Urine metabolomics links dysregulation of the tryptophan-kynurenine pathway to inflammation and severity of COVID-19.

SARS-CoV-2 causes major disturbances in serum metabolite levels, associated with severity of the immune response. Despite the numerous advantages of urine for biomarker discovery, the potential association between urine metabolites and disease severity has not been investigated in coronavirus disease 2019 (COVID-19). In a proof-of-concept study, we performed quantitative urine metabolomics in patients hospitalized with COVID-19 and controls using LC-MS/MS. We assessed whether metabolites alterations were associated with COVID-19, disease severity, and inflammation. The study included 56 patients hospitalized with COVID-19 (26 non-critical and 30 critical disease); 16 healthy controls; and 3 controls with proximal tubule dysfunction unrelated to SARS-CoV-2. Metabolomic profiling revealed a major urinary increase of tryptophan metabolites kynurenine (P < 0.001), 3-hydroxykynurenine (P < 0.001) and 3-hydroxyanthranilate (P < 0.001) in SARS-CoV-2 infected patients. Urine levels of kynurenines were associated with disease severity and systemic inflammation (kynurenine, r 0.43, P = 0.001; 3-hydroxykynurenine, r 0.44, P < 0.001). Increased urinary levels of neutral amino acids and imino acid proline were also common in COVID-19, suggesting specific transport defects. Urine metabolomics identified major alterations in the tryptophan-kynurenine pathway, consistent with changes in host metabolism during SARS-CoV-2 infection. The association between increased urinary levels of kynurenines, inflammation and COVID-19 severity supports further evaluation of these easily available biomarkers.

Idiopathic nephrotic syndrome relapse following COVID-19 vaccination: a series of 25 cases.

Background: Several cases of idiopathic nephrotic syndrome (INS) relapse following the administration of coronavirus disease 2019 (COVID-19) vaccines have recently been reported, raising questions about the potential relationship between the immune response to COVID-19 vaccination and INS pathogenesis. Methods: We performed a retrospective multicentre survey describing the clinical and biological characteristics of patients presenting a relapse of INS after COVID-19 vaccination, with an assessment of outcome under treatment. Results: We identified 25 patients (16 men and 9 women) presenting a relapse within 1 month of a COVID-19 vaccine injection. The glomerular disease was of childhood onset in half of the patients and most patients (21/25) had received at least one immunosuppressive drug in addition to steroids for frequently relapsing or steroid-dependent nephrotic syndrome (NS). All patients were in a stable condition at the time of injection and 11 had no specific treatment. In five patients, the last relapse was reported >5 years before vaccine injection. The Pfizer-BioNTech (BNT162b2) vaccine was used in 80% of the patients. In 18 cases, INS relapse occurred after the first injection, a mean of 17.5 days after vaccination. A second injection was nevertheless administered in 14 of these patients. Five relapses occurred after administration of the second dose and two relapses after the administration of the third dose. All but one of the patients received steroids as first-line treatment, with an additional immunosuppressive agent in nine cases. During follow-up, complete remission was achieved in 21 patients, within 1 month in 17 cases. Only one patient had not achieved at least partial remission after 3 months of follow-up. Conclusions: This case series suggests that, in rare patients, COVID-19 vaccination may trigger INS relapse that is generally easy to control. These findings should encourage physicians to persuade their patients to complete the COVID-19 vaccination schedule.

Idiopathic nephrotic syndrome relapse following SARS-CoV-2 vaccination: a series of 25 cases

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Nephrogenic Diabetes Insipidus following an Off-Label Administration of Sevoflurane for Prolonged Sedation in a COVID-19 Patient and Possible Influence on Aquaporin-2 Renal Expression.

During the recent COVID-19 pandemic, the rapidly progressive shortage of intravenous sedative drugs led numerous intensive care units to look for potential alternatives in patients requiring mechanical ventilation for severe acute respiratory distress syndrome (ARDS). Inhalational sedation using the AnaConDa® device for sevoflurane administration is a possible option. In a 54-year-old COVID-19 patient with severe ARDS requiring extracorporeal membranous oxygenation (ECMO), sevoflurane on AnaConDa® device was administered for 8 days but was complicated by the development of nephrogenic diabetes insipidus (NDI). Other causes of NDI or central diabetes insipidus were reasonably excluded, as in other previously published cases of NDI in ICU patients receiving prolonged sevoflurane-based sedation. In addition, the postmortem examination suggested a lower expression of aquaporin-2 in renal tubules. This observation should prompt further investigations to elucidate the role of aquaporin-2 in sevoflurane-related NDI. Inhaled isoflurane sedation is a possible alternative.

Serum uric acid, disease severity and outcomes in COVID-19.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) is highly variable between individuals, ranging from asymptomatic infection to critical disease with acute respiratory distress syndrome requiring mechanical ventilation. Such variability stresses the need for novel biomarkers associated with disease outcome. As SARS-CoV-2 infection causes a kidney proximal tubule dysfunction with urinary loss of uric acid, we hypothesized that low serum levels of uric acid (hypouricemia) may be associated with severity and outcome of COVID-19. METHODS: In a retrospective study using two independent cohorts, we investigated and validated the prevalence, kinetics and clinical correlates of hypouricemia among patients hospitalized with COVID-19 to a large academic hospital in Brussels, Belgium. Survival analyses using Cox regression and a competing risk approach assessed the time to mechanical ventilation and/or death. Confocal microscopy assessed the expression of urate transporter URAT1 in kidney proximal tubule cells from patients who died from COVID-19. RESULTS: The discovery and validation cohorts included 192 and 325 patients hospitalized with COVID-19, respectively. Out of the 517 patients, 274 (53%) had severe and 92 (18%) critical COVID-19. In both cohorts, the prevalence of hypouricemia increased from 6% upon admission to 20% within the first days of hospitalization for COVID-19, contrasting with a very rare occurrence (< 1%) before hospitalization for COVID-19. During a median (interquartile range) follow-up of 148 days (50-168), 61 (12%) patients required mechanical ventilation and 93 (18%) died. In both cohorts considered separately and in pooled analyses, low serum levels of uric acid were strongly associated with disease severity (linear trend, P < 0.001) and with progression to death and respiratory failure requiring mechanical ventilation in Cox (adjusted hazard ratio 5.3, 95% confidence interval 3.6-7.8, P < 0.001) or competing risks (adjusted hazard ratio 20.8, 95% confidence interval 10.4-41.4, P < 0.001) models. At the structural level, kidneys from patients with COVID-19 showed a major reduction in urate transporter URAT1 expression in the brush border of proximal tubules. CONCLUSIONS: Among patients with COVID-19 requiring hospitalization, low serum levels of uric acid are common and associate with disease severity and with progression to respiratory failure requiring invasive mechanical ventilation.

ISPD recommendations for the evaluation of peritoneal membrane dysfunction in adults: Classification, measurement, interpretation and rationale for intervention.

GUIDELINE 1: A pathophysiological taxonomy: A pathophysiological classification of membrane dysfunction, which provides mechanistic links to functional characteristics, should be used when prescribing individualized dialysis or when planning modality transfer (e.g. to automated peritoneal dialysis (PD) or haemodialysis) in the context of shared and informed decision-making with the person on PD, taking individual circumstances and treatment goals into account. (practice point). GUIDELINE 2A: Identification of fast peritoneal solute transfer rate (PSTR): It is recommended that the PSTR is determined from a 4-h peritoneal equilibration test (PET), using either 2.5%/2.27% or 4.25%/3.86% dextrose/glucose concentration and creatinine as the index solute. (practice point) This should be done early in the course dialysis treatment (between 6 weeks and 12 weeks) (GRADE 1A) and subsequently when clinically indicated. (practice point). GUIDELINE 2B: Clinical implications and mitigation of fast solute transfer: A faster PSTR is associated with lower survival on PD. (GRADE 1A) This risk is in part due to the lower ultrafiltration (UF) and increased net fluid reabsorption that occurs when the PSTR is above the average value. The resulting lower net UF can be avoided by shortening glucose-based exchanges, using a polyglucose solution (icodextrin), and/or prescribing higher glucose concentrations. (GRADE 1A) Compared to glucose, use of icodextrin can translate into improved fluid status and fewer episodes of fluid overload. (GRADE 1A) Use of automated PD and icodextrin may mitigate the mortality risk associated with fast PSTR. (practice point). GUIDELINE 3: Recognizing low UF capacity: This is easy to measure and a valuable screening test. Insufficient UF should be suspected when either (a) the net UF from a 4-h PET is <400 ml (3.86% glucose/4.25% dextrose) or <100 ml (2.27% glucose /2.5% dextrose), (GRADE 1B) and/or (b) the daily UF is insufficient to maintain adequate fluid status. (practice point) Besides membrane dysfunction, low UF capacity can also result from mechanical problems, leaks or increased fluid absorption across the peritoneal membrane not explained by fast PSTR. GUIDELINE 4A: Diagnosing intrinsic membrane dysfunction (manifesting as low osmotic conductance to glucose) as a cause of UF insufficiency: When insufficient UF is suspected, the 4-h PET should be supplemented by measurement of the sodium dip at 1 h using a 3.86% glucose/4.25% dextrose exchange for diagnostic purposes. A sodium dip ≤5 mmol/L and/or a sodium sieving ratio ≤0.03 at 1 h indicates UF insufficiency. (GRADE 2B). GUIDELINE 4B: Clinical implications of intrinsic membrane dysfunction (de novo or acquired): in the absence of residual kidney function, this is likely to necessitate the use of hypertonic glucose exchanges and possible transfer to haemodialysis. Acquired membrane injury, especially in the context of prolonged time on treatment, should prompt discussions about the risk of encapsulating peritoneal sclerosis. (practice point). GUIDELINE 5: Additional membrane function tests: measures of peritoneal protein loss, intraperitoneal pressure and more complex tests that estimate osmotic conductance and 'lymphatic' reabsorption are not recommended for routine clinical practice but remain valuable research methods. (practice point). GUIDELINE 6: Socioeconomic considerations: When resource constraints prevent the use of routine tests, consideration of membrane function should still be part of the clinical management and may be inferred from the daily UF in response to the prescription. (practice point).

Absence of SARS-CoV-2 in the effluent of peritoneal dialysis patients.

The pandemic of respiratory disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is life-threatening in peritoneal dialysis (PD) patients. In PD patients with systemic viral infections, peritoneal effluent may be theoretically contaminated. We searched for the presence of SARS-CoV-2 genetic material by real-time reverse transcriptase-polymerase chain reaction assays in serial PD effluents of three PD infected patients. Nasopharyngeal swabs obtained at admission showed high viral load in all three patients, whereas none of the PD effluent specimen tested positive, even after dialysate concentration. Those results support at most a very low SARS-CoV-2 dissemination risk by the peritoneal effluent of PD patients. Imposing special disposal procedures, such as the instillation of hypochlorite in the drainage bags to prevent viral spread to health-care workers, are probably not required.

SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.

Coronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). None of the patients had normoglycemic glucosuria. Proximal tubule dysfunction was independent of pre-existing comorbidities, glomerular proteinuria, nephrotoxic medications or viral load. At the structural level, kidneys from patients with COVID-19 showed prominent tubular injury, including in the initial part of the proximal tubule, with brush border loss, acute tubular necrosis, intraluminal debris, and a marked decrease in the expression of megalin in the brush border. Transmission electron microscopy identified particles resembling coronaviruses in vacuoles or cisternae of the endoplasmic reticulum in proximal tubule cells. Among features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with disease severity and with a significant increase in the risk of respiratory failure requiring invasive mechanical ventilation using Cox (adjusted hazard ratio 6.2, 95% CI 1.9-20.1) or competing risks (adjusted sub-distribution hazard ratio 12.1, 95% CI 2.7-55.4) survival models. Thus, our data establish that SARS-CoV-2 causes specific manifestations of proximal tubule dysfunction and provide novel insights into COVID-19 severity and outcome.