Jelka Lindič

Pathology, Clinical Presentations, and Outcomes of C1q Nephropathy

C1q nephropathy is an uncommon glomerular disease with characteristic features on immunofluorescence microscopy. In this report, clinicopathologic correlations and outcomes are presented for 72 patients with C1q nephropathy. The study comprised 82 kidney biopsies from 28 children and 54 adults with male preponderance (68%). Immunofluorescence microscopy showed dominant or co-dominant staining for C1q in the mesangium and occasional glomerular capillary walls. Electron-dense deposits were observed in 48 of 53 cases. Light microscopy revealed no lesions (n = 27), focal segmental glomerulosclerosis (FSGS; n = 11), proliferative glomerulonephritis (n = 20), or various other lesions (n = 14). Clinical presentations in the patients who had no lesions histology were normal urine examination (7%), asymptomatic hematuria and/or proteinuria (22%), and nephrotic syndrome (minimal change-like lesion; 63%), which frequently relapsed. All patients with FSGS presented with nephrotic syndrome. Those with proliferative glomerulonephritis usually presented with chronic kidney disease (75%) or asymptomatic urine abnormalities (20%). Of the patients with sufficient follow-up data, complete remission of the nephrotic syndrome occurred in 77% of those with a minimal change-like lesion, progression to end-stage renal disease occurred in 33% of those with FSGS, and renal disease remained stable in 57% of those with proliferative glomerulonephritis. In conclusion, this study identified two predominant clinicopathologic subsets of C1q nephropathy: (1) Podocytopathy with a minimal change-like lesion or FSGS, which typically presents with nephrotic syndrome, and (2) a typical immune complex-mediated glomerular disease that varies from no glomerular lesions to diverse forms of glomerular proliferation, which typically presents as chronic kidney disease. Clinical presentation, histology, outcomes, and presumably pathogenesis of C1q nephropathy are heterogeneous.

Review of calciphylaxis and treatment of a severe case after kidney transplantation with iloprost in combination with hyperbaric oxygen and cultured autologous fibrin‐based skin substitutes

Abstract:  Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is a rare complication in patients with end‐stage renal disease as well as in patients after renal transplantation. It should be suspected in patients with typical painful violaceous skin lesions on the extremities or on the trunk. Active multidisciplinary management approach, with intensive local wound care, is vital in these patients. Controlling parathyroid hormone, hyperbaric oxygenation, sodium thiosulphate, bisphosphonates, cinacalcet and skin grafting could be effective. In our report, we describe a case of CUA in a 43‐year‐old patient two years after kidney transplantation. Despite intensive standard treatment, his wounds progressed; therefore, we decided to use iloprost, in combination with hyperbaric oxygenation. The clean wounds were then covered with cultivated autologous skin cells to enhance wound epithelialization. Seven months after finishing iloprost and hyperbaric oxygen treatment and the first application of skin substitute, the wounds healed completely and remained healed during the four‐yr follow‐up period. We conclude that in patients with severe CUA‐induced wounds, the combined treatment with iloprost, hyperbaric oxygen and autologous cultured fibrin‐based skin substitutes can be effective. A combination of different treatment modalities is vital in patients with CUA.

Serum with phospholipase A2 receptor autoantibodies interferes with podocyte adhesion to collagen.

The majority of sera from patients with primary membranous nephropathy have autoantibodies against the M‐type phospholipase A2 receptor (PLA2R) which is expressed on human podocytes. The rabbit variant of PLA2R attaches to collagen type IV via the fibronectin type II domain, which is also present in the human variant of PLA2R.

Acute kidney injury in immunoglobulin A nephropathy: potential role of macroscopic hematuria and acute tubulointerstitial injury.

The aim of our retrospective study was to analyze the clinical course and outcome of patients with immunoglobulin A (IgA) nephropathy who presented with macroscopic hematuria and acute kidney injury (AKI). During the period from 1990 to 2005, seven out of 584 adult patients with IgA nephropathy (1.2%) fulfilled the criteria for macroscopic hematuria‐induced AKI. There was an equal gender distribution among our patients, and a rather high average age at presentation (55.7 ± 10.9 years). Four patients who were oliguric upon admission to hospital needed hemodialysis treatment. The average serum creatinine at the time of kidney biopsy was 429.8 ± 377 µmol/L (median value 378). The percutaneous kidney needle biopsies showed focal proliferative crescentic glomerulonephritis of subclass III, according to the Haas scheme, associated with prominent red blood cell tubular casts and acute tubulointerstitial nephritis. Four patients with the most prominent crescents and tubulointerstitial involvement were treated with methylprednisolone. All patients, treated and untreated, recovered their kidney function (the serum creatinine at a median follow‐up of 15 months was 111.7 ± 38 µmol/L). In conclusion, AKI in IgA nephropathy accompanied by macroscopic hematuria appears to have been a reversible condition in our series of patients. Regarding pathogenesis, the kidney biopsy study points to the important role of glomerular bleeding with consequent, widespread obstructive red blood cell tubular casts accompanied by tubular injury and interstitial nephritis.

Influence of Renin‐Angiotensin‐Aldosterone System‐Blocking Drugs on Peritoneal Membrane in Peritoneal Dialysis Patients

Therapy with renin‐angiotensin‐aldosterone system (RAAS)‐blocking drugs prevents the development of fibrosis and angiogenesis in animal models and humans. In our study we have evaluated the systemic effect of RAAS blockade and the effect on peritoneal growth factors, cytokine production and membrane transport characteristics in patients on peritoneal dialysis. Thirty‐seven peritoneal dialysis (PD) patients were enrolled in our cross‐sectional study. Aldosterone and angiotensin II concentrations were measured in serum to determine the RAAS activity. The inflammatory and profibrotic activity was evaluated by measuring the concentration of C‐reactive protein (CRP), serum albumin, and peritoneal concentration of interleukin‐6 (IL‐6), vascular endothelial growth factor (VEGF), plasminogen activator inhibitor‐1 (PAI‐1), transforming growth factor‐β (TGF‐β) and cancer antigen‐125 (CA‐125). The transport characteristics of the peritoneal membrane were analyzed with a peritoneal equilibration test (PET). Results were compared between the group with RAAS‐blocking drugs (RAAS group) and the group without them (non‐RAAS group). Mean serum aldosterone concentration was significantly lower in patients treated with ARB‐blocking drugs (P = 0.001) and serum angiotensin II concentration was lower in patients treated with ACE inhibitors (P = 0.009). RAAS blockade resulted in lower peritoneal PAI‐1 levels (748.1 to 1222.7 ng/L; P = 0.07) without any influence on CRP, peritoneal concentrations of IL‐6, VEGF, TGF‐β and CA‐125, or alteration in peritoneal membrane characteristics tested by PET. RAAS‐blocking drugs could be effective in preventing peritoneal fibrosis due to possible reduction of peritoneal PAI‐1 concentrations that have already been etiologically linked with fibrin deposition in the pathogenesis of encapsulating peritoneal sclerosis.

Successful Treatment of Severe Hantavirus Nephritis With Corticosteroids: A Case Report and Literature Review

Hantaviruses can be associated with severe form of hemorrhagic fever with renal syndrome although there are only a few cases reporting chronic kidney disease after hantavirus infection. We report a severe nonresolving chronic renal failure after protracted Dobrava hantavirus infection successfully treated with corticosteroids. Ten days after working in a basement a 33‐year‐old man fell seriously ill, with high fever, chills, diffuse myalgia, headache and abdominal pain. After hospital admission a diagnosis of hemorrhagic fever with renal syndrome caused by Dobrava hantavirus was made. Acute oliguric kidney injury developed in the first 3 days after admission, in a few days diuresis restored and he became polyuric. Nevertheless renal failure persisted and he needed hemodialysis. Because of nonresolving kidney failure, nephrogenic diabetes insipidus and renoparenchymal arterial hypertension persisting 2 months after onset of symptoms, a kidney biopsy was performed, showing severe necrotizing tubulointerstitial nephritis. High dose methylprednisolone therapy was started and his renal function significantly improved. Two months later a second renal biopsy showed persisting elements of active necrotizing tubulointerstitial nephritis. We decided to stop corticosteroid treatment and introduced aldosterone antagonist eplerenon as anti‐fibrotic agent, and his renal function further improved and remained stable. Nine months later his serum creatinine concentration was 227 μmol/L, proteinuria 0.156 g/day and well controlled nephrogenic diabetes insipidus.

Encapsulating Peritoneal Sclerosis in Patients on Peritoneal Dialysis in Slovenia

Encapsulating peritoneal sclerosis (EPS) is a rare complication in patients on peritoneal dialysis (PD), the prevalence of which increases with the time spent on PD. Various causative factors have been proposed, but the pathogenesis still remains unclear. The aim of our retrospective study was to analyze the basic clinical characteristics and outcomes of five patients diagnosed with EPS out of 423 patients treated with PD between January 1983 and December 2003. One patient was admitted due to ultrafiltration failure of the peritoneal membrane, and four patients were admitted for acute peritonitis. All of our patients presented with clinical symptoms suggestive of obstructive ileus. We confirmed the diagnosis of EPS with a computer tomography scan, a diagnostic laparotomy or laparoscopy, and a biopsy of the parietal peritoneum. We treated all of our patients with catheter removal, transferal to hemodialysis, antibiotics, complete parenteral nutrition, methylprednisolone, and tamoxifen for 6 months. One patient was treated with surgical enterolysis and died of septic complications, another patient died of sudden cardiac death during treatment. Three patients were doing well for 4–7 months after the treatment was started. The incidence of EPS was 1.2% and the mortality rate was 40%. EPS is a rare complication in longstanding PD patients in our institution. Despite treatment with hemodialysis, complete parenteral nutrition, steroids, tamoxifen and surgical intervention, the mortality rate is high and comparable to other reports.

Pulse Wave Velocity and Augmentation Index in Renal Transplant Recipients - 4.6 Years Follow Up

Introduction Chronic kidney disease (CKD) is a risk factor for cardiovascular diseases leading to rapid progression of arteriosclerosis. After renal transplantation some of the traditional and CKD-specific risk factors disappear, however, new risk factors emerge, such as metabolic effects of immunosuppression therapy and new onset diabetes mellitus (NODAT). Arterial properties can be evaluated by measuring pulse wave velocity (PWV) and augmentation index (AI). The aim of the study was to define the long-term impact of renal transplantation on arterial stiffness. Another goal of the study was to evaluate effects of diabetes mellitus on PWV and AI. Materials and Methods The study was conducted on renal graft recipients, who had successful kidney transplantation in the years between 2011 and 2013. PWV and AI were evaluated noninvasively by applanation tonometry using SphygmoCor™ (AtCor Medical Pty. Ltd., Sydney, Australia) immediately after transplantation and four to five years thereafter. Clinical and biochemical data were obtained from the hospitals database. Results and Discussion 44 graft recipients (17 women, 27 men, age 49.1±11.5 years) were included in the study. The average follow-up period between the first and the second measurement was 55.7±6.9 months. PWV did not change significantly during the follow-up period (9.1±1.8m/s vs. 8.7±1.8m/s; p=0.137). PWV in the group of non-diabetic patients decreased in the follow-up period by 0.62±1.23 m/s, while it increased for 0.43±2.1m/s in the group of diabetic patients. However, the difference between the two was not significant (p=0.057). At the second measurement the difference in PWV between diabetic and nondiabetic patients was significant (10.2±1.8 vs. 8.3±1.23m/s; p=0.02). Duration of smoking before transplantation correlated significantly with PWV (p=0.012). AI in the whole group increased significantly (from 18.3±10.3% to 25.9±9.4%; p<0.01), whereas a significant difference in AI between diabetic and nondiabetic patients was not found. Conclusion PWV of the whole group did not change significantly during the follow-up period, possibly due to stabilization of the process of arteriosclerosis after renal transplantation. In the subgroup of patients without diabetes we observed a trend of PWV reduction, whereas in the subgroup of patients with diabetes we observed the opposite. Diabetes mellitus and duration of smoking before transplantation are important risk factors for arteriosclerosis progression after renal transplantation.

Estimated Protein Excretion Rate From Second Morning Spot Urine Protein-Creatinine Ratio: A Diagnostic Study in Kidney Transplant Recipients.: Abstract# C1737

C1737 Estimated Protein Excretion Rate From Second Morning Spot Urine Protein-Creatinine Ratio: A Diagnostic Study in Kidney Transplant Recipients. M. Mrevlje,1 J. Lindic,1 G. Mlinsek,1 A. Kandus,1,2 M. Arnol.1,2 1Department of Nephrology, University Medical Centre, Ljubljana, Slovenia; 2Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. Background. Protein-creatinine ratio (PCR) in spot urine samples is recommended for proteinuria screening instead of measured 24-hr protein excretion. A second morning urine sample is more convenient to collect than the first one. We hypothesized that estimated protein excretion rate (ePER) using second morning spot PCR and estimated creatinine excretion rate (eCER) accurately predicts 24-hr protein excretion in kidney transplant recipients. Methods. Second morning spot PCR was measured in 572 prevalent transplant recipients at least 3 months post-transplant. Proteinuria (PCR>20 mg/mmol) was present in 190 patients (33%). PCR and 24-hr urine protein excretion were measured in 161 recipients who consented for the study. ePER was calculated as the product of PCR and eCER. Percent bias ([measured–estimated value/measured value]x100), precision (standard deviation of the mean bias), and accuracy (within 30% of 24hr collection) were calculated for the following values of 24-hr protein excretion: 150–299, 300–499, 500–999 and ≥1000 mg/d. Receiver operator characteristic curves were used to obtain the best sensitivity and specifi city of ePER at the selected cutoff values. Results. Mean age was 55 years, mean 24-hr creatinine clearance was 53 ml/min, median PCR 52 mg/mmol, median ePER 457 mg/d, and median 24-hr protein excretion 480 mg. The ePER tended to overestimate 24-hr protein excretion, and relative overestimation was greatest with the smallest amount of proteinuria. 24-hr protein excretion, mg/d Percent bias (95% CI), % Precision (95% CI), mg/d Accuracy, % 150-299 (n=42) -72 (-107−-37) 195 (165−226) 45 300-499 (n=41) -4 (-12−14) 235 (198−272) 54 500-999 (n=45) -1 (-15−13) 343 (292−394) 53 ≥ 1000 (n=33) -12 (-44−20) 1154 (901−1407) 64 The ePER had good discriminatory ability to predict 24-hr protein excretion >300, >500, and >1000 mg with area under the curve of 0.94, 0.97, and 0.98, respectively. ePER cutoff values of 350, 650, and 1100 mg/d had the highest sensitivity and specifi city to predict proteinuria >300, >500, and >1000 mg/d (90% and 78%, 90% and 92%, and 92% and 98%, respectively). Conclusion. In kidney transplant recipients, ePER in second morning spot urine accurately predicts 24-hr protein excretion >300 mg. However, ePER >1000 mg/d is less precise and 24-hr urine collection should be considered before clinical decisions. Abstract# C1738 Prognostic Value of Post-Transplantation Proteinuria for Cardiovascular Outcomes in Kidney Transplant Recipients. H. Jeon,1 J. Hwang,1 H. Kim,3 S. Park,3 K. Joo,1 C. Lim,2 Y. Oh,2 C. Ahn,1 Y. Kim,1 J. Lee.2 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic of; 2Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea, Republic of; 3Department of Internal Medicine, Ulsan University College of Medicine, Seoul, Korea, Republic of. Background: Proteinuria has been shown to be associated with mortality, progression to kidney failure, and cardiovascular disease events in general population. Herein, we have analyzed the effect of proteinuria on cardiovascular outcomes, graft loss, and mortality in kidney transplant recipients (KTRs). Methods: We performed a retrospective multi-center study to evaluate the effect of post-transplantation proteinuria on cardiovascular outcomes, graft loss, and patients’ survival. This study enrolled a total of 2052 KTRs in Seoul National University Hospital and Asan Medical Center, and patients were classifi ed into three groups according to the amount of proteinuria (<150mg/day [group 1] vs. 150-1500mg/day [group 2] vs. >1500mg/day [group 3]). The primary endpoint was major adverse cardiac events (MACE), defi ned as composite cardiac death, nonfatal myocardial infarction, or coronary revascularization. Results: The mean age of the recipients was 43.6 ± 11.4 years, and 58.6% were male. During a median 55.3-month follow-up, there were 38 (1.9%) cases of MACE, 71 (3.5%) graft loss, and 44 (2.1%) deaths. In a Cox model adjusted with multiple covariates, proteinuria was signifi cantly associated with MACE (group 1 [reference] vs. group 2 [HR 3.29, CI 1.02-10.60, P = 0.046] vs. group 3 [HR 5.81, CI 1.2826.31, P = 0.022]). KTRs with higher proteinuria showed signifi cantly higher graft loss rate than those without proteinuria (group 1 [reference] vs. group 3 [HR 3.97, CI 1.65-9.56, P = 0.002]). However, there was no signifi cant association between proteinuria and all-cause mortality. KTRs with proteinuria showed a greater number of acute rejection episodes (10.5% [group 1] vs. 20.5% [group 2] vs. 37.1% [group 3], P < 0.001) Conclusion: Post-transplantation proteinuria is a strong prognostic factor for cardiovascular outcomes among KTRs. Therefore, evaluation and management of proteinuria should be considered to improve graft and patients outcomes. C1738 Prognostic Value of Post-Transplantation Proteinuria for Cardiovascular Outcomes in Kidney Transplant Recipients. H. Jeon,1 J. Hwang,1 H. Kim,3 S. Park,3 K. Joo,1 C. Lim,2 Y. Oh,2 C. Ahn,1 Y. Kim,1 J. Lee.2 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic of; 2Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea, Republic of; 3Department of Internal Medicine, Ulsan University College of Medicine, Seoul, Korea, Republic of. Background: Proteinuria has been shown to be associated with mortality, progression to kidney failure, and cardiovascular disease events in general population. Herein, we have analyzed the effect of proteinuria on cardiovascular outcomes, graft loss, and mortality in kidney transplant recipients (KTRs). Methods: We performed a retrospective multi-center study to evaluate the effect of post-transplantation proteinuria on cardiovascular outcomes, graft loss, and patients’ survival. This study enrolled a total of 2052 KTRs in Seoul National University Hospital and Asan Medical Center, and patients were classifi ed into three groups according to the amount of proteinuria (<150mg/day [group 1] vs. 150-1500mg/day [group 2] vs. >1500mg/day [group 3]). The primary endpoint was major adverse cardiac events (MACE), defi ned as composite cardiac death, nonfatal myocardial infarction, or coronary revascularization. Results: The mean age of the recipients was 43.6 ± 11.4 years, and 58.6% were male. During a median 55.3-month follow-up, there were 38 (1.9%) cases of MACE, 71 (3.5%) graft loss, and 44 (2.1%) deaths. In a Cox model adjusted with multiple covariates, proteinuria was signifi cantly associated with MACE (group 1 [reference] vs. group 2 [HR 3.29, CI 1.02-10.60, P = 0.046] vs. group 3 [HR 5.81, CI 1.2826.31, P = 0.022]). KTRs with higher proteinuria showed signifi cantly higher graft loss rate than those without proteinuria (group 1 [reference] vs. group 3 [HR 3.97, CI 1.65-9.56, P = 0.002]). However, there was no signifi cant association between proteinuria and all-cause mortality. KTRs with proteinuria showed a greater number of acute rejection episodes (10.5% [group 1] vs. 20.5% [group 2] vs. 37.1% [group 3], P < 0.001) Conclusion: Post-transplantation proteinuria is a strong prognostic factor for cardiovascular outcomes among KTRs. Therefore, evaluation and management of proteinuria should be considered to improve graft and patients outcomes. Abstract# C1739 NGAL as an Early Predictor of Delayed Graft Function. J. Nieto, L. Serna, G. Zuluaga, C. Ocampo, A. Aristizabal, C. Velez, J. Vanegas, A. Bedoya, S. Lopera, N. Giraldo. Hospital Pablo Tobon Uribe, Medellin, Colombia. C1739 NGAL as an Early Predictor of Delayed Graft Function. J. Nieto, L. Serna, G. Zuluaga, C. Ocampo, A. Aristizabal, C. Velez, J. Vanegas, A. Bedoya, S. Lopera, N. Giraldo. Hospital Pablo Tobon Uribe, Medellin, Colombia. Delayed graft function (DGF) occurs in 20-50% of renal transplants and is a complication that can affect graft survival. The creatinine reduction ratio (CRR) has been the gold standard for defi ning DGF. Urinary neutrophil gelatinase-associated lipocalin (NGALu) is an early marker of acute kidney injury. The aims of this study were to describe the behavior of NGALu in deceased-donor renal transplant recipients and to compare this indicator with the CRR for the early detection of DGF. Methodology:This was a prospective cohort study, in which NGALu levels were assessed at 1, 12, 24 and 48 hours after renal transplantation and compared with the daily CRR. Descriptive statistics and nonparametric tests were performed. The best cutoff points and the optimal assessment times for both markers were explored; a comparison of the receiver operating characteristic (ROC) curves for the NGALu level and the CRR was carried out to diagnose DGF.Results:Sixty-one patients were included in the study, 54.8% male and 91.9% fi rst transplant recipients, with a median age of 36.5 years and a median cold ischemia time of 15 hours. DGF occurred in 12 patients and 4 patients required dialysis in the fi rst week. NGALu levels at all the cut-off points were higher in patients with DGF (p=0.49, p=0.0321, p=0.0421 and p=0.0035, respectively). NGALu>120 ng/ml at 48 hours predicted DGF with a sensitivity of 75% and specifi city of 67.8%. A CRR of 59% best discriminated DGF, with a sensitivity of 91 % and specifi city of 83% at 48 hours. In comparing the ROC curves for the NGALu level and the CRR, the CRR was a better marker.

Urinary Immunoglobulin G to Albumin Ratio and N-Acetyl-Beta-D-Glucosaminidase as Early Predictors of Therapeutic Response in ANCA-Associated Glomerulonephritis

Background The aim of our study was to evaluate the prognostic value of glomerular and tubular proteinuria and tubular enzymuria as early indicators of therapeutic response to induction therapy with i.v. pulse cyclophosphamide (CyC) and methylprednisolone (MP) in patients with antineutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis. Methods and Findings An observational single-center study was conducted in 30 patients with ANCA-associated glomerulonephritis. Patients were divided into subgroups with good or poor response to CyC therapy according to clinical and laboratory parameters. The diagnosis of ANCA-associated glomerulonephritis was based on the Chapel-Hill disease definitions. Good response to induction therapy was significantly associated with higher absolute values of urine N-acetyl-beta-D-glucosaminidase (NAG) to creatinine ratio (above 14.83 microcat/mol) and urine immunoglobulin G (IgG) to albumin ratio (above 0.09) at the time of diagnosis, while albuminuria or proteinuria did not have any early predictive value. The remission of renal disease was anticipated as early as 3 months after introduction of induction therapy in patients with reduction of urine NAG to creatinine ratio below the baseline value and in patients with at least 24% rise in eGFR. Conclusions Urine IgG to albumin and urine NAG to creatinine ratio are better early predictors of treatment response in patients with ANCA-associated glomerulonephritis than proteinuria or albuminuria.