Tubulointerstitial Scarring Research Articles

Clinical Relevance of Computationally Derived Tubular Features: Spatial Relationships and the Development of Tubulointerstitial Scarring in MCD/FSGS.

Visual scoring of tubular damage has limitations in capturing the full spectrum of structural changes and prognostic potential. We investigate if computationally quantified tubular features can enhance prognostication and reveal spatial relationships with interstitial fibrosis. Deep-learning and image-processing-based segmentations were employed in N=254/266 PAS-WSIs from the NEPTUNE/CureGN datasets (135/153 focal segmental glomerulosclerosis and 119/113 minimal change disease) for: cortex, tubular lumen (TL), epithelium (TE), nuclei (TN), and basement membrane (TBM). N=104 pathomic features were extracted from these segmented tubular substructures and summarized at the patient level using summary statistics. The tubular features were quantified across the biopsy and in manually segmented regions of mature interstitial fibrosis and tubular atrophy (IFTA), pre-IFTA and non-IFTA in the NEPTUNE dataset. Minimum Redundancy Maximum Relevance was used in the NEPTUNE dataset to select features most associated with disease progression and proteinuria remission. Ridge-penalized Cox models evaluated their predictive discrimination compared to clinical/demographic data and visual-assessment. Models were evaluated in the CureGN dataset. N=9 features were predictive of disease progression and/or proteinuria remission. Models with tubular features had high prognostic accuracy in both NEPTUNE and CureGN datasets and increased prognostic accuracy for both outcomes (5.6%-7.7% and 1.6%-4.6% increase for disease progression and proteinuria remission, respectively) compared to conventional parameters alone in the NEPTUNE dataset. TBM thickness/area and TE simplification progressively increased from non- to pre- and mature IFTA. Previously under-recognized, quantifiable, and clinically relevant tubular features in the kidney parenchyma can enhance understanding of mechanisms of disease progression and risk stratification.

Spectrum of Kidney Biopsy Findings Associated With Methamphetamine Use

IntroductionMethamphetamine (METH) is one of the most used drugs of abuse worldwide. However, there are few reports and series examining the toxic kidney effects of METH and associated histopathological changes are not well described. MethodsWe retrospectively identified 112 patients with a history significant for methamphetamine (METH) abuse, of whom 62 were using METH-only and 60 METH + other drugs of abuse. ResultsIn the METH-only cohort, the mean age was 41 years (IQR 33-49) and most were male (76%). Almost all cases (97%) showed evidence of kidney dysfunction at the time of biopsy. 65% had proteinuria, of which 53% were nephrotic-range and 10% had nephrotic syndrome. The most common biopsy diagnosis was acute tubular necrosis (ATN) (66%), of which 19% had myoglobin casts, followed by focal segmental glomerulosclerosis in 53% (NOS in 76% and collapsing in 18%). Biopsy findings also include tubulointerstitial nephritis (37%), thrombotic microangiopathy (24%), and diabetic glomerulosclerosis (DG) (31%).Glomerulonephritis (GN) was identified in one-third of cases, the most common of which were infection-related GN (15%) and IgA nephropathy (11%). 64% of GNs had underlying infection. Of interest, there was increased association for myoglobinuric ATN in those with concurrent ethanol-abuse (p=0.002). Moreover, the METH-only patients were more likely to have DG compared to those with multiple substance-use (p=0.01). More than half demonstrated at least moderate to severe tubulointerstitial scarring and marked hypertensive vascular disease. ConclusionMost patients with METH-use present with acute kidney injury and often have proteinuria associated with a wide spectrum of renal pathology.

New Horizons in IgA Nephropathy: A Focus on Current Treatment and Emerging Solutions

IgA nephropathy (IgAN) is a common form of glomerular disease, with wide heterogeneity of symptom occurrence and progression. Diagnosis is based on kidney biopsy findings. IgAN initiates in the mucosa with development of galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 autoantibodies, leading to deposition of these complexes in glomerular mesangium with resulting fibrosis, inflammation, tubulointerstitial scarring, and glomerular injury. This can lead to chronic kidney disease (CKD), kidney failure, and death. IgAN treatment involves optimised supportive care, including individualised strategies to address symptoms, such as high blood pressure control and cardiovascular risks. Drug treatment includes renin-angiotensin-aldosterone system (RAAS) inhibitors and immunosuppressant therapies. While the latter can successfully lower proteinuria, and have a positive effect on estimated glomerular filtration rate (eGFR), adverse effects can limit treatment duration, and increasing proteinuria and decreasing eGFR can return following treatment discontinuation. New formulations of immunosuppressant therapies include delayed-release budesonide with targeted release in the lower part of the small intestine where Gd-IgA1 production occurs. Although treatment with this drug can reduce proteinuria and sustain eGFR levels, similar to other immunosuppressant therapies, effects seem to be predominantly limited to the active treatment period. Targeting a different mechanism, sparsentan is a dual endothelin A receptor (ETA) and angiotensin II receptor type 1 (AT1) blocker that targets endothelin-1 (ET-1) and angiotensin II, both involved in IgAN progression. Initial Phase III trial results show significant differences, favouring sparsentan, compared with the AT1 blocker irbesartan, on proteinuria, with similar adverse event profiles. These agents, and several other drugs in development, will widen the armamentarium of therapies for people with IgAN, which, when used in combination, can target different aspects of IgAN pathogenesis for a more individualised treatment approach.

Histologic and Molecular Correlates in Patients with AL Amyloidosis in Hematologic Remission but with Persistent Renal Disease

ABSTRACT: Despite the high prevalence of kidney involvement in patients with light chain (AL) amyloidosis, a significant knowledge gap exists in understanding how immunoglobulin light chains drive kidney injury. The chief reason is the lack of molecular data from high-quality kidney tissue samples from this patient population. The RAIN trial (NCT03168906) was a phase 2b randomized placebo-controlled, clinical trial that evaluated the efficacy of NEOD001, a monoclonal antibody targeting amyloid fibrils, versus placebo in patients with AL nephropathy. Before drug administration, renal biopsies were taken and analyzed. OBJECTIVE: Identifying amyloid-specific molecular signatures in kidney biopsy tissue. MATERIALS & METHODS: Renal biopsies were collected on all RAIN participants before randomization to NEOD001 or placebo. Clinical data was collected and correlated to histologic and molecular findings. Histologic assessment included a composite scarring injury score (CSIC) as determined by the degree of glomerular and tubulointerstitial scarring, and a novel amyloid score (AS), as quantified by the extent and distribution of amyloid deposition. Glomerular (G) and tubulointerstitial (TI) compartments were micro-dissected and sequenced separately. To identify enriched pathways in AL nephropathy, the expression data was compared to the glomerular and tubular expression profiles of healthy living donor (LD) from the Nephrotic Syndrome Study Network (NEPTUNE) study. Differentially expressed genes (DEGs) were determined . RESULTS: Ten patients were enrolled, randomized and treated in the RAIN trial (5 NEOD001 and five placeboes) before trial closure in April 2018. Kidney tissue was available in nine of the ten patients. Cluster analysis revealed two distinct patient clusters (G1 and G2) within the glomerular and TI compartments ( See Figure 1). Key clinical data pertaining to kidney function and biopsy morphology by compartment and cluster type were documented. Despite similar eGFR and degree of proteinuria, there was a significantly higher AS score in the TI compartment (6.5 vs. 4.5; p=0.0290) of G2 which was driven most entirely by an increase in mesangial and capillary wall amyloid deposition. Pathway Enrichment in G2 versus G1: Glomeruli showed activation of fibrotic pathways accompanied by a reduction in metabolic processes including gluconeogenesis, lipid transport and xenobiotics. There was an increase in canonical signaling of LPS/IL-1 that drives increased IL1 and TNF release from macrophages. Transcriptomic evidence of TNF activation was also noted in the TI compartment. Other enriched ingenuity canonical pathways to note in the TI included ‘coagulation system’, ‘GADD45 signaling’, ‘Wnt/Ca+ pathway’, ‘intrinsic prothrombin activation pathway’ among others. Of note, genes like BRCA and CDKN1A were enriched between G1 and G2, both of which have been associated with molecular mechanisms that underly certain neoplasms ( See Figure 2). Pathway enrichment in Amyloid kidney disease versus LD: IPA analysis identified unique activation signatures in the glomeruli and tubules. In the glomeruli, there was increased signaling of TNF, NFKB, IL33, IL-8 and IL15, consistent with an important inflammatory response. There was also an enrichment in pathways related to migration, adhesion and integrin signaling. PI3K/Akt signaling was also noted. Tubules showed increased activation of transcriptional regulators TP53, TP73 and PI3K/AKT signaling. Some gene regulators of cellular proliferation such as ABL1, BCL2 and AKT1 were found to be enriched in the amyloid group. CONCLUSIONS: While the RAIN trial closed prematurely and NEOD001 cannot be evaluated, the molecular data revealed the presence of two distinct molecular subtypes of AL nephropathy. Whether these distinct molecular subtypes reflect different stages of the disease along a continuous spectrum or are of unique prognostic entities in of themselves remains unclear. Detailed studies, of a larger cohort of patients including investigating diseased tissue at a single cell resolution can help identify the response of individual kidney cell types. Understanding the cellular responses of key cell types to injury from amyloid deposits could provide novel therapeutic targets to mitigate renal injury and improve patient outcomes. Based on this early work, targeting the PI3K/Akt pathway may be a worthy pursuit in this disease.

Pregnancy in women with nephrotic-range proteinuria: A retrospective cohort study

Background Obstetric and kidney outcomes following detection of nephrotic-range proteinuria in early pregnancy have not been well described. Methods A retrospective cohort study of chronic kidney disease (CKD) in pregnancy between 2008 and 2018. Outcomes in those with nephrotic-range proteinuria before 20 weeks’ gestation were compared to those without nephrotic-range proteinuria. Results The study included 37 women with nephrotic-range proteinuria and 62 women without. Pre-pregnancy estimated glomerular filtration rate (eGFR) was similar. Nephrotic-range proteinuria was associated with higher rates of preterm (odds ratio [OR] 1.77, 95% confidence interval [CI]: 1.07–2.92) and early preterm delivery (OR 2.63, 95% CI: 1.12–6.2), and with a requirement for renal replacement therapy at 3 years post-partum (OR 10.72, 95% CI: 2.58–44.47). Tubulointerstitial scarring on kidney biopsy was associated with early preterm delivery and progression to advanced CKD, independent of pre-pregnancy eGFR. Conclusion Compared to CKD without nephrotic-range proteinuria, nephrotic-range proteinuria early in pregnancy is associated with higher rates of pre-term delivery and progression to advanced CKD.

Excessive sodium chloride ingestion promotes inflammation and kidney fibrosis in aging mice.

In aging kidneys, a decline of function resulting from extracellular matrix (ECM) deposition and organ fibrosis is regarded as "physiological." Whether a direct link between high salt intake and fibrosis in aging kidney exists autonomously from arterial hypertension is unclear. This study explores kidney intrinsic changes (inflammation, ECM derangement) induced by a high-salt diet (HSD) in a murine model lacking arterial hypertension. The contribution of cold shock Y-box binding protein (YB-1) as a key orchestrator of organ fibrosis to the observed differences is determined by comparison with a knockout strain (Ybx1ΔRosaERT+TX). Comparisons of tissue from mice fed with normal-salt diet (NSD, standard chow) or high-salt diet (HSD, 4% NaCl in chow; 1% NaCl in water) for up to 16 mo revealed that with HSD tubular cell numbers decrease and tubulointerstitial scarring [periodic acid-Schiff (PAS), Masson's trichrome, Sirius red staining] prevails. In Ybx1ΔRosaERT+TX animals tubular cell damage, a loss of cell contacts with profound tubulointerstitial alterations, and tubular cell senescence was seen. A distinct tubulointerstitial distribution of fibrinogen, collagen type VI, and tenascin-C was detected under HSD, transcriptome analyses determined patterns of matrisome regulation. Temporal increase of immune cell infiltration was seen under HSD of wild type, but not Ybx1ΔRosaERT+TX animals. In vitro Ybx1ΔRosaERT+TX bone marrow-derived macrophages exhibited a defect in polarization (IL-4/IL-13) and abrogated response to sodium chloride. Taken together, HSD promotes progressive kidney fibrosis with premature cell aging, ECM deposition, and immune cell recruitment that is exacerbated in Ybx1ΔRosaERT+TX animals.NEW & NOTEWORTHY Short-term experimental studies link excessive sodium ingestion with extracellular matrix accumulation and inflammatory cell recruitment, yet long-term data are scarce. Our findings with a high-salt diet over 16 mo in aging mice pinpoints to a decisive tipping point after 12 mo with tubular stress response, skewed matrisome transcriptome, and immune cell infiltration. Cell senescence was aggravated in knockout animals for cold shock Y-box binding protein (YB-1), suggesting a novel protective protein function.

The pathologic spectrum of adenovirus nephritis in the kidney allograft

Adenovirus nephritis (ADVN) is a rare and understudied complication of kidney transplantation. Unlike BK virus nephropathy (BKVN), our knowledge of clinicopathologic manifestations of ADVN remains rudimentary and essentially limited to case reports. To expand on this, we retrospectively studied 11 kidney transplant recipients with ADVN and compared their allograft biopsies to 33 kidney transplant recipients with BKVN using conventional microscopy and the 770 gene Nanostring Banff Human Organ Transplant Profiling Panel. Patients with ADVN had a median age of 44 years, were predominantly male, and developed ADVN at a median of 31 months post-transplantation. Eight patients presented with fever and ten had hematuria. The most common histologic manifestations included granulomas (82%), tubulocentric inflammation (73%), and tubular degenerative changes consistent with acute tubular necrosis (73%). During a median follow-up of 55 months after biopsy, three patients developed allograft failure from subsequent acute rejection. All seven patients with available follow-up PCR showed resolution of viremia at a median of 30 days after diagnosis. Compared to BKVN, ADVN demonstrated more granulomas and less tubulointerstitial scarring. On follow-up, patients with ADVN had more rapid clearance of viral DNA from plasma. Transcriptomic analyses showed that ADVN had increased expression of several pro-inflammatory transcriptomes, mainly related to innate immunity, was associated with increased expression of transcripts with inhibitory effects on inflammatory response and showed higher enrichment with neutrophils, which can cause aggressive but short-lasting damage. Thus, we demonstrate that, despite its association with aggressive neutrophil-rich inflammation, ADVN does not often lead to allograft failure. Hence, preventing subsequent acute rejection following resolution of ADVN may improve allograft survival.

Gene Expression Sets and Renal Profiling from the Rain (Renal AL Amyloid Involvement and NEOD00) Trial

INTRODUCTION: Despite the high prevalence of kidney involvement in patients with light chain (AL) amyloidosis, a significant knowledge gap exists in understanding how immunoglobulin light chains drive kidney injury. The chief reason is the lack of molecular data from high-quality kidney tissue samples from this patient population. The RAIN trial (NCT03168906) was a phase 2B randomized placebo-controlled, open-label clinical trial that evaluated the efficacy of NEOD001, a monoclonal antibody targeting amyloid fibrils, versus placebo in patients with AL nephropathy. OBJECTIVES: Identifying amyloid-specific molecular signatures in kidney biopsy tissue obtained from AL patients with nephropathy.MATERIALS& METHODS: Renal biopsies were collected on all RAIN participants before randomization to NEOD001 or placebo. Trial clinical data was incorporated to link tissue, molecular, and kidney function data. The histologic assessment included a composite scarring injury score (CSIC) as determined by the degree of glomerular and tubulointerstitial scarring, and a novel amyloid score (AS), as quantified by the extent and distribution of amyloid deposition. Glomerular (G) and tubulointerstitial compartments were micro-dissected and sequenced separately. To identify enriched pathways in AL nephropathy, the expression data was compared to the glomerular and tubular expression profiles of healthy living donor (LD) from the Nephrotic Syndrome Study Network (NEPTUNE) study. Differentially expressed genes (DEGs) were determined with the R limma package based on the voom transformed log2 count data with an FDR of <=0.05. The AL and NEPTUNE datasets were merged and batch-corrected using ComBat. RESULTS: Ten patients were enrolled and randomized in the RAIN trial (5 NEOD001 and five placeboes) before trial closure in April 2018. Kidney tissue was available in nine of the ten patients. Cluster analysis revealed two distinct patient clusters (G1 and G2) within the glomerular and tubulointerstitial compartments. Key data of kidney function and biopsy morphology by compartment and cluster type are shown in Table 1. Despite similar eGFR, there was a higher AS and a non-significant increase in 24-hour urine protein in the glomeruli of individuals in the G2 patient cluster. Subcomponent analysis of AS revealed that the increase in amyloid score in G2 was driven almost entirely by an increase in mesangial and capillary wall amyloid deposition. Pathway enrichment in Amyloid kidney disease versus LD: IPA analysis identified unique activation signatures in the glomeruli and tubules. In the glomeruli of biopsies from the G2 cluster, there was evidence of increased TNF, IFNG, IL33 and VEGFA cytokine activity and a predicted increase in canonical PI3K/Akt signaling and innate immune responses. Tubules showed increased activation of transcriptional regulators TP53, TP73, increased cytokine signaling of IFNG, TGFb1 and VEGF. There was also a predicted activation of major canonical pathways including B cell receptor signaling, PI3K/AKT and Ephrin receptor signaling (Fig 1). Pathway Enrichment in G2 versus G1: Glomeruli showed activation of fibrotic pathways accompanied by a reduction in metabolic processes including gluconeogenesis, lipid transport and xenobiotics. There was an increase in canonical signaling of LPS/IL-1 mediated inhibition of RXR function that drives increased IL1 and TNF release from macrophages. Transcriptomic evidence of TNF activation was also noted in the TI. CONCLUSIONS: The RAIN trial closed prematurely, and thus no conclusions can be reached about the efficacy of NEOD001 in patients with AL nephropathy. However, these limited data revealed the presence of two distinct molecular subtypes of AL nephropathy. Whether these distinct molecular subtypes reflect different stages of the disease along a continuous spectrum or are of unique prognostic entities in themselves remains unclear. Detailed studies, of a larger cohort of patients including investigating diseased tissue at a single cell resolution can help identify the response of individual kidney cell types. Understanding the cellular responses of key cell types to injury from amyloid deposits could provide novel therapeutic targets to mitigate renal injury and improve patient outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MICROSCOPIC POLYANGIITIS PRESENTING WITH CARDIAC TAMPONADE

MICROSCOPIC POLYANGIITIS PRESENTING WITH CARDIAC TAMPONADE

The spectrum of renal diseases with lupus-like features: a single-center study

Background A subset of patients without overt systemic lupus erythematosus (SLE) present with biopsy findings typically seen in lupus nephritis (LN). Although a minority eventually develops SLE, many do not. It remains unclear how to classify or treat these patients. Our study attempted to further understand the clinical and pathological characteristics of cases with lupus-like nephritis (LLN). Methods Among 2700 native kidney biopsies interpreted at University of Rochester Medical Center (URMC) from 2010 to 2019, we identified 27 patients with biopsies showing lupus-like features (LL-fx) and 96 with LN. Of those with LL-fx, 17 were idiopathic LLN and 10 were associated with a secondary etiology (e.g., infection/drugs). Results At the time of biopsy, the LLN-group tended to be slightly older (44 vs. 35), male (58.8 vs. 17.7%, p = .041), and Caucasian (47.0 vs. 28.1%, p = .005). Chronic kidney disease was the most common biopsy indication in LLN (21.4 vs. 2.8%, p = .001). Both LN and LLN presented with nephrotic-range proteinuria (mean 5.73 vs. 4.40 g/d), and elevated serum creatinine (mean 1.66 vs. 1.47 mg/dL). Tubuloreticular inclusions (TRIs; p < .001) and fibrous crescents (p = .04) were more often seen in LN, while more tubulointerstitial scarring was seen in LLN (p = .011). At mean follow-up of 1684 d (range: 31–4323), none of the LLN patients developed ESRD. A subset of both LN and cases with LL-fx overlapped with other autoimmune diseases. Conclusions Lupus-like pathologic features are seen in a wide array of disease processes. The findings suggest that LLN may be a manifestation of an autoimmune process that overlaps with SLE.

Albumin and Proximal Tubular Cells in Progressive Renal Disease

Abstract The presence of albuminuria has long been recognized as an adverse prognostic feature in patients with renal disease. Those patients with appreciable albuminuria are much more likely to develop tubulointerstitial scarring and fibrosis and progress to end-stage renal failure. For many years it was thought that excess albuminuria was simply a marker of a more severe renal disease which was more likely to progress as a result of this severity rather than as a result of the albuminuria itself. This conviction was strengthened by the general assumption that albumin was a benign or inert molecule serving primarily to exert oncotic pressure and act as a carrier within the circulation. More recently this view has been challenged with the accumulation of evidence suggesting that albumin is able to influence the function of cells with which it makes contact in the manner of a signaling molecule.

Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis.

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage, and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a 4-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Characterization of the Peritumoral Atrophic Band and Nonneoplastic Renal Parenchyma in Radical Nephrectomy Specimens.

Pathologic evaluation of nonneoplastic renal parenchyma in nephrectomy specimens is important for identifying chronic kidney disease and diabetic nephropathy, but increasing utilization of partial nephrectomies has led to less-sampled nonneoplastic parenchyma. The sampled tissue is often composed predominantly of the peritumoral atrophic band (PAB) directly adjacent to the tumor. We sought to determine the characteristics of the PAB and whether it could be used to reliably assess kidney pathology, including diabetic nephropathy. We investigated 59 radical nephrectomies to determine the PAB characteristics, whether the PAB is representative of distant nonneoplastic parenchyma, and if diabetic nephropathy could be reliably detected in the PAB. Mesangial sclerosis was detected within the PAB in 100% of cases with mesangial sclerosis in the distant parenchyma. Eighty percent had a history of diabetes. The PAB exhibited increased glomerular sclerosis (51% vs 13%, P < .001) and interstitial fibrosis and tubular atrophy (83% vs 13%, P < .001) compared with distant parenchyma. Diabetic nephropathy can be reliably detected in the PAB, which is important in partial nephrectomies or renal mass biopsies without ample distant renal parenchyma. The degree of glomerular and tubulointerstitial scarring within the PAB does not reflect the overall degree of chronic kidney disease.

The clinical significance of receiving a kidney allograft from deceased donor with chronic histologic changes.

Allograft survival of deceased donor kidneys with suboptimal histology (DRTx/suboptimal histology: >10% glomerulosclerosis, >10% tubulointerstitial scarring, or >mild vascular sclerosis) is inferior to both DRTx with optimal histology (DRTx/optimal histology) and living donor kidneys irrespective of histologic changes (LRTx). In this report, we explored the reasons behind this guarded outcome with a special focus on the role of alloimmunity. We initially assessed gene expression in 39 time-zero allograft biopsies using the Nanostring 770 genes PanCancer Immune Profiling Panel. Subsequently, we studied 696 consecutive adult kidney allograft recipients that were grouped according to allograft type and histology at time-zero biopsy [DRTx/suboptimal histology (n = 194), DRTx/optimal histology (n = 166), and LRTx (n = 336)]. Part-1: Several immune pathways were upregulated in time-zero biopsies from DRTx/suboptimal histology (n = 11) compared to LRTx (n = 17) but not to DRTx/optimal histology (n = 11). Part-2: Amongst the three groups of recipients, DRTx/suboptimal histology had the highest incidence of acute rejection episodes, most of which occurred during the first year after transplantation (early rejection). This increase was mainly attributed to T cell mediated rejection, while the incidence of antibody-mediated rejection was similar amongst the three groups. Importantly, early acute T cell mediated rejection was a strong independent predictor for allograft failure in DRTx/suboptimal histology (adjusted HR: 2.13, P = 0.005) but not in DRTx/optimal histology nor in LRTx. Our data highlight an increased baseline immunogenicity in DRTx/suboptimal histology compared to LRTx but not to DRTx/optimal histology. However, our results suggest that donor chronic histologic changes in DRTx may help transfer such increased baseline immunogenicity into clinically relevant acute rejection episodes that have detrimental effects on allograft survival. These findings may provide a rationale for enhanced immunosuppression in recipients of DRTx with baseline chronic histologic changes to minimize subsequent acute rejection and to prolong allograft survival.

POS-188 UNUSUAL PRESENTATION OF PRIMARY HYPEROXALURIA TYPE 1 AS POSTPARTUM ACUTE KIDNEY INJURY

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a mutation in the AGXT gene, resulting in deficiency of the alanineglyoxylate:aminotransferase enzyme. Often, the first sign is multiple recurrent nephrolithiasis, usually developped in second or third decade of life. This leads to renal interstitial and tubular damage, fibrosis, and end-stage renal disease (ESRD). We report an original case of PH type 1 without nephrolithiasis with unusual presentation as postpartum acute renal injury. A 34-year-old Tunisian woman was admitted to our center at 8 weeks postpartum with renal failure. She had no history of kidney stones or urinary tract infections. She had a family history of renal failure in her cousin. Her family history was also notable for consanguinity, her parents were first cousins. It was her first pregnancy, renal function was normal and she was delivered at 38 weeks, by elective cesarean section for persistent bleeding from low-lying placenta. The patient was seen by Nephrologist 8 week postpartum. She reported persistent bilateral flank pain, epigastralgia, nausea and vomiting, without fever. Blood pressure was 170/100 mm Hg and she appeared euvolemic. She reported maintaining fluid intake of approximately 2 L/day. Urinalysis shows no proteinuria, no hematuria and urine culture was negative. Her serum creatinine was 13,28 mg/dL, renal clearance (MDRD)= 3.4 ml/min, urea was 34.6 mmol/l, blood count revealed an hypochromic microcytic anemia (hemoglobin:6,3 g/dl; VGM=76.3; TCMH=26.7). Kidney ultrasounds show increased parenchymal echogenicity with altered corticomedullary differentiation without renal calculi (Fig.1). Kidney biopsy revealed abundant (> 90/hpf) optically clear intratubular crystalline inclusions which were accompanied by diffuse acute tubular injury, moderately severe tubulointerstitial scarring, and patchy moderate chronic interstitial inflammation, consistent with a crystalline nephropathy (Fig.2). On genetic testing, she was found to be homozygous for I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase missense mutation in the AGXT gene, consistent with PH1. The patient began intensive hemodialysis (4 h, three times a week) and she was referred for combined liver and kidney transplantation. We report an unusual presentation of PH type 1 as acute kidney injury in the postpartum period without nephrolithiasis. Nephrologist should be aware of such situation.

REFRACTORY GRANULOMATOSIS WITH POLYANGIITIS FLARE? HOW ABOUT PLASMA EXCHANGE?

SESSION TITLE: Medical Student/Resident Lung Pathology SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: ANCA-negative granulomatosis with polyangiitis (GPA) patients often have limited disease, but they may evolve to have life-threatening renal and pulmonary complications. In general, patients are treated with glucocorticoids and immunosuppression. We present a patient with GPA flare-up refractory to initial therapy who improved after undergoing plasma exchange. CASE PRESENTATION: A 78-year-old male with a past medical history of ANCA-negative GPA and chronic kidney disease (baseline Cr 2.5 mg/dL) presented to the hospital with dyspnea. He was discharged from the hospital one week prior where he was managed for a GPA flare-up (i.e., sudden onset bilateral lower extremity nonpalpable purpura) after he stopped methotrexate due to transaminitis. At that time, he was treated with pulse IV methylprednisolone and discharged home to begin rituximab. When he returned to the hospital with worsening dyspnea, vital signs were: BP 106/47, HR 83, RR 18, 93% O2 saturation on room air. His hospital course was complicated by copious amount of hemoptysis. Labs revealed: Hgb 5.2 g/dL (which dropped from 8.5 g/dL a week ago) and worsening renal function with BUN >150 mg/dL and Cr 5.1 mg/dL. Chest x-ray showed diffuse bilateral alveolar opacities. He had respiratory failure secondary to pulmonary hemorrhage, which led to intubation and transfusion of blood products. A decision was made to start the patient on seven sessions of plasma exchanges. The patient responded well to the therapy and was eventually extubated with pulmonary and renal function returning to baseline. DISCUSSION: In the past, plasma exchange in GPA was based upon the efficacy of removing autoantibodies in Goodpasture's syndrome. More recently, the PEXIVAS clinical trial demonstrated that plasma exchange neither reduced the risk of end-stage renal disease nor had a treatment effect on pulmonary hemorrhage in ANCA-associated vasculitis. Some statistical analyses regarding pulmonary hemorrhage had wide confidence intervals, suggesting that plasma exchange could still be useful. In addition, a kidney biopsy was not required to enter the PEXIVAS trial, making it difficult to delineate if mild or severe disease was present (as vasculitides patients often have a relapsing and remitting course). Those with minimal tubulointerstitial and glomerular scarring could theoretically benefit from plasma exchange. The patient in this case underwent plasma exchange as he was thought to be among a select subgroup whose benefits outweighed risks. CONCLUSIONS: The use of plasma exchange in vasculitides should be tailored according to the characteristics of each patient and the previous treatments that each patient received. Reference #1: 1. Pagnoux C. Updates in ANCA-associated vasculitis. Eur J Rheumatol. 2016; 3(3):122-133. DOI:10.5152/eurjrheum.2015.0043 Reference #2: 2. Walsh M et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020; 382(7):622-631. DOI: 10.1056/NEJMoa1803537 Reference #3: 3. Jayne D.R.W et al. Randomized Trial of Plasma Exchange or High-Dosage Methylprednisolone as Adjunctive Therapy for Severe Renal Vasculitis. JASN. 2007; 18(7):2180-2188; DOI: 10.1681/ASN.20070100904. Derebail V, Falk R. ANCA-Associated Vasculitis -- Refining Therapy with Plasma Exchange and Glucocorticoids. N Engl J Med. 2020; 382:671-673. DOI: 10.1056/NEJMe1917490

High-molecular weight hyaluronan attenuates tubulointerstitial scarring in kidney injury.

Renal fibrosis features exaggerated inflammation, extracellular matrix (ECM) deposition, and peritubular capillary loss. We previously showed that IL-10 stimulates high-molecular weight hyaluronan (HMW-HA) expression by fibroblasts, and we hypothesize that HMW-HA attenuates renal fibrosis by reducing inflammation and ECM remodeling. We studied the effects of IL-10 overexpression on HA production and scarring in mouse models of unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) to investigate whether IL-10 antifibrotic effects are HA dependent. C57BL/6J mice were fed with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU), before UUO. We observed that in vivo injury increased intratubular spaces, ECM deposition, and HA expression at day 7 and onward. IL-10 overexpression reduced renal fibrosis in both models, promoted HMW-HA synthesis and stability in UUO, and regulated cell proliferation in I/R. 4-MU inhibited IL-10-driven antifibrotic effects, indicating that HMW-HA is necessary for cytokine-mediated reduction of fibrosis. We also found that IL-10 induces in vitro HMW-HA production by renal fibroblasts via STAT3-dependent upregulation of HA synthase 2. We propose that IL-10-induced HMW-HA synthesis plays cytoprotective and antifibrotic roles in kidney injury, thereby revealing an effective strategy to attenuate renal fibrosis in obstructive and ischemic pathologies.

MO039THE 24-WEEK INTERIM ANALYSIS RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II STUDY OF ATACICEPT IN PATIENTS WITH IGA NEPHROPATHY AND PERSISTENT PROTEINURIA

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Despite being described over 50 years ago, there remains no approved therapy for this common global cause of kidney failure. The central pathogenic feature in IgAN is the formation of circulating IgA containing immune complexes which have the propensity to deposit in the kidneys and trigger glomerular inflammation and tubulointerstitial scarring. The primary substrate for immune complex formation is an excess of poorly O-galactosylated polymeric IgA1 (Gd-IgA1) in the circulation. These IgA1 O-glycoforms are thought to trigger the formation of IgA and IgG autoantibodies. Atacicept is a human TACI-Ig fusion protein that inhibits B cell-stimulating factors, BLyS and APRIL, and has been associated with reductions in levels of serum IgA and IgG, as well as reductions in mature B cells and plasma cells. A number of studies have shown elevated levels of BLyS, APRIL and Gd-IgA1 in IgAN patients which have been linked to worse clinical outcomes. IgAN patients with persistent proteinuria &amp;gt;1 g/day are at increased risk of progression to end-stage renal disease. This Phase II study examines the safety and efficacy of atacicept in reducing pathogenic Gd-IgA1 levels and measures of renal activity in IgAN. Method This Phase II study (NCT02808429) enrolled patients with IgAN and proteinuria ≥1 g/day or 0.75 mg/mg on 24-hour urine protein-creatinine ratio (UPCR) despite maximal standard of care therapy (angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker). Enrolled patients were randomized 1:1:1 to receive placebo or atacicept 25mg or 75mg once weekly by subcutaneous injection. The primary endpoint was a change in proteinuria by 24-hour UPCR at Week 48; key secondary endpoints included change in eGFR, serum immunoglobulin and Gd-IgA1 levels. Results Data from the 24-week interim analysis are reported here for enrolled patients (placebo=5; atacicept 25mg=6; atacicept 75mg=5). A consistent, dose-dependent reduction in serum immunoglobulins (IgA, IgG and IgM) and, in particular, Gd-IgA1 (Figure) were observed through Week 24. In parallel, proteinuria (24-hour UPCR) showed a higher median % reduction from baseline with atacicept at Week 24: -18.67% and -25.34% with atacicept 25 mg and 75 mg, respectively, vs +0.098% with placebo (Figure). eGFR remained stable over time. TEAEs were reported by 81% of the subjects. TEAEs were mild or moderate in severity, with no severe TEAEs reported. No serious related events, events with severe hypogammaglobulinemia or fatal outcome were reported. Conclusion These 24-week interim analysis results provide early proof of concept for the potential treatment of atacicept in patients with IgAN and persistent proteinuria.

Biomarkers of Chronic Renal Tubulointerstitial Injury.

Progression of renal parenchyma injury is characterized by increasing interstitial fibrosis and tubular atrophy, irrespective of the cause. Histopathologic assessment of renal tissue obtained by biopsy remains the gold standard for determining the presence and extent of tubulointerstitial scarring. Discovery of robust non-invasive means for capturing a snapshot and for longitudinal monitoring of parenchymal deterioration has been the focus of intense multimodal effort by investigators within the renal community and beyond. Research in this field has included the use of in vitro and in vivo experimental models and has fostered the development and evaluation of tissue and biofluid assays for novel analytes with potential translation to the diagnosis and prognosis of kidney disease. Here, we examine recent advances in the search of "biomarkers" for detection of renal tubulointerstitial scarring and prediction of renal outcome in human renal disease.

Nicousamide attenuates renal dysfunction and glomerular injury in remnant kidneys by inhibiting TGF-β1 internalisation and renin activity

Nicousamide has been shown to exert renal protective effects against diabetic nephropathy and has moved to a phase II clinical trial in China for diabetic nephropathy indication. To expand its clinical indications, 5/6-nephrectomised rats were used to mimic glomerular and vascular sclerosis and tubulointerstitial scarring, with subsequent progression towards end-stage renal disease. Adult Wistar rats underwent 5/6 nephrectomy to induce the development of chronic kidney disease, with a sham operation performed as a control. The nephrectomised animals were treated orally with either saline, nicousamide (7.5,15, or 45 mg/kg), benazepril (4 mg/kg), or losartan (10 mg/kg) daily for 20 weeks. At 8, 16, and 20 weeks of treatment, blood pressure was measured in each animal, and blood and urine samples were collected for biochemical analysis, while kidney remnants were collected for histological examination. Levels of fibronectin and transforming growth factor beta 1 (TGF-β1) were measured in kidneys by immunohistochemistry. Renin activity in the plasma was measured by an enzyme-linked immunosorbent assay. The results showed that nicousamide treatment significantly reduced systemic hypertension, proteinuria, and blood urea nitrogen (P < 0.05), effectively alleviated glomerular sclerosis scores and tubulointerstitial injuries in a dose-dependent manner (P < 0.01), and markedly decreased fibronectin and TGF-β1 levels in kidney tissues of the 5/6-nephrectomised animals. In vitro studies suggested that nicousamide could moderately inhibit the renin activity and strongly block the TGF-β1 internalisation into fibroblast cells. In summary, nicousamide may protect from renal failure through dual targeting, which involves a TGF-β1-dependent mechanism and inhibition of renin activity.