Urinary Biomarkers and Patient Outcome in Chronic Kidney Disease and Atherosclerotic Heart Disease: The value of IgM-uria and IgG-uria

Risk stratification of patients with chronic kidney disease and atherosclerotic heart disease is crucial. Microalbuminuria (MA) is associated with an increased risk of kidney and cardiovascular (CV) death, especially in patients with diabetes. However, MA in many instances is not sensitive for disease outcome; for instance, not all diabetic patients with albuminuria progress to kidney failure, and not all patients with diabetic kidney disease (DKD) have albuminuria. Furthermore, albuminuria is not essentially associated with endothelial dysfunction or glomerular lesions in non-diabetic patients. Urinary excretion of larger proteins, such as IgM and IgG would better reflect glomerular dysfunction and vascular endothelial damage. In this thesis we aimed to evaluate the value of IgG-uria and IgM-uria in predicting kidney and CV outcome in patients with diabetes, glomerulonephritis and atherosclerotic heart disease. In study I, 139 patients with type-1 diabetes, and in study II, 106 patients with type-2 diabetes, were followed at the diabetes outpatient clinic, for an average of 18 and 5 years, respectively. Type-1 & -2 diabetic patients had about a 3-fold increase in CV and renal mortality (HR = 2.7, p = 0.004, and HR = 3.6, p < 0.001, respectively) if they had an increased urine IgM excretion, even when adjusted to the degree of albuminuria. In study III, 178 consecutive patients who presented with acute chest pain to the emergency department of Lund University Hospital were followed for up to 2 years. Patients with acute coronary syndrome had significantly higher baseline IgM-uria than those with non-specific chest pain. Chest pain patients with IgM-uria at time of presentation had a 3-fold higher risk for the occurrence of subsequent major CV event (HR = 3.3, p = 0.001). In study IV, 189 patients with proteinuric primary glomerulonephritis were followed at the nephrology outpatient clinic for an average of 8 years. Patients with an increased urine IgG excretion had an increased risk for end-stage kidney disease (ESKD), even when adjusted for the degree of albuminuria and kidney function (HR = 5.9, p = 0.001). In conclusion, IgM-uria could be a useful biomarker for kidney and cardiovascular risk assessment of patients with diabetes and atherosclerotic heart disease. IgM- uria could imply an extensive atherosclerotic vascular disease. IgG-uria is helpful in identifying patients with glomerulonephritis at increased risk for disease progression to ESKD

Urinary concentration of monocyte chemoattractant protein-1 in idiopathic glomerulonephritis: a long-term follow-up study.

Monocyte chemoattractant protein-1 (MCP-1), which is up regulated in kidney diseases, is considered a marker of kidney inflammation. We examined the value of urine MCP-1 in predicting the outcome in idiopathic glomerulonephritis

Increased urine IgM excretion predicts cardiovascular events in patients with type 1 diabetes nephropathy

<p>Abstract</p> <p>Background</p> <p>Diabetic nephropathy, a major complication of diabetes, is characterized by progressive renal injury and increased cardiovascular mortality. An increased urinary albumin excretion due dysfunction of the glomerular barrier is an early sign of diabetic nephropathy. An increased urinary excretion of higher molecular weight proteins such as IgM appears with progression of glomerular injury. We aim here to study the prognostic significance of urine IgM excretion in patients with type 1 diabetes mellitus (type 1 diabetic nephropathy).</p> <p>Methods</p> <p>This is an observational study of 139 patients with type1 diabetes mellitus (79 males and 60 females) under routine care at the diabetic outpatient clinic at the Lund University Hospital. The median follow-up time was 18 years (1 to 22) years. Urine albumin and urine IgM concentration were measured at time of recruitment.</p> <p>Results</p> <p>Overall 32 (14 male and 18 female) patients died in a cardiovascular event and 20 (11 male and 9 female) patients reached end-stage renal disease. Univariate analysis indicated that patient survival and renal survival were inversely associated with urine albumin excretion (RR = 2.9 and 5.8, respectively) and urine IgM excretion (RR = 4.6 and 5.7, respectively). Stratified analysis demonstrated that in patients with different degrees of albuminuria, the cardiovascular mortality rate and the incidence of end-stage renal disease was approximately three times higher in patients with increased urine IgM excretion.</p> <p>Conclusion</p> <p>An increase in urinary IgM excretion in patients with type 1 diabetes is associated with an increased risk for cardiovascular mortality and renal failure, regardless of the degree of albuminuria.</p

The value of IgG-uria in predicting renal failure in idiopathic glomerular diseases. A long-term follow-up study.

Abstract Background. Proteinuria is the hallmark of glomerular disease and non-selective proteinuria is often associated with progression to renal failure. The predictive value of urine IgG excretion was studied comprehensively in patients with nephrotic syndrome. In the present follow-up study, we examine the predictive value of IgG-uria in patients with idiopathic glomerular diseases with a wide range of proteinuia. Methods. A total of 189 (113 males and 76 females) patients with idiopathic glomerulonephritis and serum creatinine of less than 150 μmol/L diagnosed between 1993 and 2004 were followed up to their last visit in 2009. Measurement of urine excretion of albumin, IgG, and protein HC were performed in the early morning of spot urine samples collected at the time of the diagnostic renal biopsy. Patients were stratified according to urine protein concentrations and the progression rate to end-stage renal disease (ESRD) calculated using Kaplan-Meier survival analysis. ESRD was defined as the start of renal replacement therapy. Results. During the study follow-up time of 1429 person-years; 26 (13.8%) patients reached ESRD. The overall mean kidney survival time of studied patients with serum creatinine less than 150 were 13.4 years. The incidence rate of ESRD was ∼18 per 1000 person-years. Stratified analysis identified urinary excretion of IgG, but not albuminuria, as predictor of ESRD. The progression rate to ESRD was 36 per 1000 person-years in patients with urine IgG concentration exceeding 5 mg/mmol urine creatinine, compared to a progression rate of 6/1000 person-years for patients with lower levels of urine IgG. Conclusion. The findings of the study suggest that at early stages, the level of IgG-uria is useful to be used in risk stratification of patients with proteinuric glomerular diseases

Increased mortality among acute respiratory distress patients from immigrant dense urban districts

Purpose: This study investigated whether living in immigrant dense urban districts (IDUDs) and low-income areas in the city of Malmö predicted 5-year mortality among patients admitted to the emergency department (ED) because of acute respiratory distress. Patients and methods: We randomly selected 184 patients with acute respiratory distress during 2007, visiting the ED at Skåne University Hospital, Malmö. In 2007, Malmö had 36% first- and second-generation immigrants. The main exposure was defined as being resident in any of the five IDUDs of Malmö compared to being resident in the five districts of Malmö with the highest proportion of Sweden-born inhabitants (SDUDs). We recorded vital parameters; medical triage priority according to Adaptive Process Triage (ADAPT), ICD-10 diagnoses, and the mean annual income for the patient’s urban district. We examined 5-year mortality risk using Cox proportional hazards model. Results: After adjustment for age and gender, patients from IDUDs (n=100, 54%) had an HR (95% CI) of 1.65 (1.087-2.494; P=0.019) regarding mortality at 5-year follow-up. Patients in the lowest vs highest income quartile had an HR of 2.00 (1.06-3.79; P=0.032) regarding mortality at 5-year follow-up. Age, male gender, presence of cardiopulmonary disease, and ADAPT priority also independently predicted the 5-year mortality. The excess risk of 5-year mortality associated with living in IDUDs remained significant after adjustment for age, gender, ADAPT priority, presence of cardiopulmonary disease, and income with an HR of 1.79 (1.15-2.78; P=0.010). Conclusion: Living in an IDUD is a strong independent risk factor for 5-year mortality in patients with acute respiratory distress. The cause is unknown. Our study suggests a need for better structured follow-up of cardiopulmonary disease in such patients

Urine IgM-excretion as a prognostic marker for progression of type 2 diabetic nephropathy.

Although the clinical manifestations of type 2 diabetic nephropathy and decline in kidney function are similar to those in type 1, the clinical course and the renal structural changes are more heterogeneous in type 2 diabetic patients. Previous studies have shown that an increased urine IgM excretion in patients with type 1 diabetic nephropathy was associated with poor outcome. In the present follow-up study we examine the prognostic value of baseline urine IgM excretion in patients with type 2 diabetes mellitus. METHODS: A cohort of 106 (74 male and 32 female) patients with type 2 diabetes regularly attending our diabetes out-patient clinic at Skane University Hospital in Lund. They were recruited prospectively under the period between 1992 and 2004. Patients were followed-up until January 2009. The end point was cardiovascular (CV) death or end-stage renal disease (ESRD). The median follow-up time was 5 years (0.5-13 years). Participants were divided according to degree of albuminuria and IgM-uria. RESULTS: During follow-up time, 28 (19 male and 9 female) patients died of CV events and 41 (26 male and 15 female) developed ESRD. The risk of CV mortality was 2.4 fold, and the risk of renal failure 4.9 fold higher in patients with increased urine IgM excretion compared to patients with low urine IgM excretion. Stratified analysis showed that an increased urine IgM excretion was an independent predictor of renal and cardiovascular death irrespective of the degree of albuminuria (HR=3.6, 95% CI: 2.1-6.0, P<0.001). In conclusion, type 2 diabetic nephropathy patients with high urine IgM excretion rates carry an increased risk of renal and cardiovascular death

Associations between biomarkers of multimorbidity burden and mortality risk among patients with acute dyspnea

The patients’ burden of comorbidities is a cornerstone in risk assessment, clinical management and follow-up. The aim of this study was to evaluate if biomarkers associated with comorbidity burden can predict outcome in acute dyspnea patients. We included 774 patients with dyspnea admitted to an emergency department and measured 80 cardiovascular protein biomarkers in serum collected at admission. The number of comorbidities for each patient were added, and a multimorbidity score was created. Eleven of the 80 biomarkers were independently associated with the multimorbidity score and their standardized and weighted values were summed into a biomarker score of multimorbidities. The biomarker score and the multimorbidity score, expressed per standard deviation increment, respectively, were related to all-cause mortality using Cox Proportional Hazards Model. During long-term follow-up (2.4 ± 1.5 years) 45% of the patients died and during short-term follow-up (90 days) 12% died. Through long-term follow-up, in fully adjusted models, the HR (95% CI) for mortality concerning the biomarker score was 1.59 (95% CI 1348–1871) and 1.18 (95% CI 1035–1346) for the multimorbidity score. For short-term follow-up, in the fully adjusted model, the biomarker score was strongly related to 90-day mortality (HR 1.98, 95% CI 1428–2743), whereas the multimorbidity score was not significant. Our main findings suggest that the biomarker score is superior to the multimorbidity score in predicting long and short-term mortality. Measurement of the biomarker score may serve as a biological fingerprint of the multimorbidity score at the emergency department and, therefore, be helpful for risk prediction, treatment decisions and need of follow-up both in hospital and after discharge from the emergency department

Socioeconomic and clinical predictors of mortality in patients with acute dyspnea

Background: Factors predicting long-term prognosis in patients with acute dyspnea may guide both acute management and follow-up. The aim of this study was to identify socioeconomic and clinical risk factors for all-cause mortality among acute dyspnea patients admitted to an Emergency Department. Methods: We included 798 patients with acute dyspnea admitted to the ED of Skåne University Hospital, Malmö, Sweden from 2013 to 2016. Exposures were living in the immigrant-dense urban part of Malmö (IDUD), country of birth, annual income, comorbidities, smoking habits, medical triage priority and severity of dyspnea. Mean follow-up time was 2.2 years. Exposures were related to risk of all-cause mortality using Cox proportional hazard model. Results: During follow-up 40% died. In models adjusted for age and gender, low annual income, previous or ongoing smoking, certain comorbidities, high medical triage priority and severe dyspnea were all significantly associated with increased mortality. After adjusting for age, gender and all significant exposures, the lowest quintile of income, ongoing or previous smoking, history of serious infection, anemia, hip fracture, high medical triage priority and severe dyspnea significantly and independently predicted mortality. In contrast, neither country of birth nor living in IDUD predicted a mortality risk. Conclusion: Apart from several clinical risk factors, low annual income predicts two-year mortality risk in patients with acute dyspnea. This is not the case for country of birth and living in IDUD. Our results underline the wide range of mortality risk factors in acute dyspnea patients. Knowledge of patients’ annual income as well as certain clinical features may aid risk stratification and determining the need of follow-up both in hospital and after discharge from an ED