Collapsing Glomerulopathy in Lambda Light Chain Amyloidosis: A Report of 2 Cases.

Amyloid nephropathy is an uncommon disease that frequently presents with reduced kidney function and proteinuria and, in developed nations, is most often associated with underlying paraproteinemia. The histologic appearance of glomerular amyloid deposition includes mesangial and capillary wall infiltration by an amorphous eosinophilic material, and features of endo- or extracapillary proliferation are not typically seen. Rare cases of crescentic injury have been reported in a subset of patients with amyloid nephropathy, particularly those with amyloid derived from serum amyloid A protein. Collapsing glomerulopathy, which like crescentic injury is associated with an extracapillary proliferation, has not to our knowledge been reported in the setting of amyloid nephropathy. We report 2 patients presenting with acute kidney injury and nephrotic syndrome found to have amyloid nephropathy with prominent epithelial cell hyperplasia and glomerular collapse on biopsy. This injury is likely multifactorial and related to direct podocyte injury and vascular compromise and expands further the spectrum of paraprotein-associated renal injury.

Variability in assessing for BK viremia: whole blood is not reliable and plasma is not above reproach - a retrospective analysis.

Polyomavirus nephropathy (PVN) is a major complication of kidney transplantation. Most reports describe polyomavirus viremia either precedes or is detectable at the time of diagnosis of PVN. This association is the basis of current screening recommendations. We retrospectively reviewed the PCR results of blood and urine samples from 29 kidney transplant recipients with biopsy-proven PVN. Biopsies were performed for a rise in serum creatinine or persistent high-level BK viruria. All biopsies showed polyoma virus large T-antigen expression in tubular epithelium using immunohistochemistry. All had viruria preceding or at the time of biopsy (range, 5.2 × 104 to >25 × 106 BKV DNA copies/ml). Twenty (69%) had viremia ranging from 2.5 × 103 to 4.3 × 106 copies/ml at the time of the biopsy. Via blood BK PCR assay, nine (31%) had no BK viremia detected either preceding or at the time of the biopsy. In five recipients where sufficient specimen permitted, additional plasma BK assessment revealed positive detection of viremia. A comparative analysis of assays from two centres was performed with spiked samples. BK DNA may not be detected in the blood of some kidney transplant recipients with histologically confirmed PVN. This may reflect limitation of whole blood as opposed to plasma-based BK DNA assessment.

Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images.

The multicenter Nephrotic Syndrome Study Network (NEPTUNE) digital pathology scoring system employs a novel and comprehensive methodology to document pathologic features from whole-slide images, immunofluorescence and ultrastructural digital images. To estimate inter- and intra-reader concordance of this descriptor-based approach, data from 12 pathologists (eight NEPTUNE and four non-NEPTUNE) with experience from training to 30 years were collected. A descriptor reference manual was generated and a webinar-based protocol for consensus/cross-training implemented. Intra-reader concordance for 51 glomerular descriptors was evaluated on jpeg images by seven NEPTUNE pathologists scoring 131 glomeruli three times (Tests I, II, and III), each test following a consensus webinar review. Inter-reader concordance of glomerular descriptors was evaluated in 315 glomeruli by all pathologists; interstitial fibrosis and tubular atrophy (244 cases, whole-slide images) and four ultrastructural podocyte descriptors (178 cases, jpeg images) were evaluated once by six and five pathologists, respectively. Cohen's kappa for inter-reader concordance for 48/51 glomerular descriptors with sufficient observations was moderate (0.40

Intratubular hemoglobin casts in hemolysis-associated acute kidney injury.

Kidney injury is a complication of intravascular hemolysis associated with many forms of hemolytic disease. Reports of kidney biopsy findings in patients with hemolysis-related kidney injury have focused primarily on the accumulation of hemosiderin pigment within proximal tubular epithelial cells (hemosiderosis), a feature of chronic hemolysis. The nephrotoxic effects of hemoglobin include direct cytotoxicity to tubular cells, but hemoglobin also can precipitate in distal nephron segments, forming obstructive casts. We present a case of hemolysis-associated tubular injury, characterized by acute onset of intravascular hemolysis followed by acute kidney injury with acute tubular injury and abundant intratubular casts containing hemoglobin.

Pauci-immune glomerulonephritis in children: a clinicopathologic study of 21 patients.

BACKGROUND: Pauci-immune glomerulonephritis (GN) represents a severe form of glomerular injury and is the most common cause of crescentic GN in adults. To date, the clinicopathologic features of pauci-immune GN are not well characterized in the pediatric population. METHODS: Twenty-six biopsies from 21 pediatric patients with pauci-immune GN were identified retrospectively from the pathology archives of the University of Chicago (biopsy incidence 5 % among pediatric patients). RESULTS: There was distinct female predominance (2.5:1) among the patient cohort. Serologic studies identified anti-neutrophil cytoplasmic antibodies (ANCA) in 85 % of patients, and 80 % had systemic manifestations of vasculitis. The median estimated glomerular filtration rate (eGFR) at presentation was 43 ml/min/1.73 m(2). Based on a previously proposed classification of ANCA-associated GN, we identified a spectrum of injury, including crescentic (n = 9), focal (n = 7), mixed (n = 5) and sclerotic GN (n = 5). Necrotizing arteritis was identified in a minority of patients (n = 3). The majority of those patients for whom data were available had been treated with cyclophosphamide and corticosteroids, with or without rituximab. Of the 21 pediatric patients, 58 % had developed chronic kidney disease at follow-up (eGFR <90 ml/min/1.73 m(2)), of whom 85 % of those had crescentic, mixed or sclerotic GN. CONCLUSION: Pediatric patients with pauci-immune GN are similar to their adult counterparts in terms of clinical manifestations and histopathologic findings. Among the 21 patients in our study, those with focal GN had the best outcomes while patients with crescentic, mixed or sclerotic GN overwhelmingly had a poor long-term outcome for kidney function.

Membranous nephropathy transplanted in the donor kidney: observations of resolving glomerulopathy in serial allograft biopsies.

We report a case of idiopathic, PLA2R-negative membranous nephropathy (MN) transplanted via a deceased donor kidney. Changes in glomerular immune deposits were followed in serial biopsies. The allograft recipient had end-stage disease without significant proteinuria from ischemic nephropathy due to chronic heart failure, hypertension, atherosclerosis and presumed diabetic nephropathy. Combined cardiac and renal transplants were performed. Maintenance immunosuppression consisted of prednisone, a calcineurin inhibitor and mycophenolate mofetil. MN was identified in the pre-implantation biopsy of the donor kidney. The recipient never developed significant proteinuria and there was no identifiable impact on graft function. Serial biopsies performed at Days 0, 18, 150, 234 and 812 revealed mild effacement of podocyte foot processes, progressive change from Ehrenreich-Churg Stage III-IV lesions of MN to segmental resolution by electron microscopy, and progressive decrease of IgG staining by immunofluorescence. The findings provide a novel observation of the protracted process of glomerular immune deposit resolution in healing MN transplanted in a neutral host environment.

Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction.

Cholemic nephrosis represents a spectrum of renal injury from proximal tubulopathy to intrarenal bile cast formation found in patients with severe liver dysfunction. However, the contribution of this diagnosis has been largely forgotten in the modern literature. To more precisely define this, we conducted a clinicopathologic study of 44 subjects (41 autopsies and 3 renal biopsies) from jaundiced patients at the University of Chicago. Of these, 24 patients had bile casts with involvement of distal nephron segments in 18 mild cases and extension to proximal tubules for 6 severe cases. Eleven of 13 patients with hepatorenal syndrome and all 10 with cirrhosis (due to alcoholism) had tubular bile casts. These casts significantly correlated with higher serum total and direct bilirubin levels, and a trend toward higher serum creatinine, AST, and ALT levels. Bile casts may contribute to the kidney injury of severely jaundiced patients by direct bile and bilirubin toxicity, and tubular obstruction. Both mechanisms are analogous to the injury by myeloma or myoglobin casts. Accounting for the presence of renal bile casts provides a more complete representation of the renal injury that can occur in this unique clinical setting. Thus, bile cast nephropathy is an appropriate term for the severe form of injury observed in the spectrum of cholemic nephrosis. Additional studies are needed to establish the significance of this parameter for patient management in different clinical settings.

In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis.

The most prevalent severe manifestation of systemic lupus erythematosus is nephritis, which is characterized by immune complex deposition, inflammation, and scarring in glomeruli and the tubulointerstitium. Numerous studies indicated that glomerulonephritis results from a systemic break in B cell tolerance, resulting in the local deposition of immune complexes containing Abs reactive with ubiquitous self-Ags. However, the pathogenesis of systemic lupus erythematosus tubulointerstitial disease is not known. In this article, we demonstrate that in more than half of a cohort of 68 lupus nephritis biopsies, the tubulointerstitial infiltrate was organized into well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of the in situ-expressed Ig repertoire revealed that both histological patterns were associated with intrarenal B cell clonal expansion and ongoing somatic hypermutation. However, in the GC histology, the proliferating cells were CD138(-)CD20(+) centroblasts, whereas they were CD138(+)CD20(low/-) plasmablasts in T:B aggregates. The presence of GCs or T:B aggregates was strongly associated with tubular basement membrane immune complexes. These data implicate tertiary lymphoid neogenesis in the pathogenesis of lupus tubulointerstitial inflammation.

Plasma cell densities and glomerular filtration rates predict renal allograft outcomes following acute rejection.

The contribution of T cells and graft-reactive antibodies to acute allograft rejection is widely accepted, but the role of graft-infiltrating B and plasma cells is controversial. We examined 56 consecutive human renal transplant biopsies classified by Banff schema into T-cell-mediated (N = 21), antibody-mediated (N = 18), and mixed (N = 17) acute rejection, using standard immunohistochemistry for CD3, CD20, CD138, and CD45. In a predominantly African-American population (75%), neither Banff classification nor C4d deposition predicted the return to dialysis. Immunohistochemical analysis revealed CD3(+) T cells as the dominant cell type, followed by CD20(+) B cells and CD138(+) plasma cells in all acute rejection types. Using univariate Cox Proportional Hazard analysis, plasma cell density significantly predicted graft failure while B-cell density trended toward significance. Surprisingly T-cell density did not predict graft failure. The estimated glomerular filtration rate (eGFR) at diagnosis of acute rejection also predicted graft failure, while baseline eGFR ≥6 months prior to biopsy did not. Using multivariate analysis, a model including eGFR at biopsy and plasma cell density was most predictive of graft loss. These observations suggest that plasma cells may be a critical mediator and/or an independently sensitive marker of steroid-resistant acute rejection.

Trisomy 8 in myeloid leukemia cutis confirmed by fluorescence in situ hybridization analysis.

We present a case of a 64-year-old man with refractory acute myeloid leukemia and trisomy 8 who developed leukemia cutis. Interphase fluorescence in situ hybridization (FISH) was performed on a paraffin-embedded skin section. FISH confirmed a population of cells with trisomy 8 in the blastic infiltrates involving the skin. This case illustrates a novel application of interphase FISH to confirm the diagnosis of leukemia cutis.

Native BK viral nephropathy in a pediatric heart transplant recipient.

BK viral nephropathy is a well-documented clinical entity in kidney transplant recipients and a significant cause of morbidity and allograft loss in affected patients. BK viral nephropathy in native kidneys of non-kidney transplant recipients is relatively uncommon, but has been reported in adult patients. We report the occurrence of BK viral nephropathy in a pediatric heart transplant recipient. A 10-yr-old boy with past history of Ewing's sarcoma underwent heart transplantation for dilated cardiomyopathy induced by previous chemotherapy with doxorubicin. Post-transplant course was complicated by grade 3A rejection and CMV colitis. He was diagnosed with native BK viral nephropathy approximately 18 months post-transplant due to mild, but persistent, elevation in serum creatinine associated with proteinuria. BK viral nephropathy affects non-kidney transplant recipients, and a high index of suspicion is necessary for early diagnosis and management of this condition.

Platelet CD61 expression in vascular calcineurin inhibitor toxicity of renal allografts.

Calcineurin inhibitor (CI) toxicity in renal allografts is frequently associated with arteriolar injury. Platelet activation occurs in response to vascular injury associated with CI therapy. Platelets are detectable in tissue sections by immunohistochemistry for CD61. This immunohistochemical study examines patterns of platelet deposition in CI-associated vascular toxicity of renal allografts. Renal allograft biopsies were grouped into (i) CI-associated thrombotic microangiopathy (CITMA, n = 28); (ii) vascular CI toxicity without thrombotic microangiopathy (VTox, n = 43); and (iii) allograft controls with minimal arteriolopathy abnormalities, both with CI exposure (MA, n = 10) and without CI exposure (NCI, n = 15). Two-micrometer paraffin sections were stained using a monoclonal antibody to CD61 by standard immunoperoxidase methods. Mural and luminal CD61 deposits in arterioles were graded from 0 to 3+, and proportions of arteriolar and glomerular profiles with CD61 deposits were determined for each biopsy. Granular CD61 deposits were detected in arterioles in biopsies with CITMA (92.9%) and VTox (81%) and less frequently in MA (30%) and NCI (33%). The proportion of arterioles with CD61 deposits was greater in CITMA than in VTox (46.3% +/- 28.5% vs 21.3% +/- 22.2%, P = .001) and more extensive than in controls (MA, 3.6% +/- 8.9%; NCI, 3.2% +/- 5.5%). Median arteriolar CD61 grades for CITMA exceeded grades for VTox (2 vs 0.5, P = .001), and CD61 grades in VTox were significantly greater than in controls with MA (0) and NCI (0) (P = .0001). In conclusion, arteriolar mural platelet CD61 deposition was observed in vascular CI toxicity and was most extensive and severe in CI-associated thrombotic microangiopathy. Identification of "insudative platelet arteriolopathy" in renal allograft biopsies, by immunohistochemical detection of CD61, may facilitate recognition of vascular CI toxicity.

Staphylococcal Infection-Related Glomerulonephritis With Cryoglobulinemic Features.

INTRODUCTION: Staphylococcal infection-related glomerulonephritis (GN) has been shown to represent a unique form of infection-related GN that contains IgA-dominant deposits and is often seen concurrently with the bacterial infection. Biopsies commonly reveal an endocapillary proliferative and/or exudative or mesangial proliferative GN. Rare cases have been reported to show cryoglobulin-like features, including hyaline pseudothrombi and wireloop deposits; however, detailed characterization of these cases is lacking. METHODS: The pathology archives from the University of Utah and Sharp Memorial Hospital were reviewed from January 2016 to September 2017 in search of cases with GN containing IgA-dominant deposits and features of cryoglobulinemia. RESULTS: Of 1965 native kidney biopsies, 5 showed IgA-dominant GN with cryoglobulinemic features. All patients had active staphylococcal infections at the time of biopsy. All presented with acute kidney injury (serum creatinine range: 1.7-6 mg/dl), and all had proteinuria and hematuria. All biopsies showed exudative GN, and 4 biopsies had focal crescents. All had focally prominent hyaline pseudothrombi with or without wireloop deposits, and all showed co-dominant staining for IgA and C3 on immunofluorescence microscopy. Serologic testing for cryoglobulinemia was performed in 3 patients and was transiently positive in 1 patient. Four patients required hemodialysis at last follow-up, whereas 1 patient returned to baseline kidney function. CONCLUSION: IgA-dominant GN with cryoglobulinemic features is an uncommon but severe form of glomerular injury in patients with staphylococcal infections. Four of 5 patients had crescentic glomerular injuries, all of whom required hemodialysis at last follow-up. Patients with IgA-dominant GN with features of cryoglobulinemia should be evaluated for active staphylococcal infection.

Non-neoplastic renal diseases are often unrecognized in adult tumor nephrectomy specimens: a review of 246 cases.

The pathologic evaluation of tumor nephrectomy specimens focuses on the diagnosis, grading, and staging of the neoplasm. The presence of coincidental non-neoplastic diseases in these specimens may have significant implications for patient outcomes. The purpose of this study is to determine the spectrum of non-neoplastic disease processes that may be overlooked in tumor nephrectomies, and to ascertain the extent to which surgical pathologists are trained to recognize these lesions. We reviewed the hematoxylin and eosin-stained slides of 246 adult tumor nephrectomy specimens with an emphasis on the non-neoplastic renal parenchyma. Further analysis of cases with pathologic alterations included special stains and direct immunofluorescence microscopy. The surgical pathology reports were reviewed to determine whether the non-neoplastic lesions were originally identified. We also surveyed United States pathology residency programs to determine how many require training in medical renal pathology. Forty-one cases (16.7%) had alterations, such as diffuse and/or nodular mesangial sclerosis, mesangial hypercellularity, or glomerular basement membrane thickening that warranted further study. After further work-up and clinical correlation, the pathologic changes in 24 cases were categorized as follows: diabetic nephropathy (19 cases) of which one demonstrated atheroembolic disease, thrombotic microangiopathy (3 cases), sickle cell nephropathy (1 case), and focal segmental glomerulosclerosis (1 case). Twenty-one (88%) of these diagnoses were not identified at initial pathologic evaluation. Only 35 of 98 pathology residency programs that responded to our survey require any formal training in medical renal pathology. Although accurate pathologic evaluation of renal neoplasms remains essential, surgical pathologists should be aware that coincidental non-neoplastic renal diseases are common, often not recognized, and may have important implications for patient care. Further consideration should be given to the training requirements of pathology residents and the guidelines for evaluation of nephrectomy specimens to avoid missing non-neoplastic renal lesions.

Renal allograft granulomatous interstitial nephritis: observations of an uncommon injury pattern in 22 transplant recipients.

Background: Granulomatous interstitial nephritis (GIN) is uncommon in native kidneys, and descriptions in allografts are few. We report clinical and pathologic findings in 22 allograft recipients with GIN identified in renal allograft biopsies and nephrectomies. Methods: Renal allografts with GIN were retrieved from the pathology files of two academic medical centers. Available clinical and pathologic data were compiled retrospectively for a 23-year period. Results: GIN was present in 23 specimens from 22 patients (15 males and 7 females) with allograft dysfunction [serum creatinine averaged 3.3 mg/dL (range 1.4-7.8)], at a mean age of 48 years (range 22-77). GIN was identified in 0.3% of biopsies at a mean of 552 days post transplantation (range 10-5898). GIN was due to viral (5), bacterial (5) and fungal (2) infections in 12 (54.5%), and drug exposure was the likely cause in 5 cases (22.7%). One had recurrent granulomatosis with polyangiitis. In 4 cases, no firm etiology of GIN was established. Of 18 patients with follow up data, 33.3% had a complete response to therapy, 44.5% had a partial response and 22.2% developed graft loss due to fungal and E. coli infections. All responders had graft survival for more than 1 year after diagnosis of GIN. Conclusions: Allograft GIN is associated with a spectrum of etiologic agents and was identified in 0.3% of biopsies. Graft failure occurred in 22% of this series, due to fungal and bacterial GIN; however, most had complete or partial dysfunction reversal and long-term graft survival after appropriate therapy.

Nephron segment localization of polyoma virus large T antigen in renal allografts.

This study uses CD10 and epithelial membrane antigen (EMA) as respective proximal and distal tubular segment markers to localize polyoma virus replicative activity, as determined by large T antigen (TAg) expression, in allograft polyoma virus nephropathy (PVN). Sixteen biopsies and 2 nephrectomy specimens with PVN had serial 2-mum paraffin sections stained using monoclonal antibodies to polyoma virus TAg by immunoperoxidase with diaminobenzidine as chromogen. A second immunolabeling step used CD10 as a proximal nephron marker or EMA as a distal tubular marker, and alkaline phosphatase with fast red as chromogen. BK viral DNA was detected in blood in 16 of 18 tested. Fourteen of 16 had cortex and medulla, and 2 had cortex only in the biopsy sample. Fourteen (100%) of 14 had double-positive EMA and TAg expression (EMA+TAg+) in medullary collecting ducts. T antigen was evident in loops of Henle in nephrectomies. Thirteen (81.3%) of 16 had EMA+TAg+, and 10 (62.5%) of 16 had CD10+TAg+ cortical tubular segments. CD10+TAg+ cells were observed in the parietal epithelium of Bowman's capsule in 3 biopsies (18.75%). T antigen was observed in 5.1% of CD10+ tubular profiles compared with 21% of EMA+ profiles in renal cortex (P < .0001). Polyoma virus TAg was observed in medullary collecting ducts, in distal and proximal cortical tubules, and in Bowman's capsule, in decreasing order of frequency. Loops of Henle also had TAg. This distribution suggests potential for an ascending route of infection of allograft tubules in PVN.

Revisiting post-infectious glomerulonephritis in the emerging era of C3 glomerulopathy.

BACKGROUND: Post-infectious glomerulonephritis (PIGN) is an immune complex-mediated glomerular injury that typically resolves. Dominant C3 deposition is characteristic of PIGN, but with the emergence of C3 glomerulonephritis (C3GN) as a distinct entity, it is unclear how the pathologic similarities between PIGN and C3GN should be reconciled. Therefore, nephrologists and nephropathologists need additional guidance at the time of biopsy. METHODS: We studied 23 pediatric and young adult patients diagnosed with PIGN. Patients were divided into two groups, one with co-dominance between C3 and immunoglobulins and the other meeting proposed diagnostic criteria for C3GN. Clinical and pathological features were compared. RESULTS: No clinical and/or pathological features could distinguish between those with C3-co-dominant deposits and those with C3 dominance. Nearly all patients in both groups regained their baseline renal function without clinical intervention. CONCLUSIONS: Although the identification of abnormalities of the alternative pathway of complement is characteristic of C3GN, testing is not widely available and the turnaround time often exceeds 1 month. Our study found that PIGN with either co-dominant or dominant C3 deposition in a cohort of young patients has excellent short-term outcomes. Close clinical observation for persistent abnormalities, such as hypocomplementemia, prolonged hematuria or proteinuria, is recommended to single out patients that may harbor intrinsic complement abnormalities.

Implications of immunohistochemical detection of C4d along peritubular capillaries in late acute renal allograft rejection.

BACKGROUND: Immunohistochemical detection of the C4d complement product along peritubular capillaries (PC) may indicate humoral rejection of renal allografts. We examined the frequency of PC C4d expression in renal-allograft biopsies with acute rejection (AR) arising more than 6 months after transplantation and the impact of this finding. METHODS: C4d was detected by immunoperoxidase in 2-micron paraffin sections of consecutive biopsies obtained over a 3-year period. The extent was classified as diffuse (> or =50% PC C4d+), focal (<50% C4d+), and negative (C4d-). Clinical data were obtained by retrospective chart review. Fifty-five AR episodes with Banff 97 types 1A (n = 13), 1B (n = 26), 2A (n = 11), 2B (n = 3), and 3 (n = 2) met inclusion criteria. RESULTS: PC C4d expression was diffuse in 23 (42%), focal in 9 (16%), and negative in 23 (42%) biopsies. AR episodes with focal and diffuse C4d expression had higher proportionate elevation of serum creatinine at biopsy and 4 weeks after diagnosis (P< or =0.05). Biopsies with diffuse PC C4d had interstitial hemorrhage (56.5%) and plasmacytic infiltrates (52%) more frequently than C4d- biopsies (22% and 16%), P = 0.02, but had no other distinctive histologic features. Graft loss was greater in diffuse (65%) compared with focal C4d+ (33%) and C4d- (33%) groups 1 year after diagnosis, P = 0.03. Other clinical and pathologic parameters did not differ significantly, including treatment received for AR. CONCLUSION: Evidence of acute cellular with occult humoral rejection is identified in more than 40% of late AR episodes. Late acute humoral rejection may be associated with interstitial hemorrhage and plasma cells and contributes significantly to graft loss.