The therapy of lupus nephritis (LN) is mainly based on clinical data because serial biopsies are not routinely used to evaluate kidney involvement as the disease is treated and evolves. A non-invasive, real-time method to assess renal pathology could be used to titrate treatment and improve outcome. This work was undertaken to develop a urine biomarker of tubulointerstitial inflammation (TI) in LN, an injury that predisposes to renal fibrosis and chronic kidney disease. Urine samples collected at or close to the time of biopsy for LN (n=64) were used to identify potential biomarkers of TI. TI was scored by a renal pathologist using a semi-quantitative scale. Urine monocyte chemotactic protein-1 (uMCP-1), urine hepcidin (uHepcidin), and urine liver-fatty acid binding protein (uLFABP) were measured by immunoassays. Linear discriminant analysis was used to weight variables and derive composite biomarkers that identified the level of TI. The discriminant function that described the most accurate biomarker included uMCP-1 and serum creatinine as the independent variables. This composite biomarker had a sensitivity of 100%, specificity of 81%, positive predictive value of 67%, negative predictive value of 100%, and misclassified only 14% of the biopsies. In conclusion, specific renal pathologic lesions can be modeled by composite biomarkers. These biomarkers can be used to non-invasively follow and adjust the treatment of LN based on renal injury.

The 24-h urine protein-to-creatinine ratio is the gold standard in evaluating proteinuria in lupus nephritis; however, the urine collection is inconvenient to the patient. Random spot urine protein-to-creatinine ratios, although convenient, have poor agreement with the 24-h ratios in these patients. Here, we sought to define a timed collection interval providing accurate and precise data and patient convenience. Urine from 41 patients, in 2 medical centers, with biopsy-proven lupus nephritis was collected at 6-h intervals for 24 h. The protein-to-creatinine ratio of each short collection was then compared with that of a 24-h collection made by combining the 6-h samples. A first morning void and spot urine samples were collected before and after the 24-h collection, respectively. There was significant diurnal variation with peak proteinuria at 6–12 h and nadir at 18–24 h. Each 6-h collection showed excellent correlation and concordance with the 24-h protein-to-creatinine ratio, but the 12–24-h interval had the best agreement. In contrast to the random spot urines, the first morning void also had excellent correlation and concordance, but underestimated the 24-h protein-to-creatinine ratio. Our study shows that a 12-h overnight urine collection is the best surrogate, with excellent agreement with the 24-h protein-to-creatinine ratio, and it is convenient for patients. There was little variability between centers, an important feature for clinical trials.

Background and objectives: In our center, systemic lupus erythematosus nephritis is routinely treated with an oral cyclophosphamide (POCY) regimen. POCY is easy to administer and less expensive than intravenous cyclophosphamide (IVCY) as it is currently used in the United States; however, the use of POCY has declined in favor of IVCY. Our experience with POCY suggests that it is well tolerated and consistently associated with good long-term outcomes. Here we report this experience to build a case for maintaining POCY as a therapeutic option in lupus nephritis.Design, setting, participants, & measurements: This is a single-center, retrospective analysis of the outcome of 46 patients who had systemic lupus erythematosus with nephritis and were treated with POCY between 1995 and 2006. POCY was given for 2 to 4 mo at a dosage of 1.0 to 1.5 mg/kg ideal body weight. After completing POCY, the patients received either azathioprine or mycophenolate mofetil.Results: Median follow-up was 23.5 mo, and median duration of POCY was 4 mo (range 1 to 16 mo). Durable complete or partial remission of proteinuria was achieved in 32 (70%) patients, whereas 5 (11%) progressed to ESRD. Outcomes were comparable in black and white individuals. Adverse effects occurred in fewer than 10% of the cohort, and only four patients discontinued POCY.Conclusions: These results suggest that sequential therapy of POCY followed by azathioprine or mycophenolate mofetil is comparable to IVCY regimens but that efficacy may not be affected by race.

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The idea of individualizing therapies to obtain optimal clinical results is not new but has only recently been applied to kidney diseases. Nonetheless, kidney disorders present a variety of opportunities to personalize medicine. Here, the heterogeneity of kidney disorders is reviewed to provide a rationale for pursuing personalized medicine. Data on adjusting therapy on the basis of pharmacogenetics/genomics and pharmacodynamics are summarized to demonstrate where the field is, and biomarker studies that reflect the future of personalized medicine are discussed. The goal of this review is to demonstrate that we can personalize therapy for kidney diseases but that considerable investment in new research will be required for personalized medicine to be routinely used in nephrology clinics. Clin J Am Soc Nephrol 4: 1670 -1676. doi: 10.2215 T he phrase personalized medicine has been used with increasing frequency in the lay press, and academia has embraced this concept by forming centers of personalized medicine within their health systems. The goal of determining the right drug, for the right patient, at the right time is not new, however, and has been actively pursued for some time in oncology using genomic tools to look for gene mutations or variations in gene expression that may affect therapy. Other disciplines, including nephrology, have joined this endeavor, although the data on personalized therapies for kidney diseases are still very preliminary. This mini-review presents these data to provide a framework for expanding research into individualized therapies for kidney diseases. Building a Case for Personalized Medicine in Kidney DiseasesThere is ample evidence that kidney disorders that are characterized by a specific constellation of clinical signs and symptoms display the molecular and biochemical heterogeneity that lends itself to individualized medicine. For example, despite similar clinical and histologic phenotypes, pediatric allograft rejection could be divided into three molecular groups by microarray analysis of total renal biopsy RNA expression (1). One of these acute rejection molecular groups was enriched for expression of B cell genes, and by immunohistochemistry, abundant B cells were found to be present in renal biopsy tissue from this subset of patients. Although the numbers were small, recovery from rejection and steroid responsiveness were significantly better in the patients who did not have B cells infiltrating their allografts. These data suggest that determining the molecular subtype of acute rejection before treatment may be used to identify patients who are likely to be steroid resistant and who may benefit from a different antirejection protocol (2).Molecular heterogeneity is also found in primary and secondary glomerular diseases. Pediatric patients who had FSGS and displayed nephrotic-range proteinuria or renal insufficiency could be differentiated from patients who did not have nephrosis or renal insufficiency, respectively, on the basis of unique renal cortical RNA expression (3...