All histologic features presently ascribed to IEE can occur in other esophageal diseases, notably GERD. As such, the finding of intraepithelial eosinophilia in any number is not specific for IEE. When a patient with GERD has an esophageal biopsy with an eosinophil count >20/hpf, it does not mean that the patient has IEE.

BA Vervaet et al.: CINAC, a toxin-induced lysosomal tubulopathy c l i n i c a l i n v e s t i g a t i o n Kidney International (2020) 97, 350-369 BA Vervaet et al.: CINAC, a toxin-induced lysosomal tubulopathy c l i n i c a l i n v e s t i g a t i o n

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Background and Aims Histopathological analysis of renal biopsy is the cornerstone of diagnosis in renal disease and guides treatment and prognosis. The prevalence of various renal diseases varies according to the geographical area, socioeconomic condition, race, age, demography and indication of renal biopsy. Method A retrospective study of all native and transplant kidney biopsies performed at the renal unit of Sri Jayewardenepura General Hospital, Sri Lanka, between 1st October 2012 and 30th September 2019. Samples were processed for light microscopy in all cases, with immunofluorescence in most cases. Results 771 biopsies were analyzed. Majority of biopsies 514 (67%) were male patients. Most biopsies (n= 345, 45%) were in 40 – 59yr age group, followed by 267 (35%) 20–39yr, 117 (15%) 60–69yr, 12 (1%) >70yrs, 30 (4%) 12–19yr age groups. Maximum age was 84 years. In 35 cases, tissue were inadequate. 547 (71%) were native biopsies and 224 (29%) were graft biopsies. Among transplants, majority was for an indication (n=146, 66%) followed by time-zeroes (n=59, 26%) and protocols (n=19, 9%). Rising creatinine (81%) was the strongest reason for transplant biopsies, next proteinuria (10%) and delayed graft function (7%). Time zeroes: majority were normal, few ATN, 1 chronic tubulointerstitial nephritis, and 1 hypertensive glomerulosclerosis. Grafts revealed, acute antibody-mediated rejection 41 (18%) with acute cell-mediated rejection 27 (12%), (total rejections n=68, 30%) followed by normal histology 48 (21%), acute tubular necrosis 43 (19%), chronic allograft nephropathy 23 (10%), BKV nephropathy 5 (2%), and 18% other etiologies: CNI-toxicity (n=4), hypertensive glomerulosclerosis (n=3), diabetic nephropathy (n=2), thrombotic microangiopathy (n=2), FSGS (n=2), MPGN (n=1), vasculitis (n=2), PTLD (n=1), cast nephropathy (n=1), and granulomatous interstitial nephritis (n=1). The most common indication for native biopsy was nephrotic syndrome 209 (38%), followed by non-proteinuric CKD 105 (19%), unexplained renal failure 77 (14%), sub-nephrotic proteinuria 102 (18%), nephritic syndrome 54 (9%). Primary glomerulonephritis (GN) was the commonest 291 (53%). Commonest lesion amidst primary GN was IgA nephropathy 90 (16%), followed by FSGS 63 (12%), CGN 27 (4%), minimal change 36 (6%), MPGN 32 (5%), membranous 6 (1%), DPGN 22 (4%), mesangiocapillary GN 3 (0.5%) and post-streptococcal GN 11 (2%). In the secondary forms of GN, SLE was the commonest 39 (7%), next diabetic nephropathy 29 (5%), amyloidosis 2 (0.3%). Chronic tubulointerstitial nephritis 92 (16%) was the second common, with 42 (7%) CINAC – chronic interstitial nephritis in agricultural communities. Other etiologies: acute tubulointerstitial nephritis 14 (2.5%), hypertensive glomerulosclerosis 12 (2%), thrombotic microangiopathy 6 (1%), ischemic nephropathy 9 (1%), end stage disease 6 (1%), inconclusive 13 (2%). 5 cast nephropathy due to multiple myeloma, 1 monoclonal deposition disease due to lambda chain deposition, 1 sarcoidosis, 1 cholesterol embolism. Conclusion Female: male ratio 1:2 with commonest age group being 40 – 59yrs. Strongest indication for transplant biopsy was rising creatinine. Acute rejection was the most frequent finding in grafts, with normal histology being the next, probably due to high number of time zeroes and protocols performed in our centre. Biopsy proven BKV nephropathy was 2% (n=5). Nephrotic range proteinuria was the commonest native biopsy indication, with non-proteinuric CKD being the second. Primary GN was the commonest finding with IgA nephropathy scoring the highest. This does not coincide with global data, which shows FSGS to be the leading cause. The second common histology was FSGS, and primary CTIN was third. The prevalence of biopsy-proven GN varies due to a wide array of factors and different studies have shown different leading patterns.

Background and Aims 30 years after the detection of CINAC, there is no consensus on its etiology. Heat stress/dehydration and toxic exposure are the two most likely etiologies. There are no diagnostic criteria that can directly identify CINAC patients. Method Renal biopsies (RB) (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) of patients with CINAC (CKD2-3) were examined by light (LM) and electron microscopy (EM) in comparison to RB of normal kidneys at implantation and 6 and 12 months of calcineurin inhibitor (CNI) therapy, transplant patients on CNI with indication biopsies (n=24), proteinuric nephropathies (n=15), light chain disease (n=4), cases on nephrotoxic drugs (lomustine, clomiphene, lithium, tenofovir, cisplatinum) and CKD of various causes (n=20). A rat study was conducted comparing histopathology of heat stress/dehydration with cyclosporine nephrotoxicity. Results In addition to previously described histopathological changes, there was a unique constellation of proximal tubular cell (PTC) findings: cellular/tubular atrophy, cell fragment shedding, weak to non-proliferative capacity of the PTC and dysmorphic lysosomes increased in size and number with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound “aggregates”. Identical renal lesions were observed in 55-80% of renal transplant protocol biopsies taken after 6 and 12 months of calcineurin inhibitor (CNI) therapy and in indication biopsies, in implantation biopsies the prevalence was 6%. Several cases of nephrotoxic drugs (lomustine, clomiphene, lithium) and a subset of patients with light chain disease, all conditions that can be linked to CNI, presented the same lesion. Control RBs (n=66) of normal kidney, toxic nephropathies (tenofovir, cisplatinum), and overt proteinuric patients of different etiology to some extent could demonstrate the tubular cell changes observed by LM, but not or very rarely those that were observed by EM. Rats treated with cyclosporine for 4 weeks developed similar PTC lysosomal alterations, absent in a dehydration group. Conclusion A sensitive constellation of renal PTC lesions was detected associated with CINAC and CNI nephrotoxicity in several countries, suggesting a common new paradigm where CINAC patients are experiencing a tubulotoxic mechanism similar to CNI nephrotoxicity, the latter also being known as a direct or suggested indirect effect of pesticides.

gauge was not documented in 8% of procedures. No 14G biopsy devices were used. The median number of passes per procedure was 3 for RMS and 2 for IR (p = 0.11). Median glomerular yield per biopsy was 18 for RMS and 18.6 for IR (p = 0.84). Non-diagnostic biopsies occurred in 8% of RMS and 13% of IR biopsies (p = 0.52). 3% of RMS PRB required post-PRB blood transfusion (n=2). Macroscopic haematuria occurred in 3% of RMS biopsies. None of the 23 IR PRB required transfusion however 35% received routine gel foam haemostasis. This may contribute to a decreased incidence of bleeding post-procedure. No invasive procedures for bleeding were required in either group. IR performed 0% of 71 PRB in 2014. However, by 2017 IR completed 13% of 104 PRB. Conclusions: This preliminary audit in a single centre identifies that PRB is a safe procedure in adult patients with kidney disease despite periprocedural hypertension in over half of patients. The transfusion rate at 2% was higher than the 0.9% transfusion rate previously reported. Glomerular yield per PRB was comparable between IR and RT. There were higher rates of non-diagnostic IR biopsies-however this may be confounded by referral bias. There is a trend toward an increasing number of PRB being performed by IR. These findings underscore the need for renewed and ongoing Nephrology and IR dialogue regarding clinical training, workforce roles and multidisciplinary care.

Background and Aims In CINAC patients from Sri Lanka, we recently observed a sensitive constellation of proximal tubular cell findings including cellular/tubular atrophy, cell fragment shedding and, by electron microscopy (EM), the presence of an increased number of enlarged lysosomes. Here we focused on precisely defining the EM lysosomal phenotype and evaluating its presence in CINAC/MeN/CKDu cases and controls from other countries. Method Thirthy-two renal biopsies (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) of patients with a diagnosis of CINAC (CKD 1-3A, 3B) were examined by electron microscopy (EM) in comparison to renal biopsies of normal kidneys at implantation, patients with calcineurin inhibitor (CNI) toxicity (n=17), proteinuric nephropathies (n=15), light chain disease (n=4), several cases on nephrotoxic drugs (lomustine, clomiphene, lithium, tenofovir, cisplatinum) and patients with reduced renal function of various causes (n=20). Results The aberrant lysosomal phenotypes can be defined as enlarged (>1.2µm) and dysmorphic with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound round to irregular shaped “aggregates”. In addition, indicative clusters of 4-6 smaller lysosomes with the same features could be observed. No cristae or other features of mitochondria, autophagic vacuoles, lipofuscin/ceroid droplets, peroxisomes (marginal plate), lysosomal myeloid bodies (aminoglycoside nephropathy) or electron dense laminated lysosomal inclusions (Fabry disease) were observed. Patients with calcineurin inhibitor nephrotoxicity and several cases on nephrotoxic drugs (lomustine, clomiphene, lithium) and a subset of patients with light chain disease, all conditions that can either directly or indirectly be linked to calcineurin inhibition, presented the same lesions. We present an image set demonstrating the phenotypical consistency of the diagnostic lysosomal lesion versus similar features that are non-diagnostic. Conclusion A rather sensitive constellation of lysosomal lesions in renal proximal tubular cells was detected associated with CINAC/CKDu/MeN and CNI nephrotoxicity in several countries, suggesting a common new pathomechanistic paradigm where CINAC patients are experiencing a tubulotoxic mechanism similar to CNI nephrotoxicity.

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