Background: Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such estimates. We explored effects of 24‐h height‐indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFR_Cr), muscle mass‐independent cystatin C (eGFR_Cys), and the combination of creatinine and cystatin C (eGFR_Cr‐Cys) and predicted probabilities of discordant classification given age, sex, and CER index.Methods: We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFR_Cr <60 mL/min per 1.73 m² when eGFR_Cys was <60 mL/min/1.73 m². Baseline effects of age and sex on CER index were quantified with linear models using generalized least squares. Baseline effects of CER index on eGFR were quantified with quantile regression and logistic regression. Effects of annual changes in CER index on trajectories of eGFR were quantified with linear mixed‐effects models. Missing observations in covariates were multiply imputed.Results: Mean (SD) CER index was 8.0 (1.7) and 6.1 (1.3) mmol/24 h per meter in male and female participants, respectively (P_difference < 0.001). In male participants, baseline CER index increased until 45 years of age followed by a gradual decrease, whereas a gradual decrease across the entire range of age was observed in female participants. For a 70‐year‐old male participant with low muscle mass (CER index of 2 mmol/24 h per meter), predicted baseline eGFR_Cr and eGFR_Cys disagreed by 24.7 mL/min/1.73 m² (and 30.1 mL/min/1.73 m² when creatinine was not corrected for race). Percentages (95% CI) of discordant classification in male and female participants aged 60 years and older with low muscle mass were 18.5% (14.8–22.1%) and 15.2% (11.4–18.5%), respectively. For a 70‐year‐old male participant who lost muscle during follow‐up, eGFR_Cr and eGFR_Cys disagreed by 1.5, 5.0, 8.5, and 12.0 mL/min/1.73 m² (and 6.7, 10.7, 13.5, and 15.9 mL/min/1.73 m² when creatinine was not corrected for race) at baseline, 5 years, 10 years, and 15 years of follow‐up, respectively.Conclusions: Low muscle mass may cause considerable overestimation of single measurements of eGFR_Cr. Muscle wasting may cause spurious overestimation of repeatedly measured eGFR_Cr. Implementing muscle mass‐independent markers for estimating renal function, like cystatin C as superior alternative to creatinine, is crucial to accurately assess renal function in settings of low muscle mass or muscle wasting. This would also eliminate the negative consequences of current race‐based approaches.

Coronavirus disease 2019 (COVID-19) is a contagious, life-threatening infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent findings indicate an increased risk of acute kidney injury during COVID-19. The pathophysiological mechanisms leading to acute kidney injury in COVID-19 are unclear, but may include direct cytopathic effects of the virus on kidney tubular and endothelial cells, indirect damage caused by virus-induced cytokine release, and kidney hypoperfusion due to a restrictive fluid strategy. In this case-report we propose an additional pathophysiological mechanism. We describe two cases in which patients with COVID-19 developed a decrease in kidney function due to kidney infarction. These patients did not have atrial fibrillation. One of these patients was treated with therapeutic doses of low molecular weight heparin, whereafter no further deterioration of kidney function was observed. Our findings implicate that the differential diagnosis of acute kidney injury in COVID-19 patients should include kidney infarction, which may have important preventive and therapeutic implications.

To accommodate the loss of the plethora of functions of the kidneys, patients with chronic kidney disease require many dietary adjustments, including restrictions on the intake of protein, phosphorus, sodium and potassium. Plant-based foods are increasingly recommended as these foods contain smaller amounts of saturated fatty acids, protein and absorbable phosphorus than meat, generate less acid and are rich in fibers, polyunsaturated fatty acids, magnesium and potassium. Unfortunately, these dietary recommendations cannot prevent the occurrence of many symptoms, which typically include fatigue, impaired cognition, myalgia, muscle weakness, and muscle wasting. One threat coming with the recommendation of low-protein diets in patients with non-dialysis-dependent chronic kidney disease (CKD) and with high-protein diets in patients with dialysis-dependent CKD, particularly with current recommendations towards proteins coming from plant-based sources, is that of creatine deficiency. Creatine is an essential contributor in cellular energy homeostasis, yet on a daily basis 1.6–1.7% of the total creatine pool is degraded. As the average omnivorous diet cannot fully compensate for these losses, the endogenous synthesis of creatine is required for continuous replenishment. Endogenous creatine synthesis involves two enzymatic steps, of which the first step is a metabolic function of the kidney facilitated by the enzyme arginine:glycine amidinotransferase (AGAT). Recent findings strongly suggest that the capacity of renal AGAT, and thus endogenous creatine production, progressively decreases with the increasing degree of CKD, to become absent or virtually absent in dialysis patients. We hypothesize that with increasing degree of CKD, creatine coming from meat and dairy in food increasingly becomes an essential nutrient. This phenomenon will likely be present in patients with CKD stages 3, 4 and 5, but will likely be most pronouncedly present in patients with dialysis-dependent CKD, because of the combination of lowest endogenous production of creatine and unopposed losses of creatine into the dialysate. It is likely that these increased demands for dietary creatine are not sufficiently met. The result of which, may be a creatine deficiency with important contributions to the sarcopenia, fatigue, impaired quality of life, impaired cognition, and premature mortality seen in CKD.

Background: Serum creatinine is used as initial test to derive eGFR and confirmatory testing with serum cystatin C is recommended when creatinine‐based eGFR is considered less accurate due to deviant muscle mass. Low muscle mass is associated with increased risk of premature mortality. However, the associations of serum creatinine and cystatin C with muscle mass and mortality remain unclear and require further investigation to better inform clinical decision‐making.Methods: We included 8437 community‐dwelling adults enrolled in the Dutch PREVEND study and 5033 in the US NHANES replication cohort. Associations of serum creatinine and/or cystatin C with muscle mass surrogates and mortality were quantified with linear and Cox proportional hazards regression, respectively. Missing observations in covariates were multiply imputed using Substantive Model Compatible Fully Conditional Specification.Results: Mean (SD) age of PREVEND and NHANES participants (50% and 48% male) were 49.8 (12.6) and 48.7 (18.7) years, respectively. Median (Q1–Q3) serum creatinine and cystatin C were 71 (61–80) and 80 (62–88) μmol/L and 0.87 (0.78–0.98) and 0.91 (0.80–1.10) mg/L, respectively. Higher serum creatinine was associated with greater muscle mass, while serum cystatin C was not associated with muscle mass. Adjusting both markers for each other strengthened the positive relationship between serum creatinine and muscle mass and revealed an inverse association between serum cystatin C and muscle mass. In the PREVEND cohort, 1636 (19%) deaths were registered over a median follow‐up of 12.9 (5.8–16.3) years with a 10‐year mortality rate (95% CI) of 7.6% (7.1–8.2%). In the NHANES, 1273 (25%) deaths were registered over a median follow‐up of 17.9 (17.3–18.5) years with a 10‐year mortality rate of 13.8% (12.8–14.7%). Both markers were associated with increased mortality. Notably, when adjusted for each other, higher serum creatinine was associated with decreased mortality, while the association between serum cystatin C and increased mortality strengthened. The shapes of the associations in the PREVEND study and NHANES were almost identical.Conclusions: The strong association between serum creatinine and muscle mass challenges its reliability as GFR marker, necessitating a more cautious approach in its clinical use. The minimal association between serum cystatin C and muscle mass supports its increased use as a more reliable alternative in routine clinical practice.

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent, paralleling the obesity epidemic. Ketone bodies are produced in the liver, but it is currently uncertain whether circulating ketone bodies are increased in the context of NAFLD. We investigated the association between NAFLD and circulating ketone bodies and determined the extent to which NAFLD and circulating ketone bodies are associated with all‐cause mortality.Methods: Plasma ketone bodies were measured by nuclear magnetic resonance spectroscopy in participants of the general population‐based PREVEND study. A fatty liver index (FLI) ≥60 was regarded as a proxy of NAFLD. Associations of an elevated FLI and ketone bodies with all‐cause mortality were investigated using Cox regression analyses.Results: The study included 6,297 participants aged 54 ± 12 years, of whom 1,970 (31%) had elevated FLI. Participants with elevated FLI had higher total ketone bodies (194 [153‐259] vs 170 [133‐243] µmol/L; P < .001) than participants without elevated FLI. During 7.9 [7.8‐8.9] years of follow‐up, 387 (6%) participants died. An elevated FLI was independently associated with an increased risk of mortality (HR: 1.34 [1.06‐1.70]; P = .02). Higher total ketone bodies were also associated with an increased mortality risk (HR per doubling: 1.29 [1.12‐1.49]; P < .001). Mediation analysis suggested that the association of elevated FLI with all‐cause mortality was in part mediated by ketone bodies (proportion mediated: 10%, P < .001).Conclusion: Circulating ketone bodies were increased in participants with suspected NAFLD. Both suspected NAFLD and higher circulating ketone bodies are associated with an increased risk of all‐cause mortality.