viremia and kidney function after immunosuppression reduction was performed. Results: PVN grades A and B were diagnosed on average 4.7 months post-transplant in 1 and 7 patients, respectively. Indication biopsies after immunosuppression reduction showed an increase in tubulitis and interstitial inflammation score compared to those at the time of the PVN diagnosis. Surveillance biopsies 1 year after transplantation revealed resolution of interstitial inflammation and tubulitis accompanied by clearance of BK viremia in 4 patients (50%), including 1 patient with rejection. One patient showed residual interstitial inflammation after viral clearance. In these patients, renal function returned to baseline. One patient with persisting low BK virus (BKV) in serum and kidney showed a decrease of tubulointerstitial inflammation but scarring was seen. Rejection occurred in 3 patients (38%). Conclusion: PVN-associated interstitial inflammation and tubulitis cannot be differentiated morphologically from T-cell-mediated tubulointerstitial rejection. Significant interstitial inflammation and tubulitis in PVN under low-dose immunosuppression might represent immune reconstitution injury, which is reduced after successful BKV clearance from the serum and kidney. Concomitant rejection in PVN patients on low immunosuppression might be efficiently treated with transient pulse immunosuppressive therapy.
Correspondence to:
Nika Kojc, MD, PhD
Institute of Pathology, Medical Faculty
University of Ljubljana
Korytkova 2, 1000 Ljubljana, Slovenia
Email: [email protected]
Clinical Nephrology
Rituximab for the treatment of membranous nephropathy: a single-center experience
Andreja Aleš Rigler, Alexander Jerman, Aleša Orsag, Nika Kojc, Damjan Kovač, Andrej Škoberne, Špela Borštnar, Željka Večerić Haler, Nuša Avguštin, Radoslav Kveder, Dušan Ferluga, Alenka Vizjak, and Jelka Lindič
Volume 88 (2017) p. 27 - 31
Abstract
Clinical Nephrology, Vol. 88 – Suppl. 1/2017 (S27-S31)
Rituximab for the treatment of membranous nephropathy: a single-center experience
Andreja Aleš Rigler1, Alexander Jerman1, Aleša Orsag1, Nika Kojc2, Damjan Kovač1, Andrej Škoberne1, Špela Borštnar1, Željka Večerić Haler1, Nuša Avguštin1, Radoslav Kveder1, Dušan Ferluga2, Alenka Vizjak2, and Jelka Lindič1
1Department of Nephrology, University Medical Center Ljubljana, and
2Institute of Pathology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
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.
Correspondence to:
Andreja Aleš Rigler, MD, PhD
Department of Nephrology
University Medical Center Ljubljana
Zaloška 7, 1000 Ljubljana, Slovenia
Email: [email protected]
Kidney Transplantation
Treatment of antibody-mediated rejection of kidney grafts with bortezomib and/or rituximab compared to standard regimen: experience of Slovene National Center
Teja Oblak, Jelka Lindič, Jakob Gubenšek, Radoslav Kveder, Andreja Aleš Rigler, Andrej Škoberne, Željka Večerić Haler, Špela Borštnar, Nuša Avguštin, Rafael Ponikvar, Gregor Mlinšek, Dušan Ferluga, Nika Kojc, Uroš Godnov, and Damjan Kovač
Volume 88 (2017) p. 91 - 96
Abstract
Clinical Nephrology, Vol. 88 – Suppl. 1/2017 (S91-S96)
Treatment of antibody-mediated rejection of kidney grafts with bortezomib and/or rituximab compared to standard regimen: experience of Slovene National Center
Teja Oblak1, Jelka Lindič1, Jakob Gubenšek1#2, Radoslav Kveder1, Andreja Aleš Rigler1, Andrej Škoberne1, Željka Večerić Haler1, Špela Borštnar1, Nuša Avguštin1, Rafael Ponikvar1#2, Gregor Mlinšek1, Dušan Ferluga2#3, Nika Kojc2#3, Uroš Godnov4, and Damjan Kovač1
1Department of Nephrology, University Medical Center Ljubljana, 2Faculty of Medicine, 3Insititute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, and 4Faculty of Management, University of Primorska, Koper, Slovenia
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.
Correspondence to:
Assoc. Prof. Damjan, Kovač, MD, PhD
Department of Nephrology
University Medica Centre Ljubljana
Zaloška cesta 7, 1525 Ljubljana, Slovenia
Email: [email protected]
Complement activation and cryoglobulinemia are common in monoclonal gammopathy of renal significance: Data from a case series
Andrej Škoberne, Matevž Škerget, Nika Kojc, Maja Frelih, Andreja Aleš Rigler, Željka Večerić Haler, Špela Borštnar, Nuša Avguštin Rotar, Damjan Kovač, Jelka Lindič, and Samo Zver
Volume 96 (2021) p. 16 - 23
Abstract
Clinical Nephrology, Vol. 96 – Suppl. 1/2021 (S16-S23)
Complement activation and cryoglobulinemia are common in monoclonal gammopathy of renal significance: Data from a case series
Andrej Škoberne1,3, Matevž Škerget2,3, Nika Kojc4, Maja Frelih4, Andreja Aleš Rigler1,3, Željka Večerić Haler1,3, Špela Borštnar1,3, Nuša Avguštin Rotar1,3, Damjan Kovač1,3, Jelka Lindič1,3, and Samo Zver2,3
1Department of Nephrology, 2Department of Hematology, University Medical Center Ljubljana, 3Faculty of Medicine, and 4Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Introduction: Monoclonal gammopathy of renal significance (MGRS) denotes kidney diseases caused by monoclonal immunoglobulins in patients who do not have an overt hematological malignancy. Treatment is primarily directed against the underlying clone. Complement activation and cryoglobulinemia are known factors that can contribute to tissue damage, however, the full extent of their involvement is not clear. Materials and methods: This was a retrospective study including all patients with MGRS referred for consultation to our hospital over a 3-year period. Results: We identified 17 patients, of which 12 had proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Treatment with anti-clonal or immunosuppressive therapy was successful in 60% of patients with PGNMID, and treatment success was more common in patients with λ chain (100%) compared to κ chain deposits (20%). Serum markers of complement involvement were identified in 41% of all patients (88% of tested samples), most commonly high serum C5b-9 values or anti-factor H autoantibodies (both 24%). Patients with complement involvement did not respond well to treatment, which was unsuccessful in all treated patients with anti-factor H autoantibodies and 75% of patients with high serum C5b-9 values. Cryoglobulinemia was identified in 29% of all patients (71% tested samples) and was monoclonal in 40% of positive cases and mixed in 60%. None of the patients with cryoglobulinemia had organized deposits, however, there was a trend toward more common intramembranous deposits. In patients with monoclonal cryoglobulinemia both anti-clonal and immunosuppressive treatment were unsuccessful. All patients with mixed cryoglobulinemia were treated successfully with immunosuppressive therapy. Conclusion: Treatment of patients with PGNMID was successful in most cases. Complement involvement as well as monoclonal and mixed cryoglobulinemia were relatively common in our cohort, with the first two generally associated with unsuccessful treatment and the latter with successful treatment.Correspondence to:
Andrej Škoberne, MD, PhD, Department of Nephrology, University Medical Centre Ljubljana, Zaloška cesta 7, 1000 Ljubljana, Slovenia
Email: [email protected]
Supplement
Fibrillary glomerulonephritis: A retrospective analysis of a case series from a tertiary center
Ana Dovč, Željka Večerić-Haler, Nika Kojc, Špela Borštnar, Andrej Škoberne, and Andreja Aleš Rigler
Volume 104 (2025) p. 66 - 72
Abstract
Clinical Nephrology, Vol. 104 – Suppl. 1/2025 (S66-S72)
Fibrillary glomerulonephritis: A retrospective analysis of a case series from a tertiary center
Ana Dovč1,2, Željka Večerić-Haler1,2, Nika Kojc3, Špela Borštnar1,2, Andrej Škoberne1,2, and Andreja Aleš Rigler1,2
1Department of Nephrology, Division of Internal Medicine, University Medical Center Ljubljana, 2Faculty of Medicine, and 3Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Introduction: Fibrillary glomerulonephritis is a rare diagnosis, and guidance on diagnosis and management is scant. We present a case series of patients with fibrillary glomerulonephritis from University Medical Center Ljubljana. Materials and methods: We conducted a retrospective analysis of patients with the diagnosis of fibrillary glomerulonephritis since 2006. We analyzed data on clinical presentation, treatment modalities, and kidney survival. For a subset of patients, data on DNAJB9 staining and markers of complement activation were also available. Results: We included 17 patients with fibrillary glomerulonephritis, 59% female, with a median age of 61 years (range 33 – 71). The most common clinical presentation was asymptomatic proteinuria with preserved kidney function (41%). Eight patients had complement activity testing performed, which revealed elevated serum C5b-9 at least at 1 time point in 5 patients (63%). One patient had positive anti-factor H antibodies, and 2 patients had positive anti-C1q antibodies. Nine patients had available staining results for DNAJB9, which was positive in all 9 cases. The median time of follow-up was 12 months. The most common form of treatment was with corticosteroids in 8 patients, followed by rituximab in 5 patients. Seven patients (41%) had at least partial remission with stabilization of kidney function, 8 patients (47%) reached end-stage kidney disease during follow-up. Due to the small number of patients, analysis of impact of treatment on kidney survival was not performed. Conclusion: Fibrillary glomerulonephritis is a heterogenous disease, and a significant number of patients present with a slowly progressive disease, warranting long-term treatment. New treatment strategies are necessary.
Correspondence to:
Ana Dovč, MD, Department of Nephrology, Division of Internal Medicine, University Medical Centre Ljubljana, Zaloška 7, 1000 Ljubljana, Slovenia
Email: [email protected]
Supplement
Clinical profile, treatment response, and outcomes in adult primary focal segmental glomerulosclerosis: A single-center experience
Željka Večerić-Haler, Andreja Aleš Rigler, Andrej Škoberne, Špela Borštnar, Nuša Avguštin Rotar, Damjan Kovač, Ana Dovč, Nika Kojc, and Jelka Lindič
Volume 104 (2025) p. 73 - 84
Abstract
Clinical Nephrology, Vol. 104 – Suppl. 1/2025 (S73-S84)
Clinical profile, treatment response, and outcomes in adult primary focal segmental glomerulosclerosis: A single-center experience
Željka Večerić-Haler1,2, Andreja Aleš Rigler1,2, Andrej Škoberne1,2, Špela Borštnar1,2, Nuša Avguštin Rotar1,2, Damjan Kovač1,2, Ana Dovč1,2, Nika Kojc3, and Jelka Lindič1,2
1Department of Nephrology, University Medical Center Ljubljana, 2Department of Internal Medicine, Faculty of Medicine, and 3Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Objective: Primary focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome in adults. This study evaluates the clinical profile, treatment response, and outcomes of patients with primary FSGS at the University Medical Centre (UMC) Ljubljana, Slovenia. Materials and methods: Patients diagnosed and treated at UMC Ljubljana from 2008 to 2024 were included. Clinical, laboratory, histological, and treatment data were analyzed. Results: 56 patients were followed for a median of 71 months (range: 2 – 186). At diagnosis, 91.1% had nephrotic syndrome, with proteinuria of 10.2 ± 9.8 g/day, serum albumin of 23.7 ± 6.5 g/L, and estimated glomerular filtration (eGFR) of 66.7 ± 27.7 mL/min/1.73m2. Histological subtypes included tip (37.5%), cellular (25%), collapsing (14.3%), not-otherwise specified (16.1%), while in 7.1% the variant was not defined. First-line therapy, mainly corticosteroids, led to remission in 67.3%, but 71% experienced relapses or steroid resistance. Calcineurin inhibitors (CNIs) and corticosteroids were used in 20 patients, achieving 60% remission, however the majority of patients experienced relaps following their discontinuation. Rituximab was given to 23 patients with refractory disease, with 78.2% achieving remission (56.5% complete, 21.7% partial) in 5.1 ± 4.9 months. Among initial rituximab responders, 30.4% experienced relapse. At the last follow-up, mean eGFR was 59.6 ± 33.2 mL/min/1.73m2, 21.4% progressed to end-stage renal disease (ESRD), and 5.3% died. Four patients underwent kidney transplantation, with early recurrence in 3. Conclusion: Despite high steroid resistance, use of CNIs and rituximab improved remission rates. However, ESRD remains a significant concern, highlighting the need for early intervention and optimized treatment strategies.
Correspondence to:
Željka Večerić-Haler, MD, PhD, Department of Nephrology, University Medical Center Ljubljana, Zaloška 7, 1000 Ljubljana, Slovenia
Email: [email protected]
