Agnieszka Perkowska-Ptasińska

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group

Since the Oxford Classification of IgA nephropathy (IgAN) was published in 2009, MEST scores have been increasingly used in clinical practice. Further retrospective cohort studies have confirmed that in biopsy specimens with a minimum of 8 glomeruli, mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) lesions predict clinical outcome. In a larger, more broadly based cohort than in the original Oxford study, crescents (C) are predictive of outcome, and we now recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed. A large study showed E lesions are predictive of outcome in children and adults, but only in those without immunosuppression. A review of S lesions suggests there may be clinical utility in the subclassification of segmental sclerosis, identifying those cases with evidence of podocyte damage. It has now been shown that combining the MEST score with clinical data at biopsy provides the same predictive power as monitoring clinical data for 2 years; this requires further evaluation to assess earlier effective treatment intervention. The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors.

A Multicenter Study of the Predictive Value of Crescents in IgA Nephropathy

The Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a ≥50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean±SD eGFR of 78±29 ml/min per 1.73 m2 and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in one fourth or more of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression.

One-year results of a prospective, randomized trial comparing two machine perfusion devices used for kidney preservation.

Studies have shown beneficial effects of machine perfusion (MP) on early kidney function and long‐term graft survival. The aim of this study was to investigate whether the type of perfusion device could affect outcome of transplantation of deceased donor kidneys. A total of 50 kidneys retrieved from 25 donors were randomized to machine perfusion using a flow‐driven (FD) device (RM3; Waters Medical Inc) or a pressure‐driven (PD) device (LifePort; Organ Recovery Systems), 24 of these kidneys (n = 12 pairs; 48%) were procured from expanded criteria donors (ECD). The primary endpoints were kidney function after transplantation defined using the incidence of delayed graft function (DGF), the number of hemodialysis sessions required, graft function at 12 months, and analyses of biopsy. DGF was similar in both groups (32%; 8/25). Patients with DGF in the FD group required a mean of 4.66 hemodialysis sessions versus 2.65 in the PD group (P = 0.005). Overall, 1‐year graft survival was 80% (20/25) vs. 96% (24/25) in the FD and PD groups. One‐year graft survival of ECD kidneys was 66% (8/12) in the FD group versus 92% (11/12) in the PD group. Interstitial fibrosis and tubular atrophy were significantly more common in the FD group – 45% (5/11) vs. 0% (0/9) (P = 0.03) in PD group. There were no differences in creatinine levels between the groups. Machine perfusion using a pressure‐driven device generating lower pulse stress is superior to a flow‐driven device with higher pulse stress for preserving kidney function.

Assessment of Kidneys Procured From Expanded Criteria Donors Before Transplantation

BACKGROUND Using expanded criteria donor (ECD) organs is 1 strategy to make more organs available for transplant. To reduce the number of posttransplant complications and failures, there is a need to create a comprehensive system of evaluation before transplantation, especially for kidneys harvested from ECD. The aim of this study was to assess the results of kidneys procured from ECD seeking to discover the most useful factors for kidney evaluation before transplantation. PATIENTS AND METHODS One hundred seventy-two patients received cadaveric renal transplants between January 1, 2006, and August 31, 2008. We collected data on donors, recipients, and perfusion parameters. We analyzed patient and graft survivals, as well as immediate, delayed, and slow graft function. Kidney recipient function was assessed by serum creatinine concentrations and by creatinine clearance calculated according to the Cockroft-Gault formula. Renal biopsy specimens were obtained in the perioperative periods 147 cases. RESULTS The overall 1-year graft survival was 86.9%. More than 25% of transplanted kidneys were harvested from ECD. There were no significant differences in patient survival between recipients of standard criteria donor kidneys (RSCDK) versus of expanded criteria donor kidneys (RECDK). One-year graft survival was higher among the RSCDK group than the RECDK group, namely, 94.4% versus 62.5%, (P = .004). There were no differences in the incidence of primary nonfunction or in delayed graft function between the groups. RECDK were more likely to show slow graft function (69.2% vs 37.8%; P = .033). A lower graft survival at 6 months after transplantation was observed among organs harvested from ECD compared with standard criteria donor (SCD) kidneys who showed histologic lesions or a flow at the fourth hour of machine perfusion below 0.4 mL/g. Using a logistic regression model, chronic histologic changes were shown to influence kidney survival at 6 months after transplantation. CONCLUSION There was no significant difference in patient survival between recipients of kidneys harvested from expanded versus standard criteria donors. ECD kidneys displayed lower graft survival rates. There was no significant difference in the incidence of delayed graft function between recipients of kidneys harvested from expanded versus standard criteria donors. Pretransplant evaluation of ECD kidneys should include 3 variables: donor parameters, histologic findings, and machine perfusion parameters.

Banff Histopathological Consensus Criteria for Preimplantation Kidney Biopsies.

The Banff working group on preimplantation biopsy was established to develop consensus criteria (best practice guidelines) for the interpretation of preimplantation kidney biopsies. Digitally scanned slides were used (i) to evaluate interobserver variability of histopathologic findings, comparing frozen sections with formalin‐fixed, paraffin‐embedded tissue of wedge and needle core biopsies, and (ii) to correlate consensus histopathologic findings with graft outcome in a cohort of biopsies from international medical centers. Intraclass correlations (ICCs) and univariable and multivariable statistical analyses were performed. Good to fair reproducibility was observed in semiquantitative scores for percentage of glomerulosclerosis, arterial intimal fibrosis and interstitial fibrosis on frozen wedge biopsies. Evaluation of frozen wedge and core biopsies was comparable for number of glomeruli, but needle biopsies showed worse ICCs for glomerulosclerosis, interstitial fibrosis and tubular atrophy. A consensus evaluation form is provided to help standardize the reporting of histopathologic lesions in donor biopsies. It should be recognized that histologic parameters may not correlate with graft outcome in studies based on organs deemed to be acceptable after careful clinical assessment. Significant limitations remain in the assessment of implantation biopsies.

Arteriolar Hyalinization in Implantation Kidney Biopsies as a Predictor of Graft Function

The shortage of organs suitable for transplantation has caused a constant evolution of donor acceptance criteria, making an implantation biopsy a valuable tool to predict kidney allograft survival. Preimplantation vascular changes may be divided into sclerosis or intimal fibrous thickening or arteriolar hyalinization. Increasing evidence has indicated their impact on graft function. The aim of this study was to evaluate the significance of preimplantation arteriolar hyalinization for the stability of kidney allograft function. Among a prospective cohort study of 53 kidney recipients (implantation: 2006-2007) who showed serum creatinine values between 1 and 2 mg/dL at 3 months after engraftment, the mean observation time was 24 +/- 8.7 months. At the end of the observation, kidney function as defined by the estimated glomerular filtration rate by the Cockcroft-Gault formula (eGFR C-G) was significantly diminished in individuals with preimplantation evidences of arteriolar hyalinization (mean values: 51.2 +/- 14.8 and 62.0 +/- 16.7, respectively; P < .03) or serum creatinine concentrations (1.76 +/- 0.36 vs 1.51 +/- 0.48 mg/dL; P < .09). The negative influence of arteriolar hyalinosis on allograft function was time-dependent; an early satisfactory filtration rate did not preclude progressive kidney dysfunction.

Transplant glomerulopathy: clinical and pathological correlations.

OBJECTIVE Chronic transplant glomerulopathy (TG) is one of the leading causes of severe posttransplantation proteinuria and graft loss. Our current knowledge about risk factors for the development of TG, as well as factors that affect its dynamics and prognosis, is poor. We sought to describe the pathological and clinical risk factors and correlations of TG as well as parameters that influenced the survival of grafts with that pathology. MATERIALS AND METHODS We retrospectively reevaluated 86 kidney transplant cases with TG that have been recognized on the basis of an indication biopsy since 1997. All TG as well as all pre-TG (previous) biopsies were characterized for the presence of C4d deposits in the graft. RESULTS Younger recipient age and minimal immunosuppression due to drug withdrawal or suboptimal drug doses/blood levels within 3 to 6 months preceding the biopsy were associated with C4d deposition in peritubular capillaries (PTC; P = .0053 and P = .0365, respectively). Diffuse PTC-itis (P = .029, RR [95% confidence interval] = 3.349 [1.131-9.919]) and total interstitial inflammation score (P = .015, RR [95% confidence interval] = 9.662 [1.784-52.329]) were observed to show a negative impact on graft survival. C4d deposition in PTC and glomeruli, the level of pretransplantation sensitization, episodes of acute rejection, and C4d in previous (pre-TG) biopsies did not influence the survival of grafts with TG. CONCLUSIONS Younger recipient age and minimal immunosuppression were associated with C4d positivity in grafts with TG. The survival of kidney grafts with TG was significantly affected by the magnitude of inflammation in the interstitium and PTC, but not by C4d positivity in PTC and glomeruli.

Urinary myeloid IgA Fc alpha receptor (CD89) and transglutaminase-2 as new biomarkers for active IgA nephropathy and henoch-Schönlein purpura nephritis

Background IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) are glomerular diseases that share a common and central pathogenic mechanism. The formation of immune complexes containing IgA1, myeloid IgA Fc alpha receptor (FcαRI/CD89) and transglutaminase-2 (TG2) is observed in both conditions. Therefore, urinary CD89 and TG2 could be potential biomarkers to identify active IgAN/HSPN. Methods In this multicenter study, 160 patients with IgAN or HSPN were enrolled. Urinary concentrations of CD89 and TG2, as well as some other biochemical parameters, were measured. Results Urinary CD89 and TG2 were lower in patients with active IgAN/HSPN compared to IgAN/HSPN patients in complete remission (P < 0.001). The CD89xTG2 formula had a high ability to discriminate active from inactive IgAN/HSPN in both situations: CD89xTG2/proteinuria ratio (AUC: 0.84, P < 0.001, sensitivity: 76%, specificity: 74%) and CD89xTG2/urinary creatinine ratio (AUC: 0.82, P < 0.001, sensitivity: 75%, specificity: 74%). Significant correlations between urinary CD89 and TG2 (r = 0.711, P < 0.001), proteinuria and urinary CD89 (r = − 0.585, P < 0.001), and proteinuria and urinary TG2 (r = − 0.620, P < 0.001) were observed. Conclusions Determination of CD89 and TG2 in urine samples can be useful to identify patients with active IgAN/HSPN.

Kidney disease in the elderly: biopsy based data from 14 renal centers in Poland

BackgroundLonger life expectancy is associated with an increasing prevalence of kidney disease. Aging itself may cause renal damage, but the spectrum of kidney disorders that affect elderly patients is diverse. Few studies, mostly form US, Asia and West Europe found differences in the prevalence of some types of kidney diseases between elderly and younger patients based on renal biopsy findings, with varied proportion between glomerulopathies and arterionephrosclerosis as a dominant injury found. Here, for the first time in Eastern Europe we analyzed native kidney biopsy findings and their relationship to clinical characteristics at the time of biopsy in elderly individuals (aged ≥65) in comparison to younger adults (aged 18–64).MethodsBiopsy and clinical data from 352 patients aged ≥65 were retrospectively identified, analyzed and compared with a control group of 2214 individuals aged 18–64. All kidney biopsies studied were examined at Medical University of Warsaw in years 2009–14.ResultsIn elderly patients the leading indication for biopsy was nephrotic range proteinuria without hematuria (34.2%) and the most prevalent pathologic diagnoses were: membranous glomerulonephritis (MGN) (18.2%), focal segmental glomerulosclerosis (FSGS) (17.3%) amyloidosis (13.9%) and pauci immune glomerulonephritis (12.8%). Hypertension and age-related lesions very rarely were found an exclusive or dominant finding in a kidney biopsy (1.7%) and a cause of proteinuria (1.1%) in elderly individuals. There were 18.2% diabetics among elderly individuals, and as much as 75% of them had no morphologic signs of diabetic kidney disease in the renal biopsy. Amyloidosis, MGN, pauci immune GN, crescentic GN and light and/or heavy chain deposition disease (LCDD/HCDD) were more frequent whereas IgA nephropathy (IgAN), lupus nephritis (LN) and thin basement membrane disease (TBMD) were less common among elderly than in younger patients.ConclusionsProteinuria, a dominating manifestation in elderly patients subjected to kidney biopsy was most commonly related to glomerulopathies. The relatively high prevalence of potentially curative kidney diseases in elderly individuals implicates the importance of renal biopsy in these patients.