A label-free approach by infrared spectroscopic imaging for interrogating the biochemistry of diabetic nephropathy progression.

Routine histology, the current gold standard, involves staining for specific biomolecules. However, untapped biochemical information in tissue can be gathered using biochemical imaging. Infrared spectroscopy is an emerging modality that allows label-free chemical imaging to derive biochemical information (such as protein, lipids, DNA, collagen) from tissues. Here we employed this technology in order to better predict the development of diabetic nephropathy. Using human primary kidney biopsies or nephrectomies, we obtained tissue from 4 histologically normal kidneys, 4 histologically normal kidneys from diabetic subjects, and 5 kidneys with evidence of diabetic nephropathy. A biochemical signature of diabetic nephropathy was derived that enabled prediction of nephropathy based on the ratio of only 2 spectral frequencies. Nonetheless, using the entire spectrum of biochemical information, we were able to detect renal disease with near-perfect accuracy. Additionally, study of sequential protocol biopsies from 3 transplanted kidneys showed biochemical changes even prior to clinical manifestation of diabetic nephropathy. Thus, infrared imaging can identify critical biochemical alterations that precede morphologic changes, potentially allowing for earlier intervention.

Development of organ-specific donor risk indices.

Because of the shortage of deceased donor organs, transplant centers accept organs from marginal deceased donors, including older donors. Organ-specific donor risk indices have been developed to predict graft survival with various combinations of donor and recipient characteristics. Here we review the kidney donor risk index (KDRI) and the liver donor risk index (LDRI) and compare and contrast their strengths, limitations, and potential uses. The KDRI has a potential role in developing new kidney allocation algorithms. The LDRI allows a greater appreciation of the importance of donor factors, particularly for hepatitis C virus-positive recipients; as the donor risk index increases, the rates of allograft and patient survival among these recipients decrease disproportionately. The use of livers with high donor risk indices is associated with increased hospital costs that are independent of recipient risk factors, and the transplantation of livers with high donor risk indices into patients with Model for End-Stage Liver Disease scores < 15 is associated with lower allograft survival; the use of the LDRI has limited this practice. Significant regional variations in donor quality, as measured by the LDRI, remain in the United States. We also review other potential indices for liver transplantation, including donor-recipient matching and the retransplant donor risk index. Although substantial progress has been made in developing donor risk indices to objectively assess donor variables that affect transplant outcomes, continued efforts are warranted to improve these indices to enhance organ allocation policies and optimize allograft survival.

Association Between Total Cell Free DNA and SARS-CoV-2 In Kidney Transplant Patients: A Preliminary Study.

BACKGROUND: Kidney transplant (KT) recipients are at high risk for developing severe COVID-19. Lowering immunosuppression levels in KT recipients with COVID-19 encourages native immune responses but can raise the risk of rejection. Donor-derived cell-free DNA (dd-cfDNA), reported as a fraction of total cfDNA, is a proven biomarker for KT rejection. Total cfDNA levels are elevated in patients with COVID-19, which may depress dd-cfDNA fractions, potentially leading to missed rejections. METHODS: A retrospective analysis of 29 KT recipients hospitalized with COVID-19 between April and November 2020 examined total and dd-cfDNA levels. Blood samples were collected after onset of COVID-19, with follow-up samples collected from a subset of patients, when infection had likely subsided. RESULTS: After COVID-19 diagnosis, the median total cfDNA level was elevated (7.9 multiples of median [MoM]). A significant decrease in total cfDNA levels was observed between the first and second time points (6.2 MoM, 1.0 MoM; P <001). A significant positive association was identified between total cfDNA levels and COVID-19 severity (P = .02; R2 = .19). Two patients with biopsy-proven acute cellular rejection had dd-cfDNA fractions below the 1% cutoff for rejection (0.20% and 0.78%), with elevated total cfDNA levels of 7.9 MoM and 41.8 MoM, respectively. CONCLUSIONS: In this preliminary study, total cfDNA levels were elevated in KT patients with COVID-19, subsiding after resolution of infection. High total cfDNA levels may confound dd-cfDNA results, leading to failure to identify rejection. Considering total cfDNA levels is important in interpretation of dd-cfDNA tests for assessment of rejection in KT patients with COVID-19 or other infection.

Donor exchange programs in kidney transplantation: rationale and operational details from the north central donor exchange cooperative.

The increasing need for kidney transplants has led to innovations such as donor exchange programs. These programs offer transplant recipients with incompatible donors an opportunity to receive a compatible kidney. They also provide an alternative to costly desensitization protocols that have unproven long-term outcomes. Donor exchange programs have multiple options, including simple 2-pair exchanges, more complicated domino exchanges, or chain donations. The United States currently is limited by regional programs that provide for kidney donor exchanges. However, with the increasing public interest in and need for kidney transplants, general nephrologists will be approached with questions about these donor exchange programs. The goal of this review is to discuss donor exchange programs, including their role in expanding the donor pool, various types of exchanges, regional centers that provide these programs, and the process involved in patient enrollment. General knowledge of donor exchange programs will help providers in discussing options with patients approaching end-stage kidney disease and transplant.

Appraisal of GFR-estimating equations following kidney donation.

BACKGROUND: It is not clear which serum creatinine-based glomerular filtration rate (GFR)-estimating model performs best in kidney donors. STUDY DESIGN: Study of diagnostic accuracy. SETTING & PARTICIPANTS: From a population of 3,698 kidney donors, 255 donors underwent iohexol GFR measurement (mGFR). INDEX TEST (INTERVENTION): mGFR by means of plasma disappearance of iohexol. REFERENCE TEST OR OUTCOME: GFR was estimated (eGFR) by using the Cockcroft-Gault equation (eGFR(CG)), Mayo Clinic equation (eGFR(MC)), and Modification of Diet in Renal Disease (MDRD) Study equation (eGFR(MDRD)). RESULTS: Mean mGFR was 71.8 +/- 11.8 mL/min/1.73 m(2), and 85.5% had mGFR greater than 60 mL/min/1.73 m(2). eGFR(CG) underestimated mGFR by 3.96 +/- 13.3 mL/min/1.73 m(2) and was within 30% of mGFR 89.4% of the time. eGFR(MC) overestimated mGFR by 8.44 +/- 11.9 mL/min/1.73 m(2) and was within 30% of mGFR in 83.1% of cases. eGFR(MDRD) underestimated mGFR by only 0.43 +/- 11.7 mL/min/1.73 m(2), and the proportion within 30% of mGFR was greatest in the tested model; 94.1% of the time. However, eGFR(MC) was most accurate in classifying donors according to having eGFR less than 60 mL/min/1.73 m(2). LIMITATIONS: Lack of ethnic diversity and response bias. CONCLUSIONS: The MDRD Study equation is least biased, and because it is routinely reported by most laboratories, it is the best readily available model for estimating GFR in kidney donors.

Illicit drug use, hypertension, and chronic kidney disease in the US adult population.

Illicit drug use has been associated with chronic kidney disease (CKD) in select populations, but it is unknown whether the same association exists in the general population. By using data from the National Health and Nutrition Examination Survey 2005-2008, we conducted a cross-sectional analysis of 5861 adults who were questioned about illicit drug use, including cocaine, methamphetamines, and heroin, during their lifetime. The primary outcome was CKD as defined by an estimated glomerular filtration rate ≤60 mL/min/1.73 m(2) using the Chronic Kidney Disease Epidemiology Collaboration equation or by microalbuminuria. We also examined the association between illicit drug use and blood pressure (BP) ≥120/80, ≥130/85, and ≥140/90 mm Hg. Logistic regression was used to examine the association between illicit drug use and CKD and BP. Mean estimated glomerular filtration rate was similar between illicit drug users and nonusers (100.7 vs 101.4 mL/min/1.73 m(2), P = 0.4), as was albuminuria (5.7 vs 6.0 mg/g creatinine, P = 0.5). Accordingly, illicit drug use was not significantly associated with CKD in logistic regression models (odds ratio [OR], 0.98; confidence interval [CI], 0.75-1.27) after adjusting for other important factors. However, illicit drug users had higher systolic (120 vs 118 mm Hg, P = 0.04) and diastolic BP (73 vs 71 mm Hg, P = 0.0003) compared with nonusers. Cocaine use was independently associated with BP ≥130/85 mm Hg (OR, 1.24; CI, 1.00-1.54), especially when used more during a lifetime (6-49 times; OR, 1.42; CI, 1.06-1.91). In a representative sample of the US population, illicit drug use was not associated with CKD, but cocaine users were more likely to have elevated BP.

Creatinine-based estimations of kidney function are unreliable in obese kidney donors.

Accurate assessment of kidney function by measurement of glomerular filtration rate (GFR) is essential to the risk assessment of prospective living kidney donors. We evaluated the performance of various estimating equations for creatinine clearance (Cockcroft-Gault), GFR (Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration), and 24-hour urine collections for creatinine clearance in obese potential kidney donors. We evaluated 164 potential kidney donors including 49 with a BMI of 30-35 and 32 with a BMI >35 that have completed a routine living donor evaluation with a measured GFR. All the estimating equations performed poorly in obese donors. While 24-hour urine collections performed better, only 15% had an adequate 24-hour urine collection. Since obese kidney donors may be at higher than average risk for kidney failure, accurate assessment of kidney function in these donors is crucial to ensure their long-term health postdonation.

Temporal stability of the urinary proteome after kidney transplant: more sensitive than protein composition?

The temporal urinary proteome was examined in 4 groups of individuals in order to determine the temporal stability of diverse individuals with apparently good kidney health. The groups consisted of (1) healthy volunteers at zero time, 1 and 6 months, (2) kidney donors before and after surgery, (3) recipients immediately after surgery, and (4) successful kidney transplant recipients from 1 month to 4 years after transplant. Proteins were detected by reverse phase extraction of urine followed by MALDI-TOF profile and by iTRAQ analysis. Unusual components of the MALDI-TOF profiles found only in transplant subjects occurred at m/ z = 3370, 3441 and 3385 (human neutrophil defensins), 4303, 10350, and 11732 (beta-2 microglobulin, B2M). The peaks at m/ z = 4303 and 11732 were also quite intense among kidney donors following surgery. The peaks at m/ z = 4303 and 10350 in transplant recipients were associated with higher serum creatinine. Several additional proteins detected by iTRAQ were up-regulated in a manner that correlated closely with B2M. Overall, despite large differences between protein composition in different transplant recipients, there was remarkable stability for each individual as detected by either MALDI-TOF or iTRAQ analyses. These results suggested that, within limits, stability of profile components may be as important as protein content for definition of kidney health. Longitudinal study of urinary proteins from kidney recipients may demonstrate instability as a sensitive biomarker of adverse kidney health.