John C. Lieske

Current Issues in Measurement and Reporting of Urinary Albumin Excretion

BACKGROUND Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. CONTENT The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the error-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences have been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no reference materials for either analyte in urine. The recommended reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethnicity) nor the continuous increase in risk related to albumin excretion. DISCUSSION Clinical needs have been identified for standardization of (a) urine collection methods, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.

Kidney stones and the risk for chronic kidney disease.

BACKGROUND AND OBJECTIVES Kidney stones lead to chronic kidney disease (CKD) in people with rare hereditary disorders (e.g., primary hyperoxaluria, cystinuria), but it is unknown whether kidney stones are an important risk factor for CKD in the general population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Among Olmsted County, MN, residents, all stone formers (n = 4774) whose condition was diagnosed in 1986 through 2003 were matched 1:3 to control subjects (n = 12,975). Cox proportional hazards models adjusted for age, gender, and comorbidities (hypertension, diabetes, obesity, dyslipidemia, gout, alcohol abuse, tobacco use, coronary artery disease, heart failure, cerebral infarct, and peripheral vascular disease) were used to assess the risk for incident CKD defined as a clinical diagnosis (diagnostic codes), ESRD or death with CKD, sustained (>90 d) elevated serum creatinine (>1.3 mg/dl in men, >1.1 mg/dl in women), or sustained estimated GFR <60 ml/min per 1.73 m(2). RESULTS During a mean of 8.6 yr of follow-up, stone formers were at increased risk for a clinical diagnosis of CKD, but an increased risk for ESRD or death with CKD was NS. Among patients with follow-up serum creatinine levels, stone formers were at increased risk for a sustained elevated serum creatinine and a sustained reduced GFR. CONCLUSIONS Kidney stones are a risk factor for CKD, and studies are warranted to assess screening and preventive measures for CKD in stone formers.

Temporal trends in incidence of kidney stones among children: a 25-year population based study.

PURPOSE We conducted a population based pediatric study to determine the incidence of symptomatic kidney stones during a 25-year period and to identify factors related to variation in stone incidence during this period. MATERIALS AND METHODS The Rochester Epidemiology Project was used to identify all patients younger than 18 years who were diagnosed with kidney stones in Olmsted County, Minnesota from 1984 to 2008. Medical records were reviewed to validate first time symptomatic stone formers with identification of age appropriate symptoms plus stone confirmation by imaging or passage. The incidence of symptomatic stones by age, gender and study period was compared. Clinical characteristics of incident stone formers were described. RESULTS A total of 207 children received a diagnostic code for kidney stones, of whom 84 (41%) were validated as incident stone formers. The incidence rate increased 4% per calendar year (p = 0.01) throughout the 25-year period. This finding was due to a 6% yearly increased incidence in children 12 to 17 years old (p = 0.02 for age × calendar year interaction) with an increase from 13 per 100,000 person-years between 1984 and 1990 to 36 per 100,000 person-years between 2003 and 2008. Computerized tomography identified the stone in 6% of adolescent stone formers (1 of 18) from 1984 to 1996 vs 76% (34 of 45) from 1997 to 2008. The incidence of spontaneous stone passage in adolescents did not increase significantly between these 2 periods (16 vs 18 per 100,000 person-years, p = 0.30). CONCLUSIONS The incidence of kidney stones increased dramatically among adolescents in the general population during a 25-year period. The exact cause of this finding remains to be determined.

Kidney Stones Associate with Increased Risk for Myocardial Infarction

Kidney stones are a risk factor for chronic kidney disease (CKD), which, in turn, is a risk factor for myocardial infarction (MI). The objective of this study was to determine whether kidney stones associate with an increased risk for MI. We matched 4564 stone formers (1984 through 2003) on age and gender with 10,860 control subjects among residents in Olmsted County, Minnesota. We identified incident MI by diagnostic codes and validated events by chart review through 2006. We used diagnostic codes to determine incidence of kidney stones and presence of comorbidities (CKD, hypertension, diabetes, obesity, dyslipidemia, gout, alcohol dependence, and tobacco use). During a mean of 9 years of follow-up, stone formers had a 38% (95% confidence interval 7 to 77%) increased risk for MI, which remained at 31% (95% confidence interval 2% to 69%) after adjustment for CKD and other comorbidities. In conclusion, kidney stone formers are at increased risk for MI, and this risk is independent of CKD and other risk factors.

Fat malabsorption and increased intestinal oxalate absorption are common after Roux-en-Y gastric bypass surgery.

BACKGROUND Hyperoxaluria and increased calcium oxalate stone formation occur after Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity. The etiology of this hyperoxaluria is unknown. We hypothesized that after bariatric surgery, intestinal hyperabsorption of oxalate contributes to increases in plasma oxalate and urinary calcium oxalate supersaturation. METHODS We prospectively examined oxalate metabolism in 11 morbidly obese subjects before and 6 and 12 months after RYGB (n = 9) and biliopancreatic diversion-duodenal switch (BPD-DS) (n = 2). We measured 24-hour urinary supersaturations for calcium oxalate, apatite, brushite, uric acid, and sodium urate; fasting plasma oxalate; 72-hour fecal fat; and increases in urine oxalate following an oral oxalate load. RESULTS Six and 12 months after RYGB, plasma oxalate and urine calcium oxalate supersaturation increased significantly compared with similar measurements obtained before surgery (all P ≤ .02). Fecal fat excretion at 6 and 12 months was increased (P = .026 and .055, 0 vs 6 and 12 months). An increase in urine oxalate excretion after an oral dose of oxalate was observed at 6 and 12 months (all P ≤ .02). Therefore, after bariatric surgery, increases in fecal fat excretion, urinary oxalate excretion after an oral oxalate load, plasma oxalate, and urinary calcium oxalate supersaturation values were observed. CONCLUSION Enteric hyperoxaluria is often present in patients after the operations of RYGB and BPD-DS that utilize an element of intestinal malabsorption as a mechanism for weight loss.

Design of the nephrotic syndrome study network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary studies program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy for detailed clinical, histopathologic, and molecular phenotyping at the time of clinically-indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and bi-annually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for Nephrotic Syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

Relative Performance of the MDRD and CKD-EPI Equations for Estimating Glomerular Filtration Rate among Patients with Varied Clinical Presentations

BACKGROUND The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was developed using both CKD and non-CKD patients to potentially replace the Modification of Diet in Renal Disease (MDRD) equation that was derived with only CKD patients. The objective of our study was to compare the accuracy of the MDRD and CKD-EPI equations for estimating GFR in a large group of patients having GFR measurements for diverse clinical indications. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS A cross-sectional study was conducted of patients who underwent renal function assessment for clinical purposes by simultaneous measurements of serum creatinine and estimation of GFR using the MDRD and CKD-EPI equations and renal clearance of iothalamate (n = 5238). RESULTS Bias compared with measured GFR (mGFR) varied for each equation depending on clinical presentation. The CKD-EPI equation demonstrated less bias than the MDRD equation in potential kidney donors (-8% versus -18%) and postnephrectomy donors (-7% versus -15%). However, the CKD-EPI equation was slightly more biased than the MDRD equation in native CKD patients (6% versus 3%), kidney recipients (8% versus 1%), and other organ recipients (9% versus 3%). Among potential kidney donors, the CKD-EPI equation had higher specificity than the MDRD equation for detecting an mGFR <60 ml/min per 1.73 m(2) (98% versus 94%) but lower sensitivity (50% versus 70%). CONCLUSIONS Clinical presentation influences the estimation of GFR from serum creatinine, and neither the CKD-EPI nor MDRD equation account for this. Use of the CKD-EPI equation misclassifies fewer low-risk patients as having reduced mGFR, although it is also less sensitive for detecting mGFR below specific threshold values used to define CKD stages.

Endocytosis of Calcium Oxalate Crystals and Proliferation of Renal Tubular Epithelial Cells in a Patient with Type 1 Primary Hyperoxaluria

A patient with primary hyperoxaluria who received a liver-kidney transplant is presented. A postoperative renal biopsy showed apparent tubular cell endocytosis of calcium oxalate crystals and cell proliferation, indicating that renal epithelial cells do not perceive urinary crystals as inert. Such cellular responses to crystals may have a role in nephrolithiasis.

Dual-energy dual-source CT with additional spectral filtration can improve the differentiation of non-uric acid renal stones: An ex vivo phantom study

OBJECTIVE The purpose of this study was to determine the ex vivo ability of dual-energy dual-source CT (DSCT) with additional tin filtration to differentiate among five groups of human renal stone types. MATERIALS AND METHODS Forty-three renal stones of 10 types were categorized into five primary groups on the basis of effective atomic numbers, which were calculated as the weighted average of the atomic numbers of constituent atoms. Stones were embedded in porcine kidneys and placed in a 35-cm water phantom. Dual-energy DSCT scans were performed at 80 and 140 kV with and without tin filtration of the 140-kV beam. The CT number ratio, defined as the ratio of the CT number of a given material in the low-energy image to the CT number of the same material in the high-energy image, was calculated on a volumetric voxel-by-voxel basis for each stone. Statistical analysis was performed, and receiver operating characteristic (ROC) curves were plotted to compare the difference in CT number ratio with and without tin filtration, and to measure the discrimination among stone groups. RESULTS The CT number ratio of non-uric acid stones increased on average by 0.17 (range, 0.03-0.36) with tin filtration. The CT number ratios for non-uric acid stone groups were not significantly different (p > 0.05) between any of the two adjacent groups without tin filtration. Use of the additional tin filtration on the high-energy x-ray tube significantly improved the separation of non-uric acid stone types by CT number ratio (p < 0.05). The area under the ROC curve increased from 0.78 to 0.84 without fin filtration and to 0.89-0.95 with tin filtration. CONCLUSION Our results showed better separation among different stone types when additional tin filtration was used on dual-energy DSCT. The increased spectral separation allowed a five-group stone classification scheme. Some overlapping between particular stone types still exists, including brushite and calcium oxalate.

Transplantation Outcomes in Primary Hyperoxaluria

Optimal transplantation strategies are uncertain in primary hyperoxaluria (PH) due to potential for recurrent oxalosis. Outcomes of different transplantation approaches were compared using life‐table methods to determine kidney graft survival among 203 patients in the International Primary Hyperoxaluria Registry. From 1976–2009, 84 kidney alone (K) and combined kidney and liver (K + L) transplants were performed in 58 patients. Among 58 first kidney transplants (32 K, 26 K + L), 1‐, 3‐ and 5‐year kidney graft survival was 82%, 68% and 49%. Renal graft loss occurred in 26 first transplants due to oxalosis in ten, chronic allograft nephropathy in six, rejection in five and other causes in five. Delay in PH diagnosis until after transplant favored early graft loss (p = 0.07). K + L had better kidney graft outcomes than K with death‐censored graft survival 95% versus 56% at 3 years (p = 0.011). Among 29 year 2000–09 first transplants (24 K + L), 84% were functioning at 3 years compared to 55% of earlier transplants (p = 0.05). At 6.8 years after transplantation, 46 of 58 patients are living (43 with functioning grafts). Outcomes of transplantation in PH have improved over time, with recent K + L transplantation highly successful. Recurrent oxalosis accounted for a minority of kidney graft losses.