Urine β2-Microglobulin and Retinol-Binding Protein and Renal Disease Progression in IgA Nephropathy

Background: Tubulointerstitial involvement has been reported to have a decisive influence on the progression of IgA nephropathy (IgAN). High levels of urine β2-microglobulin (β2-MG) and retinol-binding protein (RBP) were observed in patients with IgAN with tubulointerstitial lesions. However, their roles in disease progression remain unclear. This study aimed to evaluate the associations of urine β2-MG and RBP with the progression of IgAN.Methods: We retrospectively investigated a cohort of 2,153 patients with IgAN. Clinical and pathological features, outcomes, and urine β2-MG, and RBP at the time of biopsy were collected. The associations, of urine β2-MG and RBP with the composite renal outcome, defined as a decline in estimated glomerular filtration rate (eGFR) of ≥50% from baseline or end-stage renal disease (ESRD), were examined using restricted cubic splines and the Cox proportional hazards models.Results: During a median follow-up of 20.40 months, 140 (6.50%) patients reached the composite renal outcomes. Restricted cubic splines showed that patients with higher urinary β2-MG and RBP levels had worse renal outcomes. The Cox regression analysis revealed that urine β2-MG and RBP were associated with a risk of the composite renal outcome in the multivariate adjusted model [+1 SD for log β2-MG, hazard ratio (HR) = 1.462, 95% CI: 1.136–1.882, p = 0.003; +1 SD for log RBP, HR = 1.972, 95% CI: 1.486–2.617, p = 0.001]. The associations were detectable within patients with baseline eGFR <90 ml/min/1.73 m2 (+1 SD for log β2-MG, HR = 1.657, 95% CI: 1.260–2.180, p < 0.001; +1 SD for log RBP, HR = 1.618, 95% CI: 1.199–2.183, p = 0.002), but not among patients with eGFR ≥90 ml/min/1.73 m2.Conclusion: Higher levels of urine β2-MG and RBP were independent risk factors for renal disease progression in IgAN.

Renal effectiveness and safety of the sodium-glucose cotransporter-2 inhibitors: a population-based cohort study

IntroductionTo assess the comparative effectiveness and safety of renal-related outcomes associated with sodium-glucose cotransporter-2 inhibitors (SGLT2-i) initiation among patients with type 2 diabetes using real-world data.Research design and methodsWe conducted a population‐based cohort study using administrative healthcare data from Alberta (AB), Canada and primary care data from the Clinical Practice Research Datalink (CPRD), UK. From a cohort of new metformin users, we identified initiators of a SGLT2-i or dipeptidyl peptidase-4 inhibitor (DPP4-i) between January 1, 2014 and March 30, 2018 (AB) or between January 1, 2013 and November 29, 2018 (CPRD). Initiators of an SGLT2-i or DPP4-i were followed until death, disenrolment, therapy discontinuation, or study end date. The effectiveness outcome was renal disease progression, defined as a composite of new-onset macroalbuminuria, serum creatinine doubling with estimated glomerular filtration rate of ≤45 mL/min/1.73 m2, renal replacement therapy, hospital admission or death from renal causes. The safety outcome was hospitalization due to acute kidney injury (AKI). We adjusted for confounding using high-dimensional propensity score matching and estimated HRs using Cox proportional hazards regression. Aggregate data from each database were combined by random-effects meta‐analysis.ResultsAmong the 29 465 included patients (20 564 AB, 8901 CPRD), 37.5% were new SGLT2-i users in AB and 21.3% in CPRD. Compared with DPP4 initiators, SGLT2-i initiators were associated with a reduced risk of renal disease progression (pooled HR 0.79, 95% CI 0.62 to 1.00); however, there was no significant difference in the risk of AKI (pooled HR 0.89, 95% CI 0.58 to 1.36). These findings were consistent with other exposure definitions and antidiabetic comparators.ConclusionsOur findings support a renoprotective effect of SGLT2-i without an increased risk of AKI, compared with clinically relevant active comparators.

Narrative review of recent studies on the role of vitamin D in the prevention of cardiac and renal risk and additional considerations for COVID-19 vulnerability

: The role of vitamin D in maintaining a healthy cardiovascular (CV) and the renal system has received increasing attention. Low vitamin D levels are associated with the incidence of hypertension, cardiac remodeling, and chronic congestive heart failure. Low vitamin D levels also influence renal disease progression and albuminuria deterioration. Moreover, recent research indicates that vitamin D deficiency can be a potential risk factor for coronavirus disease-19 (COVID-19) infection and poorer outcomes. Data are inconclusive as to whether supplementation with vitamin D agents reduces CV disease risk or COVID-19 severity. Conversely, in patients with kidney disease, vitamin D supplementation is associated with improved kidney function and albuminuria. This narrative review considers recent data on the effects of vitamin D on the CV and renal system, as well as its possible role regarding COVID-19 complications.

Urinary Protein and Peptide Markers in Chronic Kidney Disease

Chronic kidney disease (CKD) is a non-specific type of kidney disease that causes a gradual decline in kidney function (from months to years). CKD is a significant risk factor for death, cardiovascular disease, and end-stage renal disease. CKDs of different origins may have the same clinical and laboratory manifestations but different progression rates, which requires early diagnosis to determine. This review focuses on protein/peptide biomarkers of the leading causes of CKD: diabetic nephropathy, IgA nephropathy, lupus nephritis, focal segmental glomerulosclerosis, and membranous nephropathy. Mass spectrometry (MS) approaches provided the most information about urinary peptide and protein contents in different nephropathies. New analytical approaches allow urinary proteomic–peptide profiles to be used as early non-invasive diagnostic tools for specific morphological forms of kidney disease and may become a safe alternative to renal biopsy. MS studies of the key pathogenetic mechanisms of renal disease progression may also contribute to developing new approaches for targeted therapy.

Hyperuricemia and Progression of Chronic Kidney Disease: A Review from Physiology and Pathogenesis to the Role of Urate-Lowering Therapy

The relationship between hyperuricemia, gout, and renal disease has been investigated for several years. From the beginning, kidney disease has been considered a complication of gout; however, the viewpoints changed, claiming that hypertension and elevated uric acid (UA) levels are caused by decreased urate excretion in patients with renal impairment. To date, several examples of evidence support the role of hyperuricemia in cardiovascular or renal diseases. Several mechanisms have been identified that explain the relationship between hyperuricemia and chronic kidney disease, including the crystal effect, renin–angiotensin–aldosterone system activation, nitric oxide synthesis inhibition, and intracellular oxidative stress stimulation, and urate-lowering therapy (ULT) has been proven to reduce renal disease progression in the past few years. In this comprehensive review, the source and physiology of UA are introduced, and the mechanisms that explain the reciprocal relationship between hyperuricemia and kidney disease are reviewed. Lastly, current evidence supporting the use of ULT to postpone renal disease progression in patients with hyperuricemia and gout are summarized.

Smoking accelerates renal cystic disease and worsens cardiac phenotype in Pkd1-deficient mice

Smoking has been associated with renal disease progression in ADPKD but the underlying deleterious mechanisms and whether it specifically worsens the cardiac phenotype remain unknown. To investigate these matters, Pkd1-deficient cystic mice and noncystic littermates were exposed to smoking from conception to 18 weeks of age and, along with nonexposed controls, were analyzed at 13–18 weeks. Renal cystic index and cyst-lining cell proliferation were higher in cystic mice exposed to smoking than nonexposed cystic animals. Smoking increased serum urea nitrogen in cystic and noncystic mice and independently enhanced tubular cell proliferation and apoptosis. Smoking also increased renal fibrosis, however this effect was much higher in cystic than in noncystic animals. Pkd1 deficiency and smoking showed independent and additive effects on reducing renal levels of glutathione. Systolic function and several cardiac structural parameters were also negatively affected by smoking and the Pkd1-deficient status, following independent and additive patterns. Smoking did not increase, however, cardiac apoptosis or fibrosis in cystic and noncystic mice. Notably, smoking promoted a much higher reduction in body weight in Pkd1-deficient than in noncystic animals. Our findings show that smoking aggravated the renal and cardiac phenotypes of Pkd1-deficient cystic mice, suggesting that similar effects may occur in human ADPKD.

Static and Dynamic Prediction of Chronic Renal Disease Progression Using Longitudinal Clinical Data from Taiwan’s National Prevention Programs

Kidney diseases can cause severe morbidity, mortality, and health burden. Determining the risk factors associated with kidney damage and deterioration has become a priority for the prevention and treatment of kidney disease. This study followed 1042 chronic kidney disease (CKD) patients with Stage 3–5 kidney disease who were treated at a public veteran’s hospital through the national prevention program. A total of 12.5 years of records of clinical measurements were collected and analyzed using dynamic and static Cox hazard models to predict the progression to dialysis treatment. The results showed that the statistical significance of several variables in patients with Stage 3–5 CKD was attenuated while the dynamic model was being used. The estimated glomerular filtration rate (eGFR) and urine protein to creatinine ratio (PCR) had the powerful ability to predict the progression of CKD patients with Stage 3a and Stage 3b–5 kidney disease, whereas serum calcium was also predictive for the progression of Stages 3b–5 CKD. Because these two sub-stages of Stage 3 CKD are often associated with differences in routine measurements and the risk analysis of renal dialysis, future research can use this predictive model as a reference while similar prevention programs are implemented.

Case Report: A Rare Truncating Variant of the CFHR5 Gene in IgA Nephropathy

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Despite appropriate therapy, 20–40% of affected-patients evolve toward end-stage kidney disease (ESKD). Mesangial IgA deposits are the hallmark of IgAN, and complement deposition (C3) seems to differentiate latent IgA mesangial deposits from active IgAN. Atypical hemolytic uremic syndrome (aHUS), another disease in which complement plays an important role, is caused by inherited or acquired deregulation of the alternative pathway (AP) of complement. A subgroup of IgAN shows thrombotic microangiopathy (TMA) lesions in kidney biopsies, the histological characteristic of aHUS. Genetic variants of complement Factor H (CFH), known to be present in aHUS, have been associated with rapidly progressive forms of IgAN and a clinical pattern of aHUS. Genome-wide association studies (GWAS) have confirmed that the 1q32 region, encoding for CFH and its related proteins, is an IgAN susceptibility locus. A 30 year-old man was admitted for seizures and malignant hypertension. The kidney biopsy showed IgAN associated with features of TMA. Despite five plasma exchanges, the patient remained dialysis-dependent, and ESKD was diagnosed. Functional and genetic complement analysis were performed. A monoallelic protein-truncating, likely loss-of-function variant was identified in the CFHR5 gene. Eculizumab is the treatment of aHUS. As it has been successfully used in a few cases of rapidly progressive IgAN, it was decided to administer eculizumab over a period of 12 months in addition to the usual immunosuppression for renal transplantation. After a follow-up of 3 years, there was no clinical disease recurrence. Systematic biologic and genetic screening of complement in individuals with IgAN might be useful to better delineate the role of the AP of complement in renal disease progression, and this may have therapeutic implications.

MO284UTILITY OF SERUM IGA/C3 RATIO IN PREDICTING RENAL DISEASE PROGRESSION IN IGA NEPHROPATHY

Background and Aims: IgA nephropathy is the most prevalent and predominantly slow progressing glomerular disease. Risk prediction tools like the international IgAN help to guide the prognosis in this group of patients. The IgA/C3 ratio has been shown to be a useful predictor of poor outcomes in Chinese cohort but such a study is lacking in the Caucasians. The study aims to investigate the utility of IgA/C3 score in predicting renal outcome in 5 years (50% decline in five years or reaching ESRD) in a Caucasian cohort. Method All available patients with biopsy-proven IgA nephropathy in our centre between January 2001 and December 2013 were included in this observational study (115 patients). Baseline (biopsy date) data relevant to the scores including demographics, laboratory and the histopathological features were collated at the time of biopsy. Follow up data on renal functions and renal outcome (50% decline in eGFR at 5 years) were collected until an arbitrary end date 31/12/2018. IgA/C3 ratio was available in 46 (40%) of the patients and this cohort wase split into two groups based on IgA/C3 ratio (A- ratio </=3 and B- ratio >3) and analysed. Results We had a total of 115 patients recorded over this 13-year period. The median age of our cohort at time of biopsy was 41 years with a predominance of male gender (71%). At baseline 84% were hypertensive and 11% diabetic. 77% were on a renin-angiotensin blocker, with 53% being on a statin. At 2 years follow-up the median decline in estimated glomerular filtration (eGFR) between the groups was similar (Group- A 2.65 ml/min vs Group- B 2 ml/min, p=0.557). At 5 years, the median decline in eGFR was higher in Group B though not statistically significant (9.3ml/min vs 4.6ml/min, p=0.475) (Table-1). At 5 years a higher IGA/C3 ratio was showing appositive corelation to the decline in eGFR (Figure–2). Conclusion Patients with higher IgA/C3 ratio had a higher drop in estimated glomerular filtration rate at five years of follow-up. Validation in a larger sample is warranted before this can be used clinically.