Unsupervised Clustering of Membranoproliferative Glomerulonephritis and C3 Glomerulopathy Patients Discovers Distinct Patient Groups unlike the Current Classification.

INTRODUCTION: Membranoproliferative glomerulonephritis is currently divided into immunoglobulin-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G); however, the patients often overlap with histology, complement, clinical and prognostic factors. Our aim was to investigate if an unsupervised clustering method finds different patient groups in 44 IC-MPGN/C3G patients using only histological and clinical data available in everyday clinical work. METHODS: Primary IC-MPGN/C3G adult patients were included whose diagnostic (baseline) native biopsy was obtained in 2006-2017. The biopsies were reassessed and the clinical data at baseline and during follow-up were obtained from the medical records. There were 39 baseline histological and clinical variables included in the unsupervised clustering. Follow-up information was combined with the clustering results. RESULTS: The clustering resulted in two clusters (n = 24 and n = 20 patients for clusters 1-2, respectively), where cluster 1 had a significantly higher baseline plasma creatinine (mean 213 vs. 104, respectively, p value <0.001) and a lower baseline eGFR than cluster 2 (mean 37 vs. 70, respectively, p value <0.001). Regarding histology, chronic changes such as lobulated glomeruli, mesangial matrix expansion, and glomeruli double contours were more prevalent in cluster 1 (p value <0.001). Biopsy morphology was more often crescentic and membranoproliferative in cluster 1 (p value <0.001). Although the differences were insignificant, cluster 1 patients were in dialysis in the last follow-up or had a progressive disease more often than cluster 2 patients (21% vs. 5%, 38% vs. 10%). CONCLUSIONS: Our results indicate that these patients share greater similarity than the current classification IC-MPGN versus C3G indicates.

Comorbidity and Medication Trends in Chronic Kidney Disease and Incident Atrial Fibrillation: A Nationwide Cohort Study.

INTRODUCTION: Chronic kidney disease (CKD) is associated with an increased incidence of atrial fibrillation (AF). Also, patients with AF are prone to adverse kidney outcomes. We examined comorbidities and medication use in patients with CKD and incident AF. METHODS: The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide retrospective register-linkage study including data from 168,233 patients with incident AF from 2007 to 2018, with laboratory data from 2010 onwards. Estimated glomerular filtration rate (eGFR) was available for 124,936 patients. The cohort was divided into 5 CKD stages with separate groups for dialysis and kidney transplantation. RESULTS: At AF diagnosis eGFR <60 mL/min/1.73 m2 was found in 27%, while 318 (0.3%) patients were on dialysis, and 188 (0.2%) had a functioning kidney transplant. Lowering eGFR yielded more comorbidities and medications. During 2010-2018 in patients with eGFR <60 mL/min/1.73 m2 prevalence of hypertension, dyslipidaemia, and diabetes increased from 82 to 88%, from 50 to 66% and from 25 to 33%, respectively (<0.001). Throughout the observation period, lipid-lowering medication was underused. CONCLUSION: More than one-fourth of patients with incident AF also had CKD stage 3-5 (eGFR <60 mL/min/1.73 m2). Both comorbidities and medication use increased with worsening kidney function. Prevalence of major cardiovascular (CV) risk factors increased during 2010-2018, but the use of survival-affecting medications, such as lipid-lowering medication, was suboptimal at all stages of CKD. More attention should be given to the optimal treatment of risk factors in this high CV risk population.

Better late than never: Diagnosis of recurrent atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) comprising microangiopathic hemolytic anemia, consumptive thrombocytopenia, and end-organ damage. Risk of end-stage renal disease is increased as HUS usually manifests in native and transplanted kidneys. In transplants, while de novo disease can be seen, recurrent disease is more common. The etiology is variable, being either primary or secondary. aHUS often constitutes a diagnostic and therapeutic challenge, which may lead to a considerable delay in the diagnosis and treatment. During the last decades, great progress has been made in understanding the mechanisms and therapeutic options of this devastating condition. We present a case of a 50-year-old female who received her first kidney transplant from her mother at the age of 9 years. She experienced recurrent losses of transplants, and only after the loss of her fourth transplant did the diagnosis of aHUS become evident.

Diagnostic and Prognostic Comparison of Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3 Glomerulopathy.

Membranoproliferative glomerulonephritis (MPGN) is subdivided into immune-complex-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G). Classically, MPGN has a membranoproliferative-type pattern, but other morphologies have also been described depending on the time course and phase of the disease. Our aim was to explore whether the two diseases are truly different, or merely represent the same disease process. All 60 eligible adult MPGN patients diagnosed between 2006 and 2017 in the Helsinki University Hospital district, Finland, were reviewed retrospectively and asked for a follow-up outpatient visit for extensive laboratory analyses. Thirty-seven (62%) had IC-MPGN and 23 (38%) C3G (including one patient with dense deposit disease, DDD). EGFR was below normal (≤60 mL/min/1.73 m2) in 67% of the entire study population, 58% had nephrotic range proteinuria, and a significant proportion had paraproteins in their serum or urine. A classical MPGN-type pattern was seen in only 34% of the whole study population and histological features were similarly distributed. Treatments at baseline or during follow-up did not differ between the groups, nor were there significant differences observed in complement activity or component levels at the follow-up visit. The risk of end-stage kidney disease and survival probability were similar in the groups. IC-MPGN and C3G have surprisingly similar characteristics, kidney and overall survival, which suggests that the current subdivision of MPGN does not add substantial clinical value to the assessment of renal prognosis. The high proportion of paraproteins in patient sera or in urine suggests their involvement in disease development.

Vascular Occlusion in Kidney Biopsy Is Characteristic of Clinically Manifesting Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) can sometimes manifest only histologically. Our aim was to retrospectively compare biopsy-proven adult TMA patients showing only histological (h-TMA) or both histological and clinical (c-TMA) TMA in 2006-2017. All native kidney biopsies with TMA were included. Biopsies were re-evaluated by light and electron microscopy, and immunofluorescence. Clinical characteristics, laboratory variables, and treatments were recorded from the electronic medical database. Patients were categorized into h-TMA and c-TMA and these groups were compared. In total, 30 biopsy-proven cases among 7943 kidney biopsies were identified and, of these, 15 had h-TMA and 15 c-TMA. Mean follow-up was 6.3 y, and 73.3% had secondary hemolytic uremic syndrome (HUS) and the rest were atypical HUS. Patient characteristics, treatments, and kidney, and patient survival in the groups were similar. Statistically significant differences were found in histological variables. Vascular myxoid swelling and vascular onion-skinning were almost exclusively detected in c-TMA and, thus, vascular occlusive changes indicate clinically apparent rather than merely histological TMA. In addition, regardless of clinical presentation, kidney and patient survival times were similar in the patient groups highlighting the importance of a kidney biopsy in the case of any kidney-related symptoms.

Asystole episodes and bradycardia in patients with end-stage renal disease.

BACKGROUND: Knowledge of arrhythmias in patients with end-stage renal disease (ESRD) is mainly based on ambulatory electrocardiography (ECG) studies and observations during haemodialysis (HD). We used insertable cardiac monitors (ICMs) to define the prevalence of arrhythmias, focusing on bradyarrhythmias, in ESRD patients treated with several dialysis modes including home therapies. Moreover, we assessed whether these arrhythmias were detected in baseline or ambulatory ECG recordings. METHODS: Seventy-one patients with a subcutaneous ICM were followed for up to 3 years. Asystole (≥4.0 s) and bradycardia (heart rate <30 bpm for ≥4 beats) episodes, ventricular tachyarrhythmias and atrial fibrillation (AF) were collected and verified visually. A baseline ECG and a 24- to 48-h ambulatory ECG were recorded at recruitment and once a year thereafter. RESULTS: At recruitment, 44 patients were treated in in-centre HD, 12 in home HD and 15 in peritoneal dialysis. During a median follow-up of 34.4 months, 18 (25.4%) patients had either an asystolic or a bradycardic episode. The median length of each patient's longest asystole was 6.6 s and that of a bradycardia 13.5 s. Ventricular tachyarrhythmias were detected in 16 (23%) patients, and AF in 34 (51%) patients. In-centre HD and Type II diabetes were significantly more frequent among those with bradyarrhythmias, whereas no bradyarrhythmias were found in home HD. No bradyarrhythmias were evident in baseline or ambulatory ECG recordings. CONCLUSIONS: Remarkably many patients with ESRD had bradycardia or asystolic episodes, but these arrhythmias were not detected by baseline or ambulatory ECG.

Tubular cell damage may be the earliest sign of renal extrahepatic manifestation caused by Hepatitis C.

Chronic kidney disease (CKD) is one of the most well-known extrahepatic manifestations caused by hepatitis C infection (HCV). CKD is typically discovered at a late stage. HCV-nephropathy may show different histopathologic patterns, as both glomerular and tubulointerstitial damage have been described. Identification of patients with early renal manifestations would be beneficial to provide treatment and avoid progression to CKD. The observational prospective single-center HCVKID study assessed the prevalence of early renal manifestations in patients with chronic HCV and compared these patients with HCV-negative healthy controls cross-sectionally. HCV-positive patients with and without renal manifestations were also compared to define biomarkers suitable for identifying early manifestations in standard clinical practice. Tubular proteinuria as judged by urine α 1-microglobulin was the most common early renal manifestation found in 11% in HCV-positive patients, followed by hematuria in 8%. Kidney filtration was statistically significantly lower among HCV-positive patients with renal manifestation according to any calculation method. There were no significant differences in duration of infection or stage of liver fibrosis between patients with or without renal manifestations. Tubular cell damage may be the earliest sign of renal dysfunction caused by HCV. Complement activation also correlates with the dysfunction, indicating of contribution to HCV-induced renal manifestations even in their early phase.

Fluid overload is an independent predictor of atrial fibrillation in end-stage renal disease: A prospective study using insertable cardiac and body composition monitors
.

BACKGROUND: Fluid overload and atrial fibrillation (AF) are frequently encountered in patients with end-stage renal disease (ESRD). We used subcutaneously insertable cardiac monitors (ICM) to detect AF and associated it with the hydration status, determined with a body composition monitor (BCM) in dialysis patients. MATERIALS AND METHODS: 69 patients were recruited. Fluid overload was defined based on BCM measurements as a ratio of overhydration (OH) and extracellular water (OH/ECW) of > 15% at baseline. AF episodes lasting ≥ 2 minutes were collected. RESULTS: 45 in-center hemodialysis patients, 11 on peritoneal dialysis, 12 on home hemodialysis, and 1 predialysis-stage patient were followed up for a median of 2.9 years (25th - 75th percentile 1.9 - 3.1). 29% were overhydrated at baseline, and the percentage remained similar throughout the study. Overhydrated patients had a lower body mass index, a higher prevalence of type 1 diabetes mellitus (DM) and diabetic nephropathy, higher systolic blood pressure, greater ultrafiltration (UF) during dialysis, and a smaller lean tissue index than normohydrated patients. Chronic or paroxysmal AF was known to occur in 20.3% at entry, and a further 33.3% developed AF during the study, with an overall prevalence 53.6%. In univariable logistic regression, OH/ECW > 15% was strongly associated with AF prevalence (OR 6.8, 95% CI 1.7 - 26.5, p = 0.006), as were UF, age, coronary heart disease (CHD), DM, and the echocardiogram-derived ejection fraction and left atrial diameter. In multivariable analyses, OH/ECW > 15% remained an independent predictor of AF alongside age and CHD. CONCLUSION: The occurrence of AF is independently associated with BCM-measured fluid overload, which is common among ESRD patients.

Complement dysregulation in glomerulonephritis.

Glomerulonephritis (GN) refers to a group of renal diseases affecting the glomeruli due to the damage mediated by immunological mechanisms. A large proportion of the disease manifestations are caused by disturbances in the complement system. They can be due to genetic errors, autoimmunity, microbes or abnormal immunoglobulins, like modified IgA or paraproteins. The common denominator in most of the problems is an overactive or misdirected alternative pathway complement activation. An assessment of kidney function, amount of proteinuria and hematuria are crucial elements to evaluate, when glomerulonephritis is suspected. However, the cornerstones of the diagnoses are renal biopsy and careful examination of the complement abnormality. Differential diagnostics between the various forms of GN is not possible based on clinical features, as they may vary greatly. This review describes the known mechanisms of complement dysfunction leading to different forms of primary GN (like IgA glomerulonephritis, dense deposit disease, C3 glomerulonephritis, post-infectious GN, membranous GN) and differences to atypical hemolytic uremic syndrome. It also covers the basic elements of etiology-directed therapy and prognosis of the most common forms of GN. Common principles in the management of GN include treatment of hypertension and reduction of proteinuria, some require immunomodulating treatment. Complement inhibition is an emerging treatment option. A thorough understanding of the basic disease mechanism and a careful follow-up are needed for optimal therapy.

Electrocardiographic changes before and after successful kidney transplantation and associations with cardiovascular and mortality outcomes.

INTRODUCTION: Electrocardiographic (ECG) changes before and after kidney transplantation are not well-defined. Our aim was to describe the evolution of ECG in patients on dialysis before and after successful kidney transplantation and to explore the association between ECG findings and major cardiovascular (CV) events and mortality after kidney transplantation. PATIENTS AND METHODS: Electrocardiographics were collected retrospectively 3 times: at entry to the transplantation waiting list, at transplantation, and 1 year after the transplantation from 212 kidney transplantation recipients. Altogether 19 ECG variables were analyzed. RESULTS: Left ventricular hypertrophy was present in 10.2% by the Cornell voltage-duration product criteria and 10.7% by the Sokolow-Lyon voltage criteria before kidney transplantation. The presence of ST depression (OR 3.12, 95% CI 1.12 -8.7 and P = .03) at entry to the waiting list and Q wave at the time of transplantation (OR 3.28, 95% CI 1.06-10.10 and P = .04) were both independently associated with major CV events after the transplantation. In addition, the presence of Q wave at entry to the waiting list was a risk factor of premature death after the transplantation (OR 2.92, 95% CI 1.06-8.05 and P = .04). DISCUSSION: Careful analysis of the ECG before transplantation can be used to estimate cardiovascular events and mortality risk after kidney transplantation.

Recurrent allograft C3 glomerulonephritis and unsuccessful eculizumab treatment.

There is a great lack of efficient treatments for membranoproliferative glomerulonephritis (MPGN) and recently emerged complement therapies have been proposed to be useful. We report a patient with a complement-mediated MPGN having recurrencies in kidney allografts and an unsuccessful treatment with complement inhibitor, eculizumab (anti-C5 monoclonal antibody). Nephritic factor (C3Nef), an autoantibody against C3bBb, in the patient serum activated C3 but not C5 showing that major damage was mediated by C3 activation with clearly less involvement of C5 explaining unresponsiveness to eculizumab. Analyzing C3Nef-mediated C3 and C5 activation separately could help in choosing the right patients for eculizumab therapy.

Atypical hemolytic-uremic syndrome.

Atypical hemolytic-uremic syndrome (aHUS) is a rare form of thrombotic microagiopathy caused dysregulation of the alternative pathway of the complement resulting in tissue. In aHUS, activation of the alternative pathway of the complement is in an aberrant way directed against endothelial cells and blood cells. This is either due to a mutation in a complement factor, most commonly factor H, or an autoantibody against a complement regulator. In some patients the underlying disorder is not identified despite thorough examinations. Typical aHUS-patients have acute kidney injury and microangiopathic hemolysis and, to a varying degree, disturbances of other organs. An effective inhibitor of the final product of complement, eculizumab, has revolutionized the treatment of these patients.

Metabolic syndrome in IgA glomerulonephritis.

BACKGROUND/AIMS: Metabolic syndrome (MetS) may have an independent impact on the development of chronic kidney disease. This study examines the prevalence of MetS in subjects with IgA glomerulonephritis (IgAGN) and its impact on disease progression in a retrospective fashion. PATIENTS AND METHODS: Altogether, 174 subjects (104 males) were examined 11 years (first visit) after IgAGN diagnosis and again after 16 years (second visit; 144 subjects responded). Different glomerular filtration markers were utilized. The MetS criteria by Alberti et al. [Circulation 2009;120:1640-1645] were applied, in which the presence of any three of five risk factors (elevated waist circumference, triglycerides, glucose, existence of hypertension, or reduced high-density lipoprotein cholesterol) constitutes the diagnosis. RESULTS: The prevalence of MetS at the first visit was 39%, corresponding to that of the general Finnish population. In univariate analyses, MetS was significantly associated with the progression of IgAGN at the second visit. However, in multivariate analyses, the existence of MetS was not a significant prognostic determinant. CONCLUSION: The number of subjects with MetS among IgAGN patients and the general population is equal in Finland. MetS does not seem to be an independent prognostic variable.

Adenine phosphoribosyltransferase deficiency as a rare cause of renal allograft dysfunction.

Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive disorder manifesting as urolithiasis or crystalline nephropathy. It leads to the generation of large amounts of poorly soluble 2,8-dihydroxyadenine excreted in urine, yielding kidney injury and in some patients, kidney failure. Early recognition of the disease, institution of xanthine analog therapy to block the formation of 2,8-dihydroxyadenine, high fluid intake, and low purine diet prevent CKD. Because of symptom variability and lack of awareness, however, the diagnosis is sometimes extremely deferred. We describe a patient with adenine phosphoribosyltransferase deficiency who was diagnosed during evaluation of a poorly functioning second kidney allograft. This report highlights the risk of renal allograft loss in patients with undiagnosed adenine phosphoribosyltransferase deficiency and the need for improved early detection of this disease.

Membranoproliferative glomerulonephritis complicating Propionibacterium acnes infection.

BACKGROUND: Propionibacterium acnes (P. acnes) is a common microbe of the skin and mucosal surfaces rarely considered a true pathogen. However, it has been reported to cause serious infections. Subsequent ongoing low-grade antigenaemia may, in turn, lead to an immune-mediated glomerulonephritis with various renal histologies including that of membranoproliferative glomerulonephritis (MPGN). METHODS: Here, we describe two cases of P. acnes infection-induced MPGN and their treatment. RESULTS: Both patients were successfully treated by the eradication of the infection. One patient also received immunosuppressive medication prior to the correct diagnosis. CONCLUSIONS: A vigorous exclusion of infection is warranted in MPGN type I or immune-complex-mediated MPGN and may sometimes yield a diagnosis of secondary MPGN.

Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation.

OBJECTIVE: To investigate whether bacterial lipopolysaccharide (LPS) activity in human serum is associated with the components of the metabolic syndrome (MetS) in type 1 diabetic patients with various degrees of kidney disease and patients with IgA glomerulonephritis (IgAGN). RESEARCH DESIGN AND METHODS: Serum LPS activity was determined with the Limulus Amoebocyte Lysate chromogenic end point assay in type 1 diabetic patients with a normal albumin excretion rate (n = 587), microalbuminuria (n = 144), macroalbuminuria (n = 173); patients with IgAGN (n = 98); and in nondiabetic control subjects (n = 345). The relationships of the LPS/HDL ratio and MetS-associated variables were evaluated with Pearson correlation. RESULTS: The MetS was more prevalent in type 1 diabetic patients (48%) than in patients with IgAGN (15%). Diabetic patients with macroalbuminuria had a significantly higher serum LPS/HDL ratio than patients with IgAGN. In the normoalbuminuric type 1 diabetic group, patients in the highest LPS/HDL quartile were diagnosed as having the MetS three times more frequently than patients in the lowest quartile (69 vs. 22%; P < 0.001). High LPS activity was associated with higher serum triglyceride concentration, earlier onset of diabetes, increased diastolic blood pressure, and elevated urinary excretion of monocyte chemoattractant protein-1. CONCLUSIONS: High serum LPS activity is strongly associated with the components of the MetS. Diabetic patients with kidney disease seem to be more susceptible to metabolic endotoxemia than patients with IgAGN. Bacterial endotoxins may thus play an important role in the development of the metabolic and vascular abnormalities commonly seen in obesity and diabetes-related diseases.

Alcohol consumption and kidney function in IgA glomerulonephritis.

BACKGROUND: IgA glomerulonephritis (IgAGN) is a kidney disease with variable prognosis. Several known risk factors exist for a more progressive course. Some population studies indicate that moderate alcohol consumption might protect kidney function, but the relationship between alcohol intake and IgAGN has not previously been examined. METHODS: We examined 158 (95 men) IgAGN patients (37 abstainers, 80 light drinkers, 25 moderate drinkers and 16 heavy drinkers) in a cross-sectional study. The definition of alcohol consumption was based on interviews on the amounts of alcohol intake combined with measurements of serum carbohydrate-deficient transferrin, a specific biomarker of alcohol abuse. Longitudinal data on renal function were available from 117 patients (76 men) in whom an analysis with respect to progression was also performed. RESULTS: Moderate drinkers showed the best kidney function. When adjusted by hypertension and 24-hour protein excretion, moderate alcohol consumption in a cross-sectional multivariate analysis, and both light and moderate alcohol consumption in a longitudinal multivariate analysis were significant factors of better kidney function. When the study population was divided by gender, the best kidney function was among light drinkers in women and among moderate drinkers in men. CONCLUSIONS: Moderate alcohol consumption might have a favorable impact on the progression of IgAGN. Light alcohol consumption in women and moderate consumption in men are associated with improved indices of the glomerular filtration estimates in patients with IgAGN.

IgA immune responses against acetaldehyde adducts and biomarkers of alcohol consumption in patients with IgA glomerulonephritis.

BACKGROUND: The pathogenesis of IgA glomerulonephritis (IgAGN) involves intense deposition of IgAs within the glomerulus. Although previous studies have shown that heavy drinking frequently leads to the generation of IgA antibodies against neo-antigens induced by ethanol metabolites and tissue deposition of IgAs, the associations between alcohol consumption, IgA immune responses, and kidney disease have not been examined. METHODS: A total of 158 IgAGN patients (96 men, 62 women) were classified as abstainers (n = 38), moderate drinkers (n = 114), and heavy drinkers (n = 6) based on self-reported alcohol consumption. The reference population included 143 individuals (99 men, 44 women) who were either apparently healthy abstainers (n = 31), moderate drinkers (n = 43), or heavy drinkers devoid of liver disease (n = 69). The assessments included various biomarkers of alcohol consumption: carbohydrate-deficient transferrin (CDT), glutamyl transferase, gamma-CDT (combination of GGR and CDT), mean corpuscular volume (MCV), tests for liver and kidney function, serum immunoglobulin A (IgA), and specific IgA antibodies against acetaldehyde-protein adducts. RESULTS: In male IgAGN patients, drinking status was significantly associated with MCV, p < 0.001; CDT, p < 0.01; and gamma -CDT, p < 0.05. In the reference population, all biomarkers and anti-adduct IgA levels were found to vary according to drinking status. In IgAGN patients, anti-adduct IgA levels were elevated in 63% of the cases but the titers did not associate with self-reported ethanol intake. CONCLUSIONS: These data indicate high levels of IgA antibodies against acetaldehyde-derived antigens in IgAGN patients, which may hamper the use of the immune responses as markers of alcohol consumption among such patients. Future studies on the pathogenic and prognostic significance of anti-adduct immune responses in IgAGN patients are warranted.