Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.

The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19-23, 2013, and was preceded by a 2-day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody-mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter-observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis ("isolated v") represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d-negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

Banff 2011 Meeting report: new concepts in antibody-mediated rejection.

The 11th Banff meeting was held in Paris, France, from June 5 to 10, 2011, with a focus on refining diagnostic criteria for antibody-mediated rejection (ABMR). The major outcome was the acknowledgment of C4d-negative ABMR in kidney transplants. Diagnostic criteria for ABMR have also been revisited in other types of transplants. It was recognized that ABMR is associated with heterogeneous phenotypes even within the same type of transplant. This highlights the necessity of further refining the respective diagnostic criteria, and is of particular significance for the design of randomized clinical trials. A reliable phenotyping will allow for definition of robust end-points. To address this unmet need and to allow for an evidence-based refinement of the Banff classification, Banff Working Groups presented multicenter data regarding the reproducibility of features relevant to the diagnosis of ABMR. However, the consensus was that more data are necessary and further Banff Working Group activities were initiated. A new Banff working group was created to define diagnostic criteria for ABMR in kidneys independent of C4d. Results are expected to be presented at the 12th Banff meeting to be held in 2013 in Brazil. No change to the Banff classification occurred in 2011.

Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

Ritonavir-induced acute kidney injury: kidney biopsy findings and review of literature.

Ritonavir therapy is not generally considered nephrotoxic. We report a case of acute kidney injury secondary to ritonavir, with kidney biopsy demonstrating extensive acute tubular injury. This is the first report of a kidney biopsy and pathology in acute kidney injury associated with ritonavir. A review of published medical literature on the topic is also presented.

Banff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups.

The 10th Banff Conference on Allograft Pathology was held in Banff, Canada from August 9 to 14, 2009. A total of 263 transplant clinicians, pathologists, surgeons, immunologists and researchers discussed several aspects of solid organ transplants with a special focus on antibody mediated graft injury. The willingness of the Banff process to adapt continuously in response to new research and improve potential weaknesses, led to the implementation of six working groups on the following areas: isolated v-lesion, fibrosis scoring, glomerular lesions, molecular pathology, polyomavirus nephropathy and quality assurance. Banff working groups will conduct multicenter trials to evaluate the clinical relevance, practical feasibility and reproducibility of potential changes to the Banff classification. There were also sessions on quality improvement in biopsy reading and utilization of virtual microscopy for maintaining competence in transplant biopsy interpretation. In addition, compelling molecular research data led to the discussion of incorporation of omics-technologies and discovery of new tissue markers with the goal of combining histopathology and molecular parameters within the Banff working classification in the near future.

Subclinical rejection in stable positive crossmatch kidney transplant patients: incidence and correlations.

We reviewed 116 surveillance biopsies obtained approximately 1, 3, 6 and 12 months posttransplantation from 50 +XM live donor kidney transplant recipients to determine the frequency of subclinical cell-mediated rejection (CMR) and antibody-mediated rejection (AMR). Subclinical CMR was present in 39.7% of the biopsies at 1 month and >20% at all other time points. The presence of diffuse C4d on biopsies obtained at each time interval ranged from 20 to 30%. In every case, where histological and immunohistological findings were diagnostic for AMR, donor-specific antibody was found in the blood, challenging the long-held belief that low-level antibody could evade detection due to absorption on the graft. Among clinical factors, only recipient age was associated with subclinical CMR. Clinical factors associated with subclinical AMR were recipient age, positive cytotoxic crossmatch prior to desensitization and two mismatches of HLA DR 51, 52 and 53 alleles. Surveillance biopsies during the first year post-transplantation for these high-risk patients uncover clinically occult processes and phenotypes, which without intervention diminish allograft survival and function.

Banff 07 classification of renal allograft pathology: updates and future directions.

The 9th Banff Conference on Allograft Pathology was held in La Coruna, Spain on June 23-29, 2007. A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies. The outcome of the consensus discussions on renal pathology is provided in this article. Major updates from the 2007 Banff Conference were: inclusion of peritubular capillaritis grading, C4d scoring, interpretation of C4d deposition without morphological evidence of active rejection, application of the Banff criteria to zero-time and protocol biopsies and introduction of a new scoring for total interstitial inflammation (ti-score). In addition, emerging research data led to the establishment of collaborative working groups addressing issues like isolated 'v' lesion and incorporation of omics-technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.

Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel.

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi-disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better- or worse-graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody-mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined. The availability of a simple, reproducible, clinically relevant and internationally accepted schema for grading rejection should improve the level of diagnostic accuracy and facilitate communication between all parties involved in the care of pancreas transplant recipients.

Ricinoleic acid stimulation of active anion secretion in colonic mucosa of the rat.

Perfusion of the colon with ricinoleic acid produces fluid and electrolyte accumulation. The mechanism of these changes in water and electrolyte movement is uknown. These studies were designed to determine whether ricinoleic acid effects active ion transport across isolated rat colonic mucosa. 0.5 mM Na ricinoleate produced significant increases in potential difference (3.8 +/- 0.5 mV) and short-circuit current (Isc) (99.2 +/- 10.1 muA/cm2). The increases in Isc produced by Na ricinoleate were inhibited by both removal of bicarbonate and chloride and by the presence of theophylline. The hydroxy fatty acid also resulted in a significant decrease in net Na absorption from 4.7 +/- 0.8 to 0.1 +/- 0.7 mueq/h cm2 and reversed net Cl transport from absorption (+ 4.5 +/- 0.9) to secretion (-2.2 +/- mueq/h cm2). In parallel studies 0.5 mM Na ricinoleate increased mucosal cyclic AMP content by 58%. The concentrations of Na ricinoleate required to produce detectable and maximal increases in both Isc and cyclic AMP were the same. These results provide evidence in support of the concept that hydroxy fatty acid-induced fluid and electrolyte accumulation is driven by an active ion secretory process.

HIV-1 kills renal tubular epithelial cells in vitro by triggering an apoptotic pathway involving caspase activation and Fas upregulation.

HIV-infected patients suffer several renal syndromes, which can progress rapidly from renal insufficiency to end-stage renal disease. Histologically, HIV-induced nephropathy is characterized by prominent tubulopathy with apoptosis of tubular cells. Clinical and experimental evidence suggests that renal injury may be directly related to virus infection. Although HIV-1 is a polytropic and not solely lymphotropic pathogen, the susceptibility of renal cells to HIV-1 remains to be determined. This paper demonstrates in vitro the permissiveness of proximal tubular epithelial cells (PTEC) to HIV-1 and describes the effects of PTEC infection to explain the pathogenesis of tubular damage in vivo. The results indicate that PTEC express HIV-specific receptor and coreceptors and sustain virus replication. We observed that HIV-1 infection causes the death of tubular cells by triggering an apoptotic pathway involving caspase activation. Fas upregulation but not Fas ligand expression was found in the infected PTEC. However, after HIV-1 infection, tubular cells became susceptible to apoptosis induced through Fas stimulation. Caspase inhibition prevented the death of the infected PTEC in spite of persistent viral replication. These findings may explain the prominent histopathology of HIV-associated nephropathy and demonstrate that the apoptosis of nonlymphoid cells can be directly induced by HIV-1.

Acceptance of Gold Medal From the Catalan Society of Transplantation by Drs. Lorraine Racusen and Kim Solez - With Remarks on the Banff Meeting Spirit.

The awarding of the gold medal from the Catalan Society of Transplantation to the organizers of the Banff Transplant Pathology meetings is an opportunity to acknowledge gratitude to all the people who have helped make these meetings a success over the past 26 years. Other large organizations have given up consensus conferences, but the Banff consensus process is thriving. It is unusual for any organization to have the same leadership for 26 years. It has only worked for the Banff meetings because the leadership was flexible and able to change with the times. People have often talked about the "special Banff spirit." This year's meeting gave us the opportunity to examine this spirit in detail by analyzing how the meeting consensus sessions and social events functioned. The meeting has never used expert facilitators, but instead has employed experts within the transplant pathology community to moderate discussions. The size of the working sessions is important; they have usually been less than 150 people, which is within "Dunbar's number," meaning that in gatherings of that size one can have empathetic feeling for all the people there. In larger gatherings one loses that "we are all in this together" feeling and people begin thinking "us" versus "them" thoughts. For "unknown" young people the ability to easily talk to well-known leaders in the field is rewarding and keeps them coming back for more time after time. Images of the social events do not suggest any sort of hierarchy; everyone interacts with everyone else.

Primary acute renal failure ("acute tubular necrosis") in the transplanted kidney: morphology and pathogenesis.

"Acute tubular necrosis" (ATN) in the transplanted kidney, when properly differentiated from other causes of acute renal failure, appears to be a relatively benign condition. It has been widely assumed to be pathologically identical to ATN in the native kidney, but its histopathologic features have not been studied in detail. Because immunosuppressive therapy with cyclosporine adds an additional layer of complexity to the morphologic changes observed, in the present study we have confined our observations to patients immunosuppressed with steroids and azathioprine. Thirteen renal allograft biopsies from patients with ATN and 5 biopsies from patients with normal allograft function were compared with the previously obtained series of 57 native kidney ATN biopsies and 20 control biopsies. Both qualitative and quantitative differences between transplant and native kidney ATN were found. Compared with native kidney ATN, transplant ATN showed significantly less thinning and absence of proximal tubular brush border and less variation in size and shape of cells in individual tubular cross-sections. There were also significantly fewer casts and less dilatation of Bowman's space and a significantly greater number of polarizable crystals presumed to be oxalate in transplant ATN. In native kidney ATN the tubular injury sites were mostly characterized by desquamation of individual epithelial cells leaving areas of bare basement membrane (the "non-replacement" phenomenon). In transplant ATN, sites of tubular injury, although rare and affecting only short tubular segments, were characterized by the actual presence of identifiable necrotic tubular cells, a finding seldom seen in native kidney ATN. There also was a greater interstitial infiltrate of mononuclear inflammatory cells in transplant ATN compared to native kidney ATN. Electron microscopic studies of 9 transplant ATN biopsies showed a mild reduction in proximal tubular brush border compared with controls but this alteration was significantly less than that observed in native kidney ATN. There was no significant alteration in proximal or distal basolateral infoldings and this contrasted sharply with the marked reduction in basolateral infoldings of the plasma membrane observed in native kidney ATN. Disintegrated necrotic cells were found by electron microscopy in transplant ATN whereas these were not observed in native kidney ATN. There were significantly more cells with apoptosis (shrinkage necrosis) in transplant ATN than in native kidney ATN. There were significantly more cells with apoptosis (shrinkage necrosis) in transplant ATN than in native kidney ATN. On the other hand, there were significantly greater numbers of "non-replacement" sites in the distal tubules in native kidney ATN compared to transplant ATN.(ABSTRACT TRUNCATED AT 400 WORDS)

Digital imaging of black and white photomicrographs: impact of file size.

The publication of black and white photomicrographs has a long tradition in pathology. High-resolution film and quality objectives have been the backbone of generating quality photomicrographs suitable for publication. However, the digital imaging revolution has changed the way we view and capture images. As the quality of image capture devices increases and as their price decreases, more and more investigators are using digital imaging, and the use of color digital imaging for teleconferencing, telediagnosis, and reproduction is now well established. The purpose of this study was to determine the file sizes needed to obtain publication-quality black and white images using digital imaging technology. In this study, four experts in renal pathology reviewed 70 black and white images of various file sizes obtained from specimens representing a variety of renal histopathology. Without knowledge of the file size, the four renal pathologists graded the degree of pixelation, and the overall diagnostic and publication quality of the images. In all cases, digital imaging was capable of obtaining publication quality images equal to those achieved using film. The file size needed to achieve publication quality black and white images depended on magnification, with lower magnification images requiring larger file sizes.

Plasma cell-rich acute renal allograft rejection.

BACKGROUND: Acute renal allograft rejection is usually seen within the first 3 months posttransplant, and is characterized by an intense infiltrate of T cells. Some acute rejections, however, contain many plasma cells and/or appear late posttransplant. METHODS: We have investigated 27 cases of intensely plasma cell-rich acute rejections (PCAR) from 1987 to 1997 and have compared them to 21 control cases (CAR) of typical acute rejection. Each group was divided into early (<6 months) and late (>6 months) subgroups. PCAR and CAR cases were matched for histological features of chronic allograft nephropathy. In all four groups, most cases had Banff '97 type IB and IIA acute rejection. RESULTS: A significantly greater number of PCAR cases experienced graft failure due to chronic allograft nephropathy or complications of acute rejection (P<0.05). There was no significant difference between PCAR and CAR in HLA matching, occurrence of posttransplant acute tubular necrosis, presence versus absence of previous allografts, number of previous or subsequent acute rejection episodes, Banff '97 sum scores for acute rejection, cyclosporine A or FK506 levels, or percent change from baseline creatinine at time of biopsy. Plasma cells in PCAR cases showed IgG predominance whereas those in CAR had comparable staining for IgG and IgA. Kappa and lambda light chain immunostaining of all PCAR cases revealed polyclonality. Three of 18 PCAR cases studied for the presence of Epstein-Barr virus RNA showed scattered positivity in 2-7% of lymphoid cells, although the remainder was negative. None of the PCAR cases developed post-transpland lymphoproliferative disorder. CONCLUSIONS: We conclude that PCAR can occur from 1 month to many years posttransplant, is associated with poor graft survival, and is not a manifestation of concomitant chronic allograft nephropathy or viral infection, including posttransplant lymphoproliferative disorder.

Effect of Bw4 and Bw6 epitope mismatches on antibody production, acute and chronic rejection, and graft survival in renal allografts.

BACKGROUND: Highly sensitized patients often have antibodies directed against the HLA Bw4 and Bw6 epitopes. Because of the high frequency of these epitopes, when present, these antibodies result in a high incidence of positive cross-matches. We sought to determine whether antibodies specific for Bw4 or Bw6 affected renal allograft outcome. METHODS: The effect of mismatches for the HLA class I public epitopes, Bw4 and Bw6, was examined in 72 recipients of one haplotype matched recipients of living, related donor renal allografts selected to control for degree of HLA mismatch. Analysis of the production of HLA-specific antibody was performed for 180 recipients of failed cadaveric allografts by complement-dependent cytotoxicity tests and by an enzyme-linked immunoadsorbent assay (ELISA). RESULTS: No significant difference was observed in the incidence of acute rejection, number of rejection episodes or 1-year allograft survival among Bw4/6 matched versus mismatched recipients of one haplotype matched allografts. Additionally, no significant difference in the development of chronic allograft nephropathy was noted among 56 recipients followed long-term (> or =3 years). In the recipients of failed cadaveric transplants, Bw4/6 mismatching was associated with the frequency and magnitude of production of HLA-specific antibody. However, the panel reactive antibodies correlated with the number of HLA-A and -B mismatches, and there was no additional impact of Bw4/6 mismatching. IgG, HLA-specific antibodies were found to be significantly increased among patients homozygous for Bw4 or Bw6, whether or not there was a Bw4/6 mismatch. CONCLUSIONS: Mismatching for Bw4 or Bw6 does not confer any independent, increased risk for humoral sensitization or renal allograft failure.

Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients.

BACKGROUND: Hyperacute rejection (HAR) and acute humoral rejection (AHR) remain recalcitrant conditions without effective treatments, and usually result in graft loss. Plasmapheresis (PP) has been shown to remove HLA- specific antibody (Ab) in many different clinical settings. Intravenous gamma globulin (IVIG) has been used to suppress alloantibody and modulate immune responses. Our hypothesis was that a combination of PP and IVIG could effectively and durably remove donor-specific, anti-HLA antibody (Ab), rescuing patients with established AHR and preemptively desensitizing recipients who had positive crossmatches with a potential live donor. METHODS: The study patients consisted of seven live donor kidney transplant recipients who experienced AHR and had donor-specific Ab (DSA) for one or more mismatched donor HLA antigens. The patients segregated into two groups: three patients were treated for established AHR (rescue group) and four cross-match-positive patients received therapy before transplantation (preemptive group). RESULTS: Using PP/IVIG we have successfully reversed established AHR in three patients. Four patients who were cross-match-positive (3 by flow cytometry and 1 by cytotoxic assay) and had DSA before treatment underwent successful renal transplantation utilizing their live donor. The overall mean creatinine for both treatment groups is 1.4+/-0.8 with a mean follow up of 58+/-40 weeks (range 17-116 weeks). CONCLUSIONS: In this study, we present seven patients for whom the combined therapies of PP/IVIG were successful in reversing AHR mediated by Ab specific for donor HLA antigens. Furthermore, this protocol shows promise for eliminating DSA preemptively among patients with low-titer positive antihuman globulin-enhanced, complement-dependent cytotoxicity (AHG-CDC) cross-matches, allowing the successful transplantation of these patients using a live donor without any cases of HAR.

Cohort study of the prognostic significance of acute transplant glomerulitis in acutely rejecting renal allografts.

BACKGROUND: Acute transplant glomerulitis is a unique lesion in renal allografts, the prognostic significance of which is controversial. We conducted this retrospective cohort study to examine the independent prognostic significance of moderate-to-severe transplant glomerulitis in acute rejection. METHODS: Renal allograft survival for patients with acute rejection were studied, comparing one group with significant glomerulitis (G, n=28) with those with no glomerulitis (NG, n=35). Clinical, biopsy, and demographic data and renal graft survival were compared, and the association of G with graft failure was examined. RESULTS: In the G versus NG group, a greater percentage of patients were highly sensitized (peak panel reactive antibody value >80%; P=0.009), had had a previous renal transplant (40% vs. 11%; P=0.02), or had suffered from delayed graft function (P=0.03). The G group had a trend toward earlier rejection episodes (P=0.07), a significantly higher serum creatinine at the time of index biopsy (P=0.01), a higher prevalence of vascular rejection (P=0.02), and less improvement in mean reciprocal serum creatinine at 1-2 weeks after biopsy (P=0.02). Although there was a trend toward shorter allograft survival in the G group (P=0.09), the level of significance of which increased with adjustment for transplantation time period and the duration of the transplant-biopsy interval (P=0.06), the relative risk for graft loss was no longer significant when additionally adjusted for index biopsy Banff score (relative risk, 0.97; P=0.97). CONCLUSION: In this study, G was significantly more common in highly sensitized patients and was strongly associated with vascular rejection biopsies but was not an independent predictor of graft survival.

Evaluation of pancreas transplant needle biopsy: reproducibility and revision of histologic grading system.

BACKGROUND: Tissue samples for the diagnosis of pancreatic allograft rejection are now obtained routinely through the application of the percutaneous needle biopsy technique. The availability of biopsy material (89% adequate for diagnosis in our setting) presents a challenge for pathologists who are asked to provide a fast and accurate diagnosis of rejection and its severity, while at the same time being able to differentiate rejection from other causes of graft dysfunction. METHODS: To differentiate rejection from other pathologic processes, 26 histologic features were assessed in 92 biopsies performed for confirmation of clinical diagnosis of rejection and the results were compared with 31 protocol biopsies, 12 allograft pancreatectomies with non-rejection pathology, and 30 native pancreas resections with various disease processes. RESULTS: Based on these comparisons, a constellation of findings relating to the vascular, septal, and acinar inflammation was identified for the diagnosis of rejection. Application of these features led us to revise our scheme for grading rejection (ranging from 0-normal to V-severe rejection) to include the categories of "inflammation of undetermined significance" and "minimal rejection." The scheme was used by five pathologist to grade 20 biopsies independently of any clinical data and the interobserver level of agreement was highly significant (kappa=0.83, P<0.0001). This grading scheme was applied blindly to all (183) biopsies from 77 patients with 6-52 months of follow-up. The correlation of the highest degree of rejection on each patient and ultimate graft loss (0% for grades 0-I, 11.5% for grade II, 17.3% for grade III, 37.5% for grade IV, and 100% for grade V) was highly statistically significant (P<0.002). The fraction of grafts lost due to pure immunologic causes increased proportionally to the grade of rejection (0, 50, 66, and 100% for grades II, III, IV, and V, respectively). CONCLUSIONS: This study provides strong support for the proposed pancreas rejection grading scheme and confirms its potential for practical use.

Heterogeneity of glomerular size in normal donor kidneys: impact of race.

Glomerular size has been the subject of many studies and, in a number of settings, has a direct association with the development of glomerular sclerosis. However, the normal distribution of glomerular size has not been thoroughly evaluated in the general population in the United States. To address this issue, we analyzed the baseline biopsy specimens of 103 human donor kidneys to determine the maximal planar area (MPA) of the glomerular tuft in a heterogeneous human population. The MPA of each glomerulus was determined by measurement of sections through the vascular pole and/or origin of the proximal tubule, and was determined on each section by two methods: point counting and computer planimetry. There was very high agreement between these two methods. Multivariate analysis was used to identify significant correlates with MPA. Overall, younger donors had smaller glomeruli (P < 0.0001). Black donors had a larger MPA (23.4+/-8.6 mm2 x 10(-3)) than white donors (17.9+/-6.7 mm2 x 10(-3); P < 0.001), independent of donor age. MPA was not significantly different between genders. This heterogeneity in glomerular size may confound clinical studies if not recognized and may help explain differences in glomerular structure and function in response to injurious processes.