Evaluation of urinary type IV collagen as a marker of glomerular structural damage in various clinical settings

Einleitung: Kollagen Typ IV ist einer der Hauptbestandteile der glomerulären Basalmembran. Strukturelle Veränderungen der Basalmembran lassen sich bei fibrosierenden Nierenerkrankungen früher als funktionelle Veränderungen nachweisen. Bei Patienten mit diabetischer Nephropathie konnten erhöhte Kollagen IV-Spiegel im Urin gemessen werden bevor eine Mikroalbuminurie auftrat. Die Urin-Kollagen IV-Ausscheidung gilt somit als frühzeitiger Marker für glomeruläre Schäden. In der vorliegenden Studie sollte geprüft werden, ob die Urin-Kollagen IV-Bestimmung eine sinnvolle klinische Methode zum Nachweis einer glomerulären Schädigung bei Patienten mit unterschiedlichen Nierenerkrankungen darstellt. Methoden: In Urinproben von 195 Patienten und gesunden Kontrollpersonen wurden Urin-Kollagen IV-Spiegel, Kreatinin-Clearance, Albumin und Eiweiß sowie die Serum-Kreatinin-Konzentration gemessen. Es wurden Patienten mit bioptisch gesicherten Glomerulonephritiden, arterieller Hypertonie, diabetischer Nephropathie und einer Nierenbeteiligung bei Sepsis untersucht. Die Urin-Kollagen IV-Spiegel wurden mittels eines quantitativen Enzyme-Immuno-Assay (EIA) bestimmt. Ergebnisse: Die Urin-Kollagen Typ IV-Ausscheidung ist signifikant erhöht bei Patienten mit schwerer Infektion, Diabetes mellitus, arterieller Hypertonie und bioptisch gesicherten Glomerulonephritiden verglichen mit gesunden Kontrollen. Eine Korrelation der Kollagen IV-Konzentration im Urin zur Albuminurie lässt sich bei Diabetikern nachweisen. Hier zeigte sich, dass die Korrelation umso höher ausfällt je schlechter das Diabetes mellitus - Stadium ist. Es ergab sich bei den Diabetes mellitus -Patienten keine Korrelation zum HbA1c. Auch bei Patienten mit Hypertonie bei denen bereits eine Nephropathie bestand konnte eine Korrelation zwischen der Kollagen Typ IV-Konzentration und der Albuminurie nachgewiesen werden. Patienten mit schweren Infektionen wiesen eine massiv erhöhte Kollagen Typ IV-Ausscheidung auf, welche aber nicht mit der Albuminurie korrelierte. Allerdings korreliert die Kollagen IV-Ausscheidung bei diesen Patienten mit der CRP-Konzentration im Serum. Bei Patienten mit Glomerulonephritis bestand ebenfalls keine signifikante Korrelation von der Urin-Kollagen Typ IV-Konzentration zur Albuminurie. Patienten, die an einer MCGN erkrankt sind können jedoch dadurch von den anderen Glomerulonephritiden unterschieden werden, da diese eine massiv erhöhte Albumin-Ausscheidung bei nahezu normaler Kollagen Typ IV-Konzentration im Urin aufweisen. Dadurch ergibt sich bei diesen Patienten ein Verhältnis von Albumin- zu Kollagen IV-Konzentration im Urin von ~ 900:1 bei nur sehr gering erhöhten Kollagen IV-Werten. Zusammenfassung: Abschließend kann man sagen, dass die Sensitivität der Kollagen Typ IV-Messung im Urin hoch ist, da die Kollagen IV-Konzentration bei allen Krankheitsgruppen (außer bei Pat mit MCGN) signifikant gegenüber den gesunden Kontrollen erhöht ist. Aus der Höhe der Kollagen IV-Konzentration im Urin kann man allerdings nicht auf ein bestimmte Erkrankung oder ein bestimmtes Stadium einer Erkrankung schließen, so dass der Test aufgrund dieser mangelnden Spezifität keine sinnvolle klinische Methode zur Diagnostik darstellt.Introduction: Microalbuminuria is considered the earliest marker of glomerular changes in various renal diseases. Urinary collagen IV, the major collagenous component of the glomerular basement membrane, has been shown to be an even earlier marker of glomerular injury especially in diabetic nephropathy. The present study was designed to evaluate the clinical usefulness and superiority of urinary collagen IV in patients with different renal injuries. Methods: Urinary collagen IV-levels were assessed by a one-step quantitative sandwich enzyme immunoassay and compared to various clinical parameters (e.g. urinary albumin/ creatinine levels). Urine samples were obtained from a total of 195 patients with different types of glomerulonephritis, arterial hypertension, diabetic nephropathy and renal involvement due to severe infection. Results: Urinary collagen IV-levels were significantly higher in patients with severe infection, diabetes mellitus, hypertension and biopsy proven glomerular diseases than in healthy patients. The urine collagen IV concentration was positively correlated with the albuminuria in patients with diabetic nephropathy. The study demonstrated that the correlation was as higher as worse the diabetic classification was. There was no correlation between the urine collagen IV and the HbA1c seen. The urine collagen IV level in patients with hypertensive nephrosclerosis correlated with the urinary albumin as well. Patients with severe infection showed a massive increased urinary type IV collagen, which did not correlate with the albuminuria. Therefore, it showed a correlation with the serum CRP-concentration In patients with glomerulonephritis we could not detect a significant correlation between the urine collagen type IV concentration and the urinary albumin level. Patients, which suffered from a minimal change GN could be distinguished from the other glomerulonephritis, because the minimal change GN show a massive increased albuminuria and almost normal urinary type IV collagen levels, so that a coefficient from albuminuria to u-collagen IV of ~ 900:1 results. Conclusion: Urinary collagen IV is not a useful marker for glomerular structural damage in a variety of clinical settings. Its elevation could not be related to any specific kidney disease

Lethal pulmonary hemorrhage syndrome due to Leptospira infection transmitted by pet rat

Human infection with Leptospira interrogans can be life-threatening. Multiple organ involvement frequently presents with liver and kidney failure, less commonly including severe hemolysis and pulmonary hemorrhage syndrome. Here, we present a fulminant case of leptospirosis presenting with hemolysis and pulmonary hemorrhage. A formerly healthy 34 year old patient presented to a rural hospital with dyspnea and hemoptysis after a week of influenza-like symptoms. Initial assessment revealed severe sepsis, acute kidney failure and severe hemolysis. Within the next 29 h, a multi-organ failure developed, which could eventually not be reversed despite mechanical ventilation, venovenous extracorporeal membrane oxygenation, continuous renal replacement therapy, plasmapheresis and extracorporeal cytokine absorbent therapy. The diagnosis of leptospirosis was made after the patient died. The transmitting animal was a pet rat. Leptospirosis has to be considered in case of rapid multi-organ failure presenting with pulmonary hemorrhage

Are subpleural consolidations indicators for segmental pulmonary embolism in COVID-19?

Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3- and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application

Obstructive Shock, from Diagnosis to Treatment

Shock is a life threatening pathological condition characterized by inadequate tissue oxygen supply. Four different subgroups of shock have been proposed according to the mechanism causing the shock. Of these, obstructive shock is characterized by reduction in cardiac output due to noncardiac diseases. The most recognized causes include pulmonary embolism, tension pneumothorax, pericardial tamponade and aortic dissection. Since obstructive shock typically cannot be stabilized unless cause for shock is resolved, diagnosis of the underlying disease is eminent. In this review, we therefore focus on diagnosis of obstructive shock and suggest a structured approach in three steps including clinical examination, ultrasound examination using the rapid ultrasound in shock (RUSH) protocol and radiological imaging if needed

Thrombotic circuit complications during venovenous extracorporeal membrane oxygenation in COVID-19

The novel coronavirus SARS-CoV-2 and the resulting disease COVID-19 causes pulmonary failure including severe courses requiring venovenous extracorporeal membrane oxygenation (V-V ECMO). Coagulopathy is a known complication of COVID-19 leading to thrombotic events including pulmonary embolism. It is unclear if the coagulopathy also increases thrombotic circuit complications of the ECMO. Aim of the present study therefor was to investigate the rate of V-V ECMO complications in COVID-19. We conducted a retrospective registry study including all patients on V-V ECMO treated at our centre between 01/2018 and 04/2020. COVID-19 cases were compared non- COVID-19 cases. All circuit related complications resulting in partial or complete exchange of the extracorporeal system were registered. In total, 66 patients were analysed of which 11 (16.7%) were SARS-CoV-2 positive. The two groups did not differ in clinical parameters including age (COVID-19 59.4 vs. non-COVID-19 58.1 years), gender (36.4% vs. 40%), BMI (27.8 vs. 24.2) and severity of illness as quantified by the RESP Score (1pt. vs 1pt.). 28 days survival was similar in both groups (72.7% vs. 58.2%). While anticoagulation was similar in both groups (p = 0.09), centrifugal pump head thrombosis was more frequent in COVID-19 (9/11 versus 16/55 p < 0.01). Neither the time to first exchange (p = 0.61) nor blood flow at exchange (p = 0.68) did differ in both groups. D-dimer levels prior to the thrombotic events were significantly higher in COVID-19 (mean 15.48 vs 26.59, p = 0.01). The SARS-CoV-2 induced infection is associated with higher rates of thrombotic events of the extracorporeal system during V-V ECMO therapy

Admission blood glucose level and outcome in patients requiring venoarterial extracorporeal membrane oxygenation

Background!#!Patients with cardiogenic shock or cardiac arrest undergoing venoarterial extracorporeal membrane oxygenation (V-A ECMO) frequently present with blood glucose levels out of normal range. The clinical relevance of such findings in the context of V-A ECMO is unknown. We therefore investigated the prognostic relevance of blood glucose at time of cannulation for V-A ECMO.!##!Methods!#!We conducted a single-center retrospective registry study. All patients receiving V-A ECMO from October 2010 to January 2020 were included if blood glucose level at time of cannulation were documented. Patients were divided in five groups according to the initial blood glucose level ranging from hypoglycemic (< 80 mg/dl), normoglycemic (80-140 mg/dl), to mild (141-240 mg/dl), moderate (241-400 mg/dl), and severe (> 400 mg/dl) hyperglycemia, respectively. Clinical presentation, arterial blood gas analysis, and survival were compared between the groups.!##!Results!#!392 patients met inclusion criteria. Median age was 62 years (51.5-70.0), SAPS II at admission was 54 (43.5-63.0), and 108/392 (27.6%) were female. 131/392 were discharged alive (hospital survival 33.4%). At time of cannulation, survivors had higher pH, hemoglobin, calcium, bicarbonate but lower potassium and lactate levels compared to non-survivors (all p < 0.01). Outcome of patients diagnosed with particularly high (> 400 mg/dl) and low (< 80 mg/dl) blood glucose at time of V-A ECMO cannulation, respectively, was worse compared to patients with normoglycemic, mildly or moderately elevated values (p = 0.02). Glucose was independently associated with poor outcome after adjustment for other predictors of survival and persisted in all investigated subgroups.!##!Conclusion!#!Arterial blood glucose at time of V-A ECMO cannulation predicts in-hospital survival of patients with cardiac shock or after ECPR. Whether dysglycemia represents a potential therapeutic target requires further evaluation in prospective studies

Mode of Death after Extracorporeal Cardiopulmonary Resuscitation

Introduction: Extracorporeal cardiopulmonary resuscitation (ECPR) might be a lifesaving therapy for patients with cardiac arrest and no return of spontaneous circulation during advanced life support. However, even with ECPR, mortality of these severely sick patients is high. Little is known on the exact mode of death in these patients. Methods: Retrospective registry analysis of all consecutive patients undergoing ECPR between May 2011 and May 2020 at a single center. Mode of death was judged by two researchers. Results: A total of 274 ECPR cases were included (age 60.0 years, 47.1% shockable initial rhythm, median time-to-extracorporeal membrane oxygenation (ECMO) 53.8min, hospital survival 25.9%). The 71 survivors had shorter time-to-ECMO durations (46.0 ± 27.9 vs. 56.6 ± 28.8min, p < 0.01), lower initial lactate levels (7.9 ± 4.5 vs. 11.6 ± 8.4 mg/dL, p < 0.01), higher PREDICT-6h (41.7 ± 17.0% vs. 25.3 ± 19.0%, p < 0.01), and SAVE (0.4 ± 4.8 vs. −0.8 ± 4.4, p < 0.01) scores. Most common mode of death in 203 deceased patients was therapy resistant shock in 105/203 (51.7%) and anoxic brain injury in 69/203 (34.0%). Comparing patients deceased with shock to those with cerebral damage, patients with shock were significantly older (63.2 ± 11.5 vs. 54.3 ± 16.5 years, p < 0.01), more frequently resuscitated in-hospital (64.4% vs. 29.9%, p < 0.01) and had shorter time-to-ECMO durations (52.3 ± 26.8 vs. 69.3 ± 29.1min p < 0.01). Conclusions: Most patients after ECPR decease due to refractory shock. Older patients with in-hospital cardiac arrest might be prone to development of refractory shock. Only a minority die from cerebral damage. Research should focus on preventing post-CPR shock and treating the shock in these patients

Combining lung ultrasound and Wells score for diagnosing pulmonary embolism in critically ill COVID-19 patients

Subpleural consolidations have been found in lung ultrasound in patients with COVID-19, possibly deriving from pulmonary embolism (PE). The diagnostic utility of impact of lung ultrasound in critical-ill patients with COVID-19 for PE diagnostics however is unclear. We retrospectively evaluated all SARS-CoV2-associated ARDS patients admitted to our ICU between March 8th and May 31th 2020. They were enrolled in this study, when a lung ultrasound and a computed tomography pulmonary angiography (CTPA) were documented. In addition, wells score was calculated to estimate the probability of PE. The CTPA was used as the gold standard for the detection of PE. Twenty out of 25 patients met the inclusion criteria. In 12/20 patients (60%) (sub-) segmental PE were detected by CT-angiography. Lung ultrasound found subpleural consolidations in 90% of patients. PE-typical large supleural consolidations with a size ≥ 1 cm were detectable in 65% of patients and were significant more frequent in patients with PE compared to those without (p = 0.035). Large consolidations predicted PE with a sensitivity of 77% and a specificity of 71%. The Wells score was significantly higher in patients with PE compared to those without (2.7 ± 0.8 and 1.7 ± 0.5, respectively, p = 0.042) and predicted PE with an AUC of 0.81. When combining the two modalities, comparing patients with considered/probable PE using LUS plus a Wells score ≥ 2 to patients with possible/unlikely PE in LUS plus a Wells score < 2, PE could be predicted with a sensitivity of 100% and a specificity of 80%. Large consolidations detected in lung ultrasound were found frequently in COVID-19 ARDS patients with pulmonary embolism. In combination with a Wells score > 2, this might indicate a high-risk for PE in COVID-19

Carboxyhemoglobin (CO-Hb) Correlates with Hemolysis and Hospital Mortality in Extracorporeal Membrane Oxygenation: A Retrospective Registry

Background: Patients supported with extracorporeal membrane oxygenation (ECMO) may develop elevated carboxyhemoglobin (CO-Hb), a finding described in the context of hemolysis. Clinical relevance of elevated CO-Hb in ECMO is unclear. We therefore investigated the prognostic relevance of CO-Hb during ECMO support. Methods: Data derives from a retrospective single-center registry study. All ECMO patients in a medical ICU from October 2010 through December 2019 were considered. Peak arterial CO-Hb value during ECMO support and median CO-Hb values determined by point-of-care testing for distinct time intervals were determined. Groups were divided by CO-Hb (p p = 0.003), 48–72 h (51.5% vs. 36.8%, p = 0.003), or >72 h (56.9% vs. 31.1%, p < 0.001) after ECMO cannulation. Peak CO-Hb was independently associated with lower hospital survival after adjustment for confounders. Conclusions: In ECMO, CO-Hb correlates with hemolysis and hospital survival. If high CO-Hb measured should trigger a therapeutic intervention in order to reduce hemolysis has to be investigated in prospective trials

Bronchoalveolar Lavage and Blood Markers of Infection in Critically Ill Patients—A Single Center Registry Study

Microbiological sampling is an indispensable targeted antibiotic therapy for critically ill patients. Invasive respiratory sampling by bronchoalveolar lavage (BAL) can be performed to obtain samples from the lower respiratory tract. It is debated as to whether blood markers of infection can predict the outcome of BAL in a medical intensive care unit (ICU). Retrospectively, all ICU patients undergoing BAL from 2009–2018 were included. A total of 468 BAL samples from 276 patients (average age 60 years, SAPS2 47, ICU-mortality 41.7%) were analyzed. At the time of BAL, 94.4% patients were mechanically ventilated, 92.9% had suspected pneumonia, 96.2% were on antibiotic therapy and 36.3% were immunocompromised. Relevant bacteria were cultured in 114/468 (24.4%) cases of BAL. Patients with relevant bacteria in the culture had a higher ICU mortality rate (45.6 vs. 40.4%, p = 0.33) and were significantly less likely to be on a steroid (36 vs. 52%, p p < 0.01), while procalcitonin (PCT), C-reactive protein (CRP), and white blood cell (WBC) counts were similar. The area under the receiver operating curve (AUC) values for positive culture and PCT, CRP and WBC counts were low (0.53, 0.54 and 0.51, respectively). In immunocompromised patients, AUC values were higher (0.65, 0.57 and 0.61, respectively). Therefore, microbiological cultures by BAL revealed relevant bacteria in 24.4% of samples. Our data, therefore, might suggest that indication for BAL should not be based on blood markers of infection