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
Increase in spot urine protein excretion is associated with late kidney graft rejection and predicts rejection phenotype
Miha Arnol, Manca Oblak, Gregor Mlinšek, Jelka Lindič, Aljoša Kandus, Dušan Ferluga, Nika Kojc, and Jadranka Buturović-Ponikvar
Volume 88 (2017) p. 83 - 90
Abstract
Clinical Nephrology, Vol. 88 – Suppl. 1/2017 (S83-S90)
Increase in spot urine protein excretion is associated with late kidney graft rejection and predicts rejection phenotype
Miha Arnol1#2, Manca Oblak1, Gregor Mlinšek1, Jelka Lindič1, Aljoša Kandus1, Dušan Ferluga3, Nika Kojc3, and Jadranka Buturović-Ponikvar1#2
1Department of Nephrology, University Medical Center Ljubljana, 2Faculty of Medicine, and 3Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Aims: A noninvasive test that foretells kidney graft rejection before loss of kidney function would be desirable. We hypothesized that an increase in estimated protein excretion rate (ePER) from spot urine samples is associated with graft rejection and predicts rejection phenotype. Methods: 151 patients who had undergone first-indication kidney biopsy due to graft dysfunction beyond 3 months after transplant were identified from a national cohort of 616 transplant recipients between 2000 and 2012 (25%). ePER were calculated from spot urine protein-to-creatinine ratios at baseline, 3 months before biopsy (ePER–3m), and at the time of biopsy (ePERbiopsy) and were correlated with histologic biopsy findings. Results: Levels of ePER 3 months before biopsy and at the time of biopsy were greater in 32 patients with antibody-mediated rejection (ABMR) than in 77 patients with T-cell-mediated rejection (TCMR) and 42 patients with other findings (median ePER–3m 912 vs. 320 vs. 232 mg/day/1.73m2; and median ePERbiopsy 1,672 vs. 356 vs. 268 mg/day/1.73m2; p < 0.001). Receiver operator characteristics (ROC) analyses demonstrated that ePER–3m and ePERbiopsy had good diagnostic accuracy to discriminate between biopsy specimens showing ABMR vs. those showing TCMR or other histologic findings (area under the ROC curve 0.84, 95% CI 0.75 – 0.93 and 0.89, 95% CI 0.82 – 0.97, respectively; p < 0.001). Conclusions: An increase in ePER before kidney graft dysfunction appears to be associated with graft rejection and predicts ABMR phenotype.
Correspondence to:
Miha Arnol, MD, PhD
Department of Nephrology
Center for Kidney Transplantation
University Medical Center Ljubljana
Zaloska 7, Ljubljana 1000, Slovenia
Email: [email protected]
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]
Glomerular and tubulointerstitial foscarnet nephropathy of kidney allograft with emphasis on ultrastructural findings: A case report
Jerica Pleško, Damjan Kovač, Zoran Arsov, Jelka Lindič, Andrej Škoberne, Dušan Ferluga, and Nika Kojc
Volume 96 (2021) p. 127 - 132
Abstract
Clinical Nephrology, Vol. 96 – Suppl. 1/2021 (S127-S132)
Glomerular and tubulointerstitial foscarnet nephropathy of kidney allograft with emphasis on ultrastructural findings: A case report
Jerica Pleško1, Damjan Kovač2,3, Zoran Arsov4, Jelka Lindič2,3, Andrej Škoberne2,3, Dušan Ferluga1, and Nika Kojc1
1Institute of Pathology, Faculty of Medicine, University of Ljubljana, 2Department of Nephrology, University Medical Center Ljubljana, 3Faculty of Medicine, University of Ljubljana, and 4Department of Condensed Matter Physics, Jozef Stefan Institute, Ljubljana, Slovenia
Introduction: Foscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits. Case presentation: A 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. Conclusion: Transplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.Correspondence to:
Nika Kojc, MD, PhD, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
Email: [email protected]
