Dietary Fiber,Kidney Function,Inflammation, and Mortality Risk

Background and objectives

In the United States population, high dietary fiber intake has been associated with a lower risk of inflammation and mortality in individuals with kidney dysfunction. This study aimed to expand such findings to a Northern European population.

Design, setting, participants, & measurements

Dietary fiber intake was calculated from 7-day dietary records in 1110 participants aged 70–71 years from the Uppsala Longitudinal Study of Adult Men (examinations performed during 1991–1995). Dietary fiber was adjusted for total energy intake by the residual method. Renal function was estimated from the concentration of serum cystatin C, and deaths were registered prospectively during a median follow-up of 10.0 years.

Results

Dietary fiber independently and directly associated with eGFR (adjusted difference, 2.6 ml/min per 1.73 m² per 10 g/d higher; 95% confidence interval [95% CI], 0.3 to 4.9). The odds of C-reactive protein >3 mg/L were lower (linear trend, P=0.002) with higher fiber quartiles. During follow-up, 300 participants died (incidence rate of 2.87 per 100 person-years at risk). Multiplicative interactions were observed between dietary fiber intake and kidney dysfunction in the prediction of mortality. Higher dietary fiber was associated with lower mortality in unadjusted analysis. These associations were stronger in participants with kidney dysfunction (eGFR<60 ml/min per 1.73 m²) (hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.98) than in those without (HR, 1.30; 95% CI, 0.76 to 2.22; P value for interaction, P=0.04), and were mainly explained by a lower incidence of cancer-related deaths (0.25; 95% CI, 0.10 to 0.65) in individuals with kidney dysfunction versus individuals with an eGFR≥60 ml/min per 1.73 m² (1.61; 95% CI, 0.69 to 3.74; P value for interaction, P=0.01).

Conclusions

High dietary fiber was associated with better kidney function and lower inflammation in community-dwelling elderly men from Sweden. High dietary fiber was also associated with lower (cancer) mortality risk, especially in individuals with kidney dysfunction.     

Association between Serum Inorganic Phosphorus Levels and Adverse Outcomes in Chronic Kidney Disease: The Fukushima CKD Cohort Study

Objective Although an association between serum inorganic phosphorus levels and a poor prognosis has been noted in dialysis patients, these associations have been insufficiently reported in non-dialysis-dependent chronic kidney disease (NDD-CKD) patients. This study attempted to determine the association between serum inorganic phosphorus levels and adverse outcomes in Japanese NDD-CKD patients. Methods We investigated the relationships between serum inorganic phosphorus levels and adverse outcomes, such as kidney events, cardiovascular events, and all-cause death, in Japanese NDD-CKD patients using longitudinal data from the Fukushima CKD Cohort Study with a median follow-up period of 2.8 years. The study evaluated 822 patients with NDD-CKD enrolled between June 2012 and July 2014. A kidney event was defined as a combination of doubling of the baseline serum creatinine or end-stage renal disease. Cox regression was performed to analyze the relationships of the quartile of the serum inorganic phosphorus with kidney events, cardiovascular events, and all-cause death. Results The frequency of kidney events per 1,000 person-years exhibited a U-shaped distribution based on serum inorganic phosphorus levels, with these levels not significantly associated with an increased risk of cardiovascular events and all-cause death. A multivariable Cox regression analysis showed an increased risk of kidney events for the highest quartile of the serum inorganic phosphorus levels (≥3.7 mg/dL) versus the second quartile (2.9-3.2 mg/dL, hazard ratio, 3.30; 95% confidence interval, 1.50-7.28; p=0.003). There were no significant associations between the serum calcium levels and adverse outcomes. Conclusion Serum inorganic phosphorus levels were associated with an increased risk of CKD progression in Japanese NDD-CKD patients.     

Relation of Serum Lipids and Lipoproteins with Progression of CKD: The CRIC Study

Background and objectives

Hyperlipidemia is common in patients with CKD. The objective of this study was to evaluate whether measures of plasma lipids and lipoproteins predict progression of kidney disease in patients with CKD.

Design, setting, participants, & measurements

Prospective cohort study in adults (n=3939) with CKD aged 21–74 years recruited between 2003 and 2008 and followed for a median of 4.1 years. At baseline, total cholesterol, triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), apoA-I , apoB, and lipoprotein(a) [Lp(a)] were measured. The outcomes were composite end point of ESRD or 50% decline in eGFR from baseline (rate of change of GFR).

Results

Mean age of the study population was 58.2 years, and the mean GFR was 44.9 ml/min per 1.73 m²; 48% of patients had diabetes. None of the lipid or lipoprotein measures was independently associated with risk of the composite end point or rate of change in GFR. However, there were significant (P=0.01) interactions by level of proteinuria. In participants with proteinuria<0.2 g/d, 1-SD higher LDL-C was associated with a 26% lower risk of the renal end point (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.59 to 0.92; P=0.01), and 1-SD higher total cholesterol was associated with a 23% lower risk of the renal end point (HR, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In participants with proteinuria>0.2 g/d, neither LDL-C (HR, 0.98; 95% CI, 0.98 to 1.05) nor total cholesterol levels were associated with renal outcomes. Treatment with statins was reported in 55% of patients and was differential across lipid categories.

Conclusions

In this large cohort of patients with CKD, total cholesterol, triglycerides, VLDL-C, LDL-C, HDL-C, apoA-I, apoB, and Lp(a) were not independently associated with progression of kidney disease. There was an inverse relationship between LDL-C and total cholesterol levels and kidney disease outcomes in patients with low levels of proteinuria.     

Self-Rated Health and Adverse Events in CKD

Background and objectives

Little is known about the utility of self-rated general health assessments in persons with moderate-to-severe CKD. This study examined the ability of a single self-rated health measure to predict all-cause mortality and kidney disease progression in a cohort of 443 patients with stages 3–4 CKD, recruited between 2005 and 2011, and followed until the end of 2012. The performance of models incorporating self-rated health measures was compared with previously published predictive models and more complex models comprising a multibiomarker panel.

Design, setting, participants, & measurements

Participants were asked “In general, would you say your health is excellent, very good, good, fair, or poor?” Outcomes examined were time to all-cause mortality, kidney disease progression (initiation of RRT or 30% loss of eGFR), and a composite of these events. Model performances were compared using a nonparametric area under the curve (AUC) analysis.

Results

Over a median follow-up of 3.3 years, 118 (27%) participants died and 138 (31%) had progression of kidney disease. Fair-to-poor self-rated health status was associated with significantly greater risks of mortality (fully adjusted hazard ratio [HR] for relative to good-to-excellent self-rated health, 2.76; 95% confidence interval [95% CI], 1.28 to 5.89), kidney disease progression (HR, 1.94; 95% CI, 1.49 to 2.56), and the combined end point (HR, 2.21; 95% CI, 1.66 to 2.96). For 3-year mortality prediction, the self-rated health model (AUC, 0.80; 95% CI, 0.76 to 0.85) had significantly higher AUCs than the base model (AUC, 0.71; 95% CI, 0.66 to 0.76) and the multibiomarker panel model (AUC, 0.74; 95% CI, 0.68 to 0.80) (P=0.03 and P=0.04, respectively).

Conclusions

A single, easily obtained measure of self-rated health helps identify patients with CKD at high risk of mortality and kidney disease progression. Routine evaluation of self-rated health may help target individuals who might benefit from more intensive monitoring strategies.     

A Patient with Heart Failure and Worsening Kidney Function

There is high prevalence of CKD, defined by reduced GFR, in patients with heart failure. Reduced kidney function is associated with increased morbidity and mortality in this patient population. The cardiorenal syndrome (CRS) involves a bidirectional relationship between the heart and kidneys whereby dysfunction in either may exacerbate the function of the other, but this syndrome has been difficult to precisely define because it has many complex physiologic, biochemical, and hormonal abnormalities. The pathophysiology of CRS is not completely understood, but potential mechanisms include reduced kidney perfusion due to decreased forward flow, increased right ventricular and venous pressure, and neurohormonal adaptations. Treatment options include inotropic medications; diuretics; ultrafiltration; and medications, such as β-blockers, inhibitors of the renin-angiotensin-aldosterone system, and more novel treatments that focus on unique aspects of the pathophysiology. Recent observational studies suggest that treatments that result in a decrease in venous pressure and lead to hemoconcentration may be associated with improved outcomes. Patients with CRS that is not responsive to medical interventions should be considered for ventricular assist devices, heart transplantation, or combined heart and kidney transplantation.     

Promoting Kidney Function Recovery in Patients with AKI Requiring RRT

AKI requiring RRT is associated with high mortality, morbidity, and long-term consequences, including CKD and ESRD. Many patients never recover kidney function; in others, kidney function improves over a period of many weeks or months. Methodologic constraints of the available literature limit our understanding of the recovery process and hamper adequate intervention. Current management strategies have focused on acute care and short-term mortality, but new data indicate that long-term consequences of AKI requiring RRT are substantial. Promotion of kidney function recovery is a neglected focus of research and intervention. This lack of emphasis on recovery is illustrated by the relative paucity of research in this area and by the lack of demonstrated effective management strategies. In this article the epidemiologic implications of kidney recovery after AKI requiring RRT are discussed, the available literature and its methodologic constraints are reviewed, and strategies to improve the understanding of factors that affect kidney function recovery are proposed. Measures to promote kidney function recovery are a serious unmet need, with a great potential to improve short- and long-term patient outcomes.     

Risk Factors for CKD Progression: Overview of Findings from the CRIC Study

The Chronic Renal Insufficiency Cohort (CRIC) Study is an ongoing, multicenter, longitudinal study of nearly 5500 adults with CKD in the United States. Over the past 10 years, the CRIC Study has made significant contributions to the understanding of factors associated with CKD progression. This review summarizes findings from longitudinal studies evaluating risk factors associated with CKD progression in the CRIC Study, grouped into the following six thematic categories: (1) sociodemographic and economic (sex, race/ethnicity, and nephrology care); (2) behavioral (healthy lifestyle, diet, and sleep); (3) genetic (apoL1, genome-wide association study, and renin-angiotensin-aldosterone system pathway genes); (4) cardiovascular (atrial fibrillation, hypertension, and vascular stiffness); (5) metabolic (fibroblast growth factor 23 and urinary oxalate); and (6) novel factors (AKI and biomarkers of kidney injury). Additionally, we highlight areas where future research is needed, and opportunities for interdisciplinary collaboration.     

Acute Kidney Injury,Microvascular Rarefaction,and Estimated Glomerular Filtration Rate in Kidney Transplant Recipients

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The Continuum of Acid Stress

Acid-related injury from chronic metabolic acidosis is recognized through growing evidence of its deleterious effects, including kidney and other organ injury. Progressive acid accumulation precedes the signature manifestation of chronic metabolic acidosis, decreased plasma bicarbonate concentration. Acid accumulation that is not enough to manifest as metabolic acidosis, known as eubicarbonatemic acidosis, also appears to cause kidney injury, with exacerbated progression of CKD. Chronic engagement of mechanisms to mitigate the acid challenge from Western-type diets also appears to cause kidney injury. Rather than considering chronic metabolic acidosis as the only acid-related condition requiring intervention to reduce kidney injury, this review supports consideration of acid-related injury as a continuum. This “acid stress” continuum has chronic metabolic acidosis at its most extreme end, and high-acid-producing diets at its less extreme, yet detrimental, end.     

Progression of Pediatric CKD of Nonglomerular Origin in the CKiD Cohort

Background and objectives

Congenital anomalies of the kidney and urinary tract and genetic disorders cause most cases of CKD in children. This study evaluated the relationships between baseline proteinuria and BP and longitudinal changes in GFR in children with these nonglomerular causes of CKD.

Design, setting, participants, & measurements

Urine protein-to-creatinine ratio, casual systolic and diastolic BP (normalized for age, sex, and height), and GFR decline were assessed in the prospective CKD in Children cohort study.

Results

A total of 522 children, median age 10 years (interquartile range, 7, 14 years) with nonglomerular CKD were followed for a median of 4.4 years. The mean baseline GFR in the cohort was 52 ml/min per 1.73 m² (95% confidence interval [95% CI], 50 to 54) and declined 1.3 ml/min per 1.73 m² per year on average (95%CI, 1.6 to 1.1). A 2-fold higher baseline urine protein-to-creatinine ratio was associated with an accelerated GFR decline of 0.3 ml/min per 1.73 m² per year (95% CI, 0.4 to 0.1). A 1-unit higher baseline systolic BP z-score was associated with an additional GFR decline of 0.4 ml/min per 1.73 m² per year (95% CI, 0.7 to 0.1). Among normotensive children, larger GFR declines were associated with larger baseline urine protein-to-creatinine ratios; eGFR declines of 0.8 and 1.8 ml/min per 1.73 m² per year were associated with urine protein-to-creatinine ratio <0.5 and ≥0.5 mg/mg, respectively. Among children with elevated BP, average GFR declines were evident but were not larger in children with higher levels of proteinuria.

Conclusions

Baseline proteinuria and systolic BP levels are independently associated with CKD progression in children with nonglomerular CKD.     

Nephrologist Follow-Up versus Usual Care after an Acute Kidney Injury Hospitalization (FUSION): A Randomized Controlled Trial

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Serum Creatinine Changes Associated with Critical Illness and Detection of Persistent Renal Dysfunction after AKI

Background and objectives

AKI is a risk factor for development or worsening of CKD. However, diagnosis of renal dysfunction by serum creatinine could be confounded by loss of muscle mass and creatinine generation after critical illness.

Design, setting, participants, & measurements

A retrospective, single center analysis of serum in patients surviving to hospital discharge with an intensive care unit admission of 5 or more days between 2009 and 2011 was performed.

Results

In total, 700 cases were identified, with a 66% incidence of AKI. In 241 patients without AKI, creatinine was significantly lower (P<0.001) at hospital discharge than admission (median, 0.61 versus 0.88 mg/dl; median decrease, 33%). In 160 patients with known baseline, discharge creatinine was significantly lower than baseline in all patients except those patients with severe AKI (Kidney Disease Improving Global Outcomes category 3), who had no significant difference. In a multivariable regression model, median duration of hospitalization was associated with a predicted 30% decrease (95% confidence interval, 8% to 45%) in creatinine from baseline in the absence of AKI; after allowing for this effect, AKI was associated with a 29% (95% confidence interval, 10% to 51%) increase in predicted hospital discharge creatinine. Using a similar model to exclude the confounding effect of prolonged major illness on creatinine, 148 of 700 patients (95% confidence interval, 143 to 161) would have eGFR<60 ml/min per 1.73 m² at hospital discharge compared with only 63 of 700 patients using eGFR based on unadjusted hospital creatinine (a 135% increase in potential CKD diagnoses; P<0.001).

Conclusion

Critical illness is associated with significant falls in serum creatinine that persist to hospital discharge, potentially causing inaccurate assessment of renal function at discharge, particularly in survivors of AKI. Prospective measurements of GFR and creatinine generation are required to confirm the significance of these findings.     

Nonprogressive Kidney Dysfunction and Outcomes in Older Adults with Chronic Kidney Disease

OBJECTIVES: To determine whether a subgroup of patients with severe but nonprogressive renal dysfunction exist and to characterize this subgroup. DESIGN: Retrospective longitudinal monocentric cohort study. SETTING: Nephrology clinic for chronic kidney disease (CKD). PARTICIPANTS: Between January 1998 and December 2004, 177 consecutive patients aged 80 and older were referred for the first time to nephrology for CKD. MEASUREMENTS: The characteristics of patients with nonprogressive or progressive CKD (estimated glomerular filtration rate (eGFR) decline of < and ≥1 mL/min per 1.73 m² per year, respectively) were observed and analyzed, and their risk of dying or requiring dialysis was determined. After exclusion of subjects requiring immediate dialysis or followed up for less than 6 months, 138 patients remained eligible for analysis. RESULTS: In the study cohort (initial mean eGFR 31.8 mL/min per 1.73 m², median follow‐up 47 months), patients were more likely to require dialysis than to die; 36% of patients had nonprogressive CKD. This characteristic, predicted by low proteinuria, lack of hypertension, and low cardiovascular comorbidity, was the strongest predictor of global survival. In progressors, two independent covariates (eGFR <30 mL/min per 1.73 m² and hemoglobin ≤11 g/dL at inclusion) predicted the risk of requiring dialysis. CONCLUSION: More than one‐third of subjects aged 80 and older referred to a nephrology center had severe but nonprogressive kidney dysfunction. This subgroup had a lower mortality rate than those with progressive kidney dysfunction. Simple covariates (low proteinuria, lack of hypertension, low cardiovascular comorbidity) predicted nonprogression of CKD. Distant nephrology follow‐up of such patients may be sufficient.     

Association of a Polymorphism in a Gene Encoding a Urate Transporter with CKD Progression

Background and objectives

Hyperuricemia predicts a high risk for CKD progression but there is no large clinical trial in humans indicating that this relationship is causal in nature. The rs734553 single-nucleotide polymorphism (SNP) of the GLUT9 urate transporter gene was strongly associated with uric acid (UA) levels in a large meta-analysis.

Design, setting, participants, & measurements

This prospective study adopted the Mendelian randomization approach. The rs734553 SNP was used as an instrumental variable to investigate the relationship between UA and renal outcomes in a cohort of 755 patients with CKD who were enrolled between October 18, 2005, and October 2, 2008. The association between the polymorphism and UA was preliminary confirmed in a series of 211 healthy volunteers enrolled between January 1, 2001, and July 12, 2011, from the same geographic area as the patients with CKD. The study end point was a composite renal–end point (i.e., >30% decrease in the GFR, dialysis, or transplantation). Patients were followed up for a median of 36 months.

Results

In healthy individuals, serum UA levels were highest in homozygotes for the T allele (risk allele), intermediate in heterozygotes for the same allele, and lowest in those without the risk allele (P<0.001), but no such relationship was found in patients with CKD. In the CKD cohort, homozygotes (TT) and heterozygotes (GT) for the risk allele had a 2.35 times higher risk (hazard ratio, 2.35; 95% confidence interval, 1.25 to 4.42; P=0.008) of CKD progression. The risk for CKD progression by rs734553 remained unmodified in analyses adjusting for proteinuria, GFR, and other classical and CKD-peculiar risk factors.

Conclusions

A GLUT9 polymorphism, which is strongly associated with serum UA levels in healthy individuals of the general population with normal renal function, holds a strong predictive power for CKD progression. These findings are compatible with the hypothesis that the link between UA and CKD progression is causal in nature.     

BP and Renal Outcomes in Diabetic Kidney Disease: The Veterans Affairs Nephropathy in Diabetes Trial

Background and objectives

Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease.

Design, setting, participants, & measurements

BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on–treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured.

Results

The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P<0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from <120 to ≥150 mmHg (P=0.02), with a significantly higher hazard ratio for 140–149 versus 120–129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P<0.01), with a significantly higher hazard ratio when mean diastolic BP was 80–89 versus 70–79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was <60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events.

Conclusions

In patients with proteinuric diabetic kidney disease, mean systolic BP ≥140 mmHg and mean diastolic BP ≥80 mmHg were associated with worse renal outcomes.     

Association between Serum Potassium and Outcomes in Patients with Reduced Kidney Function

Background and objectives

Patients with CKD are more likely than others to have abnormalities in serum potassium (K⁺). Aside from severe hyperkalemia, the clinical significance of K⁺ abnormalities is not known. We sought to examine the association of serum K⁺ with mortality and hospitalization rates within narrow eGFR strata to understand how the burden of hyperkalemia varies by CKD severity. Associations were examined between serum K⁺ and discontinuation of medications that block the renin-angiotensin-aldosterone system (RAAS), which are known to increase serum K⁺.

Design, setting, participants, & measurements

A cohort of patients with CKD (eGFR<60 ml/min per 1.73 m²) with serum K⁺ data were studied (n=55,266) between January 1, 2009, and June 30, 2013 (study end). Serum K⁺, eGFR, and covariates were considered on a time-updated basis. Mortality, major adverse cardiovascular events (MACE), hospitalization, and discontinuation of RAAS blockers were considered per time at risk.

Results

During the study, serum K⁺ levels of 5.5–5.9 and ≥6.0 mEq/L were most prevalent at lower eGFR: they were present, respectively, in 1.7% and 0.2% of patient-time for eGFR of 50–59 ml/min per 1.73 m² versus 7.6% and 1.8% of patient-time for eGFR<30 ml/min per 1.73 m². Serum K⁺ level <3.5 mEq/L was present in 1.2%–1.4% of patient-time across eGFR strata. The median follow-up time was 2.76 years. There was a U-shaped association between serum K⁺ and mortality; pooled adjusted incidence rate ratios were 3.05 (95% confidence interval, 2.53 to 3.68) and 3.31 (95% confidence interval, 2.52 to 4.34) for K⁺ levels <3.5 mEq/L and ≥6.0 mEq/L, respectively. Within eGFR strata, there were U-shaped associations of serum K⁺ with rates of MACE, hospitalization, and discontinuation of RAAS blockers.

Conclusions

Both hyperkalemia and hypokalemia were independently associated with higher rates of death, MACE, hospitalization, and discontinuation of RAAS blockers in patients with CKD who were not undergoing dialysis. Future studies are needed to determine whether interventions targeted at maintaining normal serum K⁺ improve outcomes in this population.     

Chronic Kidney Disease and Cognitive Function in Older Adults: Findings from the Chronic Renal Insufficiency Cohort Cognitive Study

OBJECTIVES: To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains, and to determine whether the relationship between chronic kidney disease (CKD) and cognitive function is independent of demographic and clinical factors. DESIGN: Cross‐sectional. SETTING: Chronic Renal Insufficiency Cohort Study. PARTICIPANTS: Eight hundred twenty‐five adults aged 55 and older with CKD. MEASUREMENTS: Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m²) was estimated using the four‐variable Modification of Diet in Renal Disease equation. Cognitive scores on six cognitive tests were compared across eGFR strata using linear regression; multivariable logistic regression was used to examine level of CKD and clinically significant cognitive impairment (score ≤1 standard deviations from the mean). RESULTS: Mean age of the participants was 64.9, 50.4% were male, and 44.5% were black. After multivariable adjustment, participants with lower eGFR had lower cognitive scores on most cognitive domains (P<.05). In addition, participants with advanced CKD (eGFR<30) were more likely to have clinically significant cognitive impairment on global cognition (adjusted odds ratio (AOR) 2.0, 95% CI=1.1–3.9), naming (AOR=1.9, 95% CI=1.0–3.3), attention (AOR=2.4, 95% CI=1.3–4.5), executive function (AOR=2.5, 95% CI=1.9–4.4), and delayed memory (AOR=1.5, 95% CI=0.9–2.6) but not on category fluency (AOR=1.1, 95% CI=0.6–2.0) than those with mild to moderate CKD (eGFR 45–59). CONCLUSION: In older adults with CKD, lower level of kidney function was associated with lower cognitive function on most domains. These results suggest that older patients with advanced CKD should be screened for cognitive impairment.