Low-Dose Rapamycin (Sirolimus) Effects in Autosomal Dominant Polycystic Kidney Disease: An Open-Label Randomized Controlled Pilot Study

Background and objectives

The two largest studies of mammalian target of rapamycin inhibitor treatment of autosomal dominant polycystic kidney disease (ADPKD) demonstrated no clear benefit on the primary endpoint of total kidney volume (TKV) or on eGFR. The present study evaluated two levels of rapamycin on the 12-month change in ¹²⁵I-iothalamate GFR (iGFR) as the primary endpoint and TKV secondarily.

Design, setting, participants, & measurements

In a 12-month open-label pilot study, 30 adult patients with ADPKD were randomly assigned to low-dose (LD) rapamycin (rapamycin trough blood level, 2–5 ng/ml) (LD group, n=10), standard-dose (STD) rapamycin trough level (>5–8 ng/ml) (STD group, n=10), or standard care (SC group, n=10). They were evaluated with iGFR and noncontrast computed tomography.

Results

Change in iGFR at 12 months was significantly higher in the LD group (7.7±12.5 ml/min per 1.73 m²; n=9) than in the SC group (−11.2±9.1 ml/min per 1.73 m²; n=9) (LD versus SC: P<0.01). Change in iGFR at 12 months in the STD group (1.6±12.1 ml/min per 1.73 m²; n=8) was not significantly greater than that in the SC group (P=0.07), but it was in the combined treatment groups (LD+STD versus SC: P<0.01). Neither eGFR calculated by the CKD-Epidemiology Collaboration equation nor TKV (secondary endpoint) changed significantly from baseline to 12 months in any of the groups. On the basis of results of the mixed model, during the study, patients in the LD group had significantly lower trough blood levels of rapamycin (mean range±SD, 2.40±0.64 to 2.90±1.20 ng/ml) compared with those in the STD group (3.93±2.27 to 5.77±1.06 ng/ml) (P<0.01).

Conclusion

Patients with ADPKD receiving LD rapamycin demonstrated a significant increase in iGFR compared with those receiving standard care, without a significant effect on TKV after 12 months.     

Glomerular hyperfiltration and renal progression in children with autosomal dominant polycystic kidney disease

Summary

Background and objectives

The purpose of this study was to determine whether glomerular hyperfiltration (GH) occurring early in autosomal dominant polycystic kidney disease (ADPKD) is indicative of more rapid disease progression in children.

Design, setting, participants, & measurements

One hundred eighty children with ADPKD (ages 4 to 18 years) with normal renal function were examined by renal ultrasound. Renal volume was calculated using a standard formula for a modified ellipsoid. Creatinine clearance was calculated from serum creatinine and 24-hour urine creatinine. GH was defined as creatinine clearance ≥140 ml/min per 1.73 m².

Results

Thirty-two children had GH (mean age 11.4 ± 3.6 years) and 148 had normal renal function (mean age 10.8 ± 3.9 years). Patients with GH at baseline demonstrated an increased rate of total renal volume growth (β: rate of change = +19.3 ± 10.8 cm³/year) over 5 years compared with those without GH at baseline (β = −4.3 ± 7.7 cm³/year), P = 0.008. Those with GH at baseline experienced a faster decline in creatinine clearance in subsequent years (β = −5.0 ± 0.8 ml/min per 1.73 m² per year) compared with those without GH at baseline (β = +1.0 ± 0.4 ml/min per 1.73 m² per year), P < 0.0001.

Conclusions

This study revealed that occurrence of GH in ADPKD children is associated with a significantly faster decline in renal function and higher rate of kidney enlargement over time. GH combined with the increased renal volume may therefore be used as an early marker for a more severe progression of ADPKD in children.     

Long-Term Renal Function after Endovascular Aneurysm Repair

Background and objectives

Endovascular repair (EVAR) is a common treatment for abdominal aortic aneurysm (AAA). However, its long-term effects on renal function remain unclear. We aimed to assess long-term renal dysfunction after EVAR using a contemporary estimate of GFR and to compare long-term renal outcomes in patients after EVAR with open aneurysm repair (OAR) and in patients without an AAA.

Design, settings, participants, & measurements

We performed a nested case-matched analysis of 726 patients (using a prospectively maintained database for repairs that took place between January 2000 and May 2010 in a tertiary center): 121 patients undergoing OAR (with data at baseline and 5 years postrepair) were case matched (age, sex, smoking, diabetes, baseline eGFR) to patients undergoing suprarenal and infrarenal fixation EVAR (242 in each group) and to 121 patients undergoing carotid endarterectomy (CEA) without AAA. Changes in eGFR were compared (1 and 5 years).

Results

The OAR patients lost an average of 7.4 ml/min per 1.73 m² at 5 years (95% confidence interval [95% CI], 4.8 to 10.6), compared with 8.2 ml/min per 1.73 m² (95% CI, 6.5 to 10.8; P<0.001) for infrarenal-fixation EVAR, 16.9 ml/min per 1.73 m² (95% CI, 13.0 to 21.9, P<0.001) for suprarenal-fixation EVAR, and 5.4 ml/min per 1.73 m² (95% CI, 1.7 to 7.5; P<0.001) for CEA. The decrease in eGFR was steeper during the first postoperative year, with each group losing −2.2 ml/min per 1.73 m² (infrarenal-fixation EVAR), −10.7 ml/min per 1.73 m² (suprarenal-fixation EVAR), and −4.6 ml/min per 1.73 m² (OAR), compared with −1.9 ml/min per 1.73 m² for CEA.

Conclusions

Elective EVAR is associated with a significant decline in eGFR after 5 years, which is steeper in the first postoperative year and more pronounced compared with a similar population with atherosclerotic disease.     

Age-specific associations of reduced estimated glomerular filtration rate with concurrent chronic kidney disease complications

Summary

Background and objectives

It has been suggested that moderate reductions in estimated GFR (eGFR) among older adults may not reflect chronic kidney disease (CKD).

Design, setting, participants, & measurements

We examined age-specific (<60, 60 to 69, 70 to 79, and ≥80 years) associations between eGFR level and six concurrent CKD complications among 30,528 participants from the National Health and Nutrition Examination Survey (NHANES) 1988 to 1994 and 1999 to 2006 (n = 8242 from NHANES 2003 to 2006 for hyperparathyroidism). Complications included anemia (hemoglobin <12 g/dl women, <13.5 g/dl men), acidosis (bicarbonate <22 mEq/L), hyperphosphatemia (phosphorus ≥4.5 mg/dl), hypoalbuminemia (albumin <3.5 mg/dl), hyperparathyroidism (intact parathyroid hormone ≥70 pg/ml), and hypertension (systolic/diastolic BP ≥140/90 mmHg or antihypertensive use).

Results

Among participants ≥80 years old, compared with those with estimated GFR (eGFR) ≥60 ml/min per 1.73 m², the multivariable adjusted prevalence ratios (95% confidence interval) associated with eGFR levels of 45 to 59 and <45 ml/min per 1.73 m² were 1.39 (1.11 to1.73) and 2.06 (1.59 to 2.67) for anemia, 1.33 (0.89 to 1.98) and 2.47 (1.52 to 4.00) for acidosis, 1.11 (0.70 to 1.76) and 2.16 (1.36 to 3.42) for hyperphosphatemia, 2.04 (1.39 to 3.00) and 2.83 (1.76 to 4.53) for hyperparathyroidism and 1.09 (1.03 to 1.14), and 1.12 (1.05 to 1.19) for hypertension, respectively. Higher prevalence ratios for these complications at lower eGFR levels were also present at younger ages. Reduced eGFR was associated with hypoalbuminemia only for adults <70.

Conclusions

Reduced eGFR was associated with a higher prevalence of several concurrent CKD complications, regardless of age.     

Serum 25-Hydroxyvitamin D Level and Kidney Function Decline in a Swiss General Adult Population

Background and objectives

Molecular evidence suggests that levels of vitamin D are associated with kidney function loss. Still, population-based studies are limited and few have considered the potential confounding effect of baseline kidney function. This study evaluated the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline, and incidence of CKD and albuminuria.

Design, setting, participants, & measurements

Baseline (2003–2006) and 5.5-year follow-up data from a Swiss adult general population were used to evaluate the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline (annual loss >3 ml/min per 1.73 m²), and incidence of CKD and albuminuria. Serum 25-hydroxyvitamin D was measured at baseline using liquid chromatography–tandem mass spectrometry. eGFR and albuminuria were collected at baseline and follow-up. Multivariate linear and logistic regression models were used considering potential confounding factors.

Results

Among the 4280 people included in the analysis, the mean±SD annual eGFR change was −0.57±1.78 ml/min per 1.73 m², and 287 (6.7%) participants presented rapid eGFR decline. Before adjustment for baseline eGFR, baseline 25-hydroxyvitamin D level was associated with both mean annual eGFR change and risk of rapid eGFR decline, independently of baseline albuminuria. Once adjusted for baseline eGFR, associations were no longer significant. For every 10 ng/ml higher baseline 25-hydroxyvitamin D, the adjusted mean annual eGFR change was −0.005 ml/min per 1.73 m² (95% confidence interval, −0.063 to 0.053; P=0.87) and the risk of rapid eGFR decline was null (odds ratio, 0.93; 95% confidence interval, 0.79 to 1.08; P=0.33). Baseline 25-hydroxyvitamin D level was not associated with incidence of CKD or albuminuria.

Conclusions

The association of 25-hydroxyvitamin D with eGFR decline is confounded by baseline eGFR. Sufficient 25-hydroxyvitamin D levels do not seem to protect from eGFR decline independently from baseline eGFR.     

Residual Associations of Inflammatory Markers with eGFR after Accounting for Measured GFR in a Community-Based Cohort without CKD

Background and objectives

eGFR on the basis of creatinine (eGFRcre) associates differently with cardiovascular disease and mortality than eGFR on the basis of cystatin C (eGFRcys). This may be related to risk factors affecting the level of creatinine and cystatin C along non-GFR pathways, which may confound the association between eGFR and outcome. Nontraditional risk factors are usually not measured in epidemiologic studies of eGFR and cannot be adjusted for to reduce confounding. We examined whether the inflammatory markers soluble TNF receptor type 2 (sTNFR2), C-reactive protein (CRP), and fibrinogen associated differently with eGFR than with measured GFR (mGFR).

Design, setting, participants, & measurements

GFR was measured by iohexol clearance in 1627 middle-aged participants without kidney disease, diabetes, or cardiovascular disease enrolled in the Renal Iohexol Clearance Survey Study from the Sixth Tromsø Study between 2007 and 2009. Generalized estimating equations were used to assess the residual associations between eGFR (eGFRcre, eGFRcys, and eGFR on the basis of creatinine and cystatin C) and the inflammatory markers relative to mGFR.

Results

sTNFR2, CRP, and fibrinogen were associated with a higher eGFRcre after accounting for mGFR in multivariable-adjusted models (2.63 ml/min per 1.73 m²; 95% confidence interval [95% CI], 2.1 to 3.2 per SD increase in sTNFR2, 0.93 ml/min per 1.73 m²; 95% CI, 0.3 to 1.5 per SD increase in log CRP, and 1.19 ml/min per 1.73 m²; 95% CI, 0.6 to 1.8 per SD increase in fibrinogen). sTNFR2 and CRP were inversely associated with eGFRcys (−1.4 ml/min per 1.73 m²; 95% CI, −2.1 to −0.6 per SD increase in sTNFR2, and −0.76 ml/min per 1.73 m²; 95% CI, −1.4 to −0.1 per SD increase in log CRP).

Conclusions

eGFRcre and eGFRcys are associated with inflammatory factors after accounting for mGFR but in opposite directions. These non-GFR–related associations may bias risk estimates by eGFR and, in part, explain the different risks predicted by eGFRcre and eGFRcys in longitudinal studies.     

Urine volume and change in estimated GFR in a community-based cohort study

Summary

Background and objectives

The effect of increased fluid intake on kidney function is unclear. This study evaluates the relationship between urine volume and renal decline over 6 years in a large community-based cohort.

Design, setting, participants, & measurements

This prospective cohort study was undertaken in Canada from 2002 to 2008. We obtained 24-hour urine samples from adult participants with an estimated GFR (eGFR) ≥60ml/min per 1.73 m² at study entry. Percentage annual change in eGFR from baseline was categorized as average decline <1% per year, between 1% and 4.9% (mild-to-moderate decline) or ≥5% (rapid decline).

Results

2148 participants provided valid 24-hour urine samples, grouped as <1 L/d (14.5%); 1 to 1.9 L/d (51.5%); 2 to 2.9 L/d (26.3%); and ≥3 L/d (7.7%). Baseline eGFR for each category of urine volume was 90, 88, 84, and 87 ml/min per 1.73 m², respectively. Overall, eGFR declined by 1% per year, with 10% demonstrating rapid decline and 40% demonstrating mild-to-moderate decline. An inverse, graded relationship was evident between urine volume and eGFR decline: For each increasing category of 24-hour urine volume, percentage annual eGFR decline was progressively slower, from 1.3%, 1.0%, 0.8%, to 0.5%, respectively; P = 0.02. Compared with those with urine volume 1 to 1.9 L/d, those with urine volume ≥3 L/d were significantly less likely to demonstrate mild-to-moderate decline (adjusted odds ratio 0.66; 95% confidence interval 0.46 to 0.94) or rapid decline (adjusted odds ratio 0.46; 95% confidence interval 0.23 to 0.92); adjusted for age, gender, baseline eGFR, medication use for hypertension (including diuretics), proteinuria, diabetes, and cardiovascular disease.

Conclusions

In this community-based cohort, decline in kidney function was significantly slower in those with higher versus lower urine volume.     

Relationship between blood pressure and incident chronic kidney disease in hypertensive patients

Summary

Background and objectives

Hypertension is an important cause of chronic kidney disease (CKD). Identifying risk factors for progression to CKD in patients with normal kidney function and hypertension may help target therapies to slow or prevent decline of kidney function. Our objective was to identify risk factors for development of incident CKD and decline in estimated GFR (eGFR) in hypertensive patients.

Design, setting, participants, & measurements

Cox proportional hazards models were used to assess the relationship between incident CKD (defined as eGFR <60 ml/min per 1.73 m²) and potential risk factors for CKD from a registry of hypertensive patients.

Results

Of 43,305 patients meeting the inclusion criteria, 12.1% (5236 patients) developed incident CKD. Diabetes was the strongest predictor of incident CKD (hazard ratio, 1.96; 95% confidence interval, 1.84 to 2.09) and was associated with the greatest rate of decline in eGFR (−2.2 ml/min per 1.73 m² per year). Time-varying systolic BP was associated with incident CKD with risk increasing above 120 mmHg; each 10-mmHg increase in baseline and time-varying systolic BP was associated with a 6% increase in the risk of developing CKD (hazard ratio, 1.06; 95% confidence interval, 1.04 to 1.08 for both). Time-weighted systolic BP was associated with a more rapid decline in eGFR of an additional 0.2 ml/min per 1.73 m² per year decline for every 10-mmHg increase in systolic BP.

Conclusions

We found that time-varying systolic BP was associated with incident CKD, with an increase in risk above a systolic BP of 120 mmHg among individuals with hypertension.     

Cardiac magnetic resonance assessment of left ventricular mass in autosomal dominant polycystic kidney disease

Summary

Background and objectives

Autosomal dominant polycystic kidney disease (ADPKD) is associated with a substantial cardiovascular disease burden including early onset hypertension, intracranial aneurysms, and left ventricular hypertrophy (LVH). A 41% prevalence of LVH has been reported in ADPKD, using echocardiographic assessment of LV mass (LVM). The HALT PKD study was designed to assess the effect of intensive angiotensin blockade on progression of total kidney volume and LVM. Measurements of LVM were performed using cardiac magnetic resonance (MR).

Design, setting, participants, & measurements

Five hundred forty-three hypertensive patients with GFR >60 ml/min per 1.73 m² underwent MR assessment of LVM at baseline. LVM was adjusted for body surface area and expressed as LVM index (LVMI; g/m²).

Results

Baseline BP was 125.1 ± 14.5/79.3 ± 11.6 mmHg. Average duration of hypertension was 5.79 years. Prior use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was present in 59.5% of patients. The prevalence of LVH assessed using nonindexed LVM (g) was 3.9% (n = 21, eight men and 13 women) and 0.93% (n = 5, one man and four women) using LVMI (g/m²). In exploratory analyses, the prevalence of LVH using LVM indexed to H^2.7, and the allometric index ppLVmass_HW, ranged from 0.74% to 2.23% (n = 4 to 12). Multivariate regression showed significant direct associations of LVMI with systolic BP, serum creatinine, and albuminuria; significant inverse associations with LVMI were found with age and female gender.

Conclusions

The prevalence of LVH in hypertensive ADPKD patients <50 years of age with short duration of hypertension, and prior use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is low. Early BP intervention in ADPKD may have decreased LVH and may potentially decrease cardiovascular mortality.     

Pediatric GFR Estimating Equations Applied to Adolescents in the General Population

Summary

Background and objectives

We examined the distribution of estimated GFR (eGFR) in a healthy cohort of adolescents to inform clinical and research use.

Design, setting, participants, & measurements

Various creatinine-based (n = 3256) and/or cystatin C–based (n = 811) equations, including the recently developed complete and bedside equations from the Chronic Kidney Disease in Children (CKiD) study, were applied to U.S. adolescents 12 to 17 years of age participating in the 1999–2002 National Health and Nutrition Examination Survey (NHANES).

Results

The median serum creatinine and cystatin C were 0.7 mg/dl and 0.83 mg/L, respectively. The distribution of eGFR varied widely, with the median GFR ranging from a low of 96.6 ml/min per 1.73 m² (CKiD) to a high of 140.0 ml/min per 1.73 m² (original Schwartz). The proportions of participants with eGFRs <75 ml/min per 1.73 m² are as follows: bedside CKiD 8.9%, Counahan 6.3%, Leger 0.4%, original Schwartz 0%, Filler 1.3%, Grubb 3.1%, Bouvet 2.5%, CKiD 1.8%, and Zappitelli 5.6%. By any equation examined, no group of participants with eGFR ≤10th percentile had an increased prevalence of comorbid conditions consistent with a low measured GFR.

Conclusions

Most pediatric-specific GFR estimating equations resulted in 25% to 50% of the participants having an eGFR <100 ml/min per 1.73 m². However, participants with eGFR in the lower ranges did not have an increased prevalence of morbidities associated with chronic kidney disease. Clinical validation of creatinine- or cystatin C–based estimated GFRs in healthy children is needed before it is possible to screen the general population for chronic kidney disease.     

Evaluation of Neurocognition in Youth with CKD Using a Novel Computerized Neurocognitive Battery

Background and objectives

Neurocognitive problems in CKD are well documented; time-efficient methods are needed to assess neurocognition in this population. We performed the first study of the efficient 1-hour Penn Computerized Neurocognitive Battery (CNB) in children and young adults with CKD.

Design, setting, participants, & measurements

We administered the Penn CNB cross-sectionally to individuals aged 8–25 years with stage 2–5 CKD (n=92, enrolled from three academic nephrology practices from 2011 to 2014) and matched healthy controls (n=69). We analyzed results from 12 tests in four domains: executive control, episodic memory, complex cognition, and social cognition. All tests measure accuracy and speed; we converted raw scores to age-specific z-scores on the basis of Philadelphia Neurodevelopmental Cohort (n=1790) norms. We analyzed each test in a linear regression with accuracy and speed z-scores as dependent variables and with (1) CKD versus control or (2) eGFR as explanatory variables, adjusted for race, sex, and maternal education.

Results

Patients with CKD (mean±SD eGFR, 48±25 ml/min per 1.73 m²; mean age, 16.3±3.9 years) and controls (mean eGFR, 98±20 ml/min per 1.73 m²; mean age, 16.0±4.0 years) were similar demographically. CKD participants had lower accuracy than controls in tests of complex cognition, with moderate to large effect sizes: −0.53 (95% confidence interval [95% CI], −0.87 to −0.19) for verbal reasoning, −0.52 (95% CI, −0.83 to −0.22) for nonverbal reasoning, and −0.64 (95% CI, −0.99 to −0.29) for spatial processing. For attention, patients with CKD had lower accuracy (effect size, −0.35 [95% CI, −0.67 to −0.03]) but faster response times (effect size, 0.44 [95% CI, 0.04 to 0.83]) than controls, perhaps reflecting greater impulsivity. Lower eGFR was associated with lower accuracy for complex cognition, facial and visual memory, and emotion identification tests.

Conclusions

CKD is associated with lower accuracy in tests of complex cognition, attention, memory, and emotion identification, which related to eGFR. These findings are consistent with traditional neurocognitive testing in previous studies.     

Skin autofluorescence and the association with renal and cardiovascular risk factors in chronic kidney disease stage 3

Summary

Background and objectives

Tissue advanced glycation end products (AGE) accumulation is a measure of cumulative metabolic stress. Assessment of tissue AGE by skin autofluorescence (SAF) correlates well with cardiovascular (CV) outcomes in diabetic, transplant, and dialysis patients, and may be a useful marker of CV risk in earlier stages of chronic kidney disease (CKD).

Design, setting, participants, & measurements

1707 patients with estimated GFR 59 to 30ml/min per 1.73 m² were recruited from primary care practices for the Renal Risk In Derby (RRID) study. Detailed medical history was obtained, and each participant underwent clinical assessment as well as urine and serum biochemistry tests. SAF was assessed (mean of three readings) as a measure of skin AGE deposition using a cutaneous AF device (AGE Reader™, DiagnOptics, Groningen, The Netherlands).

Results

Univariate analysis revealed significant correlations between AF readings and several potential risk factors for cardiovascular disease (CVD) and progression of CKD. SAF readings (arbitrary units) were also significantly higher among males (2.8 ± 0.7 versus 2.7 ± 0.6), diabetics (3.0 ± 0.7 versus 2.7 ± 0.6), patients with evidence of self-reported CVD (2.9 ± 0.7 versus 2.7 ± 0.6), and those with no formal educational qualifications (2.8 ± 0.6 versus 2.6 ± 0.6; P < 0.01 for all). Multivariable linear regression analysis identified hemoglobin, diabetes, age, and eGFR as the most significant independent determinants of higher SAF (standardized coefficients −0.16, 0.13, 0.12, and −0.10, respectively; R² = 0.17 for equation).

Conclusion

Increased SAF is independently associated with multiple CV and renal risk factors in CKD 3. Long-term follow-up will assess the value of SAF as a predictor of CV and renal risk in this population.     

Masked Hypertension and Elevated Nighttime Blood Pressure in CKD: Prevalence and Association with Target Organ Damage

Background and objectives

Masked hypertension and elevated nighttime BP are associated with increased risk of hypertensive target organ damage and adverse cardiovascular and renal outcomes in patients with normal kidney function. The significance of masked hypertension for these risks in patients with CKD is less well defined. The objective of this study was to evaluate the association between masked hypertension and kidney function and markers of cardiovascular target organ damage, and to determine whether this relationship was consistent among those with and without elevated nighttime BP.

Design, setting, participants, & measurements

This was a cross-sectional study. We performed 24-hour ambulatory BP in 1492 men and women with CKD enrolled in the Chronic Renal Insufficiency Cohort Study. We categorized participants into controlled BP, white-coat, masked, and sustained hypertension on the basis of clinic and 24-hour ambulatory BP. We obtained echocardiograms and measured pulse wave velocity in 1278 and 1394 participants, respectively.

Results

The percentages of participants with controlled BP, white-coat, masked, and sustained hypertension were 49.3%, 4.1%, 27.8%, and 18.8%, respectively. Compared with controlled BP, masked hypertension independently associated with low eGFR (−3.2 ml/min per 1.73 m²; 95% confidence interval, −5.5 to −0.9), higher proteinuria (+0.9 unit higher in log₂ urine protein; 95% confidence interval, 0.7 to 1.1), and higher left ventricular mass index (+2.52 g/m^2.7; 95% confidence interval, 0.9 to 4.1), and pulse wave velocity (+0.92 m/s; 95% confidence interval, 0.5 to 1.3). Participants with masked hypertension had lower eGFR only in the presence of elevated nighttime BP (−3.6 ml/min per 1.73 m²; 95% confidence interval, −6.1 to −1.1; versus −1.4 ml/min per 1.73 m²; 95% confidence interval, −6.9 to 4.0, among those with nighttime BP <120/70 mmHg; P value for interaction with nighttime systolic BP 0.002).

Conclusions

Masked hypertension is common in patients with CKD and associated with lower eGFR, proteinuria, and cardiovascular target organ damage. In patients with CKD, ambulatory BP characterizes the relationship between BP and target organ damage better than BP measured in the clinic alone.     

Metabolic Syndrome and Kidney Disease: A Systematic Review and Meta-analysis

Summary

Background and objectives

Observational studies have reported an association between metabolic syndrome (MetS) and microalbuminuria or proteinuria and chronic kidney disease (CKD) with varying risk estimates. We aimed to systematically review the association between MetS, its components, and development of microalbuminuria or proteinuria and CKD.

Design, setting, participants and measurements and population

We searched MEDLINE (1966 to October 2010), SCOPUS, and the Web of Science for prospective cohort confidence interval (CI) studies that reported the development of microalbuminuria or proteinuria and/or CKD in participants with MetS. Risk estimates for eGFR <60 ml/min per 1.73 m² were extracted from individual studies and pooled using a random effects model. The results for proteinuria outcomes were not pooled because of the small number of studies.

Results

Eleven studies (n = 30,146) were included. MetS was significantly associated with the development of eGFR <60 ml/min per 1.73 m² (odds ratio, 1.55; 95% CI, 1.34, 1.80). The strength of this association seemed to increase as the number of components of MetS increased (trend P value = 0.02). In patients with MetS, the odds ratios (95% CI) for development of eGFR <60 ml/min per 1.73 m² for individual components of MetS were: elevated blood pressure 1.61 (1.29, 2.01), elevated triglycerides 1.27 (1.11, 1.46), low HDL cholesterol 1.23 (1.12, 1.36), abdominal obesity 1.19 (1.05, 1.34), and impaired fasting glucose 1.14 (1.03, 1.26). Three studies reported an increased risk for development of microalbuminuria or overt proteinuria with MetS.

Conclusions

MetS and its components are associated with the development of eGFR <60 ml/min per 1.73 m² and microalbuminuria or overt proteinuria.     

Hospital-acquired Acute Kidney Injury: An Analysis of Nadir-to-Peak Serum Creatinine Increments Stratified by Baseline Estimated GFR

Summary

Background and objectives

Serum creatinine (sCr) increments currently used to define acute kidney injury (AKI) do not take into consideration the baseline level of kidney function. The objective of this study was to establish whether baseline estimated GFR (eGFR) provides additional risk stratification to sCr-based increments for defining AKI.

Design, setting, participants, & measurements

29,645 adults hospitalized at an acute care facility were analyzed. Hospital-acquired AKI was defined by calculating the difference between the nadir and subsequent peak sCr.

Results

Different thresholds of nadir-to-peak sCr were found to be independently associated with increased in-hospital mortality according to baseline eGFR strata. A nadir-to-peak sCr minimum threshold of ≥0.2, ≥0.3, and ≥0.5 mg/dl was required to be independently associated with increased in-hospital mortality among patients with baseline eGFR ≥60 ml/min per 1.73 m² (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.13 to 2.47), 30 to 59 ml/min per 1.73 m² (OR 2.69; 95% CI, 1.82 to 3.97), and <30 ml/min per 1.73 m² (OR 2.15; 95% CI 1.02 to 4.51), respectively. There was a significant interaction between the nadir-to-peak sCr and baseline eGFR for in-hospital mortality (P < 0.001). Using these thresholds, survivors of AKI episodes had an increased hospital length of stay and were more likely to be discharged to a facility rather than home. Sensitivity analyses showed a significant interaction between baseline eGFR strata and relative increases in sCr, as well as absolute and relative decreases in eGFR for in-hospital mortality (P < 0.001).

Conclusions

This study suggests that future sCr-based definitions of AKI should take into consideration baseline eGFR.     

Clinical Correlates of Insulin Sensitivity and Its Association with Mortality among Men with CKD Stages 3 and 4

Background and objectives

Insulin resistance participates in the pathogenesis of multiple metabolic and cardiovascular diseases. CKD patients have impaired insulin sensitivity, but the clinical correlates and outcome associations of impaired insulin sensitivity in this vulnerable population are not well defined.

Design, setting, participants, & measurements

The prospective cohort study was from the third examination cycle of the Uppsala Longitudinal Study of Adult Men, a population-based survey of elderly men ages 70–71 years; insulin sensitivity was assessed by glucose disposal rate as measured with euglycemic clamps. Inclusion criterion was eGFR<60 ml/min per 1.73 m² (n=543). Exclusion criteria were incomplete data on euglycemic clamp and diabetes (n=97), leaving 446 men with CKD stages 3 and 4 (eGFR median=51.9 ml/min per 1.73 m²; range=20.2–59.5 ml/min per 1.73 m²).

Results

The mean of glucose disposal rate was 5.4±1.9 mg/kg per minute. In multivariable analysis, the independent clinical correlates of glucose disposal rate were eGFR (slope, 0.02; 95% confidence interval, 0.01 to 0.04), hypertension (−0.48; 95% confidence interval, −0.86 to −0.11), hyperlipidemia (−0.51; 95% confidence interval, −0.84 to −0.18), and body mass index (−0.32; 95% confidence interval, −0.37 to −0.27). During follow-up (median=10.0 years; interquartile range=8.7–11.0 years), 149 participants died. In Cox regression models, glucose disposal rate was not associated with all-cause or cardiovascular mortality. Multiplicative interactions (P<0.05) were observed between glucose disposal rate and physical activity or smoking in total mortality association. After subsequent stratification, glucose disposal rate was an independent correlate of all-cause mortality in smokers (adjusted hazard ratio, 0.72; 95% confidence interval, 0.54 to 0.96 per 1 mg/kg per minute glucose disposal rate increase) and physically inactive individuals (hazard ratio, 0.77; 95% confidence interval, 0.61 to 0.97) but not their counterparts.

Conclusion

eGFR, together with various components of the metabolic syndrome, contributed to explain the variance of insulin sensitivity in men with CKD stages 3 and 4. Insulin sensitivity was associated with a lower mortality risk in individuals who smoked and individuals who were physically inactive.     

Albuminuria and Estimated Glomerular Filtration Rate as Predictors of Diabetic End-Stage Renal Disease and Death

Summary

Background and objectives

We investigated predictive value of albuminuria and estimated GFR (eGFR) for ESRD in Pima Indians with type 2 diabetes.

Design, setting, participants and measurements

Beginning in 1982, 2420 diabetic Pima Indians ≥18 years old were followed until they developed ESRD or died or until December 31, 2005. Individuals were classified at baseline by urinary albumin-to-creatinine ratio (ACR) and by eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. Predictors of ESRD and mortality were examined by proportional hazards regression.

Results

During a mean follow-up of 10.2 years, 287 individuals developed ESRD. Incidence of ESRD among individuals with macroalbuminuria (ACR ≥ 300 mg/g) was 9.3 times that of those with normoalbuminuria (ACR < 30 mg/g), controlled for age, gender, and duration of diabetes. Incidence among individuals with eGFR 15 to 29 ml/min per 1.73 m² was 81.9 times that of those with eGFR 90 to 119 ml/min per 1.73 m². Models that combined albuminuria and eGFR added significant predictive information about risk of ESRD or death compared with models containing eGFR or albuminuria alone. The hazard ratio for ESRD associated with a 10-ml/min per 1.73 m² lower eGFR was 1.36, whereas that associated with an increase in albuminuria category was 2.69; corresponding hazard ratios for death were 1.15 and 1.37.

Conclusions

These results suggest that incorporation of quantitative information about albuminuria into staging systems based on eGFR adds significant prognostic information about risk for diabetic ESRD and death.     

Rate of Kidney Function Decline and Risk of Hospitalizations in Stage 3A CKD

Background and objectives

Risk of hospitalizations is increased in patients with CKD. We sought to examine the association between rate of kidney function decline and risk of hospitalization in a cohort of patients with early CKD.

Design, settings, participants, & measurements

We built a cohort of 247,888 United States veterans who had at least one eGFR measurement between October 1999 and September 2003 and an additional eGFR between October 2003 and September 2004. We selected patients whose initial eGFR was between 45 and 59 ml/min per 1.73 m². Rate of eGFR change (in milliliters per minute per 1.73 m² per year) was categorized as no decline (>0), mild (0 to −1, and served as the referent group), moderate (−1 to −5), or severe (>−5) eGFR decline. We built survival models to examine the association between the rate of kidney function decline and the risk of hospitalization and readmission and linear regression to estimate length of hospital stay.

Results

Over a median observation of 9 years (interquartile range, 5.28–9.00), patients with moderate and severe eGFR decline exhibited a higher risk of hospitalizations (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.19 to 1.26; and HR, 1.33; 95% CI, 1.28 to 1.39, respectively). Among patients with moderate and severe eGFR decline, the association between the rate of decline and the risk of hospitalizations was more pronounced with an increased number of hospitalizations (P<0.01). Patients with moderate and severe eGFR decline had a higher risk of readmission (HR, 1.19; 95% CI, 1.13 to 1.26; and HR, 1.53; 95% CI, 1.43 to 1.63, respectively). Among patients with severe eGFR decline, the association between the rate of kidney function decline and the risk of readmission was stronger with an increased number of readmissions (P<0.01). Patients with moderate and severe eGFR decline experienced an additional length of stay of 1.40 (95% CI, 0.88 to 1.92) and 5.00 days per year (95% CI, 4.34 to 5.66), respectively.

Conclusions

The rate of kidney function decline is associated with a higher risk of hospitalizations, readmissions, and prolonged length of hospital stay.     

Serum Uric Acid and Risk of CKD in Type 2 Diabetes

Background and objective

Serum uric acid may predict the onset and progression of kidney disease, but it is unclear whether uric acid is an independent risk factor for diabetic nephropathy. Our aim was to study the relationship between uric acid levels and the development of CKD components in patients with type 2 diabetes.

Design, setting, participants, & measurements

Longitudinal study of a cohort of patients with type 2 diabetes from the database of the Italian Association of Clinical Diabetologists network. From a total of 62,830 patients attending the diabetes centers between January 1, 2004, and June 30, 2008, we considered those with baseline eGFR values ≥60 ml/min per 1.73 m² and normal albumin excretion (n=20,142). Urinary albumin excretion, GFR, and serum uric acid were available in 13,964 patients. We assessed the association of serum uric acid quintiles with onset of CKD components by multinomial logistic regression model adjusting for potential confounders. We calculated the relative risk ratios (RRRs) for eGFR <60 ml/min per 1.73 m², albuminuria, and their combination at 4 years.

Results

At 4-year follow-up, 1109 (7.9%) patients developed GFR <60 ml/min per 1.73 m² with normoalbuminuria, 1968 (14.1%) had albuminuria with eGFR ≥60 ml/min per 1.73 m², and 286 (2.0%) had albuminuria with eGFR <60 ml/min per 1.73 m². The incidence of eGFR <60 ml/min per 1.73 m² increased in parallel with uric acid quintiles: Compared with the lowest quintile, RRRs were 1.46 (95% confidence interval [CI], 1.14 to 1.88; P=0.003), 1.44 (95% CI, 1.11 to 1.87; P=0.006), 1.95 (95% CI, 1.48 to 2.58; P<0.001), and 2.61 (95% CI, 1.98 to 3.42; P<0.001) for second, third, fourth, and fifth quintiles, respectively. Serum uric acid was significantly associated with albuminuria only in presence of eGFR <60 ml/min per 1.73 m².

Conclusions

Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes.     

The Association between a Mediterranean-Style Diet and Kidney Function in the Northern Manhattan Study Cohort

Background and objectives

Various dietary strategies have been investigated to slow kidney function decline. However, it is unknown whether a Mediterranean diet, which has been associated with improved cardiovascular risk, is associated with change in kidney function.

Design, setting, participants, & measurements

This study used the Northern Manhattan Study, a prospective, multiethnic, observational cohort of participants who were stroke free at baseline. Data were collected between 1993 and 2008. Serum creatinine measurements were taken a mean 6.9 years apart. A baseline dietary questionnaire was extrapolated into a previously used 9-point scoring system (MeDi). The primary outcome was incident eGFR<60 ml/min per 1.73 m²using the Modification of Diet in Renal Disease formula. A secondary outcome was the upper quartile of annualized eGFR decline (≥2.5 ml/min per 1.73 m² per year). Conditional logistic regression models adjusted for demographics and baseline vascular risk factors.

Results

Mean baseline age was 64 years, with 59% women and 65% Hispanics (N=900); mean baseline eGFR was 83.1 ml/min per 1.73 m². Incident eGFR<60 ml/min per 1.73 m² developed in 14% . In adjusted models, every 1-point increase in the MeDi score, indicating increasing adherence to a Mediterranean diet, was associated with decreased odds of incident eGFR<60 ml/min per 1.73 m² (odds ratio, 0.83; 95% confidence interval, 0.71 to 0.96) and decreased odds of being in the upper quartile of eGFR decline (odds ratio, 0.88; 95% confidence interval, 0.79 to 0.98).

Conclusions

A Mediterranean diet was associated with a reduced incidence of eGFR<60 ml/min per 1.73 m² and upper quartile of eGFR decline in a multiethnic cohort.