Carbamylated Proteins in Renal Disease: Aggravating Factors or Just Biomarkers?

Carbamylation is a nonenzymatic post-translational modification resulting from the reaction between cyanate, a urea by-product, and proteins. In vivo and in vitro studies have demonstrated that carbamylation modifies protein structures and functions, triggering unfavourable molecular and cellular responses. An enhanced formation of carbamylation-derived products (CDPs) is observed in pathological contexts, especially during chronic kidney disease (CKD), because of increased blood urea. Significantly, studies have reported a positive correlation between serum CDPs and the evolutive state of renal failure. Further, serum concentrations of carbamylated proteins are characterized as strong predictors of mortality in end-stage renal disease patients. Over time, it is likely that these modified compounds become aggravating factors and promote long-term complications, including cardiovascular disorders and inflammation or immune system dysfunctions. These poor clinical outcomes have led researchers to consider strategies to prevent or slow down CDP formation. Even if growing evidence suggests the involvement of carbamylation in the pathophysiology of CKD, the real relevance of carbamylation is still unclear: is it a causal phenomenon, a metabolic consequence or just a biological feature? In this review, we discuss how carbamylation, a consequence of renal function decline, may become a causal phenomenon of kidney disease progression and how CDPs may be used as biomarkers.

Microhematuria Enhances the Risks of Relapse and Renal Progression in Primary Membranous Nephropathy

Objective: To determine whether there is an association between microhematuria and relapse or kidney disease progression in patients with primary membranous nephropathy (PMN).Methods: A cohort of 639 patients with biopsy-proven PMN from two centers was followed for a median of 40 months. The exposures were initial hematuria, time-averaged hematuria, and cumulative duration of hematuria. The outcomes were relapse and renal progression, which were defined by a 40% reduction in renal function or end-stage renal disease. Cox proportional hazards regression and competing risk analyses were performed to yield hazard ratios (HRs) and subdistribution hazard ratios (sHRs) with 95% confidence intervals (CIs). Sensitivity and interaction analyses were also performed.Results: After adjusting for confounders, a higher level of initial hematuria was associated with a 1.43 (95% CI, 1.15–1.78) greater hazard of relapse. Worsening hematuria remarkably increased the risk of short-term relapse (HR, 4.64; 3.29–6.54). Time-averaged hematuria (sHR, 1.35; 1.12–1.63) and cumulative duration of hematuria (sHR, 1.17; 1.02–1.34) were independent predictors of renal progression. Hematuria remission was related to a reduced risk of renal progression over time in patients with positive microhematuria (sHR, 0.63; 0.41–0.96).Conclusions: A higher level of initial hematuria was a remarkable predictor of relapse in patients with PMN, and the magnitude and persistence of microhematuria were independently associated with kidney disease progression.

Association of Polypharmacy with Kidney Disease Progression in Adults with CKD

Background and objectivePolypharmacy is common in patients with CKD and reportedly associated with adverse outcomes. However, its effect on kidney outcomes among patients with CKD has not been adequately elucidated. Hence, this investigation was aimed at exploring the association between polypharmacy and kidney failure requiring KRT.Design, setting, participants, and measurementsWe retrospectively examined 1117 participants (median age, 66 years; 56% male; median eGFR, 48 ml/min per 1.73 m2) enrolled in the Fukushima CKD Cohort Study to investigate the association between the number of prescribed medications and adverse outcomes such as kidney failure, all-cause mortality, and cardiovascular events in Japanese patients with nondialysis-dependent CKD. Polypharmacy and hyperpolypharmacy were defined as the regular use of 5–9 and ≥10 medications per day, respectively.ResultsThe median number of medications was eight; the prevalence of polypharmacy and hyperpolypharmacy was each 38%. During the observation period (median, 4.8 years), 120 developed kidney failure, 153 developed cardiovascular events, and 109 died. Compared with the use of fewer than five medications, adjusted hazard ratios (95% confidence intervals) associated with polypharmacy and hyperpolypharmacy were 2.28 (1.00 to 5.21) and 2.83 (1.21 to 6.66) for kidney failure, 1.60 (0.85 to 3.04) and 3.02 (1.59 to 5.74) for cardiovascular events, and 1.25 (0.62 to 2.53) and 2.80 (1.41 to 5.54) for all-cause mortality.ConclusionsThe use of a high number of medications was associated with a high risk of kidney failure, cardiovascular events, and all-cause mortality in Japanese patients with nondialysis-dependent CKD under nephrology care.