Browsing by Subject "renal failure"

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    A 20-year multicenter analysis of dialysis-dependent patients who had aortic or mitral valve replacement: Implications for valve selection
    (Elsevier, 2019) Manghelli, Joshua L.; Carter, Daniel I.; Khiabani, Ali J.; Gauthier, Jason M.; Moon, Marc R.; Munfakh, Nabil A.; Damiano, Ralph J.; Corvera, Joel S.; Melby, Spencer J.; Surgery, School of Medicine
    Objective Valve selection in dialysis-dependent patients can be difficult because long-term survival is diminished and bleeding risks during anticoagulation treatment are greater in patients with renal failure. In this study we analyzed long-term outcomes of dialysis-dependent patients who underwent valve replacement to help guide optimal prosthetic valve type selection. Methods Dialysis-dependent patients who underwent aortic and/or mitral valve replacement at 3 institutions over 20 years were examined. The primary outcome was long-term survival. A Cox regression model was used to estimate survival according to 5 ages, presence of diabetes, and/or heart failure symptoms. Results Four hundred twenty-three available patients were analyzed; 341 patients had biological and 82 had mechanical valves. Overall complication and 30-day mortality rates were similar between the groups. Thirty-day readmission rates for biological and mechanical groups were 15% (50/341) and 28% (23/82; P = .005). Five-year survival was 23% and 33% for the biological and mechanical groups, respectively. After adjusting for age, New York Heart Association (NYHA) class, and diabetes using a multivariable Cox regression model, survival was similar between groups (hazard ratio, 0.93; 95% confidence interval, 0.66-1.29; P = .8). A Cox regression model on the basis of age, diabetes, and heart failure, estimated that patients only 30 or 40 years old, with NYHA class I-II failure without diabetes had a >50% estimated 5-year survival (P < .001). Conclusions Dialysis-dependent patients who underwent valve replacement surgery had poor long-term survival. Young patients without diabetes or NYHA III or IV symptoms might survive long enough to justify placement of a mechanical valve; however, a biological valve is suitable for most patients.
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    Effects of Lysophosphatidic Acid (LPA) and Antidiuretic Hormone (ADH) on Cl- Secretory Responses in Polycystic Kidney Disease (PKD)
    (Office of the Vice Chancellor for Research, 2013-04-05) Martinez, Gabriel M.; Flaig, Stephanie; Blazer-Yost, Bonnie L.
    Polycystic kidney disease (PKD) is a genetic disease that causes the formation of fluid-filled cysts in the kidney and other organs such as the liver and pancreas. Kidney function is seemingly unaltered despite substantial cyst development over the first four to six decades of life, but then the decline in renal function is precipitous often leading to complete renal failure in 5 years. Antidiuretic hormone (ADH) causes an increase in Cl- secretion into the cyst lumen, and one of the drugs in human clinical trials for treatment of PKD is an ADH receptor antagonist. The hormone works by stimulating cAMP production, which leads to the Cl- secretion. Interestingly, we have found that cyst fluid from human patients also causes a secretory Cl- flux that can lead to the growth of the remaining intact cysts. The active component of the cyst fluid is LPA, a phospholipid that acts as an extracellular signaling molecule. This secretion is important in late stage disease when large cysts are likely to leak or burst contributing to the rapid decline in renal function. Electrophysiological techniques were implemented to compare the ion fluxes stimulated by ADH and LPA. In the mpkCCDc14 (mouse principal cells of the cortical collecting duct clone 4) cell line we found that the Cl- secretory pathways stimulated by the two factors are separate and independent. Further indication of this separation is our finding that LPA stimulation does not increase cAMP levels. Therefore we have identified an additional target for potential pharmaceutical intervention in the treatment of PKD.
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    Magnetic Resonance Diffusion Tensor Imaging and Diffusion Compartmental Modeling in an Animal Model of Chronic Kidney Disease
    (Office of the Vice Chancellor for Research, 2015-04-17) Mustafi, Sourajit M.; Territo, Paul R.; McCarthy, Brian P.; Riley, Amanda A.; Lei, Jiang; Lin, Chen; Molitoris, Bruce A.; Hutchins, Gary D.; Wu, Yu-Chien
    Purpose: According to National Health and Nutrition Examination Survey (NHANES), Chronic Kidney Disease (CKD) affects 25% of the US population over age 601. Renal fibrosis, a common pathological consequence of CKD, is a progressive process that ultimately leads to end-stage renal failure that requires dialysis or kidney transplantation2. There is a compelling need for non-invasive biomarkers that track changes in the tissue microenvironment associated with CKD. Several studies using magnetic resonance diffusion tensor imaging (DTI) have been proposed as imaging biomarkers for CKD3. In this study, in addition to DTI, we explored a diffusion-compartmental modeling technique4 to study the microstructures of hypoxia induced animal models of CKD. Method: Preparation of the animal CKD model: Experiments were performed in 4 Wistar Rats using protocols approved by the Institutional Animal Care and Use Committee (IACUC). Two days prior to the first magnetic resonance imaging (MRI) scan; surgical intervention in right renal artery was performed in all the animals to create hypoxia induced renal fibrosis. The MRI scans were repeated at an interval of approximately one month. During the imaging session, the rats were sedated and kept in head-first supine position. MRI imaging: The MRI diffusion pulse sequence was a single-shot spin-echo echo-planar imaging (SS-SE-EPI) sequence with multiple diffusion-weighting b-values (i.e. 3 shells with b-values of 150, 300 and 450 s/mm2) and multiple diffusion-weighting directions at each shell (i.e., 10, 19 and 30, respectively). Diffusion directions in each shell and in the projected sphere with all directions (i.e., total 59) were optimized for uniform diffusion sampling in the spherical space5. The repetition time (TR) is 2200 ms and echo time (TE) is 73.6 ms. A total of four signal averages was performed. The imaging parameters were field-of-view (FOV) = 128 x 64 mm, matrix size = 128 x 64, isotropic voxel size of 1 mm3, and 20 oblique coronal slices. Image data processing: DTI derived parameters including axial diffusivity (Da), radial diffusivity (Dr), mean diffusivity (MD), and fractional anisotropy (FA) were computed6. The diffusion compartmental model originally proposed for the brain called neutrite orientation dispersion and density imaging (NODDI)4 was modified to fit the water diffusivities of kidneys. The NODDI model with Watson stick framework produces the volume fraction of stick like diffusion compartment that may explain the active diffusion (transport) of water in the interstitial space between renal tubules, ellipsoid like diffusion compartment that may explain diffusion inside renal tubule, and a fast isotropic diffusion to account for the pseudo-diffusion term relating to bulk vascular flow. The normalized diffusion intensity was fit with a non-linear mathematical model given by A = (1-Viso) (VicAic+(1-Vic) Aec) + VisoAiso ; where Vic and Viso are the volume fraction of active water transport and free diffusion compartments in the kidney, respectively. Aic, Aec and Aiso are the normalized diffusion signal contribution from stick, tubule and free diffusion compartments, respectively. In the raw DW data, the b-value=0 volume clearly shows three distinct layers in the rat kidney representing the inner medulla, outer medulla and cortex (Figure1). Non-overlapping ROI's were constructed from the b-value =0 images. Figure 1: The DTI and Diffusion compartmental modeling parameter for RAT Kidney 2 days after surgical intervention. The Cortex (C), the Outer Medulla (OM) and Inner Medulla (IM) are shown in raw b0 maps. The orientation of the images follows radiology convention. Results: On post-surgical day 2, the overall water diffusivity (i.e., mean diffusivity (MD)) decreased significantly in the outer medullae and inner medullae of the surgical kidneys (Figure 2 B green bars). In the compartmental model, the volume fraction of the stick (interstitial) diffusion compartment (Vic) in right outer and inner medulla was significantly increased compared to the left (Figure 2A blue bars), whereas the volume fraction of water diffusion inside the tubules (Vec = (1-Vic)) decreased significantly. In addition, isotropic free diffusion compartment (Viso) was significantly lower in the inner medullae of the right kidneys. The axial diffusivity (Da) that may describe the diffusion parallel to the tubules decreased significantly in outer and inter medullae of the right surgical kidneys (Figure 2 B blue bars). The radial diffusivity (Dr) that may describe the water diffusion perpendicularly to the renal tubules decreased significantly in only the outer medullae of the right kidneys (Figure 2B gray bars). While FA shows high value in the inner medullae for both left and right kidneys, no significant results were found between left and right kidneys and between two time points. Over the one-month period of time, right inner medullae continued the significant changes in the diffusivity measurements (Figure 2C and D, right groups), but the diffusivities remained similar in the outer medullae (Figure 2 C and D, middle groups). No significant findings were found in the renal cortices between the right and left kidneys on post-surgical day 2 (Figure 2 A and B). Interestingly, the right renal cortices did have significant increase in Vic and decreases in Da, Dr, and MD over the one-month time period (Figure 2 C and D). Figure 2: Diffusion Compartmental (Figure 2A) and DTI (Figure 2B) parameters for Right Cortex (RC) and Left Cortex (LC), Right Outer Medulla (ROM) and Left Outer Medulla (LOM) and Right Inner Medulla (RIM) and Left Inner Medulla (LIM) on post-surgical day 2. (Figure 2C) Is the time series study of diffusion compartmental parameters and (Figure 2D) for DTI parameters for the right kidneys at post-surgical day 2 and 30, respectively. The bars represent diffusion measurements of all four rats. The overhead connecting lines represent significant statistical student t-test with p-value < 0.01. Discussions and Conclusion: The DTI and NODDI analogous diffusion compartment derived parameters are sensitive to the micro-structural changes in kidneys after surgical hypoxia intervention. The outer and inner medullae appear most sensitive to the surgical hypoxia intervention as early as post-surgical day 2. The preliminary result suggests that water diffusion decreases due to renal fibrosis, and more so inside the Henle tubules. In post-surgical day 30, renal cortices start to show changes in water diffusivities while inner medullae continue pathological changes. The NODDI compartmental model shows promising preliminary results in revealing renal microenvironments under the influences of hypoxia induced renal fibrosis. Further study is required to optimize and validate the model.
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    Renal Cyst Fluid From Human Polycystic Kidney Disease Patients Stimulates Cl- Transport: Active Factor and Cl- Channels
    (Office of the Vice Chancellor for Research, 2011-04-08) Blazer-Yost, Bonnie L.; Blacklock, Brenda; Bacallao, Robert L.; Gattone, Vincent H.
    Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the slow growth of fluid-filled cysts predominately in the kidney and in liver bile ducts. The factors involved in modifying the rate of cyst growth through epithelial proliferation or secretion are critical to understanding the progression of the disease. In addition, elucidation of mechanisms that potentiate the normal progression to renal failure will provide the basis for therapeutic intervention. Of note are the observations that the decline in renal function in middle age is precipitous and that renal injury results in an exacerbation of cyst growth. Using electrophysiological and biochemical techniques, we identified LPA (lysophosphatic acid) as a component of cyst fluid that stimulates secretory Cl- transport via two anion channels, CFTR and TMEM16a, in the mpkCCDcl4 model of renal principal cells. The LPA effect is manifested through receptors located on the basolateral membrane of polarized renal cells resulting in stimulation of channel activity in the apical membrane. Concentrations of LPA measured in ADPKD cyst fluid and in normal serum are sufficient to maximally stimulate ion transport. Thus, cyst fluid seepage into the interstitial space and/or leakage of vascular LPA are capable of stimulating epithelial cell secretion resulting in cyst enlargement. Research Support: IUPUI Membrane Biosciences Signature Center Grant