Continuous function of 80 primary renal allografts for 30-47 years with maintenance prednisone and azathioprine/mycophenolate mofetil therapy: A clinical mosaic of long-term successes.

Eighty primary renal allograft recipients, 61 living-related and 19 deceased donor, transplanted from 1963 through 1984 had continuous graft function for 30-47 years. They were treated with three different early immunosuppression programs (1963-1970: thymectomy, splenectomy, high oral prednisone; 1971-1979: divided-dose intravenous methylprednisolone; and 1980-1984: antilymphocyte globulin) each with maintenance prednisone and azathioprine, and no calcineurin inhibitor. Long-term treatment often included the anti-platelet medication, dipyridamole. Although both recipient and donor ages were young (27.2 ± 9.5 and 33.1 ± 12.0 years, respectively), six recipients with a parent donor had >40-year success. At 35 years, death-censored graft survival was 85.3% and death with a functioning graft 84.2%; overall graft survival was 69.5% (Kaplan-Meier estimate). Biopsy-documented early acute cellular and highly probable antibody-mediated rejections were reversed with divided-dose intravenous methylprednisolone. Complications are detailed in an integrated timeline. Hypogammaglobulinemia identified after 20 years doubled the infection rate. An association between a monoclonal gammopathy of undetermined significance and non-plasma-cell malignancies was identified. Twenty-seven azathioprine-treated patients tested after 37 years had extremely low levels of T1/T2 B lymphocytes representing a "low immunosuppression state of allograft acceptance (LISAA)". The lifetime achievements of these patients following a single renal allograft and low-dose maintenance immunosuppression are remarkable. Their success evolved as a clinical mosaic.

Expanded Imaging Classification of Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: The Mayo Clinic imaging classification of autosomal dominant polycystic kidney disease (ADPKD) uses height-adjusted total kidney volume (htTKV) and age to identify patients at highest risk for disease progression. However, this classification applies only to patients with typical diffuse cystic disease (class 1). Because htTKV poorly predicts eGFR decline for the 5%-10% of patients with atypical morphology (class 2), imaging-based risk modeling remains unresolved. METHODS: Of 558 adults with ADPKD in the HALT-A study, we identified 25 patients of class 2A with prominent exophytic cysts (class 2Ae) and 43 patients of class 1 with prominent exophytic cysts; we recalculated their htTKVs to exclude exophytic cysts. Using original and recalculated htTKVs in association with imaging classification in logistic and mixed linear models, we compared predictions for developing CKD stage 3 and for eGFR trajectory. RESULTS: Using recalculated htTKVs increased specificity for developing CKD stage 3 in all participants from 82.6% to 84.2% after adjustment for baseline age, eGFR, BMI, sex, and race. The predicted proportion of class 2Ae patients developing CKD stage 3 using a cutoff of 0.5 for predicting case status was better calibrated to the observed value of 13.0% with recalculated htTKVs (45.5%) versus original htTKVs (63.6%). Using recalculated htTKVs reduced the mean paired difference between predicted and observed eGFR from 17.6 (using original htTKVs) to 4.0 ml/min per 1.73 m2 for class 2Ae, and from -1.7 (using original htTKVs) to 0.1 ml/min per 1.73 m2 for class 1. CONCLUSIONS: Use of a recalculated htTKV measure that excludes prominent exophytic cysts facilitates inclusion of class 2 patients and reclassification of class 1 patients in the Mayo classification model.

Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials.

BACKGROUND: Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. STUDY DESIGN: Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. SETTING & PARTICIPANTS: 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments. MEASUREMENTS: Longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. PREDICTORS: Demographic, clinical, laboratory, and imaging features of participants. OUTCOMES: Probability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories. RESULTS: Most (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations. LIMITATIONS: Relatively short follow-up of a clinical trial population. CONCLUSIONS: Although many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

Dietary salt restriction is beneficial to the management of autosomal dominant polycystic kidney disease.

The CRISP study of polycystic kidney disease (PKD) found that urinary sodium excretion associated with the rate of total kidney volume increase. Whether sodium restriction slows the progression of Autosomal Dominant PKD (ADPKD) is not known. To evaluate this we conducted a post hoc analysis of the HALT-PKD clinical trials of renin-angiotensin blockade in patients with ADPKD. Linear mixed models examined whether dietary sodium affected rates of total kidney volume or change in estimated glomerular filtration rate (eGFR) in patients with an eGFR over 60 ml/min/1.73 m2 (Study A) or the risk for a composite endpoint of 50% reduction in eGFR, end-stage renal disease or death, or the rate of eGFR decline in patients with an eGFR 25-60 ml/min/1.73 m2 (Study B) all in patients initiated on an under100 mEq sodium diet. During the trial urinary sodium excretion significantly declined by an average of 0.25 and 0.41 mEq/24 hour per month in studies A and B, respectively. In Study A, averaged and time varying urinary sodium excretions were significantly associated with kidney growth (0.43%/year and 0.09%/year, respectively, for each 18 mEq urinary sodium excretion). Averaged urinary sodium excretion was not significantly associated with faster eGFR decline (-0.07 ml/min/1.73m2/year for each 18 mEq urinary sodium excretion). In Study B, the averaged but not time-varying urinary sodium excretion significantly associated with increased risk for the composite endpoint (hazard ratio 1.08 for each 18 mEq urinary sodium excretion) and a significantly faster eGFR decline (-0.09 ml/min/1.73m2/year for each mEq 18 mEq urinary sodium excretion). Thus, sodium restriction is beneficial in the management of ADPKD.

Angiotensin blockade in late autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin-angiotensin-aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin II-receptor blocker (ARB). METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m(2) of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years. RESULTS: There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril-telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups. CONCLUSIONS: Monotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559.).

Blood pressure in early autosomal dominant polycystic kidney disease.

BACKGROUND: Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS: The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002). CONCLUSIONS: In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).

Prognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the HALT-PKD clinical trial.

BACKGROUND: Patients with mild autosomal dominant polycystic kidney disease (ADPKD) are less likely to be informative in randomized clinical trials (RCTs). We previously developed an imaging classification of ADPKD (typical diffuse cyst distribution Class 1A-E and atypical cyst distribution Class 2) for prognostic enrichment design in RCTs. We investigated whether using this classification would have increased the power to detect a beneficial treatment effect of rigorous blood pressure (BP) control on HALT-PKD participants with early disease (Study A). METHODS: Post hoc analysis of the early disease HALT-PKD study, an RCT that studied the effect of rigorous versus standard BP control on rates of total kidney volume (TKV) increase and estimated glomerular filtration rate (eGFR) decline in ADPKD patients with eGFR >60 mL/min/1.73 m2. RESULTS: Five hundred and fifty-one patients were classified by two observers (98.2% agreement) into Class 1A (6.2%), 1B (20.3%), 1C (34.1%), 1D (22.1%), 1E (11.8%) and 2 (5.4%). The TKV increase and eGFR decline became steeper from Class 1A through 1E. Rigorous BP control had been shown to be associated with slower TKV increase, without a significant overall effect on the rate of eGFR decline (faster in the first 4 months and marginally slower thereafter). Merging Classes 1A and 2 (lowest severity), 1B and 1C (intermediate severity) and 1D and 1E (highest severity) detected stronger beneficial effects on TKV increase and eGFR decline in Class 1D and E with a smaller number of patients. CONCLUSIONS: Strategies for prognostic enrichment, such as image classification, should be used in the design of RCTs for ADPKD to increase their power and reduce their cost.

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.

Liver involvement in early autosomal-dominant polycystic kidney disease.

BACKGROUND & AIMS: Polycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes. METHODS: We performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I-converting enzyme inhibitor and angiotensin II-receptor blocker was superior to the inhibitor alone, and whether low blood pressure (<110/75 mm Hg) was superior to standard blood pressure (120-130/70-80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15-49 y). RESULTS: We found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life. CONCLUSIONS: Hepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. ClinicalTrials.gov identifier: NCT00283686.

Health-related quality of life in patients with autosomal dominant polycystic kidney disease and CKD stages 1-4: a cross-sectional study.

BACKGROUND: In people with early autosomal dominant polycystic kidney disease (ADPKD), average total kidney volume (TKV) is 3 times normal and increases by an average of 5% per year despite a seemingly normal glomerular filtration rate (GFR). We hypothesized that increased TKV would be a source of morbidity and diminished quality of life that would be worse in patients with more advanced disease. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,043 patients with ADPKD, hypertension, and a baseline estimated GFR (eGFR)> 20mL/min/1.73m(2). PREDICTORS: (1) eGFR, (2) height-adjusted TKV (htTKV) in patients with eGFR> 60mL/min/1.73m(2). OUTCOMES: 36-Item Short Form Health Survey (SF-36) and the Wisconsin Brief Pain Survey. MEASUREMENTS: Questionnaires were self-administered. GFR was estimated from serum creatinine using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. htTKV was measured by magnetic resonance imaging. RESULTS: Back pain was reported by 50% of patients, and 20% experienced it "often, usually, or always." In patients with early disease (eGFR> 60mL/min/1.73m(2)), there was no association between pain and htTKV, except in patients with large kidneys (htTKV> 1,000mL/m). Comparing across eGFR levels and including patients with eGFRs< 60mL/min/1.73m(2), patients with eGFRs of 20-44mL/min/1.73m(2) were significantly more likely to report that pain impacted on their daily lives and had lower SF-36 scores than patients with eGFRs of 45-60 and ≥60mL/min/1.73m(2). Symptoms relating to abdominal fullness were reported by 20% of patients and were related significantly to lower eGFRs in women, but not men. LIMITATIONS: TKV and liver volume were not measured in patients with eGFR < 60mL/min/1.73m(2). The number of patients with eGFRs< 30mL/min/1.73m(2) is small. Causal inferences are limited by cross-sectional design. CONCLUSIONS: Pain is a common early symptom in the course of ADPKD, although it is not related to kidney size in early disease (eGFR> 60mL/min/1.73m(2)), except in individuals with large kidneys (htTKV> 1,000 mL/m). Symptoms relating to abdominal fullness and pain are greater in patients with more advanced (eGFR, 20-45mL/min/1.73m(2)) disease and may be due to organ enlargement, especially in women. More research about the role of TKV in quality of life and outcomes of patients with ADPKD is warranted.

Influence of menstrual cycle on indices of contraction-induced muscle damage.

Limited evidence suggests women exhibit a dampened response to contraction-induced muscle damage (CIMD). The purpose of this study was to examine if differences in symptoms of CIMD exist when induced in the menstrual cycle follicular or luteal phase. Sixteen resistance exercise trained women between the ages of 18-37 completed 75 eccentric-biased extension exercises with their nondominant arm. Creatine kinase (CK), elbow joint angles, arm volume, strength, and soreness were measured over 7 days. Estrogen was higher (p < 0.001) in the luteal group. The high estrogen group (luteal) had an overall greater strength decrement and higher CK concentration at 96 hours. Significant time effects were present for CK, elbow extension, elbow flexion, arm volume, and soreness. With the exception of strength and CK, signs and symptoms of CIMD were independent of menstrual cycle phase. Estrogen concentration in women may have limited effects on symptoms associated with muscle damage, but further research in this area is warranted.

Prophylactic ankle taping: influence on treadmill-running kinematics and running economy.

Prophylactic ankle taping (PAT) is commonly used in sport. Prophylactic ankle taping may restrict ankle motion, which would affect the kinetic chain and alter gait. The purpose of this study was to examine the effects of PAT on lower extremity (LE) kinematics and running economy during treadmill running. Twelve recreational runners (9 women, 3 men; M ± SD age = 31.33 ± 8.04 years, height = 1.67 ± 0.81 m, mass = 61.84 ± 9.38 kg) completed two 20-minute running sessions (PAT and no tape: control [CON]) at a self-selected pace. Before each run, reflective markers were placed along the right side of the body. Sagittal plane kinematic data (60 Hz) were captured 4 times, and expired gases were measured for 2-minute after each video capture during both trials. Stride frequency, stride length, LE kinematic variables at initial contact and end contact (EC) were calculated. Cardiorespiratory variables and heart rate were also measured. Running economy was normalized to oxygen uptake per unit body mass per kilometer (milliliter per kilogram per kilometer) as running speeds varied. At EC, the PAT hip angle significantly decreased (p = 0.01) by 3.82°, whereas CON decreased by 0.85°. The range of motion tended to decrease over the 20-minute run (p = 0.08). Heart rate significantly increased over time (6.7%) but was not different between conditions. Prophylactic ankle taping did not significantly affect the physiological measures associated with the metabolic cost of treadmill running or the other kinematic variables. These findings suggest that the hip angle continued to decrease during the PAT condition at push-off in recreational runners without impacting the metabolic cost of transport.

Contrasting patterns of viral load response in transplant recipients with BK polyomavirus DNAemia on leflunomide therapy.

BACKGROUND: Reduction in immunosuppression is considered the therapy of proven benefit for BKV infection in renal transplantation, but the use of leflunomide has also been reported. It was observed at this center that the patterns of viral load response while on leflunomide appear to fall into two distinct types. METHODS: Medical records of 22 kidney and kidney-pancreas recipients at a single center who received leflunomide therapy for BKV DNAemia were reviewed. Information was collected on demographics, BKV viral loads, other antiviral therapy, immunosuppressive drug levels and doses, adverse effects, and graft and patient outcomes. RESULTS: Eighteen of 22 cleared BKV viremia, and 12 of 22 had preserved allograft function; only two graft losses occurred in the screening era among leflunomide-treated patients. Two patterns of viral load reduction were observed, termed the "smooth" and the "zigzag" pattern, which differed in mean time to clear of BKV DNA (2.9 vs. 19.5 months, p = 0.0073). Graft preservation was correlated with lower serum creatinine (SCr) at the start of leflunomide therapy. CONCLUSIONS: Long courses and "zigzag" fluctuations in viral load can occur in patients who eventually clear BKV on leflunomide with preserved allograft function. Intermittent increases in viral load do not necessarily portend therapeutic failure. Although the utility of leflunomide is still debated in the transplant community, this information may be useful to clinicians who choose to use it in selected patients.

Calcium lignosulphonate: re-evaluation of relevant endpoints to re-confirm validity and NOAEL of a 90-day feeding study in rats.

A 90-day feeding study in Han/Wistar rats with calcium lignosulphonate was evaluated by the EFSA. The study was considered to be inadequate due to potentially impaired health status of the animals based upon a high incidence of minimal lymphoid hyperplasia in mesenteric/mandibular lymph nodes and Peyer's patches, and minimal lymphoid cell infiltration in the liver in all animals. The EFSA Panel further disagreed with the conclusion that the treatment-related observation of foamy histiocytosis in mesenteric lymph nodes was non-adverse and asked whether this observation would progress to something more adverse over time. A PWG was convened to assess the sections of lymph nodes, Peyer's patches and liver. In addition, all lymphoid tissues were re-examined. The clinical pathology and animal colony health screening data were re-evaluated. The question whether the foamy histiocytosis could progress to an adverse finding with increasing exposure duration was addressed by read-across. In conclusion, the animals on the 90-day feeding study were in good health, the study was adequate for safety evaluation, and the foamy histiocytes in the mesenteric lymph nodes were not considered adverse, but rather an adaptive response that was considered unlikely to progress to an adverse condition with time. The NOAEL was re-affirmed to be 2000 mg/kgbw/d.

Analysis of baseline parameters in the HALT polycystic kidney disease trials.

HALT PKD consists of two ongoing randomized trials with the largest cohort of systematically studied patients with autosomal dominant polycystic kidney disease to date. Study A will compare combined treatment with an angiotensin-converting inhibitor and receptor blocker to inhibitor alone and standard compared with low blood pressure targets in 558 early-stage disease patients with an eGFR over 60 ml/min per 1.73 m(2). Study B will compare inhibitor-blocker treatment to the inhibitor alone in 486 late-stage patients with eGFR 25-60 ml/min per 1.73 m(2). We used correlation and multiple regression cross-sectional analyses to determine associations of baseline parameters with total kidney, liver, or liver cyst volumes measured by MRI in Study A and eGFR in both studies. Lower eGFR and higher natural log-transformed urine albumin excretion were independently associated with a larger natural log-transformed total kidney volume adjusted for height (ln(HtTKV)). Higher body surface area was independently associated with a higher ln(HtTKV) and lower eGFR. Men had larger height-adjusted total kidney volume and smaller liver cyst volumes than women. A weak correlation was found between the ln(HtTKV) and natural log-transformed total liver volume adjusted for height or natural log liver cyst volume in women only. Women had higher urine aldosterone excretion and lower plasma potassium. Thus, our analysis (1) confirms a strong association between renal volume and functional parameters, (2) shows that gender and other factors differentially affect the development of polycystic disease in the kidney and liver, and (3) suggests an association between anthropomorphic measures reflecting prenatal and/or postnatal growth and disease severity.

Blood lactate concentration at the maximal lactate steady state is not dependent on endurance capacity in healthy recreationally trained individuals.

The aim of the study was to investigate the independent relationship between maximal lactate steady state (MLSS), blood lactate concentration [La] and exercise performance as reported frequently. Sixty-two subjects with a wide range of endurance performance (MLSS power output 199 ± 55 W; range: 100-302 W) were tested on an electronically braked cycle ergometer. One-min incremental exercise tests were conducted to determine maximal variables as well as the respiratory compensation point (RCP) and the second lactate turn point (LTP2). Several continuous exercise tests were performed to determine the MLSS. Subjects were divided into three clusters of exercise performance. Dietary control was employed throughout all testing. No significant correlation was found between MLSS [La] and power output at MLSS. Additionally, the three clusters of subjects with different endurance performance levels based on power output at MLSS showed no significant difference for MLSS [La]. MLSS [La] was not significantly different between men and women (average of 4.80 ± 1.50 vs. 5.22 ± 1.52 mmol l(-1)). MLSS [La] was significantly related to [La] at RCP, LTP2 and at maximal power. The results of this study support previous findings that MLSS [La] is independent of endurance performance. Additionally, MLSS [La] was not influenced by sex. Correlations found between MLSS [La] and [La] at maximal power and at designated anaerobic thresholds indicate only an association of [La] response during incremental and MLSS exercise when utilizing cycle ergometry.

The effects of a downhill running bout on running economy.

This study investigated whether downhill (DH) running (10-min @ 214.4 m·min(-1) and -10% grade) would elicit acute and delayed effects on running economy (RE) upon completion of DH running (RE2) and daily over 72 h (RE3, RE4, RE5). Fifteen runners (8 female, 7 male) completed the protocol. RE was measured during level running performed at 70% VO2peak. A baseline RE test (RE1) was used for comparison. Muscle soreness was significantly elevated at RE3 and RE4 vs. RE1. Oxygen uptake was significantly elevated at RE2 relative to RE3, RE4 and RE5 but was not different from RE1. Heart rate was similarly elevated at RE2. Measures of ankle, knee and hip joint angles at heel strike and toe off were not affected at any time-point in a subset of subjects (N = 6). A short DH running bout did not elicit significant delayed adverse effects on oxygen uptake or gait parameters relative to baseline.

Volume Progression and Imaging Classification of Polycystic Liver in Early Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: The progression of polycystic liver disease is not well understood. The purpose of the study is to evaluate the associations of polycystic liver progression with other disease progression variables and classify liver progression on the basis of patient's age, height-adjusted liver cystic volume, and height-adjusted liver volume. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective longitudinal magnetic resonance images from 670 patients with early autosomal dominant polycystic kidney disease for up to 14 years of follow-up were evaluated to measure height-adjusted liver cystic volume and height-adjusted liver volume. Among them, 245 patients with liver cyst volume >50 ml at baseline were included in the longitudinal analysis. Linear mixed models on log-transformed height-adjusted liver cystic volume and height-adjusted liver volume were fitted to approximate mean annual rate of change for each outcome. The association of sex, body mass index, genotype, baseline height-adjusted total kidney volume, and Mayo imaging class was assessed. We calculated height-adjusted liver cystic volume ranges for each specific age and divided them into five classes on the basis of annual percentage increase in height-adjusted liver cystic volume. RESULTS: The mean annual growth rate of height-adjusted liver cystic volume was 12% (95% confidence interval, 11.1% to 13.1%; P<0.001), whereas that for height-adjusted liver volume was 2% (95% confidence interval, 1.9% to 2.6%; P<0.001). Women had higher baseline height-adjusted liver cystic volume than men, but men had higher height-adjusted liver cystic volume growth rate than women by 2% (95% confidence interval, 0.4% to 4.5%; P=0.02). Whereas the height-adjusted liver cystic volume growth rate decreased in women after menopause, no decrease was observed in men at any age. Body mass index, genotype, and baseline height-adjusted total kidney volume were not associated with the growth rate of height-adjusted liver cystic volume or height-adjusted liver volume. According to the height-adjusted liver cystic volume growth rate, patients were classified into five classes (number of women, men in each class): A (24, six); B (44, 13); C (43, 48); D (28, 17); and E (13, nine). CONCLUSIONS: Compared with height-adjusted liver volume, the use of height-adjusted liver cystic volume showed greater separations in volumetric progression of polycystic liver disease. Similar to the Mayo imaging classification for the kidney, the progression of polycystic liver disease may be categorized on the basis of patient's age and height-adjusted liver cystic volume.

The relative risk of overall graft loss and acute rejection among African American renal transplant recipients is attenuated with advancing age.

BACKGROUND: Graft loss rates are elevated among African American (AA) kidney transplant recipients. This may be attributable to immunological responses, socioeconomic disparities, comorbid conditions and access to care, but it is unclear whether risks are uniform in the AA population. METHODS: We utilized multivariable models with the national SRTR database for adult recipients transplanted from 2000 to 2009 (n = 112,120) to investigate whether risks of graft loss, death and acute rejection between AAs and Caucasians vary with age. RESULTS: Relative to Caucasians, AA recipients had significantly higher risk of overall graft loss among patients aged 18-49 (AHR = 1.37, 95% CI 1.30-1.43) but comparable risk among patients aged >65 (AHR = 1.04, 95% CI 0.96-1.13). Among recipients aged 18-34, AAs had higher risk of acute rejection (AOR = 1.33, 95% CI 1.12-1.57) but similar likelihood among recipients aged >65 (AOR = 0.94, 95% CI 0.75-1.17). Differences between race groups, as well as the relatively higher risks among younger AAs, were most pronounced following one yr post-transplantation and diminished with presence of other risk factors. CONCLUSIONS: Elevated risks of overall graft loss and acute rejection are present among younger but not older AA kidney transplant recipients. These findings may have important implications for treatment decisions, follow-up protocols and designation of "high-risk" patients.