Waldenström macroglobulinemia is a rare low-grade hematologic malignancy due to clonal proliferation of B lymphocytes responsible for immunoglobulin M (IgM) monoclonal gammopathy secreted in serum. ...This disease is characterized by lymphoplasmacytic tumoral infiltration of bone marrow and various organs, especially the liver and spleen. Kidney involvement in Waldenström macroglobulinemia has been described previously with reports of various forms of glomerular injury: large intracapillary IgM pseudothrombi, cryoglobulinemia-associated membranoproliferative glomerulonephritis, or amyloidosis. Interstitial infiltration by tumoral B lymphocytes is another classic pattern. Conversely, tubular involvement in the form of myeloma-like casts or basement membrane deposition of monoclonal light chain (light-chain deposition disease) is unusual. We report the occurrence of cast nephropathy associated with light-chain deposition disease in 2 patients with Waldenström macroglobulinemia, which resulted in severe and prolonged kidney failure.
Acute organ injury, such as acute kidney injury (AKI) and disease (AKD), are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function ...but the impact of asymptomatic HU on the different phases of AKI/AKD is incompletely understood. We hypothesized that asymptomatic HU would attenuate AKD because soluble, in contrast to crystalline, uric acid (sUA) can attenuate sterile inflammation. In vitro, 10 mg/dL sUA decreased reactive oxygen species and interleukin-6 production in macrophages, while enhancing fatty acid oxidation as compared with a physiological concentration of 5 mg/dL sUA or medium. In transgenic mice, asymptomatic HU of 7-10 mg/dL did not affect post-ischemic AKI/AKD but accelerated the recovery of kidney excretory function on day 14. Improved functional outcome was associated with better tubular integrity, less peritubular inflammation, and interstitial fibrosis. Mechanistic studies suggested that HU shifted macrophage polarization towards an anti-inflammatory M2-like phenotype characterized by expression of anti-oxidative and metabolic genes as compared with post-ischemic AKI-chronic kidney disease transition in mice without HU. Our data imply that asymptomatic HU acts as anti-oxidant on macrophages and tubular epithelial cells, which endorses the recovery of kidney function and structure upon AKI.
Aims
SALL4 is a marker of germ cell tumours. The aim of this study was to investigate SALL4 expression in blastemal tumours, particularly in hepatoblastoma.
Methods and results
The study included 12 ...hepatoblastomas. Eight hepatoblastomas were pure epithelial tumours, and four were mixed epithelial and mesenchymal tumours. The patients were nine males and three females with a mean age of 14.6 months. Immunohistochemistry was performed with an antibody against SALL4, using an automated immunostainer. Seven of 12 hepatoblastomas showed nuclear staining only in the embryonal component. Fetal and mesenchymal components were negative.
Conclusions
SALL4 is expressed in blastemal tumours, particularly in the embryonal subtype of hepatoblastoma. Pathologists need to be aware of such expression so that misdiagnosis can be avoided.
In clinical practice, the diagnosis of alcohol-associated hepatitis (AH) is mostly based on non-invasive criteria, which were defined at a consensus conference by the National Institute on Alcohol ...Abuse and Alcoholism (NIAAA). These criteria were recently modified by adding C-reactive protein (CRP) and termed NIAAAm-CRP criteria, which showed superior diagnostic accuracy for presence of alcohol-associated steatohepatitis (ASH) on liver histology. The aim of our study was to validate the diagnostic accuracy of both original NIAAA criteria and NIAAAm-CRP criteria for presence of ASH on liver histology in an independent cohort.
Data from a large multinational cohort of 445 patients with alcohol-associated liver disease (ALD) that served to establish a novel grading and staging system of alcohol-associated liver disease were analyzed retrospectively. Diagnosis of ASH was based on presence of hepatocyte ballooning plus lobular neutrophil infiltration and established in virtual consensus meetings of multiple expert liver pathologists.
Complete data including CRP values were available in 346 patients. Overall diagnostic accuracy for prediction of ASH was 73% for NIAAA criteria and 77% for NIAAAm-CRP criteria. In a subgroup with suspected severe AH (MELD >20, n = 123), overall diagnostic accuracy for prediction of ASH was 69% for NIAAA criteria and 74% for NIAAAm-CRP criteria.
Our findings confirm recent data on suboptimal diagnostic accuracy of original NIAAA criteria and validate slightly better but still suboptimal performance of NIAAAm-CRP criteria for presence of ASH.
Alcohol-associated steatohepatitis (ASH) is diagnosed on liver histology but liver biopsy is not always feasible. Non-invasive diagnosis based on clinical findings has been proposed using the National Institute on Alcohol Abuse and Alcoholism (NIAAA) criteria and recently improved using NIAAAm-CRP criteria. Our findings validate slightly better but still suboptimal performance of NIAAAm-CRP criteria for the presence of histological ASH. Clinical trials of novel drugs should focus on histologically proven ASH.
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•Alcohol-associated steatohepatitis is defined by histology, but biopsy is not always feasible.•Non-invasive criteria for probable alcohol-associated hepatitis were proposed at a NIAAA consensus conference.•A recent study developed modified NIAAAm-CRP criteria with improved yet suboptimal accuracy.•In the present study we validate slightly superior but still suboptimal diagnostic accuracy of the new NIAAAm-CRP criteria.
Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated ...steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers.
Liver biopsies, collected within an 8 h-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers.
Herein, we provide a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ signaling were predicted as important contributors to altered rhythmicity.
MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained.
This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy collection was known, we show that time-of-day variations observed in histologically normal livers are gradually perturbed in liver steatosis and metabolic dysfunction-associated steatohepatitis. Importantly, these observations, albeit obtained across a restricted time window, provide further support for preclinical studies demonstrating alterations of rhythmic patterns in diseased livers. On a practical note, this study indicates the importance of considering time-of-day as a critical biological variable which may significantly affect data interpretation in animal and human studies of liver diseases.
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•Temporal patterns in mRNA transcripts and metabolites are observed in the human liver.•Time-of-day-dependent patterns are lost or gained in human steatotic and MASH livers.•Core clock gene expression is resilient to disease progression.•Time-of-day variations in lipid and amino acid metabolites are most significant.
Background
Sodium lactate seemed to improve fluid balance and avoid fluid overload. The objective of this study was to determine if these beneficial effects can be at least partly explained by an ...improvement in disseminated intravascular coagulation (DIC)-associated renal microvascular thrombosis.
Methods
Ancillary work of an interventional randomized open label controlled experimental study. Fifteen female “Large White” pigs (2 months old) were challenged with intravenous infusion of
E. coli
endotoxin. Three groups of five animals were randomly assigned to receive different fluids: a treatment group received sodium lactate 11.2% (SL group); an isotonic control group received 0.9% NaCl (NC group); a hypertonic control group, with the same amount of osmoles and sodium than SL group, received sodium bicarbonate 8.4% (SB group). Glomerular filtration rate (GFR) markers, coagulation and inflammation parameters were measured over a 5-h period. Immediately after euthanasia, kidneys were withdrawn for histological study. Statistical analysis was performed with nonparametric tests and the Dunn correction for multiple comparisons. A
p
< 0.05 was considered significant.
Results
The direct immunofluorescence study revealed that the percentage of capillary sections thrombosed in glomerulus were significantly lesser in SL group 5 (0–28) % compared to NC 64 (43–79) %,
p
= 0.01 and SB 64 (43–79),
p
= 0.03 groups. Alterations in platelet count and fibrinogen level occurred earlier and were significantly more pronounced in both control groups compared to SL group (
p
< 0.05 at 210 and 300 min). The increase in thrombin–antithrombin complexes was significantly higher in NC 754 (367–945) μg/mL;
p
= 0.03 and SB 463 (249–592) μg/mL;
p
= 0.03 groups than in SL group 176 (37–265) μg/mL. At the end of the experiment, creatinine clearance was significantly higher in SL group 55.46 (30.07–67.85) mL/min compared to NC group 1.52 (0.17–27.67) mL/min,
p
= 0.03.
Conclusions
In this study, we report that sodium lactate improves DIC-associated renal microvascular thrombosis and preserves GFR. These findings could at least partly explain the better fluid balance observed with sodium lactate infusion.
The pharmacokinetic variability of tacrolimus can be partly explained by CYP3A5 activity. Our objective was to evaluate a tacrolimus sparing policy on renal graft outcome according to CYP3A5 6986A>G ...genetic polymorphism. This retrospective study included 1114 recipients with a median follow-up of 6.3 years. Genotyping of the 6986A>G allelic variant corresponding to CYP3A5*3 was systematically performed. One year after transplantation, tacrolimus blood trough concentration (C0) target range was 5–7 ng/mL. However, daily dose was capped to 0.10 mg/kg/day regardless of the CYP3A5 genotype. A total 208 CYP3A5*1/- patients were included. Despite a higher daily dose, CYP3A5*1/- recipients exhibited lower C0 during follow-up (p < 0.01). Multivariate analysis did not show any significant influence of CYP3A5*1/- genotype (HR = 0.70, 0.46–1.07, p = 0.10) on patient-graft survival. Glomerular Filtration Rate (GFR) decline was significantly lower for the CYP3A5*1/- group (p = 0.02). The CYP3A5*1/- genotype did not significantly impact the risk of biopsy-proven acute rejection (BPAR) (HR = 1.01, 0.68–1.49, p = 0.97) despite significantly lower C0. Based on our experience, a strategy of tacrolimus capping is associated with a better GFR evolution in CYP3A5*1/- recipients without any significant increase of BPAR incidence. Our study raised some issues about specific therapeutic tacrolimus C0 targets for CYP3A5*1/- patients and suggests to set up randomized control studies in this specific population.
Abstract
Background and Aims
Membranous nephropathy (MN) is a frequent cause of nephrotic syndrome of non-diabetic origin in adults, and a leading cause of end stage renal disease. Its origin is ...primary in up to 80% of cases but can also be secondary to underlying diseases such as cancer, lupus or other systemic disease, infections or drugs. Important recent advances have been made in our understanding of primary MN physiopathology with the identification of various antibodies such as PLA2R, THSD7A, Exostosin 1,2 suggesting autoimmunity. However, distinction between primary and secondary MN remains difficult and can lead to numerous and expensive complementary exams and postpone treatment. Some authors (Cambier, Ronco, CJASN 2012) proposed an algorithm based on histological and biological features in order to distinguish primary from secondary MN. Yet this algorithm has never been tested. The main objective of our study was to evaluate the efficiency of a combined histological and biological criterion in order to establish the diagnosis of primary MN.
Method
We conducted a pluricentric retrospective cohort study in Northern France. All patients with histological proved membranous nephropathy between January 2010 and December 2016 were included. All kidney biopsies were re-analysed in order to specify the predominant IgG subclass and PLA2R staining. The combined criterion was considered present if: PLA2R was detected (in biopsy or serum), with no endocapillary proliferation and an IgG4 subclass predominance (or co-predominance) on kidney biopsy. The gold standard to diagnose primary MN was the exclusion of other causes of MN after biological and radiological investigation, in particular the absence of cancer detected after at least 2 years of following. We tested the sensitivity, specificity, and predictive values of this combined criterion in order to diagnose primary MN.
Results
173 patients were included. 66 (38.2%) patients were women. At the time of diagnosis mean age was 52.1 years old (SD: 17.4), mean albumine and creatinine were respectively 25.2 g/L (9.02) and 14 mg/L (17.7). Mean protein to creatinine ratio was 5.75 g/g. 119 (68.8%) patients had primary membranous nephropathy. Secondary membranous nephropathy were due to lupus, other auto immune disease and cancer in respectively 25 (14.5%), 14 (8.0%), and 15 (8.0%) cases. 59 patients had a positive combined criterion. Sensitivity of the criterion was: 0.50 95%CI: 0.40-0.59, Specificity was: 0.90 95%CI: 0.80-0.98 compared to a specificity of 0.50 95%CI 0.34-0.54 for single criterion PLa2R on biopsy. Negative predictive value was 0.45 95%CI: 0.31-0.59 and positive predictive value was 0.92 95%CI: 0.84-0.99. Histological features associated with primary membranous nephropathy were: no extracapillary proliferation (p=0.003), presence of PLA2R (p<0.001), IgG4 predominant staining (p<0.001) and low Ig1 staining (2.24 + in secondary MN versus 1.86 + in MN) p=0.011.
Conclusion
Our histological combined criterion had a high specificity: 0.90 95%CI 0.80-0.98 and positive predictive value 0.92 95%CI: 0.84-0.99. Presence of this combined criterion could allow the clinician to reduce the number of complementary analyses and help conclude faster to the primary etiology of the MN.
Abstract
Background and Aims
Acute kidney injury (AKI) and disease (AKD) are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function. ...While there is no doubt that crystalline uric acid (UA) causes acute and chronic UA nephropathy, urolithiasis and kidney stone disease, the pathogenesis of asymptomatic HU in AKI/AKD is incompletely understood. In animal studies, elevated serum UA levels may lead to endothelial dysfunction, renin-angiotensin system activation and oxidative stress. However, such models do not mimic human HU. To overcome this issue, we established a model of AKI/AKD with clinically relevant serum UA levels and hypothesized that asymptomatic HU improves the outcomes after AKI/AKD by restoring metabolic activity and mitochondrial biogenesis in macrophages and tubular epithelial cells.
Method
Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were injected with tamoxifen and placed on a chow diet enriched with inosine. Hyperuricemic mice (serum UA ≥7 mg/dL) and mice without HU (serum UA 4-5 mg/dL) underwent uninephrectomy followed by unilateral ischemia-reperfusion (IR) to induce AKI/AKD. Serum and kidneys were collected on day 3 and 14 after AKI/AKD, and kidney function, tubular injury, inflammation, mitochondrial dysfunction, metabolic activity (fatty acid oxidation) and macrophage infiltration were quantified using GFR measurement, immunohistochemistry, colorimetric assays, electron microscopy, RT-PCR and flow cytometry.
Results
We observed an increase in serum UA levels from 7 to 10 mg/dL in hyperuricemic mice on day 3 after IR-induced AKI/AKD that returned to 7 mg/dL after 14 days (Figure left). While there was no difference in GFR between hyperuricemic and mice without HU with AKI/AKD on day 3, we found an improved kidney function in hyperuricemic mice on day 14 (Figure middle). This was associated with significantly less tubular injury and inflammation as well as an increase in the number of infiltrating anti-inflammatory M2-like macrophages as compared to mice without HU. Intrarenal mRNA expression level of the pro-oxidant heme-oxygenase-1 was reduced in hyperuricemic mice. However, the expression of anti-oxidant enzymes (Nrf-1 and Sod) and metabolic genes associated with fatty acid oxidation (Cpt1, Pparg, and Pgc1b) significantly increased as compared to mice without HU 14 days after AKI/AKD. In addition, HU increased the number of phospho-Histone-3 and intact proximal tubules and restored tubular mitochondrial morphology as indicated by an increased mitochondrial aspect ratio (Figure right).
Conclusion
Our data imply that asymptomatic HU improves kidney outcomes after IR-induced AKI/AKD because HU attenuates tubular injury and inflammation. In addition, we found that HU enhances the metabolic activity and anti-inflammatory M2-like macrophage polarization as well as restores mitochondrial biogenesis in tubular epithelial cells, suggesting that HU acts as antioxidant by improving kidney recovery after AKI/AKD.
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