Microvasculature Ultrasound Super-resolution in Transplant Delayed Graft Function

Overview

This pilot study is testing a new ultrasound imaging method called Super-Resolution Ultrasound (SRU) to look at blood flow and tiny blood vessels in transplanted kidneys in very detailed images after kidney transplant surgery. The goal is to see whether changes in the kidney's small blood vessels can help predict how well the transplanted kidney will work early after transplant, including whether delayed graft function may occur. Investigators hope this technique can become a safe, noninvasive way to evaluate transplanted kidneys without needing as many invasive biopsies. It may also help doctors better assess donor kidneys at higher-risk of suboptimal functioning.

Detailed description

Specific Aim 1: Utilize super-resolution ultrasound (SRU) to analyze tiny blood vessels in transplanted kidneys under very detailed imaging and evaluate kidney allografts and predict post-transplantation function.

Delayed graft function (DGF) is a common complication that can happen soon after a kidney transplant and may lead to longer recovery times and other health problems. Kidney biopsies are typically required to find the cause, which are invasive procedures. Current imaging tests cannot clearly show the tiny blood vessel changes inside the transplanted kidney that may contribute to the development of DGF.

Hypothesis: Investigators hypothesize that SRU can noninvasively predict DGF outcomes by measuring changes in the structure of tiny kidney blood vessels and the blood flow within them.

Approach:

Aim 1a: Compare SRU-derived measures of renal microvasculature-including microvascular density, tortuosity, and cortical perfusion-between patients who develop DGF and those with uncomplicated graft function.

Aim 1b: Correlate SRU parameters with clinical outcomes at 30 and 90 days post-transplant, as determined from inpatient and outpatient data within the electronic medical record.

Experimental Plan. Allograft SRU will be performed in 20 renal allograft recipient patients up to 14 days after transplant (n=10 with DGF, n=10 without DGF). Patients will be identified and recruited from within UPMC. After injection with Definity, SRU images and measurements will be obtained as described elsewhere in this protocol. Measures are noninvasive, with the transducer applied to the body surface over the allograft. Measurements will be compared between the two groups, and correlations made with eGFR at 30 and 90 days, total days of dialysis, resistive indices, and interstitial fibrosis/tubular atrophy (IFTA) on the standard 3-month protocol biopsy.

Anticipated Results, Potential Pitfalls, and Future Directions. Investigators expect that renal blood volume and microvessel density will be higher in patients with functioning grafts, and that these parameters will be positively correlated with better outcomes, demonstrating that SRU is a promising and noninvasive prognostic tool.

Expected Outcomes and Impact: Investigators anticipate that SRU will identify microvascular densities predictive of DGF, providing a novel, noninvasive biomarker to guide post-transplant management. Successful completion of this aim will establish SRU as a clinically useful tool to reduce reliance on invasive biopsy and improve early allograft evaluation.

Specific Aim 2: Utilize super-resolution ultrasound (SRU) to evaluate early microvascular changes in high-KDPI kidneys up to 14 days after transplantation to predict early graft function.

Rationale: Donor kidneys with a high Kidney Donor Profile Index (KDPI) are often discarded due to their perceived risk of poor function, despite limited physiologic data on their microvascular integrity. Early post-transplant microvascular alterations may serve as critical indicators of graft viability and short-term function.

Hypothesis: Investigators hypothesize that SRU-detected microvascular changes occurring within the first 48 hours after transplantation can predict early transplanted kidney function and distinguish between high- and low-KDPI kidneys.

Experimental Plan:

Investigators will perform SRU imaging within 14 days of transplantation in kidney allograft recipients, using the same SRU parameters described in Aim 1. Investigators will compare SRU-derived measures such as structure, size, characteristics, and blood flow -between two groups: recipients of high-risk kidneys (KDPI \>75; n = 10) and recipients of more optimal kidneys (KDPI \<35; n = 10). SRU findings will be correlated with key clinical outcomes, including the incidence of delayed graft function (DGF), need for dialysis, measures of kidney function at 30 and 90 day marks, and the degree of scarring of the functional units of the kidney observed on 90-day protocol biopsies.

Anticipated Results, Potential Pitfalls, and Future Directions:

Investigators anticipate that kidneys with higher KDPI values will demonstrate reduced vascular density and perfusion within 48 hours post-transplant, and that these findings will correlate with inferior 30- and 90-day outcomes. If no significant differences or correlations are observed, investigators will reconsider the utility of the 48-hour timepoint in future studies or examine whether recipient-specific factors (e.g., age, hemodynamic status, blood pressure) influence SRU measurements. Findings from this aim will inform whether SRU can serve as an early, noninvasive measurement of transplanted kidney quality and may challenge current allocation practices that exclude high-KDPI kidneys (high-risk of suboptimal functioning kidneys)

Interventions

• Diagnostic test Ultrasound contrast agent (Contrast-enhanced ultrasound)
  Super-resolution ultrasound using lipid microsphere contrast
• Drug Optison (Perflutren Protein-Type A Microspheres Injectable Suspension)
  Approved drug or biologic being evaluated for a new indication, population, route of administration, or dosage level not specified in the FDA approved labeling for kidney imaging.
• Drug Lumason® contrast agent
  Approved drug or biologic being evaluated for a new indication, population, route of administration, or dosage level not specified in the FDA approved labeling for kidney imaging.
• Drug DEFINITY®
  Approved drug or biologic being evaluated for a new indication, population, route of administration, or dosage level not specified in the FDA approved labeling for kidney imaging.

Primary outcome measures

• Kidney vascularity [Time frame: Less than 30 minutes]

Secondary outcome measures (1)

• Kidney blood vessel tortuosity [Time frame: up to 30 minutes]

Eligibility criteria

Inclusion criteria

For stage 1 of the study:

• We will enroll patients ≥18 years of age
• Patients who received a kidney transplant 2a. Patients requiring dialysis in the first 14 days after transplant 2b. Patients with working allografts not requiring dialysis (control group)

For stage 2 of the study

• We will enroll patients at least 18 years of age or older
• Patients who received a kidney transplant 2a. Patients who received kidney transplants from low KDPI kidneys (KDPI < 35) 2b. Patients who received kidney transplants from high KDPI kidneys (KDPI > 75)

Exclusion criteria

• BMI > 40
• Inability to provide informed consent
• Pregnant woman
• Breastfeeding women
• Hypersensitivity to perfluten lipid microsphere and components including polyethylene glycol (PEG)
• Unstable cardiopulmonary condition (acute myocardial infarction, acute coronary artery symptoms, worsening or unstable congestive heart failure, serious ventricular arrhythmias).
• Known history of cardiac shunts
• Patients who have known sickle cell disease or trait

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 1 center

• University of Pittsburgh Medical Center — Pittsburgh

Publications

• Steegh FM, Gelens MA, Nieman FH, van Hooff JP, Cleutjens JP, van Suylen RJ, Daemen MJ, van Heurn EL, Christiaans MH, Peutz-Kootstra CJ. Early loss of peritubular capillaries after kidney transplantation. J Am Soc Nephrol. 2011 Jun;22(6):1024-9. doi: 10.1681/ASN.2010050531. Epub 2011 May 12. PMID 21566051
• Aubert O, Reese PP, Audry B, Bouatou Y, Raynaud M, Viglietti D, Legendre C, Glotz D, Empana JP, Jouven X, Lefaucheur C, Jacquelinet C, Loupy A. Disparities in Acceptance of Deceased Donor Kidneys Between the United States and France and Estimated Effects of Increased US Acceptance. JAMA Intern Med. 2019 Oct 1;179(10):1365-1374. doi: 10.1001/jamainternmed.2019.2322. PMID 31449299
• van der Windt DJ, Mehta R, Jorgensen DR, Bou-Samra P, Hariharan S, Randhawa PS, Sood P, Molinari M, Wijkstrom M, Ganoza A, Tevar AD. Donor acute kidney injury and its effect on 1-year post-transplant kidney allograft fibrosis. Clin Transplant. 2020 Feb;34(2):e13770. doi: 10.1111/ctr.13770. Epub 2020 Feb 11. PMID 31829462
• Naesens M, Heylen L, Lerut E, Claes K, De Wever L, Claus F, Oyen R, Kuypers D, Evenepoel P, Bammens B, Sprangers B, Meijers B, Pirenne J, Monbaliu D, de Jonge H, Metalidis C, De Vusser K, Vanrenterghem Y. Intrarenal resistive index after renal transplantation. N Engl J Med. 2013 Nov 7;369(19):1797-806. doi: 10.1056/NEJMoa1301064. PMID 24195547
• Chen Q, Yu J, Lukashova L, Latoche JD, Zhu J, Lavery L, Verdelis K, Anderson CJ, Kim K. Validation of Ultrasound Super-Resolution Imaging of Vasa Vasorum in Rabbit Atherosclerotic Plaques. IEEE Trans Ultrason Ferroelectr Freq Control. 2020 Aug;67(8):1725-1729. doi: 10.1109/TUFFC.2020.2974747. Epub 2020 Feb 18. PMID 32086204
• Horbelt M, Lee SY, Mang HE, Knipe NL, Sado Y, Kribben A, Sutton TA. Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am J Physiol Renal Physiol. 2007 Sep;293(3):F688-95. doi: 10.1152/ajprenal.00452.2006. Epub 2007 Jul 11. PMID 17626153
• Sharma N, Mahajan A, Qazi YA. Marginal kidney transplantation: the road less traveled. Curr Opin Organ Transplant. 2019 Feb;24(1):92-96. doi: 10.1097/MOT.0000000000000603. PMID 30507708
• Hall IE, Schroppel B, Doshi MD, Ficek J, Weng FL, Hasz RD, Thiessen-Philbrook H, Reese PP, Parikh CR. Associations of deceased donor kidney injury with kidney discard and function after transplantation. Am J Transplant. 2015 Jun;15(6):1623-31. doi: 10.1111/ajt.13144. Epub 2015 Mar 11. PMID 25762442

Identifiers

NCT: NCT07645599 · STUDY25100091

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗