Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function.

Primary hyperoxaluria (PH) is a metabolic defect that results in oxalate overproduction by the liver and leads to kidney failure due to oxalate nephropathy. As oxalate tissue stores are mobilized after transplantation, the transplanted kidney is at risk of recurrent disease. We evaluated surveillance kidney transplant biopsies for recurrent calcium oxalate (CaOx) deposits in 37 kidney transplants (29 simultaneous kidney and liver [K/L] transplants and eight kidney alone [K]) in 36 PH patients and 62 comparison transplants. Median follow-up posttransplant was 9.2 years (IQR: [5.3, 15.1]). The recurrence of CaOx crystals in surveillance biopsies in PH at any time posttransplant was 46% overall (41% in K/L, 62% in K). Higher CaOx crystal index (which accounted for biopsy sample size) was associated with higher plasma and urine oxalate following transplant (p < .01 and p < .02, respectively). There was a trend toward higher graft failure among PH patients with CaOx crystals on surveillance biopsies compared with those without (HR 4.43 [0.88, 22.35], p = .07). CaOx crystal deposition is frequent in kidney transplants in PH patients. The avoidance of high plasma oxalate and reduction of CaOx crystallization may decrease the risk of recurrent oxalate nephropathy following kidney transplantation in patients with PH. This study was approved by the IRB at Mayo Clinic.

Kidney Transplantation in Patients With Monoclonal Gammopathy of Renal Significance (MGRS)-Associated Lesions: A Case Series.

RATIONALE & OBJECTIVE: Data on kidney transplantation outcomes among patients with monoclonal gammopathy of renal significance (MGRS) are lacking. STUDY DESIGN: Case series of patients with MGRS, some of whom received clone-directed therapies before kidney transplantation. SETTING & PARTICIPANTS: 28 patients who underwent kidney transplantation from 1987 through 2016 after diagnosis with MGRS-associated lesions including light-chain deposition disease (LCDD), C3 glomerulopathy with monoclonal gammopathy (C3G-MG), and light-chain proximal tubulopathy (LCPT). FINDINGS: Of the 19 patients with LCDD, 10 were treated before kidney transplantation and 9 were treatment-naive. Among the treated patients with LCDD, 3 (30%) experienced histologic recurrence, 2 (20%) grafts failed, and 2 (20%) died during a median follow-up of 70 (range, 3-162) months after transplant. In the treatment-naive LCDD group, 8 (89%) had histologic recurrence, 6 (67%) grafts failed, and 4 (44%) patients died during a median follow-up of 60 (range, 35-117) months. Of the 5 patients who had a complete response before transplant, none died, and only 1 experienced graft failure, 162 months after transplant. Of 5 patients with C3G-MG, 3 were treatment-naive before transplant. Both patients who were treated before transplant had histologic recurrence, and 1 experienced graft failure and died. Among the 3 patients with treatment-naive C3G-MG, histologic recurrence occurred in all, and graft loss and death were observed in 2 and 1, respectively. In the LCPT group (n=4), histologic recurrence was observed in all 3 patients who did not receive clone-directed therapies before transplant, and 2 of these patients died, 1 with a functioning kidney. The 1 patient with LCPT who received therapy before transplant did not have histologic recurrence or graft loss and survived. LIMITATIONS: Small sample size, nonstandardized clinical management, retrospective design. CONCLUSIONS: Recurrence is very common in all MGRS-associated lesions after kidney transplant. Achieving a complete hematologic response may reduce the risks of recurrence, graft loss, and death. More studies are needed to determine the effects of hematologic response on outcomes for each MGRS-associated lesion.

Post-COVID-19 related osteonecrosis of the jaw (PC-RONJ): an alarming morbidity in COVID-19 surviving patients.

PURPOSE: The recent coronavirus disease (COVID-19) pandemic mainly affects the respiratory system; however, several oral and maxillofacial post-COVID-19 complications have also been observed. This series reports the growing number of osteonecrosis cases associated with post-COVID-19 patients. MATERIALS AND METHODS: This is a retrospective, multi-center case series that reports cases with maxillary osteonecrosis after various periods of SARS-CoV-2 infection in the period between January and August 2021 based on the PROCESS guidelines. RESULTS: Twelve cases were reported with post-COVID-19 manifestation of spontaneous osteonecrosis of the maxillary jaw. Five patients were hospitalized during COVID-19 management and all of the twelve cases had at least one systematic Co-morbidity, and undertake corticosteroids prescription based on the COVID-19 disease treatment protocol. The mean onset of osteonecrosis symptoms appearance was 5.5 ± 2.43 weeks calculated from the day of the negative PCR test. The management was successfully done through surgical debridement and pre and post-operative antibiotics. No anti-fungal medications were prescribed as the fungal culture and the histopathological report were negative. CONCLUSION: Post-COVID-related osteonecrosis of the jaw (PC-RONJ) could be now considered as one of the potential post-COVID-19 oral and maxillofacial complications that occurs unprovokedly and mainly in the maxilla.

Chronic graft-versus-host disease in pancreas after kidney transplant recipients - An unrecognized entity.

Graft-versus-host disease (GVHD), a common complication after peripheral blood stem cell or bone marrow transplantation, rarely occurs in kidney and pancreas transplant recipients. The true incidence may be confounded by the rarity of the disorder, with a resultant lack of appreciation of the diagnosis as a potential cause of common clinical manifestations such as cytopenias and immune dysfunction. Reports of GVHD in kidney and pancreas transplant recipients almost uniformly describe patients in the early posttransplant period (days to months) with the typical manifestations of acute GVHD involving the skin, liver, and intestines. In contrast, reports of solid organ transplant recipients with clinical features more consistent with chronic GVHD (cGVHD) are lacking, raising concern of underrecognition of this severe complication. Occurrence later after transplant may be even more likely to result in lack of recognition. We report 2 cases of possible cGVHD occurring in recipients of pancreas after kidney transplantation, which were diagnosed at 5.5 and 42 months after pancreas transplant. Both patients presented with severe pancytopenia, multiple opportunistic infections, and features suggestive of cGVHD. Transplant professionals should be aware of the possibility of acute and cGVHD in pancreas after kidney transplant recipients and be able to recognize the clinical manifestations.

Thrombotic microangiopathy involving kidney allograft and peripheral nerves.

While thrombotic microangiopathy (TMA) can commonly affect the kidney, peripheral nerve involvement has not been reported to date. A 56-year-old man, recipient of a kidney allograft, reported severe headaches, tremors, and diarrhea followed by sudden-onset right foot drop after increasing his dose of tacrolimus. He then developed acute right hand pain, numbness, and weakness. At presentation, neurological examination and electroneuromyography confirmed the presence of right worse than left, sciatic and ulnar mononeuropathies. Kidney biopsy showed evidence of a thrombotic microangiopathy. Similarly, nerve biopsy showed thrombosis of epineurial blood vessels with minimal inflammation. Herein, we demonstrated that thrombotic microangiopathy can involve the peripheral nerves, resulting in major morbidity. Distinguishing TMA from vasculitis is important because it has major treatment implications.

Recurrence of DNAJB9-Positive Fibrillary Glomerulonephritis After Kidney Transplantation: A Case Series.

RATIONALE & OBJECTIVE: Fibrillary glomerulonephritis (FGN) is a rare glomerular disease that often progresses to kidney failure requiring kidney replacement therapy. We have recently identified a novel biomarker of FGN, DnaJ homolog subfamily B member 9 (DNAJB9). In this study, we used sequential protocol allograft biopsies and DNAJB9 staining to help characterize a series of patients with native kidney FGN who underwent kidney transplantation. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Between 1996 and 2016, kidney transplantation was performed on 19 patients with a reported diagnosis of FGN in their native/transplant kidneys. Using standard diagnostic criteria and DNAJB9 staining, we excluded 5 patients (4 atypical cases diagnosed as possible FGN and 1 donor-derived FGN). Protocol allograft biopsies had been performed at 4, 12, 24, 60, and 120 months posttransplantation. DNAJB9 immunohistochemistry was performed using an anti-DNAJB9 rabbit polyclonal antibody. Pre- and posttransplantation demographic and clinical characteristics were collected. Summary statistical analysis was performed, including nonparametric statistical tests. OBSERVATIONS: The 14 patients with FGN had a median posttransplantation follow-up of 5.7 (IQR, 2.9-13.8) years. 3 (21%) patients had recurrence of FGN, detected on the 5- (n=1) and 10-year (n=2) allograft biopsies. Median time to recurrence was 10.2 (IQR, 5-10.5) years. Median levels of proteinuria and iothalamate clearance at the time of recurrence were 243mg/d and 56mL/min. The remaining 11 patients had no evidence of histologic recurrence on the last posttransplantation biopsy, although the median time of follow-up was significantly less at 4.4 (IQR, 2.9-14.4) years. 3 (21%) patients had a monoclonal protein detectable in serum obtained pretransplantation; none of these patients had recurrent FGN. LIMITATIONS: Small study sample and shorter follow-up time in the nonrecurrent versus recurrent group. CONCLUSIONS: In this series, FGN had an indolent course in the kidney allograft in that detectable histologic recurrence did not appear for at least 5 years posttransplantation.

Protocolized exercise improves frailty parameters and lower extremity impairment: A promising prehabilitation strategy for kidney transplant candidates.

BACKGROUND: Frailty and decreased functional status are risk factors for adverse kidney transplant (KT) outcomes. Our objective was to examine the efficacy of an exercise intervention on frailty and decreased functional status in a cohort of patients with advanced chronic kidney disease (CKD). METHODS: We conducted a prospective study involving 21 adults with ≥stage 4 CKD who were (a) frail or pre-frail by Fried phenotype and/or (b) had lower extremity impairment [short physical performance battery score ≤10]. The intervention consisted of two supervised outpatient exercise sessions per week for 8 weeks. RESULTS: Among our cohort, median participant age was 62 years (interquartile range, 53-67) and 85.7% had been evaluated for KT. Following the study, participants reported satisfaction with the intervention and multiple frailty parameters improved significantly, including fatigue, physical activity, walking time, and grip strength. Lower extremity impairment also improved (90.5%-61.9%, P = .03). No study-related adverse events occurred. CONCLUSIONS: Preliminary data from this study suggest that a supervised, outpatient exercise intervention is safe, acceptable, feasible, and associated with improved frailty parameters, and lower extremity function, in patients with advanced CKD. Further studies are needed to confirm these findings and determine whether this prehabilitation strategy improves KT outcomes.

Development of field cancerization in the clinically normal oral mucosa of shisha smokers.

OBJECTIVES: This study aimed to investigate the changes that occur in the oral mucosa of shisha smokers and compare them to cigarette smokers, nonsmokers and smokers of both shisha and cigarettes and to detect whether these changes could be detected biochemically in saliva. METHODS: Four groups of subjects were included in our study (16 in each group); cigarette smokers, shisha smokers, nonsmokers and smokers of both. A salivary sample and a mucosal biopsy were obtained from each subject. Salivary detection of CYFRA 21-1 was performed on each salivary sample. The mucosal biopsy was examined by routine H&E techniques. Furthermore, immunohistochemical expression of p53 was studied in all cases. RESULTS: A statistically significant difference in p53 expression was present between nonsmokers and the three smoker groups. However, no statistically significant variation was present between the 3 smoker groups. Furthermore, no statistically significant changes were found in the CYFRA 21-1 levels among the four groups. CONCLUSION: Shisha smoking has the same damaging effect on the oral mucosa as cigarette smoking. Furthermore, no correlation was detected between the histological findings and the salivary biomarker used (CYFRA 21-1).

Cardiac Troponin T Risk Stratification Model Predicts All-Cause Mortality Following Kidney Transplant.

BACKGROUND: We evaluated the role of increased cardiac troponin T (cTnT), vascular, and cardiac diseases in predicting 5 and 10-year all-cause mortality after kidney transplantation. METHODS: We reviewed a cohort of 764 kidney transplant recipients and analyzed pertinent cardiovascular risk factors at the time of transplant evaluation. Proportional hazards regression analysis with bootstrapping method was utilized to provide a risk stratification score for mortality. RESULTS: Mean age was 58.8 years (SD 12.1) and median follow-up was 7.0 years (range 1 day to 18.0 years). Fifty-four percent of patients (n = 415) had cTnT measured (median 0.02 ng/mL, range 0.01-4.91). Fifty-three percent (n = 407) had vascular disease, 59% (n = 448) had diabetes, and 44% (n = 336) had cardiac disease pre-transplant. Sixty percent (n = 460) required dialysis. Older age, increased cTnT, pre-transplant vascular and cardiac diseases predicted mortality in multivariate analysis. We derived 2 scoring systems with and without cTnT - the ACV and ACTV scores (age, cardiac disease, elevated cTnT, and vascular disease) - as predictors of mortality after kidney transplant. Point assignments were: age 60-69 years (1), age ≥70 years (2), cardiac disease (1), cTnT ≥0.04 ng/mL (1), and vascular disease (1). Both scoring systems significantly predicted mortality. The ACTV score better delineated risk stratification across score levels (0-2, 3-4, and 5 points). CONCLUSIONS: We developed a risk schema predictive of all-cause mortality after kidney transplant in a derivation cohort. The ACTV score, including an elevated cTnT, provided superior prediction compared to a scoring system without cTnT. Further studies to validate these findings are needed.

De novo donor-specific antibody following BK nephropathy: The incidence and association with antibody-mediated rejection.

BACKGROUND AND OBJECTIVES: The risk of de novo donor-specific antibody (dnDSA) development following BK viremia (BKV) or nephropathy (BKN) after kidney transplant remains unclear. We aimed to evaluate the relationships among dnDSA, BKV (BK blood PCR > 15 000 copies), BKN, antibody-mediated rejection (AMR), and allograft loss. PATIENTS AND METHODS: We performed a retrospective cohort study of 904 solitary kidney transplant recipients transplanted between 10/2007 and 5/2014. Cox proportional hazards regression with time-dependent covariates were used to assess the relationships among BKN, isolated BKV, dnDSA, and the subsequent risk of AMR and allograft loss. RESULTS: In multivariate analysis, we observed that BKN, but not BKV was a risk factor for dnDSA (HR, 3.18, P = .008). Of the patients with BK nephropathy, 14.0% (6/43) developed dnDSA, which occurred within 14 months of BK diagnosis. DnDSA in this setting remains a risk factor for subsequent AMR (HR 4.75, P = .0001) and allograft loss (HR 2.63, P = .018). CONCLUSIONS: BKN is an independent risk factor for development of dnDSA. Improved understanding of the characteristics of patients with BKN who are at highest risk for development of dnDSA would be valuable to customize immunosuppression reduction in this population.

Primary ameloblastic carcinoma: literature review with case series.

Ameloblastic carcinoma (AC) is an extremely rare malignant odontogenic tumour arising from odontogenic epithelium. It was classified into primary type and secondary type. A previous study revealed that primary ameloblastic carcinoma cases were associated with more favourable prognosis than secondary cases. The aim of the present work was: to report the clinical, histopathological, immunohistochemical, and ploidy status, and therapeutic details of four cases of primary AC, and to review the literature with regard to clinical, follow-up, prognosis, histopathological, and immunohistochemical information of primary AC. The Medline database was searched using the term ameloblastic carcinoma and primary type. The review of English literature revealed that primary ameloblastic carcinoma favours the posterior mandible with profound male predilection and appears as an ill-defined radiolucency. Metastasis and invasion are more likely to occur in maxillary cases. The treatment of choice is wide surgical resection with or without cervical lymph node dissection. Adjuvant postoperative radiotherapy is beneficial in incomplete resection cases and advanced soft tissue invasion. The most specific diagnostic methods of AC, as concluded from review, are α-SMA in epithelial cells in conjunction with Ki-67 index value and SPF more than 11.5%.

Oral Cancer Awareness Level Within the Dental Community: Results from a Large Scale Survey in Cairo.

The incidence of head and neck cancer was reported to be higher in more developed countries with an increase in incidence lately among younger age groups. The need for improvement of awareness of oral cancer and potentially malignant oral disorders is crucial. This study aims to identify the level of awareness of diagnostic and management protocols in the dental community. An English survey was arranged and sent via email to undergraduate students, postgraduate students, and faculty members at the dental school Cairo University. The questions focused on the early detection and level of awareness of oral cancer. Results were then analyzed to assess levels of awareness at the different education levels of the participants. Eight hundred sixty-eight responded out of the sent 5052 during the period between October 2015 and January 2016. The average results of the faculty staff members were higher than that of the student groups and participants with regular continuous assessment and knowledge refreshment achieved higher results. The results of this survey have pointed out areas of lack of awareness among the targeted population. The results have been brought up to the knowledge of policy makers to enable the improvement of level of awareness and assessment of risk factors for oral cancer.

Ameloblastic fibro-odontoma with chondroid tissue formation.

Ameloblastic fibro-odontoma (AFO) is an uncommon, benign, mixed odontogenic tumour occurring predominantly in children and adolescents. The purpose of this study was to report an unusual case of AFO in the mandible of a five-year-old male patient showing evidence of chondroid tissue formation. Clinical, radiographic, histopathological and immunohistochemical findings were presented. Intraoral examination revealed a swelling extending from the right deciduous lateral incisor to the left second molar area. Computed tomography (CT) showed a large, well-demarcated multilocular radiolucency with radiopaque deposits. Histologically, the lesion was composed of connective tissue stroma resembling the dental papilla, with epithelial islands, and amorphous masses of enamel and dentin consistent with a diagnosis of AFO, as well as, evidence of large areas showing cartilaginous tissue formation. Immunohistochemistry using cytokeratin, vimentin and s-100 were helpful in determining the origin of the different odontogenic tissues. Surgical excision of the lesion was performed. The patient has been monitored and the lesion has not recurred. We report the first case of AFO showing an unusual behaviour of chondroid tissue formation.

Relationship between pre-transplant physical function and outcomes after kidney transplant.

BACKGROUND: Performance-based measures of physical function predict morbidity following non-transplant surgery. Study objectives were to determine whether physical function predicts outcomes after kidney transplant and assess how physical function changes post-transplant. METHODS: We conducted a prospective study involving living donor kidney transplants recipients at our center from May 2012 to February 2014. Physical function was measured using the Short Physical Performance Battery (SPPB [balance, chair stands, gait speed]) and grip strength testing. Initial length of stay (LOS), 30- day rehospitalizations, allograft function, and quality of life (QOL) were assessed. RESULTS: The majority of the 140 patients in our cohort had excellent pre-transplant physical function. In general, balance scores were more predictive of post-transplant outcomes than the SPPB. Decreased pre-transplant balance was independently associated with longer LOS and increased rehospitalizations but not with post-transplant QOL; 35% of patients experienced a clinically meaningful (≥ 1.0 m/s) improvement in gait speed 4 months post-transplant. CONCLUSIONS: Decreased physical function may be associated with longer LOS and rehospitalizations following kidney transplant. Further studies are needed to confirm this association. The lack of relationship between pre-transplant gait speed and outcomes in our cohort may represent a ceiling effect. More comprehensive measures, including balance testing, may be required for risk stratification.

Peripheral arterial disease preoperatively may predict graft failure and mortality in kidney transplant recipients.

Patients with end-stage renal disease undergoing kidney transplant often have diffuse atherosclerosis and high cardiovascular morbidity and mortality rates. We analyzed the correlation of peripheral arterial disease (PAD), here quantified by an abnormal ankle-brachial index (ABI) measured within the 5 years prior to kidney transplant, with graft failure and mortality rates (primary end points) after adjusting for known cardiovascular risk factors (age, sex, smoking history, hypertension, diabetes, stroke, known coronary artery disease or heart failure, years of dialysis). Of 1055 patients in our transplant population, 819 had arterial studies within the 5 years prior to transplant. Secondary end points included myocardial infarction; cerebrovascular accident; and limb ischemia, gangrene, or amputation. Low ABI was an independent and significant predictor of organ failure (OR, 2.77 (95% CI, 1.68-4.58), p<0.001), secondary end points (HR, 1.39 (95% CI, 0.97-1.99), p<0.076), and death (HR, 1.84 (95% CI, 1.26-2.68), p=0.002). PAD was common in this population: of 819 kidney transplant recipients, 46% had PAD. Low ABI was associated with a threefold greater risk of graft failure, a twofold greater risk of death after transplant, and a threefold greater risk of secondary end points. Screening for PAD is important in this patient population because of the potential impact on long-term outcomes.

A kidney transplant recipient with renal medullary viral cytopathic changes.

We present a case of JC polyomavirus (JCV)-associated nephropathy (PyVAN) in an asymptomatic deceased-donor kidney transplant recipient. Despite the presence of viral cytopathic effect in the kidney biopsy and positive BK polyomavirus (BKV) in situ hybridization (ISH), BKV real-time polymerase chain reaction (PCR) results of plasma and urine were negative. JCV ISH was performed and was found to be positive. JCV real-time PCR on urine, plasma, and the kidney biopsy tissue was positive. Reduction in immunosuppression resulted in resolution of JCV viremia. This case highlights that JC-PyVAN is a distinct clinical entity and is likely to have a better clinical outcome than BK-PyVAN. Concurrent infection with BKV and JCV may occur, but may be difficult to confirm due to the potential for cross-reactivity between BKV and JCV ISH stains.