Serum uric acid and progression of diabetic nephropathy in type 1 diabetes

Aims

Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes.

Fórmula de CKD‐EPI versus Cockcroft‐Gault na predição de nefropatia induzida por contraste após intervenção coronária percutânea,em pacientes sem disfunção renal significativa

Introduction

Individuals with glomerular filtration rate (GFR) ≥ 60 ml/min/1.73 m² estimated by the Cockcroft‐Gault formula (CG) who undergo percutaneous coronary intervention (PCI) frequently develop contrast‐induced nephropathy (CIN). This study aimed to assess whether individuals with significant renal impairment assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) formula, but not by CG, more often develop CIN following PCI than those without renal impairment by either formula.

Preservation of Renal Haemodynamic Response to an Oral Protein Load in Non-insulin-dependent Diabetes Mellitus

Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) were determined, for 2h prior to and 3h following the ingestion of a 1.2 g kg^?1 meat meal, in seven normotensive normoalbuminuric Type 2 diabetic patients exhibiting good glycaemic control (fasting plasma glucose (mean ± SD): 7.2 ± 2.0 mmol l^?1; glycosylated haemoglobin: 8.1 ± 1.7%) and in nine normal subjects selected for similar basal GFR values. Baseline GFR and ERPF (corrected to 1.73 m² surface area) were 83 ± 10 and 410 ± 76 ml min^?1 for the Type 2 diabetic patients and 86 ± 11 and 405 ± 113 ml min^?1 for the normals. GFR increased by 38 ± 8 and 32 ± 15% in the diabetic patients and normals, to 108 ± 25 and 105 ± 26 ml min^?1 (p < 0.01 vs baseline). Peak ERPF was 501 ± 127 and 476 ± 119 ml min^?1 for the two respective groups (p < 0.01 vs baseline). Filtration fractions at peak GFR and EPRF values were unchanged from baseline for either groups. Fractional clearance of albumin for the Type 2 diabetic patients was unaltered by protein ingestion. Therefore, protein ingestion in Type 2 diabetes, as in normals, results in an acute elevation of GFR. Absolute and incremental changes in GFR were identical for the two groups. These data demonstrate a preserved capacity for renal vasodilatation in Type 2 diabetic patients despite their greater chronological age.     

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.     

Hemoglobin Decline in Children with Chronic Kidney Disease: Baseline Results from the Chronic Kidney Disease in Children Prospective Cohort Study

Background and objectives: The level of glomerular filtration rate at which hemoglobin declines in chronic kidney disease is poorly described in the pediatric population.Design, setting, participants, & measurements: This cross-sectional study of North American children with chronic kidney disease examined the association of glomerular filtration rate, determined by the plasma disappearance of iohexol, and hemoglobin concentration.Results: Of the 340 patients studied, the mean age was 11 ± 4 yr, the mean glomerular filtration rate was 42 ± 14 ml/min per 1.73 m², and the mean hemoglobin was 12.5 ± 1.5. Below a glomerular filtration rate of 43, the hemoglobin declined by 0.3 g/dl (95% confidence interval −0.2 to −0.5) for every 5-ml/min per 1.73 m² decrease in glomerular filtration rate. Above a glomerular filtration rate of 43 ml/min per 1.73 m², the hemoglobin showed a nonsignificant decline of 0.1 g/dl for every 5-ml/min per 1.73 m² decrease in glomerular filtration rate.Conclusions: In pediatric patients with chronic kidney disease, hemoglobin declines as an iohexol-determined glomerular filtration rate decreases below 43 ml/min per 1.73 m². Because serum creatinine–based estimated glomerular filtration rates may overestimate measured glomerular filtration rate in this population, clinicians need to be mindful of the potential for hemoglobin decline and anemia even at early stages of chronic kidney disease, as determined by current Schwartz formula estimates. Future longitudinal analyses will further characterize the relationship between glomerular filtration rate and hemoglobin, including elucidation of reasons for the heterogeneity of this association among individuals.The adverse health effects of anemia in adult and pediatric patients with chronic kidney disease (CKD) are both common and profound. Anemia has been associated with increased mortality, limitations in physical activity, and adverse effects on quality of life. Among children in the 2005 End Stage Renal Disease Clinical Performance Measures Project, 95% of 1598 prevalent pediatric patients with ESRD were anemic; 95% of patients who were receiving hemodialysis and 94% of patients who were receiving peritoneal dialysis were prescribed erythropoiesis-stimulating agents (ESA) (1). A lower prevalence of anemia is observed at earlier stages of CKD in pediatric patients. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) stages CKD as follows: Stage 1, evidence of kidney damage with normal or increased GFR; stage 2, GFR 60 to 89 ml/min per 1.73 m²; stage 3, GFR 30 to 59 ml/min per 1.73 m²; stage 4, GFR 15 to 29 ml/min per 1.73 m²; stage 5, GFR <15 ml/min per 1.73 m² or on dialysis (2). In a recent single-center, cross-sectional study of 366 children and adolescents with CKD, approximately 30% of patients with stages 1 and 2 CKD reported prevalent anemia, defined as hemoglobin <12 mg/dl or medical treatment for anemia, whereas 66% of patients with stage 3 and 93% of patients with stages 4 and 5 CKD were anemic. GFR was estimated from serum cystatin C in this study (3).The lower prevalence of anemia in patients with earlier stages of CKD suggests an association between hemoglobin and GFR. In adults, hemoglobin has been reported to decline below a GFR threshold of 40 to 60 ml/min per 1.73 m² as measured by the Modification of Diet in Renal Disease (MDRD) or Cockcroft-Gault equation (4,5). This association, including the existence of a “GFR threshold,” has not been clearly described in children. This study aimed to define more clearly the relationship between hemoglobin and GFR in the pediatric CKD population. To accomplish this, we used the relatively large sample size and precise measurement of GFR offered by the Chronic Kidney Disease in Children Prospective Cohort Study (CKiD).     

Estimating Glomerular Filtration Rate: Cockcroft–Gault and Modification of Diet in Renal Disease Formulas Compared to Renal Inulin Clearance

Background and objectives: Evaluation of renal function by estimation of the glomerular filtration rate (GFR) is very important for the diagnosis and treatment of patients with chronic kidney disease (CKD). The Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas are the most commonly used estimations.Design, setting, participants, & measurements: Estimated GFR values by each formula were compared with measured GFR (mGFR) by renal inulin clearance in 2208 European adults (46% women, 1.4% Caribbean blacks), with and without CKD, and mean mGFR 72.4 ± 39.0 (range 2.2 to 177.2) ml/min/1.73 m².Results: Overall, the CG and MDRD formulas showed bias (mean difference) −3.5 ml/min/1.73 m² (5.3%), P < 0.001, and −9.8 ml/min/1.73 m² (−6.4%), P < 0.001; precision (SD of bias) 21.5 ml/min/1.73 m² (43.1%) and 20.0 ml/min/1.73 m² (33.0%); limits of agreement (2 SD by Bland–Altman method) 39.5 to −46.5 (range 86.0) ml/min/1.73 m² and 30.2 to −49.8 (range 80.0) ml/min/1.73 m²; and accuracy within ±30% of mGFR 70.8 and 69.0%, respectively. Both formulas showed a trend for decreasing accuracy with lower mGFR levels. According to the Kidney Disease Outcomes Quality Initiative (K/DOQI)-CKD classification''s five GFR groups, the CG and MDRD formulas properly assigned 61.6 and 57.1% of the entire population and had a range of positive predictive values 42.6 to 81.8% and 39.6 to 85.2% and of negative predictive values 81.7 to 96.6% and 76.4 to 97.5%, respectively.Conclusions: The CG and MDRD formulas had some limitations for proper GFR estimation and K/DOQI-CKD classification by GFR levels alone.The best overall index of renal function is considered to be the glomerular filtration rate (GFR) and a gold standard for its assessment is the renal inulin clearance (Cin) (1,2). Unfortunately, the Cin cannot be used routinely in daily practice because of its complexity as a test, and the same is true for other methods using radiolabeled isotopes or nonradioactive contrast agents (3–5). For practical reasons, several serum creatinine-based formulas for predicting GFR were created in the past (5). The most frequently used ones are the Cockcroft–Gault (CG) formula and the Modification of Diet in Renal Disease (MDRD) study prediction equation. The CG formula was developed by using the mean 24-h urine creatinine excretion from two urine collections obtained in 249 adult men, whereas for women an arbitrary correction coefficient of 0.85 was suggested (6). This formula estimates creatinine clearance (Ccr) instead of GFR. Because creatinine is not only filtered by the glomeruli but also secreted by the tubules, Ccr overestimates the GFR (7). The MDRD formula was created by a stepwise regression analysis of measured GFR (mGFR) by renal clearance of a single-bolus subcutaneous injection of ¹²⁵I-iothalamate (Cio) in 1628 participants of the MDRD study, which included only patients with chronic kidney disease (CKD) and mean serum creatinine (SCr) 2.3 ± 1.2 mg/dl (8). Previously, some studies reported that Cio overestimates Cin in normal subjects and lupus nephropathy (9,10), and ¹²⁵I-iothalamate is excreted not only by glomerular filtration but also by tubular secretion (11). Furthermore, in one of these studies (9), we calculated bias (mean/relative differences) between Cio and Cin ranging from −0.6 to 4.6/−2.7 to 23.3 and 18.8 to 26.6/17.4 to 27.1 (ml/min/1.73 m²/%), in two groups of subjects with mean Cin ranging from 17.6 to 24.3 and 95.9 to 108.3 ml/min/1.73 m², respectively.The Kidney Disease Outcome Quality Initiative (K/DOQI) clinical practice guidelines for CKD recommended, with few exceptions, the use of CG or MDRD formulas for GFR estimation (2). After the K/DOQI-CKD classification was published, assessment of the GFR became an essential tool in the daily clinical practice. Hence, accurate evaluation of the GFR is of paramount importance for purposes of CKD staging because different clinical action plans according to GFR levels were recommended.The primary objective of the study presented here was to assess the ability of CG and MDRD formulas to properly estimate the GFR measured by Cin in a large cohort of adults with a broad spectrum of GFR and diverse demographic characteristics and renal pathology.     

Renal impairment caused by temporary loop ileostomy

Purpose

Creation of a temporary loop ileostomy is a standard surgical procedure. This study was undertaken to determine whether dehydration associated with the ileostomy causes renal impairment.

Methods

The prospective data from 107 consecutive patients undergoing temporary loop ileostomy between 2004 and 2009 was evaluated. GFR was calculated at the time of hospital discharge after constructing the ileostomy and at the time of deciding to close the ileostomy.

Results

The average GFR at the time of discharge after constructing the ileostomy was a median of 92.50 (60.75?C223.88); at the time of deciding to close the ileostomy, it was 75.25 (4?C135.13) ml/min/1.73?m² (p?2 during the ileostomy period; in six of these 20 patients, the decrease was severe (GFR <30?ml/min/1.73?m²). Underlying diseases, reasons for constructing ileostomies, sex, and time interval to closure did not affect renal function. Patients in whom GFR was decreased at the time of deciding to close the ileostomy presented with significantly more closure-related surgical complications.

Conclusions

Renal impairment is a well-known potential complication of loop ileostomy. To avoid this complication, close control and backup support is recommended in these patients.     

Effect of naproxen on renal haemodynamics in elderly patients with arthritis

The effects of naproxen on renal haemodynamics were observed in ten elderly arthritic patients who were otherwise healthy and without clinical evidence of renal disease. Glomerular filtration rate (GFR,51Cr-EDTA clearance) and effective renal plasma flow (ERPF, 125I-iodohippurate clearance) were measured after 2 weeks' treatment with naproxen 500 mg twice daily and again after 2 weeks off the drug, in random order. Baseline values for GFR and ERPF were within normal limits (mean 72 ml/min/1.73 m2, 110% predicted and 326 ml/min/1.73 m2, 111% predicted, respectively). On naproxen, ERPF and renal blood flow decreased by 10% and 9%, respectively (-32 ml/min/1.73 m2; p = 0.05 and -49 ml/min/1.73 m2; p less than 0.01). These events produced no untoward clinical effects. Nevertheless, this response might impair the kidney's ability to preserve GFR if a further stress were to supervene. Consequently, temporary withdrawal of non-steroidal anti-inflammatory drugs from elderly patients should be considered in response to intercurrent illness or drug therapy likely to compromise renal blood flow.     

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.     

Effect of metabolic regulation on renal leakiness to Dextran molecules in short-term insulin-dependent diabetics

Summary Renal clearance of dextran of two ranges of molecular size and glomerular filtration rate (GFR,⁵¹Cr-EDTA) were measured in seven short-term insulin-dependent diabetics (mean age 25 years). Measurements were carried out in the same patient during good and poor metabolic regulation (plasma glucose, mean±SEM, 6.5±0.9 and 14.8±1.5 ] mmol/l, respectively). GFR was elevated in all patients during poor metabolic regulation (119±6 ml/min/1.73 m², versus 99±2 ml/min/1.73 m² during good control, p<0.01). The average renal clearance of dextran with molecular weights ranging from 25,000 to 35,000 and 35,000 to 45,000 increased during poor metabolic regulation from 14.8±0.8 to 19.8±1.8 ml/min/1.73 m², and 5.2±0.3 to 6.8±0.6 ml/min/1.73 m², respectively (p< 0.05). The elevated GFR and renal dextran clearance found during poor metabolic regulation were normalized within one to three weeks of effective insulin treatment. This rapid reversibility can hardly be explained by the previously demonstrated enlargement in glomerular size and filtration surface area, since these alterations remain unchanged after more than one month of insulin treatment. The metabolic regulation did not influence the size-selective properties of the glomerular wall. Therefore, we suggest that the dominating mechanism involved in the GFR and renal dextran clearance alterations is functional, viz. increased filtration pressure.     

Renal function after autologous bone marrow transplantation in children: a long-term prospective study

We measured glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and the concentrating capacity of the kidneys in children after autologous BMT. Twenty-six patients had received TBI in their conditioning regimen and 14 patients had received chemotherapy only. Median follow-up was 10 years. Mean GFR before BMT was close to normal in both groups. Mean GFR decreased from 124 [CI 114,134] ml/min/1.73 m(2) before BMT to 99 [CI 82,115] ml/min/1.73 m(2) 6 months after BMT in the + TBI group (P < 0.001). There was no significant change in the -TBI group. Mean ERPF before BMT was high: 1110 [95% CI 830,1390] ml/min/1.73 m(2) in the + TBI group and 910 [CI 570,1250] ml/min/1.73 m(2) in the - TBI group. Six months after BMT, there was a tendency to a decrease in ERPF in the +TBI group, to 760 [CI 580,940] ml/min/1.73 m(2) (P = 0.064). After this initial decrease, GFR and ERPF remained essentially unchanged in both groups. The mean concentrating capacity of the kidneys was normal before and after BMT. In seven patients chronic renal impairment developed after BMT (GFR <70 ml/min/1.73 m(2)). All had received TBI. They had also received more nephrotoxic antibiotics than the other patients. We conclude that TBI was the principal cause of deterioration of renal function after BMT, possibly by limiting compensatory hyperperfusion and resulting in a fall in GFR. Antibiotic treatment may have contributed.     

Metabolic Abnormalities,Cardiovascular Disease Risk Factors,and GFR Decline in Children with Chronic Kidney Disease

Summary

Background and objectives

Metabolic abnormalities and cardiovascular disease (CVD) risk factors have rarely been systematically assessed in children with chronic kidney disease (CKD). We examined the prevalence of various CKD sequelae across the GFR spectrum.

Design, setting, participants, & measurements

Data were used from 586 children participating in the Chronic Kidney Disease in Children (CKiD) study (United States and Canada) with GFR measured by iohexol plasma disappearance. Laboratory values and CVD risk factors were compared across GFR categories and with an age-, gender-, and race-matched community sample.

Results

CKiD participants were 62% male, 66% Caucasian, 23% African American, and 15% Hispanic with a median age of 11 years and a median GFR of 44 ml/min per 1.73 m². Compared with those with a GFR ≥ 50 ml/min per 1.73 m², having a GFR < 30 ml/min per 1.73 m² was associated with a three-fold higher risk of acidosis and growth failure and a four- to five-fold higher risk of anemia and elevated potassium and phosphate. Median GFR change was −4.3 ml/min per 1.73 m² and −1.5 ml/min per 1.73 m² per year in children with glomerular and nonglomerular diagnoses, respectively. Despite medication and access to nephrology care, uncontrolled systolic hypertension was present in 14%, and 16% had left ventricular hypertrophy. Children with CKD frequently were also shorter and had lower birth weight, on average, compared with norms.

Conclusions

Growth failure, metabolic abnormalities, and CVD risk factors are present at GFR >50 ml/min per 1.73 m² in children with CKD and, despite therapy, increase in prevalence two- to four-fold with decreasing GFR.     

Effects of high dose aleglitazar on renal function in patients with type 2 diabetes

Background

Aleglitazar is a new, balanced dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist designed to optimize lipid and glycemic benefits and minimize PPAR-related adverse effects.

Methods

SESTA R was a 26-week, randomized, double-blind, multicenter study comparing the effects of a supratherapeutic dosage of aleglitazar (600 μg/day) with pioglitazone (45 mg/day) on change in measured GFR (mGFR) in 174 patients with type 2 diabetes and normal to mildly impaired renal function (estimated GFR [eGFR] 60 to 120 ml/min/1.73 m²).

Results

In 118 patients with evaluable GFR measurements, baseline mean (± SD) mGFR was 97.6 ± 17.5 ml/min/1.73 m² in the aleglitazar group and 101.9 ± 21.6 ml/min/1.73 m² in the pioglitazone group. Mean percent change from baseline mGFR was −16.9% (90% confidence interval −22.0 to −11.5) with aleglitazar and −4.6% (−10.15 to 1.35) with pioglitazone, a mean treatment difference of −13.0% (−19.0 to −6.5). The 17% decrease from baseline in mGFR was consistent with the 19% decrease in eGFR Modification of Diet in Renal Disease (MDRD) observed with aleglitazar, which reached a plateau after 4 weeks, with no further progression until treatment discontinuation. Following aleglitazar withdrawal, eGFR values returned to pretreatment levels within the 4-8-week follow-up, which suggests reversible hemodynamic changes in renal function.

Conclusions

Despite the increased incidence of expected, dose-dependent PPAR class side effects (e.g., peripheral edema, weight gain, and congestive heart failure) limiting further development of this supratherapeutic dosage of aleglitazar (600 μg/day), these data, together with the data from the dose-ranging SYNCHRONY study, suggest aleglitazar may be a potential new treatment for cardiovascular risk reduction in post-acute coronary syndrome patients at the therapeutic 150 μg daily dose.     

Systemic and renal effect of nicotine in non-smokers: influence of vitamin C

OBJECTIVES: To investigate whether the administration of the anti-oxidant vitamin C could prevent the systemic and renal effects of nicotine in healthy non-smoker volunteers. METHODS: The acute effects of oral, 4 mg, nicotine gum (n = 10), intravenous vitamin C (12 mmol, n = 8) or both (n=9) on mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and urinary cyclic guanosine monophosphate (cGMP) were assessed in non-smokers. RESULTS: In subjects receiving nicotine, MAP (+8 +/- 4 mmHg, P<0.0001) and HR (+13 +/- 8 beats/min, P < 0.001) increased whereas ERPF (-65 +/- 69 ml/min per 1.73 m2, P < 0.01), GFR (-14.5 +/- 16.8 ml/min per 1.73 m2, P < 0.01) and cGMP (-180 +/- 173 pmol/min, P < 0.01) decreased as compared to baseline values. The concomitant administration of nicotine and vitamin C caused similar haemodynamic changes; however, cGMP remained unchanged. In subjects receiving only vitamin C, there were no significant changes in MAP, heart rate, ERPF, GFR and cGMP. CONCLUSIONS: The present findings indicate that vitamin C was unable to prevent the renal vasoconstriction, but it prevented the fall in cGMP provoked by nicotine in non-smokers. This suggests that nicotine induces a degradation of nitric oxide mediated by oxygen-derived free radicals which may be prevented by vitamin C administration. The nicotine-induced renal vasoconstriction may be related to other mechanism(s).     

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.     

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.     

Low-level environmental exposure to lead and progressive chronic kidney diseases

Purpose

To determine whether low-normal body lead burden (BLB) accelerates progressive renal insufficiency in nondiabetic patients with chronic kidney diseases (CKD).

Methods

One hundred eight CKD patients (serum creatinine between 1.5 and 2.9 mg/dL) with low-normal BLB (<80 μg) and no lead exposure history were observed for 24 months. Following the observation, 32 patients with low-normal BLB (≥20 μg and <80 μg) were randomly assigned to chelation and control groups. The chelation group patients were given edetate calcium disodium (EDTA) chelation therapy for 3 months and repeated chelation therapy during the following 24 months to maintain their BLB below 20 μg, while the control group patients underwent placebo therapy. The primary endpoint was an increased serum creatinine level to 1.25 times the baseline value. The secondary endpoint was temporal changes in renal function.

Results

The primary endpoint occurred in 14 patients in the observation period. Baseline BLB was the important risk factor in determining progressive renal insufficiency. The mean glomerular filtration rate (GFR) change in the chelation group patients was 6.6 ± 10.7 mL/min/1.73m², compared with −4.6 ± 4.3 mL/min/1.73m² in control group patients (P <.001) at the end of the intervention period. The mean decrease in GFR per year of chelation group patients was lower than that of control group patients during the repeated chelation period.

Conclusion

Environmental exposure to lead, even at low level, may accelerate progressive renal insufficiency of nondiabetic patients with CKD.     

Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis

Objective

Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage.

Design

Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages.

Data extraction

Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis.

Results

Thirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFR?>?60 ml/min/1.73 m², decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR?<?60 ml/min/1.73 m² had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT.

Conclusion

ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease.     

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus

Aims/hypothesis

High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus.

Methods

Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFR_INULIN] ≥135 ml? min^?1 1.73 m^?2, n?=?28) or normofiltration (n?=?21) and healthy control individuals (n?=?18).

Results

Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA_1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165?±?9 vs 113?±?2 and 116?±?4 ml min^?1 1.73 m^?2, respectively, p?<?0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p?<?0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophage-derived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colony-stimulating factor (p?≤?0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p?<?0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p?<?0.01).

Conclusions/interpretation

Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.     

Nonrecovery of Kidney Function and Death after Acute on Chronic Renal Failure

Background and objectives: Relatively little is known about clinical outcomes, especially long-term outcomes, among patients who have chronic kidney disease (CKD) and experience superimposed acute renal failure (ARF; acute on chronic renal failure).Design, setting, participants, & measurements: We tracked 39,805 members of an integrated health care delivery system in northern California who were hospitalized during 1996 through 2003 and had prehospitalization estimated GFR (eGFR) <45 ml/min per 1.73 m². Superimposed ARF was defined as having both a peak inpatient serum creatinine greater than the last outpatient serum creatinine by ≥50% and receipt of acute dialysis.Results: Overall, 26% of CKD patients who suffered superimposed ARF died during the index hospitalization. There was a high risk for developing ESRD within 30 d of hospital discharge that varied with preadmission renal function, being 42% among hospital survivors with baseline eGFR 30–44 ml/min per 1.73 m² and 63% among hospital survivors with baseline eGFR 15–29 ml/min per 1.73 m². Compared with patients who had CKD and did not experience superimposed ARF, those who did had a 30% higher long-term risk for death or ESRD.Conclusions: In a large, community-based cohort of patients with CKD, an episode of superimposed dialysis-requiring ARF was associated with very high risk for nonrecovery of renal function. Dialysis-requiring ARF also seemed to be an independent risk factor for long-term risk for death or ESRD.The clinical and public health importance of chronic kidney disease (CKD) is well established, with the most recent estimates indicating that the population prevalence of CKD exceeds 10% in the United States (1,2). Reduced estimated GFR (eGFR) is a strong and independent risk factor for hospitalization, cardiovascular events, and death (3). This association is most robust among people with eGFR <45 ml/min per 1.73 m² (3).Although CKD is a widely known risk factor for acute renal failure (ARF; also known as acute kidney injury [AKI]) (4,5), surprisingly little is known about clinical outcomes, especially long-term outcomes, among patients who have CKD and experience superimposed ARF (acute on chronic renal failure). Most published studies about ARF have focused exclusively on in-hospital outcomes with often scant, if any, follow-up after discharge. Furthermore, the few studies that did investigate long-term sequelae among survivors of ARF did not focus on patients with abnormal baseline kidney function (6–9).We conducted this study to investigate outcomes after an episode of ARF among hospitalized patients with reduced baseline kidney function, defined as an eGFR <45 ml/min per 1.73 m². Our end points included nonrecovery of renal function as well as death and development of ESRD that was treated with renal replacement therapy months to years after discharge.