Renal Washout Research Articles

Challenges in the development of novel methodologies for measuring glomerular filtration rate

Measurement of glomerular filtration rate (GFR) is crucial in assessing kidney function status. Estimating GFR using clearance methodologies is cumbersome, as plasma and urinary concentrations and timed urine collections are required. Recently, a transcutaneous sensor has been developed whereby the rate of renal washout of a fluorescent marker administered intravenously allows calculation of GFR. The challenge is to ensure that the values of GFR obtained using the washout approach are in accord with those obtained conventionally.

Reducing kidney uptake of radiolabelled exendin-4 using variants of the renally cleavable linker MVK

BackgroundPeptidic radiotracers are preferentially excreted through the kidneys, which often results in high persistent renal retention of radioactivity, limiting or even preventing therapeutic clinical translation of these radiotracers. Exendin-4, which targets the glucagon-like-peptide 1 receptor (GLP-1R) overexpressed in insulinomas and in congenital hyperinsulinism, is an example thereof. The use of the tripeptide MVK, which is readily cleaved between methionine and valine by neprilysin at the renal brush border membrane, already showed promising results in reducing kidney uptake as reported in the literature. Based on our previous findings we were interested how linker variants with multiple copies of the MV-motive influence renal washout of radiolabelled exendin-4.ResultsThree exendin-4 derivatives, carrying either one MVK, a MV-MVK or a MVK-MVK linker were synthesized and compared to a reference compound lacking a cleavable linker. In vivo results of a biodistribution in GLP-1R overexpressing tumour bearing mice at 24 h post-injection demonstrated a significant reduction (at least 57%) of renal retention of all 111In-labeled exendin-4 compounds equipped with a cleavable linker compared to the reference compound. While the insertion of the single linker MVK led to a reduction in kidney uptake of 70%, the dual approach with the linker MV-MVK slightly, but not significantly enhanced this effect, with 77% reduction in kidney uptake compared to the reference. In vitro IC50 and cell uptake studies were conducted and demonstrated that though the cleavable linkers negatively influenced the affinity towards the GLP-1R, cell uptake remained largely unaffected, except for the MV-MVK cleavable linker conjugate, which displayed lower cell uptake than the other compounds. Importantly, the tumour uptake in the biodistribution study was not significantly affected with 2.9, 2.5, 3.2 and 1.5% iA/g for radiolabelled Ex4, MVK-Ex4, MV-MVK-Ex4 and MVK-MVK-Ex4, respectively.ConclusionCleavable linkers are highly efficient in reducing the radioactivity burden in the kidney. Though the dual linker approach using the instillation of MV-MVK or MVK-MVK between exendin-4 and the radiometal chelator did not significantly outperform the single cleavable linker MVK, further structural optimization or the combination of different cleavable linkers could be a stepping stone in reducing radiation-induced nephrotoxicity.

Early Injection of Furosemide Increases Detection Rate of Local Recurrence in Prostate Cancer Patients with Biochemical Recurrence Referred for 68Ga-PSMA-11 PET/CT.

The aim of this study was twofold. First, we aimed to assess the impact of forced diuresis with early furosemide injection on the detection rate of local recurrence in prostate cancer patients with biochemical recurrence referred for 68Ga-labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (68Ga-PSMA-11) PET/CT. Second, we determined whether intravenous administration of furosemide shortly after tracer injection increases renal washout of 68Ga-PSMA-11 before it binds to the PSMA receptor with possible influence on biodistribution and intensity of tracer uptake in organs with physiologic tracer accumulation. Methods: In a retrospective analysis, 2 different groups with 220 prostate cancer patients each, referred for 68Ga-PSMA-11 PET/CT because of biochemical recurrence after primary therapy, were compared: patients in group 1 (median prostate-specific antigen, 1.30 ng/mL) received no preparation before imaging, whereas patients in group 2 (median prostate-specific antigen, 0.82 ng/mL) were injected with 20 mg of furosemide and 500 mL of sodium chloride (NaCl 0.9%) immediately after tracer injection. The presence of local recurrence was assessed visually. In addition, the intensity of tracer accumulation in organs with physiologic tracer uptake was evaluated. Results: The detection rate of lesions judged positive for local recurrence was significantly higher in patients receiving furosemide than in patients without preparation: 56 cases (25.5%) versus 38 cases (17.3%), respectively (P = 0.048). Median maximum SUVs (SUVmax) of organs with physiologic uptake of 68Ga-PSMA-11 in groups 1 and 2 were urinary bladder (63.0 vs. 8.9), kidney (55.6 vs. 54.5), liver (9.9 vs. 9.4), spleen (11.2 vs. 11.9), small bowel (16.2 vs. 17.1), parotid gland (19.2 vs. 19.6), lacrimal gland (8.9 vs. 10.9), blood-pool activity (2.2 vs. 2.3), muscle (1.0 vs. 1.1), and bone (1.6 vs. 1.6). Apart from bladder activity, no significant reduction of tracer accumulation was found in the patient group receiving furosemide. Conclusion: Injection of 20 mg of furosemide at the time point of radiotracer administration significantly increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence referred for 68Ga-PSMA-11 PET/CT. As intensity of 68Ga-PSMA-11 uptake in organs with physiologic uptake is not significantly reduced, a negative impact of early furosemide injection on targeting properties and biodistribution of 68Ga-PSMA-11 seems unlikely.

177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: Indigenously Developed Freeze Dried Cold Kit and Biological Response in In-Vitro and In-Vivo Models.

Somatostatin receptors (SStR) based 177Lu-DOTATATE therapy is known as one of the highly effective neuroendocrine tumors (NETs) treatment strategy. Development of DOTATATE freeze-dried kit for imaging and therapy of SStR positive NETs is a prime goal in neuroendocrine cancer research. The present work describes the development of 177Lu-DOTATATE freeze dried cold kit for indigenous needs, through technology development fund (TDF) program offered by Higher Education Commission (HEC) Pakistan. The parameters for freeze dried kit production was optimized and tested the stored lyophilized cold kits for different time intervals after labeling with 177Lu radioisotope. The effect of ligand to radionuclide ratio, pH and reaction time at 90°C was recorded. Five times greater molar concentration of ligand, pH 5 and 30 min reaction time were the effective reaction conditions for maximum radiochemical yield. The radiolabeling yield at 1 day, 1-week and 4-week post storing period showed ∼100% radiochemical yield. The biodistribution study using rat model depicted the absence of non-targeted accumulation while glomerular filtration rate also explains the rapid renal washout. Cytotoxicity study showed quite favorable results for subjecting the radiopharmaceutical to clinical practice in Pakistan.

Evaluation of prognostic integrin α2β1 PET tracer and concurrent targeting delivery using focused ultrasound for brain glioma detection.

The ability to early detect and assess the treatment response of recurrent and/or disseminated metastatic glioblastoma is critical for the effective management of this group of patients. Accumulating experimental evidence indicates that integrin α2β1 might be a prognostic biomarker for advanced phenotype of cancers. In this study, a novel (68)Ga-labeled integrin α2β1-targeted PET tracer (68)Ga-NOTA-PEG4-cyclo (GDGEAyK) ((68)Ga-A2B1) was designed and evaluated for the potential prognostic imaging of glioblastoma tumor in preclinical model. To prospectively verify the prognostic value of integrin α2β1, the in vitro Western blot and flow cytometry studies were performed to validate the integrin expression level of human glioblastoma (U87MG) cells. Extremely high expression level of integrin α2β1 justifies its role as a potential targeting marker. Thus, (68)Ga-A2B1 positron emission tomography was performed in subcutaneous U87MG tumor bearing athymic mice at 15 min postinjection after injection of 7-8MBq tracers. The receptor targeting specificity was confirmed in a competition blocking experiment. The tumor uptake of (68)Ga-A2B1 in the control and blockage groups was 1.57 ± 0.13 %ID/g (n = 3) and 0.96 ± 0.23 %ID/g** (n = 3), respectively. However, because of the quick renal washout rate and labile nature of peptide tracers in circulation conditions, the focus ultrasound (FUS) mediated delivery method was adopted to enhance tumor uptake and retention of tracers. To test the FUS delivery efficacy in vivo, three experimental arms were designed as follows: tumor bearing mice were administrated with (68)Ga-A2B1 only or microbubbles (MBs) with FUS treatment ((68)Ga-A2B1 + FUS + MBs) or embedded (68)Ga-A2B1-microbubbles ((68)Ga-A2B1-MBs + FUS) followed with FUS sonication. The average radioactivity accumulation within a tumor was quantified from the multiple region of interest volumes using the %ID/g value and was analyzed in accordance with the ex vivo autoradiographic and pathologic data. The significant tumor uptake in (68)Ga-A2B1 + FUS +MBs group (n = 6) and (68)Ga-A2B1-MBs + FUS group (n = 4) following FUS treatment were calculated as 2.25 ± 0.50 %ID/g* and 2.6 ± 0.49 %ID/g**, comparing with (68)Ga-A2B1 only group 1.48 ± 0.42 %ID/g (n = 10). These results suggest that there is significant difference in (68)Ga-A2B1 tumor uptake by FUS treatment either with or without tracer integration with microbubbles, which demonstrate a promising delivery strategy and critical multimodal setting for phenotyping imaging of aggressive glioma tumor. In conclusion, (68)Ga labeled (68)Ga-A2B1 allows noninvasive imaging of tumor-associated α2β1 expression and can be embedded in MB lipid shell for enhanced delivery and controlled release by sonoporation.

503 The ultrasonographic evolution of the hydronephrosis and renal parenchyma thickness in patients with congenital ureteropelvic junction (UPJ) obstruction who underwent pyeloplasty

INTRODUCTION AND OBJECTIVES: Introduction: Pyeloplasty is an established treatment for pelviureteric junction (UPJ) obstruction. After pyeloplasty diuretic renograms are often obtained to document surgical success by demonstrating better urinary drainage. However, while diuretic renograms may be the most accurate way to evaluate surgical outcome in the early postoperative period, renal ultrasound is more commonly used for long-term followup because it is less invasive and more cost-effective. OBJECTIVE: The aim of this study was to determine the ultrasonographic evolution of the pelvic and caliceal dilatations and of the renal parenchyma thickness in patients with congenital hydronephrosis who underwent pyeloplasty. METHODS: Materials and Methods: From January 2006 to January 2010, 265 patients with prenatally diagnosed hydronephrosis underwent a protocol of antibiotic prophylaxis, ultrasound, diuretic renography(DTPA) and voiding cystourethrography. Of the 265 patients, 85 (32%) who showed a trend of progressive hydronephrosis underwent pyeloplasty and were included. All the patients were evaluated with DTPA scans on the sixth month after surgery. The ultrasound performed before the surgery as well as all performed in the first 3,6,12,24 and 36 months after the pyeloplasty were reviewed and compared. The trends in the changes in these studies were studied. Statistical analyses were performed with SPSS (Statistical Package for the Social Sciences) version 18.0. RESULTS: All patients significantly improved the renal washout time (T1⁄2) in DTPA scans at six months postoperatively. The rate of caliceal dilatation decrease in the first 3, 6 and 12 months after surgery were 60%, 91,7%, and 100%, respectively. In a follow-up period of at least 1 year, 43 (50,6%) renal units had complete resolution of the pelvic dilation and 72 (84.7%) of the caliceal dilatation. The renal parenchyma was normal or had increased in 76 (89,4 %) of cases. CONCLUSIONS: The decrease in pelvic and caliceal dilatations occurred in the majority of the patients, but its complete resolution is relatively slow. Serial ultrasound is noninvasive and could replace serial invasive renal scans decreasing costs, instrumentation, and radiation exposure.

Pelvic Reduction During Pyeloplasty for Antenatal Hydronephrosis: Does It Affect Outcome in Ultrasound and Nuclear Scan Postoperatively?

To compare ultrasound (US) scan and nuclear renography findings in patients who underwent pyeloplasty with and without pelvic reduction in a randomized prospective study. A total of 42 patients, all prenatally diagnosed with unilateral hydronephrosis, were included. Hydronephrosis was confirmed postnatally. Twenty patients were randomly selected to undergo pyeloplasty with pelvic reduction and 22 underwent pelvis-sparing pyeloplasty. Patients were evaluated with mercaptoacetyltriglycine-3 scans on the sixth month and US scans on the first, third, and sixth months, postoperatively. Mean follow-up was 37 +/- 5.6 weeks. Statistical analyses were performed using chi-square test and significance was set as P <.05. Power analyses were performed by the NCSS-PASS program. Power value of 0.84 was calculated for a sample size of 42. The anteroposterior pelvic diameter decreased significantly in the pelvic reduction group compared with pelvis-sparing group in the first- and third-month US scans. However, the difference was not significant in the sixth month. The improvements in the US findings for the pelvis-sparing group match with those of the pelvic reduction group later in the postoperative period. Pelvic reduction significantly improved the renal washout time (T(1/2)) in mercaptoacetyltriglycine-3 renography when compared with pyeloplasty group without reduction at postoperative sixth month. Differential renal function was found to be unaffected from pelvic reduction. Resolution of anteroposterior diameter in US scan is more prominent in the pelvic reduction group at earlier stages of the postoperative period. Although T(1/2) decreases more prominently in the pelvic reduction group, the utility of this procedure is still indecisive. This feature can reveal possible surgical failures earlier and strengthen the values of US and renography postoperatively.

The renal washout parameter as an indicator of transplant rejection.

The accumulation of intravascular fibrin thrombosis in both acute and chronic renal rejection leads to a delay in the transit of perfusion. This study examines the renal washout parameter as an indicator of transit time. By mathematical simulation of renal time-activity curves various factors which can influence this parameter are investigated, a simple analysis is proposed and clinical results are correlated with biopsy findings. A washout parameter greater than 28 s is found to be consistent with histologically diagnosed rejection over a range of bolus qualities.

Prospective Evaluation of Renal Allograft Dysfunction with 99mTechnetium-Diethylenetriaminepentaacetic Acid Renal Scans

A prospective, single-blinded study was done to determine the ability of serial 99mtechnetium-diethylenetriaminepentaacetic acid scans to diagnose renal allograft rejection. Among 28 transplant recipients 111 renal scans were obtained 1 day postoperatively and every 3 to 4 days thereafter for 3 weeks in all patients retaining an allograft. Computer-generated time-activity blood flow curves were analyzed semiquantitatively for the 1) interval between curve peaks of the allograft and iliac artery, 2) renal transit time and 3) renal washout of radionuclide. Excretory function was assessed by degree and interval to appearance of radionuclide in the calices and bladder. Deterioration of renal blood flow and excretion compared to the initial scan was considered rejection. Of 52 scans performed during clinical rejection 47 (90.4 per cent) were interpreted as showing rejection (sensitivity). Of 53 scans interpreted as showing rejection 47 (88.7 per cent) were positive for clinical rejection. The remaining 6 patients (initial false positive results) suffered clinical rejection within 24 to 72 hours. We conclude that 99mtechnetium-diethylenetriaminepentaacetic acid renal scans are useful in the differential diagnosis of renal allograft dysfunction.

Measurement of intrarenal anatomic distribution of krypton-85 in endotoxic shock in dogs

Renal blood flow distribution was measured in control dogs and dogs in endotoxic shock by utilizing a modification of 85Kr washout. Kidneys, injected with 85Kr via a renal arterial cannula, were removed at several specific intervals after injection, rapidly frozen, and sectioned transversely so that pieces of tissue could be isolated and counted for radioactivity. Control outer cortical blood flow was 462 ml/min per 100 g tissue wt, but 122 ml/min per 100 g during shock. Control inner cortical outer medullary flow was 396 ml/min per 100 g, but 166 ml/min per 100 g in shock. Control flow in the inner stripe of the outer zone of the medulla was 130 ml/min per 100 g and 134 ml/min per 100 g in shock. In shock the initial volume of radioactivity distributed to outer cortex was smaller, to inner cortex the same, and to inner stripe outer zone of the medulla larger than in controls. This study delineates renal washout of 85Kr from specific areas of the kidney and indicates the alterations in extent and magnitude of this washout in endotoxic shock.

Intrarenal blood flow in congestive heart failure.

Intrarenal blood flow distribution was measured by the 133 xenon washout technic in 10 patients with heart disease who were studied at time of left and right heart catheterization. Renal washout curves were analyzed by computer using a weighted least-squares nonlinear regression technic. In three patients with heart disease without edema the compartment I blood flow rates (outer cortex) were not significantly different from those found in nine normal kidney donors. In seven patients with hemodynamic evidence of heart failure and clinical edema the compartment I flow rates were significantly lower than those of the normal control group and of a group of sodium-depleted hypertensive patients. The rate constants of isotope removal from more central regions of the kidney (compartments II and III) were not depressed to a similar degree. Infusion of furosemide into the renal artery induced diuresis in eight studies which was accompained by preferential increases in compartment I flow rates in six. The data suggest that preferential vasoconstriction of renal cortical vessels may contribute to increased sodium retention by the kidneys and to edema formation in patients with congestive heart failure.