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Autoimmunity against the Goodpasture antigen [alpha]3IV-NC1 results in antiglomerular basement membrane glomerulonephritis. Although antibodies are central to the pathogenesis, there is good evidence for the participation of T cells in this disease. To define the contribution of T cells, we used the model of experimental autoimmune glomerulonephritis. Immunization of DBA/1 mice with [alpha]3IV-NC1 resulted in proteinuria, a biphasic course of the disease, and an eventual loss of kidney function. In the initial phase, the mice developed an [alpha]3IV-NC1-specific IgG response, had IgG deposition along the glomerular basement membrane, and steadily increased proteinuria, but only marginal signs of inflammation with limited leukocyte infiltration. After 9-13 weeks, mice proceeded to develop crescentic glomerulonephritis, extensive tubulointerstitial damage, and massive macrophage infiltration. T-cell infiltration was less pronounced, mostly confined to the interstitium, and T cells displayed an activated phenotype with a significant fraction of Th1 or Th17 CD4(+) T cells. Close examination revealed the presence of autoreactive T cells producing IFN[gamma] upon restimulation with [alpha]3IV-NC1. Thus, our results suggest that accumulation of effector T cells, including autoreactive T cells, represents a critical step in the progression from mild glomerulonephritis, with limited glomerular damage, to severe crescentic glomerulonephritis accompanied by tubulointerstitial inflammation and loss of kidney function. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sirolimus has been promoted as an agent to provide immunosuppression for kidney transplant recipients that, in contrast to calcineurin inhibitors, would not be nephrotoxic. However, several reports have observed proteinuria in patients treated with sirolimus, ranging from low grade to nephrotic range. Accordingly, we compared markers of tubular and glomerular damage in an ancillary study of a randomized trial comparing sirolimus and cyclosporine. STUDY DESIGN: Single-center, open-label, randomized, prospective trial. SETTING & PARTICIPANTS: Patients undergoing cadaveric or living donor kidney transplant at the University Hospital in Basel, Switzerland, between January 2001 and July 2004. INTERVENTION: Immunosuppression regimen consisting of cyclosporine, mycophenolate mofetil, and prednisone versus sirolimus, mycophenolate mofetil, and prednisone. OUTCOMES: The primary outcome was kidney function, assessed using serum creatinine level. Secondary outcomes included patient and graft survival, number of rejections, and evidence of kidney damage, assessed using glomerular and tubular urine biomarker levels. MEASUREMENTS: Urine and serum were collected at 0, 7, 30, and 90 days. Kidney function was estimated using serum creatinine level. Urinary markers included alpha(1)-microglobulin and retinol-binding protein (tubular), transferrin and albumin (glomerular), and semiquantitative assessment of glucosuria. Protocol kidney biopsies were performed at days 90 and 180. RESULTS: There were 63 patients randomly assigned to cyclosporine-based regimens, and 64, to sirolimus-based regimens. Kidney function was similar in both groups, whereas levels of markers associated with glomerular damage (albumin, 19.5 vs 8.96 mg/mmol creatinine; P < 0.001; transferrin, 13.1 vs 5.7 mg/mmol creatinine; P < 0.001) and those associated with tubular damage (alpha(1)-microglobulin, 11 vs 7.6 mg/mmol creatinine; P = 0.004; retinol-binding protein, 19.6 vs 9.6 mg/mmol creatinine; P = 0.002) were higher beginning at day 7 in patients randomly assigned to sirolimus therapy, with similar findings through day 90. Glucosuria incidence was higher in patients randomly assigned to sirolimus therapy beginning by day 30 (65% vs 30% on day 30; P = 0.002; 51% vs 22% on day 90; P < 0.001). On histologic examination, the overall severity of tubular lesions was significantly higher in patients randomly assigned to sirolimus therapy. LIMITATIONS: Small sample size, short-term follow-up likely insufficient to appreciate calcineurin-associated nephropathy. CONCLUSION: Compared with a cyclosporine-based immunosuppression regimen, a sirolimus-based regimen is associated with de novo low-grade glomerular proteinuria, increased excretion of markers associated with tubular damage, and evidence of tubular damage on kidney biopsy. [ABSTRACT FROM AUTHOR]

Fibronectin glomerulopathy (FG) is caused by fibronectin 1 ( FN1 ) gene mutations. A renal biopsy was performed on a 4-year-old girl with incidentally discovered proteinuria (150 mg/dL); her family history of renal disease was negative. Markedly enlarged glomeruli (mean glomerular diameter: 196 μm; age-matched controls: 140 μm), α-SMA-positive and Ki-67-positive mesangial cell proliferation (glomerular proliferation index 1.76), the mild expansion of mesangial areas, no immune or electron-dense deposits, normal glomerular basement membrane, and diffusely effaced foot processes were observed. Genetic testing identified a de novo heterozygous mutation (Gly417Val) in the collagen-binding site of the FN II-2 domain, prompting fibronectin immunostaining. Strong mesangial positivity was noted, hence FG was diagnosed. The follow-up period of 29 months revealed nephrotic range proteinuria, intermittent microhematuria, glomerular hyperfiltration, and preserved renal function. The biopsy features of early childhood-onset FG were compared to a case of FG with a lobular pattern diagnosed in a 44-year-old patient with undulating proteinuria, microhematuria, hypertension known for a year, and a positive family history. Early childhood-onset FG was characterized by glomerular enlargement, mesangial proliferation, and no changes that suggested fibronectin deposition disease. In summary, the novel aspects of the case were that the mutation was located at the collagen-binding site of the FN1 gene, not identified earlier, and the histologic spectrum of FG was expanded by the observed mesangial proliferative pattern and striking glomerulomegaly. Now, FG should also be considered among the monogenic causes of proteinuric kidney diseases in pediatric nephrology practice.

Fermentation is critical for producing high-quality cocoa, yet its kinetics and resulting chemical and sensory outcomes are poorly understood and thus difficult to manage. Cocoa sweatings (CS), the liquid runoff produced early during fermentation and typically drained off, may beneficially affect fermentation outcome when added back into the fermenting mass. Here, we report how back-addition of CS affects composition and sensory perception of roasted cocoa liquor after 5, 6, and 7 days of fermentation. Cocoa liquor (= 100% chocolate) made from beans fermented for 5 days with the addition of CS were similar in sensory perception to those fermented for 7 days without added CS. Twenty-one flavor compounds showed similar patterns to the sensory results: In the beans fermented with CS, these compounds remained at similar levels after 5, 6, and 7 days of fermentation, while the same compounds significantly changed in the samples fermented conventionally, without CS addition. These results suggest a link between changes in flavor composition and sensory differences in roasted cocoa. Future work is needed to reveal the mechanism of flavor stabilization throughout fermentation resulting from the back-addition of CS. PRACTICAL APPLICATION: Roasted cocoa liquor fermented with cocoa sweating (CS) is sensorily similar when fermented for 5 or 7 days and produces cocoa that is sensorily similar to traditionally fermented cocoa in shorter time (5 days vs. 7 days). The addition of CS seems to stabilize 21 flavor compounds throughout fermentation mimicking changes in sensory perception. The back-addition of CS could help standardize cocoa fermentation as indicated by more consistent temperature evolution., (© 2024 The Author(s). Journal of Food Science published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.)

Several molecular mismatch assessment approaches exist, but data on their combined use are limited. In this study, we aimed to define distinct risk groups for rejection based on the combination of three molecular mismatch assessment approaches (i.e., eplet mismatch count, the number of highly immunogenic eplets and PIRCHE-II score) in 439 consecutive immunological standard risk transplantations. For each molecular mismatch assessment approach, ROC analyses were used to define cut-offs for prediction of (sub) clinical rejection according to Banff 2019 classification within the first year post-transplant as a reference. If all three scores were below the cut-off, the patient was assigned to the low-risk group (19% of patients); if all three scores were above the cut-off, the patient was assigned to the high-risk group (21% of patients). The one-year incidence of (sub) clinical rejection was 12% in the low-risk group and 33% in the high-risk group (p = 0.003). Internal validation of the assigned risk groups for prediction of other outcomes revealed a high consistency: clinical rejection (6% vs. 24%; p = 0.004), ATG-treated rejection (1% vs. 16%; p < 0.001) and development of de novo HLA-DSA at 5 years post-transplant (6% vs. 25%; p = 0.003). The molecular mismatch risk group was an independent predictor for (sub) clinical rejection (high-risk vs. low-risk: hazard ratio 3.11 [95%-CI 1.50-6.45]; p = 0.002). We conclude that combining molecular mismatch approaches allows us to distinguish low- and high-risk groups among standard renal allograft recipients. Independent validation in other patient populations and different ethnicities is required., (© 2024 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Background: Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection., Methods: We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes (FCGR3AV/F158 [rs396991], KLRC2wt/del, KLRK1HNK/LNK [rs1049174], and rs9916629-C/T)., Results: MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P = 0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P = 0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P = 0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI, 0.89-4.37; P = 0.097), without influence on estimated glomerular filtration trajectories. FCGR3A variants were associated with MVI only in patients with preformed and/or de novo donor-specific antibodies (OR 4.14; 95% CI, 0.99-17.47; P = 0.052)., Conclusions: Missing self and NK-cell genetics may contribute to MVI, underscoring the important role of NK cells in transplant rejection., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)