An International Survey of Genitourinary and Renal Pathologists Regarding Evaluation of the Non-Neoplastic Parenchyma in Kidney Cancer Specimens.

Increasing survivorship in kidney cancer patients has shifted treatment strategies to optimize renal function preservation. In 2010, the College of American Pathologists (CAP) updated their synoptic reporting guidelines for tumor nephrectomies to require evaluation of the nonneoplastic kidney parenchyma. We conducted this study to understand current practice behaviors regarding the evaluation of the nonneoplastic kidney parenchyma in tumor nephrectomy specimens. We emailed a 14-item multiple-choice survey to members of the Renal Pathology Society and Genitourinary Pathology Society. We also emailed a 12-item survey to program and associate program directors of American pathology residencies to assess the current state of renal pathology education. Ninety-eight genitourinary and 104 renal pathologists responded to the survey on the nonneoplastic kidney parenchyma. Ninety-five percent of respondents who examine tumor nephrectomies reported evaluating the nonneoplastic kidney parenchyma. Seventy-five percent of genitourinary pathologists and 67% of renal pathologists use synoptic reporting, and 81% use the CAP protocol. Thirty-nine percent of respondents report always contacting the clinician when they find evidence of medical renal disease. Forty-two program leaders responded to our renal pathology education survey, and 64% of them have a mandatory renal pathology rotation that on average lasts about 2 to 4 weeks. The majority of pathologists examine the nonneoplastic kidney parenchyma of tumor nephrectomies and frequently report incidences of new medical renal disease directly to clinicians, but there remains room for improvement and educational gaps during residency training. Further efforts to standardize both this evaluation and renal pathology education will improve patient care.

The Detrimental Impact of End-Stage Kidney Disease Is Not Reflected in Autopsy Reports.

CONTEXT.­: End-stage kidney disease (ESKD) is defined as renal impairment requiring renal replacement therapy to sustain life. With a 1-year mortality of ∼20% to 30%, many die of complications related to this disease. OBJECTIVE.­: To determine the percentage of autopsy cases of decedents with ESKD in which the contribution of ESKD to death is accurately reflected in the final report. DESIGN.­: Autopsy case records were retrospectively reviewed at 4 institutions (Yale New Haven Hospital, University of Chicago Medical Center, University of Illinois at Chicago Hospital, University of Iowa Hospital). Clinical, macroscopic, and microscopic autopsy findings were reviewed, with attention to renal disease findings. RESULTS.­: One hundred sixty decedents with documented ESKD and premortem dialysis who underwent autopsy assessment were identified. ESKD was implicated as a cause of death (CoD) or significant contributing factor in 44 cases (28%), but not in the remaining 116 cases (72%). Cardiovascular disease was the most common CoD in ESKD. There was significant interpathologist variation in the inclusion of ESKD as a CoD across institutions. These rates ranged from 85% correlation (23 of 27 cases), to 13% (4 of 31 and 8 of 62 cases at 2 institutions), and 22.5% (9 of 40 cases) across the 4 participating institutions. CONCLUSIONS.­: The recognition at autopsy of ESKD as a CoD or contributing CoD at autopsy in patients undergoing dialysis remains low (28%). The detrimental impact of ESKD is not reflected in hospital autopsy reports, which carries implications for collection of vital statistics and allocation of research funding for kidney diseases.

Digital spatial profiling of collapsing glomerulopathy.

Collapsing glomerulopathy is a histologically distinct variant of focal and segmental glomerulosclerosis that presents with heavy proteinuria and portends a poor prognosis. Collapsing glomerulopathy can be triggered by viral infections such as HIV or SARS-CoV-2. Transcriptional profiling of collapsing glomerulopathy lesions is difficult since only a few glomeruli may exhibit this histology within a kidney biopsy and the mechanisms driving this heterogeneity are unknown. Therefore, we used recently developed digital spatial profiling (DSP) technology which permits quantification of mRNA at the level of individual glomeruli. Using DSP, we profiled 1,852 transcripts in glomeruli isolated from formalin fixed paraffin embedded sections from HIV or SARS-CoV-2-infected patients with biopsy-confirmed collapsing glomerulopathy and used normal biopsy sections as controls. Even though glomeruli with collapsing features appeared histologically similar across both groups of patients by light microscopy, the increased resolution of DSP uncovered intra- and inter-patient heterogeneity in glomerular transcriptional profiles that were missed in early laser capture microdissection studies of pooled glomeruli. Focused validation using immunohistochemistry and RNA in situ hybridization showed good concordance with DSP results. Thus, DSP represents a powerful method to dissect transcriptional programs of pathologically discernible kidney lesions.

Extraglomerular immune complex deposition in lupus nephritis.

BACKGROUND: Lupus nephritis (LN) is a common manifestation and a major cause of morbidity and mortality in systemic lupus erythematosus (SLE) patients. It is characterized by glomerular and often extraglomerular immune complex deposition. PURPOSE: Given the emerging importance of the tubulointerstitial compartment, we conducted a retrospective study of 78 LN biopsies to enumerate the spectrum of extraglomerular immune complex deposition that can be observed in lupus nephritis by electron microscopy and to identify possible clinical or pathologic correlates. RESULTS: The presence of tubulointerstitial immune complex deposition often accompanied interstitial inflammation, but some discrepancies were also seen. CONCLUSIONS: As target antigens are identified, correlation with glomerular, tubulointerstitial, and vascular immune complex deposition will be of increasing interest.

Mutation of complement factor B causing massive fluid-phase dysregulation of the alternative complement pathway can result in atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. Its pathogenesis is driven most frequently by dysregulated cell-surface control of the alternative pathway of complement secondary to inherited and/or acquired factors. Here we evaluated two unrelated patients with atypical hemolytic uremic syndrome. The first, a five-year-old Caucasian female, presented at 10 months with schistocytes, thrombocytopenia and kidney injury. The second, a 55-year-old Caucasian female, presented at age 31 following caesarean section for preeclampsia. Complement biomarker testing was remarkable for undetectable levels of C3 in both. Circulating levels of C5 and properdin were also low consistent with over-activity of the alternative and terminal pathways of complement. Genetic testing identified a heterozygous novel variant in CFB (c.1101 C>A, p.Ser367Arg) in both patients. Functional studies found strong fluid-phase C3 cleavage when normal and proband sera were mixed. Cell-surface C3b deposition was strongly positive when patient serum was supplemented with C3. In vitro control of C3 convertase activity could be restored with increased concentrations of factor H. Thus, CFB p.Ser367Arg is a gain-of-function pathogenic variant that leads to dysregulation of the alternative pathway in the fluid-phase and increased C3b deposition on cell surfaces. Our study highlights the complexities of complement-mediated diseases like atypical hemolytic uremic syndrome and illustrates the importance of functional studies at the variant level to gain insight into the disease phenotype.

The Importance of Nephropathology in Kidney Cancer.

As early detection and advances in the treatment for renal cell carcinoma continue to lead to excellent oncologic outcomes, the preservation of renal function in kidney cancer patients has emerged as an increasingly important clinical objective. Given that diabetes, hypertension, obesity, cigarette smoking, and aging are independent risk factors for renal cell carcinoma, the corresponding non-neoplastic kidney diseases frequently are present, but often undiagnosed. In addition, the subsequent clinical management of the ensuing chronic kidney disease historically has not included nephrologists. Awareness of these practice gaps remain low among nephrologists, surgeons, and pathologists. This article discusses the common non-neoplastic kidney diseases that are encountered in cancer nephrectomy specimens. The accurate and timely diagnosis of these disorders will result in additional gains in clinical outcomes. There is a unique opportunity for the nephrology community to play a central role in the management of chronic kidney disease that often is present in kidney cancer patients.

End-Stage Kidney Disease Is Overlooked as a Proximate Cause of Death at Autopsy.

OBJECTIVES: To determine how often end-stage kidney disease (ESKD) is implicated as a cause of death (COD) at autopsy. METHODS: We searched our autopsy database (2007-2017) using queries "end-stage renal disease," "end-stage kidney disease," "ESRD," "chronic renal disease," and "chronic kidney disease." Final diagnosis and summaries were reviewed to determine if ESKD was appropriately correlated with the COD. Cases in which the COD was unrelated to kidney function were excluded. RESULTS: Eighty-five patients with a history of ESKD and histologic confirmation thereof were identified. Their CODs were cardiovascular (36%), infection/sepsis (41%), pulmonary (6%), gastrointestinal/hepatic (2%), central nervous system (3%), other systemic disease (7%), and unspecified (5%). ESKD was implicated as a contributing COD in 24 (28%) cases. CONCLUSIONS: ESKD is often overlooked at autopsy, particularly in patients with cardiovascular or infectious disease. Accurate documentation of ESKD contributing to mortality is important for education, counseling, record maintenance, and directing research efforts.

An Evaluation of CD61 Immunohistochemistry in Identification of Vascular Invasion in Follicular Thyroid Neoplasms.

The identification of vascular invasion in follicular thyroid neoplasms is essential for categorizing lesions as benign (follicular adenomas) or malignant (follicular thyroid carcinomas). Among the histologic criteria diagnostic of true vascular invasion is tumor-cell associated thrombosis, including fibrin deposition and platelet clumping. This study aims to evaluate whether an immunohistochemical stain for the platelet-associated protein CD61 could assist in identifying tumor-associated thromboses and thereby confirm vascular invasion in follicular thyroid neoplasms. Histologic review and CD61 immunostaining of 19 atypical follicular adenomas, 13 non-metastatic follicular thyroid carcinomas, and 11 metastatic follicular thyroid carcinomas was performed. Linear arrays or clustered groups of CD61-expressing intravascular platelets were present in 51% of cases overall, including 54% of follicular thyroid carcinomas and 47% of follicular adenomas, mostly within intracapsular or peritumoral vessels. In three follicular thyroid carcinomas (all with distant metastases), CD61-expressing platelets were present in association with intravascular tumor cells. This finding was not present in adenomas. CD61 staining alone did not distinguish between atypical follicular adenomas, non-metastatic carcinomas, and metastatic carcinomas. When present in association with intravascular tumor cells, however, CD61-expressing platelets may serve as a marker for vascular invasion and aid in the diagnosis of follicular thyroid carcinoma.