Iothalamate Glomerular Filtration Rate Research Articles

Statin therapy in patients with early-stage autosomal dominant polycystic kidney disease: Design and baseline characteristics

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort. AimsThe aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD. MethodsOne hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m2 will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years. OutcomesThe primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress. ConclusionThis study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing.Registration: This study is registered on Clinicaltrials.gov # NCT03273413

Molecular programs associated with glomerular hyperfiltration in early diabetic kidney disease

Hyperfiltration is a state of high glomerular filtration rate (GFR) observed in early diabetes that damages glomeruli, resulting in an iterative process of increasing filtration load on fewer and fewer remaining functional glomeruli. To delineate underlying cellular mechanisms of damage associated with hyperfiltration, transcriptional profiles of kidney biopsies from Pima Indians with type 2 diabetes with or without early-stage diabetic kidney disease were grouped into two hyperfiltration categories based on annual iothalamate GFR measurements. Twenty-six participants with a peak GFR measurement within two years of biopsy were categorized as the hyperfiltration group, and 26 in whom biopsy preceded peak GFR by over two years were considered pre-hyperfiltration. The hyperfiltration group had higher hemoglobin A1c, higher urine albumin-to-creatinine ratio, increased glomerular basement membrane width and lower podocyte density compared to the pre-hyperfiltration group. A glomerular 1240-gene transcriptional signature identified in the hyperfiltration group was enriched for endothelial stress response signaling genes, including endothelin-1, tec-kinase and transforming growth factor-β1 pathways, with the majority of the transcripts mapped to endothelial and inflammatory cell clusters in kidney single cell transcriptional data. Thus, our analysis reveals molecular pathomechanisms associated with hyperfiltration in early diabetic kidney disease involving putative ligand-receptor pairs with downstream intracellular targets linked to cellular crosstalk between endothelial and mesangial cells.

Association of the Estimated Glomerular Filtration Rate With vs Without a Coefficient for Race With Time to Eligibility for Kidney Transplant

Kidney transplant is associated with improved survival and quality of life among patients with kidney failure; however, significant racial disparities have been noted in transplant access. Common equations that estimate glomerular filtration rate (eGFR) include adjustment for Black race; however, how inclusion of the race coefficient in common eGFR equations corresponds with measured GFR and whether it is associated with delayed eligibility for kidney transplant listing are unknown. To compare eGFR with measured GFR and evaluate the association between eGFR calculated with vs without a coefficient for race and time to eligibility for kidney transplant. This prospective cohort study used data from the Chronic Renal Insufficiency Cohort, a multicenter cohort study of participants with chronic kidney disease (CKD). Self-identified Black participants from that study were enrolled between April 2003 and September 2008, with follow-up through December 2018. Statistical analyses were completed on November 11, 2020. Estimated GFR, measured annually and estimated using the creatinine-based Chronic Kidney Disease-Epidemiology (CKD-EPI) equation with and without a race coefficient. Iothalamate GFR (iGFR) measured in a subset of participants (n = 311) and time to achievement of an eGFR less than 20 mL/min/1.73 m2, an established threshold for kidney transplant referral and listing. Among 1658 self-identified Black participants, mean (SD) age was 58 (11) years, 848 (51%) were female, and mean (SD) eGFR was 44 (15) mL/min/1.73 m2. The CKD-EPI eGFR with the race coefficient overestimated iGFR by a mean of 3.1 mL/min/1.73 m2 (95% CI, 2.2-3.9 mL/min/1.73 m2; P < .001). The mean difference between CKD-EPI eGFR without the race coefficient and iGFR was of smaller magnitude (-1.7 mL/min/1.73 m2; 95% CI, -2.5 to -0.9 mL/min/1.73 m2). For participants with an iGFR of 20 to 25 mL/min/1.73 m2, the mean difference in eGFR with vs without the race coefficient and iGFR was 5.1 mL/min/1.73 m2 (95% CI, 3.3-6.9 mL/min/1.73 m2) vs 1.3 mL/min/1.73 m2 (95% CI, -0.3 to 2.9 mL/min/1.73 m2). Over a median follow-up time of 4 years (interquartile range, 1-10 years), use of eGFR calculated without vs with the race coefficient was associated with a 35% (95% CI, 29%-41%) higher risk of achieving an eGFR less than 20 mL/min/1.73 m2 and a shorter median time to this end point of 1.9 years. In this cohort study, inclusion of the race coefficient in the estimation of GFR was associated with greater bias in GFR estimation and with delayed achievement of a clinical threshold for kidney transplant referral and eligibility. These findings suggest that nephrologists and transplant programs should be cautious when using current estimating equations to determine kidney transplant eligibility.

305-OR: Glycemic Variability and Progression of CKD: PERL Substudy

To test the hypothesis that glucose variability may impact the progression of kidney disease in type 1 diabetes (T1D), we studied a subgroup of the Preventing Early Renal Loss (PERL) study population with T1D and mild to moderate diabetic kidney disease, using blinded continuous glucose monitoring (CGM) for up to 14 days for each wear period. We studied 175 participants wearing 366 blinded FreeStyle Libre CGMs on one to five occasions between weeks 96 and 164 of the follow-up in the parent study. The mean age of the population was 52.2 ± 10.9 (mean ± SD) years, mean duration of T1D was 36.1 ± 12.2 years. Baseline BMI, A1C, and iothalamate GFR (iGFR) were 29.9 ± 6.3 kg/m2, 8.2 ± 1.2%, and 67.5 ± 17.2 ml/min/1.73m2 respectively. During the study, mean glucose (MG) and coefficient of variation glucose (CV) were 174.5 ± 41.4 mg/dL and 44.5± 8.8% respectively. Mean amplitude of glycemic excursions (MAGE) was 146.0 ± 43.9 mg/dL while time-in-range (TIR) was 50.5 ± 16.1%. A 10% increase in the mean CV was associated with a 1.4 ml/min/1.73m2 decrease in iGFR at the end of the study [95%CI (-3.33, 0.44); p=0.13] while a 10 mg/dL increase in MAGE was associated with a 0.01 ml/min/1.73m2 decrease [95%CI (-0.41, 0.38); p=0.95]. For those with CV &amp;gt;36, iGFR was 2.56 ml/min/1.73m2 lower compared with those with CV &amp;lt;36 [95%CI (-7.44, 2.31); p=0.30]. Low blood glucose index, high blood glucose index, MG, and TIR were not significantly associated with iGFR. Given the non-significant associations between CGM metrics and iGFR, we conclude in this study of a population with T1D and mild to moderate kidney disease that there is no evidence that glycemic variability or glucose control impacts the rate of loss of iGFR. Limitations of the study include the observational study design, the relatively small sample size, the variability of how frequently CGM data were collected, and the short duration of observation. A larger prospective study using real-time CGM to improve glycemic parameters and reduce glycemic variability is required to answer this question definitively. Disclosure J.B. McGill: Advisory Panel; Self; Aegerion Pharmaceuticals, Bayer AG, Lilly Diabetes, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc. Research Support; Self; Medtronic, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Aegerion Pharmaceuticals, Dexcom, Inc., Janssen Pharmaceuticals, Inc. I.B. Hirsch: Consultant; Self; Abbott, Bigfoot Biomedical, Roche Diabetes Care. Research Support; Self; Medtronic, Omnipod. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. A. Galecki: None. K. Ruedy: None. C. Wu: None. A. Doria: Research Support; Self; Sanofi. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-TD1014); National Institute of Diabetes and Digestive and Kidney Diseases (R03DK094484, R34DK097808, UC4DK101108); JDRF (17-2012-377)

Arterial Blood Pressure at Liver Transplant Evaluation Predicts Renal Histology in Candidates With Renal Dysfunction.

Renal dysfunction is common in liver transplantation (LT) candidates, but differentiating between reversible and irreversible renal injury can be difficult. Kidney biopsy might be helpful in differentiating reversible from irreversible renal injury, but it is associated with significant complications. We aimed to identify pre-LT predictors of potentially reversible renal injury using histological information obtained on pre-LT renal biopsy. Data on 128 LT candidates who underwent pre-LT kidney biopsy were retrospectively collected and correlated with renal histological findings. Indications for kidney biopsy were iothalamate glomerular filtration rate (iGFR) ≤40mL/minute, proteinuria >500mg/day, and/or hematuria. According to the biopsy diagnosis, patients were grouped into the following categories: normal (n=13); acute tubular necrosis (ATN; n=25); membranoproliferative glomerulonephritis (n=19); minimal histological changes (n=24); and advanced interstitial fibrosis (IF) and glomerulosclerosis (GS) (n=47). Compared with patients having advanced IF/GS, patients with normal biopsies and those with ATN had lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) and higher international normalized ratio and total bilirubin levels (<0.05 for all). Both SBP and DBP directly correlated with the degree of IF and GS (R=0.3, P≤0.02 for all). SBP ≤90mmHg was 100% sensitive and 98% specific in correlating with normal biopsies or ATN, whereas SBP ≥140mmHg was 22% sensitive and 90% specific in correlating with advanced IF/GS. Model for End-Stage Liver Disease score, serum creatinine, iGFR, urinary sodium excretion, and renal size did not correlate with biopsy diagnosis or degree of IF or GS. In conclusion, SBP at the time of LT evaluation correlates with renal histology, and it should be included along with other clinical and laboratory markers in the decision-making process to list patients with renal dysfunction for LT alone versus simultaneous liver-kidney transplantation.

523-P: Axon Guidance Pathway (AGP) Proteins Associate with ESKD and Kidney Lesions in Type 2 Diabetes

Seven AGP proteins associate with ESKD in Caucasians with diabetes. We explored the association of these proteins with ESKD and kidney lesions in Pima Indians with type 2 diabetes. EPHA1, EPHA2, EPHB6, EFNA4, EFNA5, UNC5Cand UNC5D were measured in serum of 162 Pimason a SOMAscan platform. Hazard ratio (HR) for ESKD for a 1 SD increase of each protein was computed by Cox regression after adjustment for age, sex, A1c, iothalamate glomerular filtration rate (GFR), and albumin:creatinine ratio (ACR). Serum samples obtained a median of 2.5 years later were measured in a subset of 67 Pimas who underwent kidney biopsy. Relationships between changes in protein concentrations and kidney lesions were explored by Spearman correlations. Baseline, mean age was 45±10 years, diabetes duration 15±6 years, GFR 155±53 ml/minute, and median ACR 54 (13-250) mg/g. During median follow-up of 12.5 years, 54 participants developed ESKD. Higher concentrations of 6 proteins (UNC5C HR1.51 [95CI 1.07-2.13]; EPHB6 1.67 [1.15-2.41]; EFNA4 1.72 [1.29-2.31]; UNC5D 1.73 [1.12-2.69] EFNA5 1.99 [1.36-2.91] and EPHA2 2.15[1.46-3.17]) were associated with ESKD. Increasing concentrations of these proteins were associated with structural lesions of diabetes (Figure). Proteins related to cell surface molecules of the Ephrin family were associated with kidney lesions and with progression to ESKD in Pima Indians with type 2 diabetes. Disclosure P. Saulnier: None. E. Satake: None. H.C. Looker: None. J. Skupien: None. A. Krolewski: None. R. Nelson: None. Funding American Diabetes Association (1-08-CR-42 to R.N.)

OR14-4 Early Glomerular Hyperfiltration and Long Term Kidney Outcomes in Type 1 Diabetes: The DCCT/EDIC Experience

INTRODUCTION Glomerular hyperfiltration has long been considered to be a major contributing factor to the development of diabetic kidney disease but most studies assessed increased albumin excretion rather than reduced GFR as an outcome. To address whether early glomerular hyperfiltration results in subsequent increased risk of clinically significant loss of GFR, namely Stage 3 CKD (eGFR <60 ml/min/1.73m2), we analyzed 30 year GFR follow-up data in participants undergoing 125I-iothalamate clearance on entry into the DCCT/EDIC Study. METHODS125I-iothalamate clearance was added to the DCCT protocol in 1986 and was assessed at DCCT baseline in 446 participants. This analysis reports long-term eGFR (CKD-EPI equation) follow-up data on these participants. The association of baseline hyperfiltration (primary cutpoint of ≥140 ml/min/1.73m2) with the risk of developing Stage 3 CKD (eGFR < 60 ml/min/1.73m2) was analyzed using Cox proportional hazards models. RESULTS Of the 446 participants, 178 had iothalamate GFR levels ≥ 130 mL/min/1.73m2 and of these, 106 had levels ≥ 140 mL/min/1.73m2 and 55 had levels ≥ 150 mL/min/1.73m2 upon entry into the DCCT. Among these 446 participants, 53 developed an eGFR < 60 mL/min/1.73m2 events over a median follow-up time of 28 years (rate of 4.69 events per 1000 individuals at risk for one year), and 34 developed a sustained (i.e., two consecutive visits) eGFR <60 mL/min/1.73m2 events over a median follow-up time of 28 years (rate of 2.98 sustained events per 1000 individuals at risk for one year) in DCCT/EDIC. The proportion maintaining an eGFR ≥ 60 mL/min/1.73m2 was not decreased and was actually somewhat greater in the hyperfiltration group (95/106 = 89.6% vs. 298/340 = 87.6%) using the cutoff of 140 mL/min/1.73m2. The cumulative incidences of developing an eGFR < 60 mL/min/1.73m2 were again similar in the two hyperfiltration groups (≥140 vs. < 140 mL/min/1.73m2 - 4.1% vs. 5.9% after 20 years and 11% vs. 12.8% after 28 years). Hyperfiltration as assessed by iothalamate GFR ≥140 mL/min/1.73m2 was not associated with subsequent risk of developing an eGFR < 60 mL/min/1.73m2 in an unadjusted Cox PH model (HR= 0.83, 95%CI [0.43, 1.62]) nor in the adjusted model (HR= 0.77, 95%CI [0.38, 1.54]). Similar results were obtained for the developing of a sustained eGFR < 60 mL/min/1.73m2. Hyperfiltration cut-offs of 130 and 150 ml/min/1.73m2 showed similar findings. CONCLUSIONS Early hyperfiltration in patients with type 1 diabetes was not associated with any long-term decrease in kidney function. Though it is known with certainty that long-term improved glycemic control reduces the development of microalbuminuria, macroalbuminuria and Stage 3 CKD, the notion that early hyperfiltration is a marker of poor long term renal outcome is not supported by these findings.

Tissue hypoxia, inflammation, and loss of glomerular filtration rate in human atherosclerotic renovascular disease

The relationships between renal blood flow (RBF), tissue oxygenation, and inflammatory injury in atherosclerotic renovascular disease (ARVD) are poorly understood. We sought to correlate RBF and tissue hypoxia with glomerular filtration rate (GFR) in 48 kidneys from patients with ARVD stratified by single kidney iothalamate GFR (sGFR). Oxygenation was assessed by blood oxygenation level dependent magnetic resonance imaging (BOLD MRI), which provides an index for the levels of deoxyhemoglobin within a defined volume of tissue (R2*). sGFR correlated with RBF and with the severity of vascular stenosis as estimated by duplex velocities. Higher cortical R2* and fractional hypoxia and higher levels of renal vein neutrophil-gelatinase-associated-lipocalin (NGAL) and monocyte-chemoattractant protein-1 (MCP-1) were observed at lower GFR, with an abrupt inflection below 20 ml/min. Renal vein MCP-1 levels correlated with cortical R2* and with fractional hypoxia. Correlations between cortical R2* and RBF in the highest sGFR stratum (mean sGFR 51 ± 12 ml/min; R= -0.8) were degraded in the lowest sGFR stratum (mean sGFR 8 ± 3 ml/min; R= -0.1). Changes in fractional hypoxia after furosemide were also absent in the lowest sGFR stratum. These data demonstrate relative stability of renal oxygenation with moderate reductions in RBF and GFR but identify a transition to overt hypoxia and inflammatory cytokine release with severely reduced GFR. Tissue oxygenation and RBF were less correlated in the setting of reduced sGFR, consistent with variable oxygen consumption or a shift to alternative mechanisms of tissue injury. Identifying transitions in tissue oxygenation may facilitate targeted therapy in ARVD.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

Essential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se.

Acid Load and Phosphorus Homeostasis in CKD

The kidneys maintain acid-base homeostasis through excretion of acid as either ammonium or as titratable acids that primarily use phosphate as a buffer. In chronic kidney disease (CKD), ammoniagenesis is impaired, promoting metabolic acidosis. Metabolic acidosis stimulates phosphaturic hormones, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) invitro, possibly to increase urine titratable acid buffers, but this has not been confirmed in humans. We hypothesized that higher acid load and acidosis would associate with altered phosphorus homeostasis, including higher urinary phosphorus excretion and serum PTH and FGF-23. Cross-sectional. 980 participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Net acid excretion as measured in 24-hour urine, potential renal acid load (PRAL) estimatedfrom food frequency questionnaire responses, and serum bicarbonate concentration< 22 mEq/L. 24-hour urine phosphorus and calcium excretion and serum phosphorus, FGF-23, and PTH concentrations. Using linear and log-linear regression adjusted for demographics, kidney function, comorbid conditions, body mass index, diuretic use, and 24-hour urine creatinine excretion, we found that 24-hour urine phosphorus excretion was higher at higher net acid excretion, higher PRAL, and lower serum bicarbonate concentration (each P<0.05). Serum phosphorus concentration was also higherwith higher net acid excretion and lower serum bicarbonate concentration (each P=0.001). Only higher net acid excretion associated with higher 24-hour urine calcium excretion (P<0.001). Neither net acid excretion nor PRAL was associated with FGF-23 or PTH concentrations. PTH, but notFGF-23, concentration (P=0.2) was 26% (95% CI, 13%-40%) higher in participants with a serumbicarbonate concentration<22 versus≥22 mEq/L (P<0.001). Primary results were similar if stratified by estimated glomerular filtration rate categories or adjusted for iothalamate glomerular filtration rate (n=359), total energy intake, dietary phosphorus, or urine urea nitrogen excretion, when available. Possible residual confounding by kidney function or nutrition; urine phosphorus excretion was included in calculation of the titratable acid component of net acid excretion. In CKD, higher acid load and acidosis associate independently with increased circulating phosphorus concentration and augmented phosphaturia, but not consistently with FGF-23 or PTH concentrations. This may be an adaptation that increases titratable acid excretion and thus helps maintain acid-base homeostasis in CKD. Understanding whether administration of base can lower phosphorus concentrations requires testing in interventional trials.

Relationship of dietary phosphate intake with risk of end-stage renal disease and mortality in chronic kidney disease stages 3-5: The Modification of Diet in Renal Disease Study.

KDIGO guidelines recommend dietary phosphate restriction to lower serum phosphate levels in CKD stage 3-5. Recent studies suggest that dietary phosphate intake is only weakly linked to its serum concentration, and the relationship of phosphate intake with adverse outcomes is uncertain. To further evaluate this, we used Cox proportional hazards models to assess associations of baseline 24 hour urine phosphate excretion with risk of end stage renal disease (ESRD), all-cause mortality, and mortality subtypes (cardiovascular disease (CVD) and non-CVD) using the Modification of Diet in Renal Disease data. Models were adjusted for demographics, CVD risk factors, iothalamate GFR, and urine protein and nitrogen excretion. Phosphate excretion was modestly inversely correlated with serum phosphate concentrations. There was no association of 24 hour urinary phosphate excretion with risk of ESRD, CVD-, non-CVD- or all-cause mortality. For comparison, higher serum phosphate concentrations were associated with all-cause mortality (hazard ratio per 0.7 mg/dL higher, 1.15 [95% CI 1.01, 1.30]). Thus, phosphate intake is not tightly linked with serum phosphate concentrations in CKD stage 3-5, and there was no evidence that greater phosphate intake, assessed by 24 hour phosphate excretion, is associated with ESRD, CVD-, non CVD-, or all-cause mortality in CKD stage 3-5. Hence, factors other than dietary intake may be key determinants of serum phosphate concentrations and require additional investigation.

Fractional excretion of sodium in hepatorenal syndrome: Clinical and pathological correlation.

AIMTo determine the accuracy of fractional excretion of sodium (FeNa) in the diagnosis of hepatorenal syndrome (HRS).METHODSEighty-eight liver transplantation candidates with renal dysfunction and/or proteinuria were included in the study sample. The baseline characteristics of the patients were obtained. All the 88 patients underwent iothalamate glomerular filtration rate testing, 24-h urine collection for urinary sodium and protein excretions, random urine for sodium and creatinine testing, and percutaneous kidney biopsy. FeNa was calculated using the equation [(urine sodium × serum creatinine)/(serum sodium × urine creatinine)] × 100%. Diuretic use was recorded among the participants. Patients on renal replacement therapy were not included in the original sample.RESULTSSeventy-seven (87%) of the 88 patients had FeNa < 1%. FeNa < 1% was present in 10/10, 10/12, 11/13, 12/15 and 34/38 in patients with HRS, acute tubular necrosis, membranoproliferative glomerulonephritis, minimal histological findings (≤ 30%) and advanced (≥ 30%-40%) interstitial fibrosis and/or glomerulosclerosis, respectively (P = 0.4). FeNa < 1% was 100% sensitive and 14% specific in diagnosing HRS. Receiver operating characteristic curve confirmed the poor accuracy of FeNa < 1% in diagnosing HRS (area under the curve = 0.58, P = 0.47). Calculated positive predictive value and negative predictive value for FeNa < 1% in HRS diagnosis were 46% and 100%, respectively. When used as a continuous variable, FeNa did not correlate with kidney biopsy findings (P = 0.41).CONCLUSIONFeNa < 1% was common in cirrhotic patients with renal dysfunction and it did not differentiate between HRS and other causes of renal pathologies. HRS diagnosis should be avoided in patients with FeNa > 1%.

Determination of Single-Kidney Glomerular Filtration Rate in Human Subjects by Using CT.

To test the hypothesis that computed tomography (CT)-derived measurements of single-kidney glomerular filtration rate (GFR) obtained in human subjects with 64-section CT agree with those obtained with iothalamate clearance, a rigorous reference standard. The institutional review board approved this HIPAA-compliant study, and written informed consent was obtained. Ninety-six patients (age range, 51-73 years; 46 men, 50 women) with essential (n = 56) or renovascular (n = 40) hypertension were prospectively studied in controlled conditions (involving sodium intake and renin-angiotensin blockade). Single-kidney perfusion, volume, and GFR were measured by using multidetector CT time-attenuation curves and were compared with GFR measured by using iothalamate clearance, as assigned to the right and left kidney according to relative volumes. The reproducibility of CT GFR over a 3-month period (n = 21) was assessed in patients with renal artery stenosis who were undergoing stable medical treatment. Statistical analysis included the t test, Wilcoxon signed rank test, linear regression, and Bland-Altman analysis. CT GFR values were similar to those of iothalamate clearance (mean ± standard deviation, 38.2 mL/min ± 18 vs 41.6 mL/min ± 17; P = .062). Stenotic kidney CT GFR in patients with renal artery stenosis was lower than contralateral kidney GFR or essential hypertension single-kidney GFR (mean, 23.1 mL/min ± 13 vs 36.9 mL/min ± 17 [P = .0008] and 45.2 mL/min ± 16 [P = .019], respectively), as was iothalamate clearance (mean, 26.9 mL/min ± 14 vs 38.5 mL/min ± 15 [P = .0004] and 49.0 mL/min ± 14 [P = .001], respectively). CT GFR correlated well with iothalamate GFR (linear regression, CT GFR = 0.88*iothalamate GFR, r(2) = 0.89, P < .0001), and Bland-Altman analysis was used to confirm the agreement. CT GFR was also moderately reproducible in medically treated patients with renal artery stenosis (concordance coefficient correlation, 0.835) but was unaffected by revascularization (mean, 25.3 mL/min ± 15.2 vs 30.3 mL/min ± 18.5; P = .097). CT assessments of single-kidney GFR are reproducible and agree well with a reference standard. CT can be useful to obtain minimally invasive estimates of bilateral single-kidney function in human subjects.

Daily fluid intake and outcomes in kidney recipients: post hoc analysis from the randomized ABCAN trial.

Generous and even excessive fluid intake is routinely recommended to kidney transplant recipients despite minimal evidence to support this practice. We hypothesized that increased fluid intake, ascertained by 24-h urine volume output, may adversely affect graft outcomes as it would impose an extra workload on a limited number of nephrons. Kidney transplant recipients who were randomized to losartan vs. placebo in the Angiotensin II Blockade for Chronic Allograft Nephropathy (ABCAN) trial (n = 153) underwent baseline, five-yr biopsies, and annual iothalamate glomerular filtration rate assessment. Recipients with higher urine volume at randomization had higher urinary sodium and also higher urinary protein. The proportion using diuretics or CNI based regimens were similar across urinary volume tertiles. The highest urinary volume tertile (>2.56 L/d) did not predict the development of interstitial volume doubling or end-stage renal disease (ESRD) from interstitial fibrosis/tubular atrophy (OR = 3.52, 95% CI 0.4, 31.24, p = 0.26), interstitial volume doubling or all-cause ESRD (OR = 7.04, 95% CI 0.66, 74.87, p = 0.11), and was not associated with the conventional endpoint of doubling serum creatinine, all-cause ESRD, or death (OR = 0.89, 95% CI 0.21, 3.71, p = 0.87). These results suggest that the current practice of liberal fluid intake may not be beneficial in low risk and mostly Caucasian transplant recipients.

Renal outcomes of liver transplant recipients who had pretransplant kidney biopsy.

Kidney biopsy has been recommended to guide kidney allocation in selected liver transplant (LT) candidates with renal dysfunction. However, post-LT-alone renal outcomes in recipients who showed evidence of reversible renal injury and limited chronicity on pre-LT kidney biopsy are unclear. Renal outcomes of 41 LT recipients who had pre-LT kidney biopsy for unexplained renal dysfunction, proteinuria, and hematuria were retrospectively reviewed. All biopsies showed less than 30% interstitial fibrosis and less than 30% to 40% glomerulosclerosis. Study endpoints were renal replacement therapy (RRT) at 1 month and the need for kidney transplantation at 1 year from LT. Six patients were on RRT at time of biopsy. Median (range) iothalamate glomerular filtration rate and 24-hr urinary protein excretion for the remaining 35 patients were 29 (6-88) mL/min per 1.73 m(2) and 65 (0-4,338) mg/day, respectively. Glomerulonephritis and acute tubular necrosis were present in 28 (68%) and 16 (39%) of the cases. Six patients (15%) did not recover kidney function at 1 month and RRT at time of LT was the only factor associated with this endpoint (P=0.04). Seven of the 31 (22%) patients with 1-year data met criteria for kidney transplantation within the first post-LT year. Surgical re-exploration was the only factor associated with the need for kidney transplantation at 1 year (P=0.05). The most LT recipients with minimal chronic changes on pre-LT kidney biopsy recovered kidney function within 1 month from LT. A small but significant percentage met criteria for kidney transplantation at 1 year because of the development of unforeseen post-LT complications.

The body composition and excretory burden of lean, obese, and severely obese individuals has implications for the assessment of chronic kidney disease

Obesity could affect associations between creatinine generation, estimated body surface area, and excretory burden, with effects on chronic kidney disease assessment. We therefore examined the impact of obesity on the performances of estimated glomerular filtration rate (eGFR), the urine albumin:creatinine ratio (ACR), and excretory burden in 3611 participants of the Chronic Renal Insufficiency Cohort. Urine creatinine excretion significantly increased with body mass index (BMI) (34 and 31% greater at 40 kg/m(2) or more versus the normal of 18.5-25 kg/m(2)) in men and women, respectively, such that patients with a normal BMI and an ACR of 30 mg/g had the same 24-h albuminuria as severely obese patients with ACR 23 mg/g. The bias of eGFR (referenced to body surface area-indexed iothalamate (i-)GFR) had a U-shaped relationship to obesity in men but progressively increased in women. Nevertheless, obesity-associated body surface area increases were accompanied by a greater absolute (non-indexed) iGFR for a given eGFR, particularly in men. Two men with eGFRs of 45 ml/min per 1.73 m(2), height 1.76 m, and BMI 22 or 45 kg/m(2) had absolute iGFRs of 46 and 62 ml/min, respectively. The excretory burden, assessed as urine urea nitrogen and estimated dietary phosphorus, sodium, and potassium intakes, also increased in obesity. However, obese men had lower odds of anemia, hyperkalemia, and hyperphosphatemia. Thus, for a given ACR and eGFR, obese individuals have greater albuminuria, absolute GFR, and excretory burden. This has implications for chronic kidney disease management, screening, and research.

Impairment of Renal Function at One Year After Liver Transplantation Is a Prognostic Factor for Mortality.

Renal dysfunction/failure are risk factors for poor outcome after liver transplantation (LTX). Our aim is to determine if renal dysfunction has impact on the long term outcome after LTX. We used multiple cutoffs for GFR at 1 year post LTX to look for association with later mortality. 985 primary LTX transplant recipients from a single institution were studied. All included survived >1 year after LTX and underwent iothalamate glomerular filtration rate (GFR) testing. Patients were stratified by GFR at 1 year post LTX [GFR≤40 (n=140), 41-60 (n=290), >60 ml/min (n=555)]. 37 patients had GFR≤30, of which 13 had GFR≤20. The GFR≤40 group had significantly more patients >60 years old, female gender, cyclosporine maintenance, anemia, but did not differ by HTN, DM, liver disease etiology. The 5-year Kaplan Meier survival (6 years post LTX) was 81.6%, 89.1%, and 91.6% for 1-year GFR of ≤40, 41-60,>60 respectively (p=0.01), and dropped to 75.6% if GFR ≤30, compared to 90.1% for GFR>30 (p<0.001), and further to 53.8% if GFR≤20 compared to 84.5-91.6% for GFR>20 (p<0.001). Recurrence of liver disease did not correlate with GFR. Multivariate Cox regression analysis showed statistically significant increased risk of mortality for African American recipients [risk ratio (RR) 2.35,p=0.0002), GFR≤40 (RR 1.95, p=0.0009). Analysis for GFR≤30 showed a RR for mortality of 2.91 (p=0.009). Kaplan Meier 5-year graft survival was 81% for GFR≤40, compared to 88.7% with GFR>40 (p=0.024), and 72.7% if GFR≤30 (p=0.005). In conclusion, a GFR of 40 ml/min or lower at 1 year post LTX is associated with higher mortality and graft loss and therefore requires more agressive follow-up and intervention and thus has therapeutic implications. This GFR threshold is higher than previously anticipated. An accurate GFR measurement is essential for intermediate and long-term prognosis after LTX.

Impact of urinary tract infection on allograft function after kidney transplantation

Urinary tract infection (UTI) is the most common infectious complication after kidney transplantation. We aim to determine its impact on allograft function as indicated by several measures such as iothalamate glomerular filtration rate (iGFR), estimated glomerular filtration rate (eGFR), and creatinine value. We performed a single-center retrospective cohort study to determine the impact of UTI on kidney allograft outcome. The study population consisted of 301 kidney transplant recipients; 84% were living donor transplants. One hundred and one patients (34%) developed at least one episode of UTI and the incidence of UTI during the first year after transplantation was 25%. At the end of the follow-up, the iGFR was lower among patients who had developed at least one UTI (p = 0.044). However, eGFR and creatinine values were not significantly different between UTI and non-UTI groups. When kidney function was measured by eGFR and creatinine, there was no significant difference in allograft function between kidney recipients with or without UTI. However, when kidney function was measured by nuclear studies, there was a tendency toward impairment in allograft function among patients who developed atleast one UTI after transplantation.

Fibrate Use Increases Creatinine Without Affecting Iothalamate GFR

Fibrate Use Increases Creatinine Without Affecting Iothalamate GFR

Cystatin C Enhances Glomerular Filtration Rate Estimating Equations in Kidney Transplant Recipients

Background: The glomerular filtration rate (GFR) estimating equation incorporating both cystatin C and creatinine perform better than those using creatinine or cystatin C alone in patients with reduced GFR. Whether this equation performs well in kidney transplant recipients cross-sectionally, and more importantly, over time has not been addressed. Methods: We analyzed four GFR estimating equations in participants of the Angiotensin II Blockade for Chronic Allograft Nephropathy Trial (NCT 00067990): Chronic Kidney Disease Epidemiology Collaboration equations based on serum cystatin C and creatinine (eGFR (CKD-EPI-Creat+CysC)), cystatin C alone (eGFR (CKD-EPI-CysC)), creatinine alone (eGFR (CKD-EPI-Creat)) and the Modification of Diet in Renal Disease study equation (eGFR (MDRD)). Iothalamate GFR served as a standard (mGFR). Results: mGFR, serum creatinine, and cystatin C shortly after transplant were 56.1 ± 17.0 ml/min/1.73 m², 1.2 ± 0.4 mg/dl, and 1.2 ± 0.3 mg/l respectively. eGFR (CKD-EPI-Creat+CysC) was most precise (R² = 0.50) but slightly more biased than eGFR (MDRD); 9.0 ± 12.7 versus 6.4 ± 15.8 ml/min/1.73 m², respectively. This improved precision was most evident in recipients with mGFR >60 ml/min/1.73 m². For relative accuracy, eGFR (MDRD) and eGFR (CKD-EPI-Creat+CysC) had the highest percentage of estimates falling within 30% of mGFR; 75.8 and 68.9%, respectively. Longitudinally, equations incorporating cystatin C most closely paralleled the change in mGFR. Conclusion: eGFR (CKD-EPI-Creat+CysC) is more precise and reflects GFR change over time reasonably well. eGFR (MDRD) had superior performance in recipients with mGFR between 30 and 60 ml/min/1.73 m².