scholarly journals Novel Renal Autologous Cell Therapy for Type 2 Diabetes Mellitus Chronic Diabetic Kidney Disease: Clinical Trial Design

2022 ◽  
pp. 1-9
Author(s):  
Joseph Stavas ◽  
David Gerber ◽  
Steven G. Coca ◽  
Arnold L. Silva ◽  
Ashley Johns ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Function ◽  
Treatment Group ◽  
Kidney Disease ◽  
Phase Ii ◽  
Trial Design ◽  
Diabetic Kidney Disease ◽  
Autologous Cell ◽  
Autologous Cell Therapy

<b><i>Background:</i></b> Cell therapies explore unmet clinical needs of patients with chronic kidney disease with the potential to alter the pathway toward end-stage kidney disease. We describe the design and baseline patient characteristics of a phase II multicenter clinical trial utilizing the novel renal autologous cell therapy (REACT), by direct kidney parenchymal injection via the percutaneous approach in adults with type 2 diabetic kidney disease (T2DKD), to delay or potentially avoid renal replacement therapy. <b><i>Design:</i></b> The study conducted a prospective, multicenter, randomized control, open-label, phase II clinical trial between an active treatment group (ATG) receiving REACT from the beginning of the trial and a contemporaneous deferred treatment group (DTG) receiving standard of care for 12 months before crossing over to receive REACT. <b><i>Objectives:</i></b> The objective of this study was to establish the safety and efficacy of 2 REACT injections with computed tomography guidance, into the renal cortex of patients with T2DKD administered 6 months apart, and to compare the longitudinal change in renal function between the ATG and the DTG. <b><i>Setting:</i></b> This was a multicenter study conducted in major US hospitals. <b><i>Patients:</i></b> We enrolled eighty-three adult patients with T2DKD, who have estimated glomerular filtration rates (eGFRs) between 20 and 50 mL/min/1.73 m<sup>2</sup>. <b><i>Methods:</i></b> All patients undergo an image-guided percutaneous kidney biopsy to obtain epithelial phenotype selective renal cells isolated from the kidney tissue that is then expanded ex vivo over 4–6 weeks, resulting in the REACT biologic product. Patients are randomized 1:1 into the ATG or the DTG. Primary efficacy endpoints for both study groups include eGFR measurements at baseline and at 3-month intervals, through 24 months after the last REACT injection. Safety analyses include biopsy-related complications, REACT injection, and cellular-related adverse events. The study utilizes Good Clinical and Manufacturing Practices and a Data and Safety Monitoring Board. The sample size confers a statistical power of 80% to detect an eGFR change in the ATG compared to the DTG at 24 months with an α = 0.05. <b><i>Limitations:</i></b> Blinding cannot occur due to the intent to treat procedure, biopsy in both groups, and open trial design. <b><i>Conclusion:</i></b> This multicenter phase II randomized clinical trial is designed to determine the efficacy and safety of REACT in improving or stabilizing renal function among patients with T2DKD stages 3a–4.

scholarly journals Protocol and Baseline Data on Renal Autologous Cell Therapy Injection in Adults with Chronic Kidney Disease Secondary to Congenital Anomalies of the Kidney and Urinary Tract

2021 ◽  
pp. 1-6
Author(s):  
Joseph Stavas ◽  
Maria Diaz-Gonzalez de Ferris ◽  
Ashley Johns ◽  
Deepak Jain ◽  
Tim Bertram
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Urinary Tract ◽  
Kidney Disease ◽  
Cell Therapy ◽  
Congenital Anomalies ◽  
Preliminary Analysis ◽  
Autologous Cell ◽  
Tissue Acquisition ◽  
Autologous Cell Therapy

Background: Advanced cell therapies with autologous, homologous cells show promise to affect reparative and restorative changes in the chronic kidney disease (CKD) nephron. We present our protocol and preliminary analysis of an IRB-approved, phase I single-group, open-label trial that tests the safety and efficacy of Renal Autologous Cell Therapy (REACT; NCT 04115345) in adults with congenital anomalies of the kidney and urinary tract (CAKUT). Methods: Adults with surgically corrected CAKUT and CKD stages 3 and 4 signed an informed consent and served as their “own” baseline control. REACT is an active biological ingredient acquired from a percutaneous tissue acquisition from the patient’s kidney cortex. The specimen undergoes a GMP-compliant manufacturing process that harvests the selected renal cells composed of progenitors for renal repair, followed by image-guided locoregional reinjection into the patient’s renal cortex. Participants receive 2 doses at 6-month intervals. Primary outcomes are stable renal function and stable/improved quality of life. Additional exploratory endpoints include the impact of REACT on blood pressure, vitamin D levels, hemoglobin, hematocrit and kidney volume by MRI analysis. Results: Four men and 1 woman were enrolled and underwent 5 cell injections. Their characteristics were as follows: mean 52.8 years (SD 17.7 years), 1 Hispanic, 4 non-Hispanic, and 5 white. There were no renal tissue acquisition, cell injection, or cell product-related complications at baseline. Conclusion: REACT is demonstrating feasibility and patient safety in preliminary analysis. Autologous cell therapy treatment has the potential to stabilize or improve renal function in CAKUT-associated CKD to delay or avert dialysis. Patient enrollment and follow-up are underway.

scholarly journals Advanced Glycation End Products Predict Loss of Renal Function and Correlate With Lesions of Diabetic Kidney Disease in American Indians With Type 2 Diabetes

Diabetes ◽  
2016 ◽  
Vol 65 (12) ◽  
pp. 3744-3753 ◽  
Author(s):  
Pierre-Jean Saulnier ◽  
Kevin M. Wheelock ◽  
Scott Howell ◽  
E. Jennifer Weil ◽  
Stephanie K. Tanamas ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
Kidney Disease ◽  
American Indians ◽  
Advanced Glycation End Products ◽  
Diabetic Kidney Disease ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

scholarly journals Diabetic kidney disease: new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on “The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function”

2019 ◽  
Vol 33 (1) ◽  
pp. 9-35 ◽  
Author(s):  
Giuseppe Pugliese ◽  
◽  
Giuseppe Penno ◽  
Andrea Natali ◽  
Federica Barutta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
Kidney Disease ◽  
Natural History ◽  
Impaired Renal Function ◽  
Diabetic Kidney Disease ◽  
Italian Society ◽  
Diabetic Kidney ◽  
History Of

Abstract Aims This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. Data Synthesis Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., “nonalbuminuric renal impairment” and “progressive renal decline”, suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. Conclusions The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.

Diabetic Foot Ulcer as a Cause of Significant Decline in the Renal Function Among South Indian Population With Type 2 Diabetes: Role of TGF-β1 and CCN Family Proteins

2019 ◽  
Vol 18 (4) ◽  
pp. 354-361 ◽  
Author(s):  
T. P. Smina ◽  
M. Rabeka ◽  
Vijay Viswanathan
Keyword(s):  
Type 2 Diabetes ◽  
Renal Function ◽  
Kidney Disease ◽  
Diabetic Foot ◽  
Diabetic Kidney Disease ◽  
Foot Ulcer ◽  
Diabetic Foot Ulcer ◽  
South Indian ◽  
Tgf Β1

In the present study, a total of 428 South Indian subjects were divided into four different groups, consisting of individuals with type 2 diabetes without any other complications (T2DM), T2DM subjects with stage 2 and 3 diabetic kidney disease (CKD), T2DM subjects with grade 2 or 3 diabetic foot ulcer (DFU) and T2DM subjects having both diabetic kidney disease and diabetic foot ulcer (CKDDFU). The study was conducted ambispectively by comparing the changes in renal function among two consecutive periods, i.e., the period prior to the development of grade 2 and 3 diabetic foot ulcer (retrospectively) and after the development of DFU (prospectively). A gradual and uniform reduction of eGFR was observed throughout the study period in the subjects affected with either CKD or DFU alone. Whereas in subjects with both CKD and DFU, there was a sharp decline in the eGFR during the six months prior to the baseline, i.e., the period in which the development of ulcer and its progression to grade 2 or 3 happened. Remarkable elevations in the levels of TGF-β1 and CCN2 (CTGF), as well as a significant reduction in the level of CCN3 (NOV), were observed in the serum of CKDDFU group subjects, compared to the other groups. Increased production of TGF-β1 in response to the inflammatory stimulus from multiple sites in CKDDFU subjects caused a subsequent down-regulation of CCN3, followed by the activation of a large quantity of CCN2.

scholarly journals Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ferdinando Carlo Sasso ◽  
Pia Clara Pafundi ◽  
Vittorio Simeon ◽  
Luca De Nicola ◽  
Paolo Chiodini ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trial ◽  
Cardiovascular Risk ◽  
Kidney Disease ◽  
Primary Endpoint ◽  
Diabetic Kidney Disease ◽  
Multifactorial Intervention ◽  
Diabetic Kidney

Abstract Background Multiple modifiable risk factors for late complications in patients with diabetic kidney disease (DKD), including hyperglycemia, hypertension and dyslipidemia, increase the risk of a poor outcome. DKD is associated with a very high cardiovascular risk, which requires simultaneous treatment of these risk factors by implementing an intensified multifactorial treatment approach. However, the efficacy of a multifactorial intervention on major fatal/non-fatal cardiovascular events (MACEs) in DKD patients has been poorly investigated. Methods Nephropathy in Diabetes type 2 (NID-2) study is a multicentre, cluster-randomized, open-label clinical trial enrolling 395 DKD patients with albuminuria, diabetic retinopathy (DR) and negative history of CV events in 14 Italian diabetology clinics. Centres were randomly assigned to either Standard-of-Care (SoC) (n = 188) or multifactorial intensive therapy (MT, n = 207) of main cardiovascular risk factors (blood pressure < 130/80 mmHg, glycated haemoglobin < 7%, LDL, HDL and total cholesterol < 100 mg/dL, > 40/50 mg/dL for men/women and < 175 mg/dL, respectively). Primary endpoint was MACEs occurrence by end of follow-up phase. Secondary endpoints included single components of primary endpoint and all-cause death. Results At the end of intervention period (median 3.84 and 3.40 years in MT and SoC group, respectively), targets achievement was significantly higher in MT. During 13.0 years (IQR 12.4–13.3) of follow-up, 262 MACEs were recorded (116 in MT vs. 146 in SoC). The adjusted Cox shared-frailty model demonstrated 53% lower risk of MACEs in MT arm (adjusted HR 0.47, 95%CI 0.30–0.74, P = 0.001). Similarly, all-cause death risk was 47% lower (adjusted HR 0.53, 95%CI 0.29–0.93, P = 0.027). Conclusion MT induces a remarkable benefit on the risk of MACEs and mortality in high-risk DKD patients. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925

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