Lenvatinib-related renal microangiopathy: a case series.

Tyrosine kinase inhibitors play an important role in the armamentarium against cancer. Lenvatinib is a multiple kinase inhibitor approved by the Food and Drugs Administration (FDA) for the treatment of advanced and radioresistant thyroid carcinomas and, in combination with everolimus, for renal cell carcinoma and unresectable hepatocellular carcinoma. The anti-tumoral activity is largely dependent on inhibition of neo-angiogenesis, and established side effects of anti-angiogenetic therapeutics include renal thrombotic microangiopathy (TMA). Here, we describe three cases of biopsy-proven renal TMA clinically presenting with proteinuria and stable serum creatinine in patients receiving lenvatinib for thyroid cancer. Microangiopathic lesions included glomerular basement membrane reduplication with segmental cellular interposition, mesangiolysis, and focal intracapillary and arteriolar thrombi. Drug-dose reduction or withdrawal was effective in renal function preservation, but cancer progressed in all patients. The management of lenvatinib-induced renal TMA remains a challenge. The best therapy in these patients is still uncertain. Earlier and more precise measurement of urine protein levels, allowing for early dose adjustment, could be effective in preventing further damage and drug discontinuation.

BK Virus RNA in Renal Allograft Biopsies.

BK polyomavirus-associated nephropathy (BKpyVAN) remains a cause of graft loss in kidney transplant recipients on immunosuppressive therapy. Its diagnosis relies on the identification of BK virus (BKV) in the renal allograft biopsy by positive immunohistochemical (IHC) stain for the viral SV40 large T antigen, although in situ hybridization (ISH) for viral DNA is used in some centers. We examined tissue detection of BKV RNA by RNAscope, a novel, automated ISH test, in 61 allograft biopsies from 56 patients with BKpyVAN. We found good correlation between the estimate of BKV tissue load by RNAscope ISH and SV40 IHC (R2 = 0.65, p<0.0001). RNAscope ISH showed 88% sensitivity and 79% specificity and, as an alternative test, could confirm the presence of BKV tissue in presumed BKpyVAN and rule out BKV as the causative agent in JC virus nephropathy. We also used tissue BK viral load estimates by both RNAscope ISH and SV40 IHC to examine the relation between tissue and plasma BK levels and found significant correlation only between BK viremia and tissue BK measured by RNAscope ISH. Our findings suggest that the RNAscope ISH assay could be a reliable test for BKV detection in allograft biopsies.

Microvascular inflammation in renal allograft biopsies assessed by endothelial and leukocyte co-immunostain: a retrospective study on reproducibility and clinical/prognostic correlates.

The most prominent histologic lesion in antibody-mediated rejection is microvascular inflammation (MVI); however, its recognition and scoring can be challenging and poorly reproducible between pathologists. We developed a dual immunohistochemical (IHC)-stain (anti-CD34/anti-CD45 for endothelium/leukocytes) as ancillary tool to improve on the semi-quantitative Banff scores and allow quantification of MVI. We examined the relationship between CD34-CD45 IHC-based quantitative MVI score (the inflamed peritubular capillary ratio, iptcr) and renal-graft failure or donor-specific antibodies (DSA) strength at the time of biopsy. Quantitative iptcr score was significantly associated with renal graft failure (hazard ratio 1.81, per 1 SD-unit [0.13 points] of iptcr-increase; P = 0.026) and predicted the presence and strength of DSA (ordinal odds ratio: 2.42; P = 0.005; 75 biopsies/60 kidney transplant recipients; 30 HLA- and/or ABO-incompatible). Next, we assessed inter-pathologist agreement for ptc score and ptc extent (focal/diffuse) using CD34-CD45 IHC as compared to conventional stain. Compared to conventional stain, CD34-CD45 IHC significantly increased inter-pathologist agreement on ptc score severity and extent (κ-coefficient from 0.52-0.80 and 0.46-0.68, respectively, P < 0.001). Our findings show that CD34-CD45 IHC improves reproducibility of MVI scoring and facilitates MVI quantification and introduction of a dual anti-CD34/CD45 has the potential to improve recognition of MVI ahead of DSA results.

Membranoproliferative glomerulonephritis recurrence after kidney transplantation: using the new classification.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) is an uncommon glomerular disorder that may lead to end stage renal disease (ESRD). With new understanding of the disease pathogenesis, the classical classification as MPGN types I, II, III has changed. Data on post-transplant MPGN, in particular with the newly refined classification, is limited. We present our center's experience of MPGN after kidney transplantation using the new classification. METHODS: This is a retrospective study of 34 patients with ESRD due to MPGN who received 40 kidney transplants between 1994 and 2014. We reviewed the available biopsies' data using the new classification. We assessed post transplantation recurrence rate, risk factors of recurrence, the response to therapy and allografts' survival. RESULTS: Median time of follow up was 5.3 years (range 0.5-14 years). Using the new classification, we found that pre-transplant MPGN disease was due to immune complex-mediated glomerulonephritis (ICGN) in 89 % of cases and complement-mediated glomerulonephritis (CGN) in 11 %. Recurrence was detected in 18 transplants (45 %). Living related allografts (P = 0.045), preemptive transplantations (P = 0.018), low complement level (P = 0.006), and the presence of monoclonal gammopathy (P = 0.010) were associated with higher recurrence rate in ICGN cases. Half of the patients with recurrence lost their allografts. The use of ACEi/ARB was associated with a trend toward less allograft loss. CONCLUSIONS: MPGN recurs at a high rate after kidney transplantation. The risk of MPGN recurrence increases with preemptive transplantation, living related donation, low complement level, and the presence of monoclonal gammopathy. Recurrence of MPGN leads to allograft failure in half of the cases.

Granulomatous interstitial nephritis.

Granulomatous interstitial nephritis (GIN) is a rare entity detected in ∼0.5-0.9% of all renal biopsies. GIN has been linked to several antibiotics such as cephalosporins, vancomycin, nitrofurantoin and ciprofloxacin. It is also associated with NSAIDs and granulomatous disorders such as sarcoidosis, tuberculosis, fungal infections, and granulomatosis with polyangiitis. Renal biopsy is critical in establishing this diagnosis, and the extent of tubular atrophy and interstitial fibrosis may aid in determining prognosis. Retrospective data and clinical experience suggest that removal of the offending agent in conjunction with corticosteroid therapy often results in improvement in renal function. We describe a patient with a history of multiple spinal surgeries complicated by wound infection who presented with confusion and rash with subsequent development of acute kidney injury. Urinalysis demonstrated pyuria and eosinophiluria, and renal biopsy revealed acute interstitial nephritis with granulomas. These findings were attributed to doxycycline treatment of his wound infection. This review explores the clinical associations, presentation, diagnosis, and treatment of this uncommon cause of acute kidney injury.

The clinical characteristics and pathological patterns of postinfectious glomerulonephritis in HIV-infected patients.

BACKGROUND: Postinfectious glomerulonephritis (PIGN), a form of immune complex GN, is not well-defined in HIV-infected patients. This study characterizes PIGN in this patients' population and determine the impact of histopathological patterns on renal outcome and mortality. METHODS: HIV-infected patients with PIGN from September 1998 to July 2013 were identified. Archived slides were reviewed by a blinded renal pathologist, classified into acute, persistent and healed PIGN. Groups were compared using Wilcoxon rank-sum and Fisher's exact test. Survival analyses were performed to determine association of histopathological pattern with renal outcome and mortality. RESULTS: Seventy-two HIV-infected predominantly African American males were identified with PIGN. Median (interquartile range) age and creatinine at the time of renal biopsy was 48 years (41, 53) and 2.5 mg/dl (1.5, 4.9) respectively. Only 2 (3%) had acute PIGN, 42 (58%) had persistent PIGN and 28 (39%) had healed PIGN. Three patients (4%) had IgA-dominant PIGN. Only 46% of the patients had confirmed positive cultures with Staphylococcus the most common infectious agent. During a median follow up of 17 months, the pathological pattern had no impact on renal outcome (P = 0.95). Overall mortality was high occurring in 14 patients (19%); patients with healed PIGN had significantly increased mortality (P = 0.05). CONCLUSION: In HIV-infected patients, Staphylococcus is the most common cause of PIGN. Renal outcome was not influenced by the histopathological pattern but those with healed PIGN had greater mortality which was potentially due to a confounder not accounted for in the study.

Atypical hemolytic uremic syndrome recurrence after kidney transplantation.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a high recurrence rate after kidney transplantation. In most cases, aHUS are caused by genetic mutations of components of the complement alternative pathway. In this single-center series, we present our data of 12 consecutive patients with aHUS and the outcome after kidney transplantation. METHODS: In this 10-year retrospective study, we identified 12 patients with aHUS who were managed in our center since 2003. We reviewed clinical data, including genetic testing, posttransplant course and response to therapy including the prophylactic use of eculizumab. RESULTS: Overall, eight patients are women. Six of our patients have at least one genetic mutation causing aHUS, including 4 with complement factor H mutations. Nine patients had at least one previous kidney transplant that failed secondary to recurrent aHUS (75% of our patients). Three patients were treated with eculizumab and plasmapheresis for recurrent aHUS after kidney transplantation; two of them responded to the therapy. Four patients received prophylactic eculizumab; three of them received 6 months and one has been on life long therapy. No signs of recurrence have been observed in these 4 patients so far. CONCLUSION: Genetic mutations of the complement alternative pathway were confirmed in half of our patients, most of those mutations are in CHF. We demonstrate that treatment or prophylaxis with eculizumab was effective in reversing or preventing aHUS whether or not genetic complement mutations were identified.

Time course of pathologic changes in kidney allografts of positive crossmatch HLA-incompatible transplant recipients.

BACKGROUND: Recipients of incompatible allografts are at increased risk of graft loss. We hypothesized that analysis of sequential biopsies from these grafts could define progression of graft lesions and identify features predictive of progression. METHODS: We studied the time course of histologic injury in 745 kidney graft biopsies from 129 patients transplanted with a positive crossmatch human leukocyte antigen-incompatible kidney between 2000 and 2010 (follow-up of 1-9 years). RESULTS: Graft survival was 98% at 1 year and 80% at 5 years after transplantation. Throughout follow-up, 70% of patients experienced rejection, with 52% showing subclinical rejection in the first year. Cell-mediated rejection was more frequent than antibody-mediated rejection throughout follow-up. Transplant glomerulopathy (TxGN; cg≥1) developed in 47% of patients over the period of the study, as early as 3 months in a few patients. TxGN was preceded by glomerulitis in more than 90% of cases, with a median time interval of 12 months. Glomerulitis and detectable posttransplantation donor-specific antibodies were risk factors for TxGN (P<0.0001 and P<0.05). C4d-negative antibody-mediated rejection manifesting as capillaritis (g≥1 and ptc≥1) with detectable donor-specific antibodies was observed in some recipients (<20%). There was progressively higher average tubulointerstitial scarring (ci+ct) from 3 to 6 to 12 months (P<0.001). CONCLUSIONS: Despite good graft survival, a significant incidence of biopsy-proven rejection occurred in this subset of closely monitored human leukocyte antigen-incompatible recipients throughout follow-up. Microcirculation inflammation, particularly glomerulitis, irrespective of C4d, is associated with a high risk of development of TxGN at 1 year.

Rituximab for remission induction in recurrent ANCA-associated glomerulonephritis postkidney transplant.

Kidney transplantation (KTX) is the treatment of choice for patients with end-stage renal disease (ESRD) due to ANCA-associated vasculitis (AAV). Recurrent ANCA-associated glomerulonephritis (GN) occurs after KTX and may adversely affect allograft survival. Cyclophosphamide (CYC) combined with glucocorticoids has been the cornerstone of treatment for recurrent GN. Rituximab (RTX), a B-cell-depleting monoclonal antibody, is approved for remission induction in AAV. We report the clinical presentation and outcomes of five KTX recipients treated with RTX for biopsy-confirmed recurrent GN. The median age at the time of KTX was 26 years (four Caucasian, three females). All patients were in remission with four being ANCA positive at time of KTX. Recurrent GN occurred at a median of 26 months post-KTX. All relapses were treated with RTX and glucocorticoids. Four patients achieved disease remission; the fifth patient was refractory to treatment with RTX and CYC. Follow-up biopsies (n = 3) showed resolution of active GN in two patients and persistent active GN in one patient. RTX is an alternative to CYC for remission induction in recurrent AAV-associated GN in KTX patients.

Antineutrophil cytoplasmic antibody vasculitis associated with influenza vaccination.

BACKGROUND: Administration of influenza vaccines has been associated with the development of autoantibodies and autoimmune rheumatic disease. PATIENTS: We discuss 2 patients who developed antineutrophil cytoplasmic antibody-associated vasculitis (AAV) in temporal association with influenza immunization. AAV was diagnosed 2 and 4 weeks after immunization in these patients. Both patients had renal involvement with one requiring dialysis. Both patients were treated with cyclophosphamide and corticosteroids, and plasmapheresis was added to the immunosuppressive regimen in one patient with dialysis-dependent renal failure. Both patients achieved disease remission. The patient with initial dialysis-dependent renal failure reached end-stage renal disease. There are 6 previous cases of AAV in the literature described in temporal association with administration of influenza vaccines. CONCLUSION: A causal role of vaccines in AAV cannot be confirmed with these case reports. The temporality suggests that the influenza vaccine may be a triggering factor for induction of vasculitis in predisposed individuals. We review the literature on reported cases of AAV following influenza vaccine administration and discuss possible mechanisms for influenza vaccine-associated AAV.

Pathology of calcific aortic stenosis.

With the aging of the general population in industrialized nations, calcific aortic stenosis (CAS) is becoming an increasingly important medical problem. The etiology is for the most part, dependent on the age at presentation; the two predominant causes in the western world are calcific aortic valve disease arising in a tricuspid aortic valve and bicuspid aortic valve (BAV). CAS is a progressive disease, exhibiting a spectrum of pathologic findings, ranging from valvular sclerosis to severe nodular calcification. Aortic valve replacement is the recommended treatment for severe disease but tissue valves may also calcify over time. Various atherosclerotic risk factors have been linked to aortic stenosis and there are mechanistic similarities between atherosclerosis and CAS. The precise pathologic mechanisms underlying aortic stenosis are poorly understood.

Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Tendencias actuales en la clasificación de la muerte súbita cardiaca según los datos de autopsias: una revisión de los estudios sobre la etiología de la muerte súbita cardiaca / No disponible

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Histopathologic assessment of myocardial regeneration.

Cardiac regeneration in the form of cell-based therapy offers hope of becoming the breakthrough technology that transforms the state of cardiac medicine. Before attempting to develop the techniques to assess the effectiveness of myocardial regeneration in humans, researchers must have at least a basic understanding of the human heart in its embryonic, normal, and diseased states. To this end, we provide an overview of the histology of the heart, including the current theories on normal embryogenesis and the histology of normal and ischemic myocardium as visualized by pathologists. Knowledge of the cellular constituents, including the controversial existence of resident cardiac stem and/or progenitor cells, and their actions and interactions in the normal state and under the conditions of myocardial ischemia is also crucial before embarking on the quest for cardiac regeneration. Despite widespread optimism in the success of cell-based therapy, inherent difficulties remain in the identification of effective cell populations proposed for cell-based therapy in the human heart.

Mitral annular reduction with subablative therapeutic ultrasound: pre-clinical evaluation of the ReCor device.

AIMS: To evaluate the potential for mitral annular (MA) size reduction using a novel device utilising therapeutic ultrasound (TU). METHODS AND RESULTS: The ReCor device (ReCor Medical, Inc., Ronkonkoma, NY, USA, Investigational device, not for use in human application) was studied in a closed chest canine animal model (35 dogs). Under fluoroscopy, a 12 Fr TU balloon catheter was advanced into the left atrium (transseptal approach). The TU balloon was inflated with contrast-saline, positioned at the MA and energy delivered circumferentially, to heat the tissue locally. Five TU applications were delivered (at least 60W for at least 40 sec). Relative to baseline, mitral valve annular diameter reduction (measured by transthoracic echocardiography) was 8.4% immediately post procedure(p<0.001), 8.6% at one week (p<0.001), 8.8% at two weeks (p<0.001), 9.3% at three weeks (p<0.001), 10.8% at four weeks (p<0.001), 8.6% at three months (p<0.001) and 5.7% at six months (p<0.001). Histology showed an increase in elastin associated with tissue thickening at the annular level. Transmission electron microscopy demonstrated a decrease in diameter of individual collagen fibres in treated regions compared to controls. CONCLUSIONS: Therapeutic ultrasound (TU) energy application to the mitral annulus is feasible percutaneously. A reduction in annular dimensions occurs immediately and appears to be durable without peri-annular damage.

Relationship of thrombus healing to underlying plaque morphology in sudden coronary death.

OBJECTIVES: The aim of this study was to assess differences in thrombus healing between ruptured and eroded plaques, given the natural difference in lesion substrate and that thrombi might exist days to weeks before the presentation of sudden coronary death. BACKGROUND: Although the ability to distinguish ruptures and erosions remains a major clinical challenge, in-hospital patients dying with acute myocardial infarction establish that erosions account for 25% of all deaths, where women experience a higher incidence compared with men. METHODS: Coronary lesions with thrombi (ruptures, n = 65; erosions, n = 50) received in consultation from the Medical Examiner's Office from 111 sudden death victims were studied. Thrombus healing was classified as early (<1 day) or late stage characterized in phases of lytic (1 to 3 days), infiltrating (4 to 7 days), or healing (>7 days). Morphometric analysis included vessel dimensions, necrotic core size, and macrophage density. RESULTS: Late-stage thrombi were identified in 79 of 115 (69%) culprit plaques. Women more frequently had erosion with a greater prevalence of late-stage thrombi (44 of 50, 88%) than ruptures (35 of 65, 54%, p < 0.0001). The internal elastic lamina area and percent stenosis were significantly smaller in erosions compared with ruptures (p < 0.0001 and p = 0.02), where plaque burden was greater (p = 0.008). Although macrophage infiltration in erosions was significantly less than ruptures (p = 0.03), there was no established relationship with thrombus organization. Other parameters of thrombus length and occlusive versus nonocclusive showed no association with healing. CONCLUSIONS: Approximately two-thirds of coronary thrombi in sudden coronary deaths are organizing, particularly in young individuals-especially women, who perhaps might require a different strategy of treatment.

A comparison of the diffusion of two innovations -- a pilot study: telemicroscopy versus teleradiology.

Despite speculation that Telemicroscopy and Digital Microscopy will follow the same diffusion curves as their counterparts in the world of Radiology - Teleradiology and Filmless Radiology, no study has offered definitive evidence in support of this hypothesis. To address this gap in the informatics knowledge base, dual survey instruments were created to measure current opinions on both technologies among Pathologists and Radiologists and disseminated to Pathologists and Radiologists at two major academic medical centers.