|
1
|
Perspectives on the Role of Magnetic Resonance Imaging (MRI) for Noninvasive Evaluation of Diabetic Kidney Disease. J Clin Med 2021; 10:jcm10112461. [PMID: 34199385 PMCID: PMC8199575 DOI: 10.3390/jcm10112461] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 01/09/2023] Open
Abstract
Renal magnetic resonance imaging (MRI) techniques are currently in vogue, as they provide in vivo information on renal volume, function, metabolism, perfusion, oxygenation, and microstructural alterations, without the need for exogenous contrast media. New imaging biomarkers can be identified using these tools, which represent a major advance in the understanding and study of the different pathologies affecting the kidney. Diabetic kidney disease (DKD) is one of the most important diseases worldwide due to its high prevalence and impact on public health. However, its multifactorial etiology poses a challenge for both basic and clinical research. Therefore, the use of novel renal MRI techniques is an attractive step forward in the comprehension of DKD, both in its pathogenesis and in its detection and surveillance in the clinical practice. This review article outlines the most promising MRI techniques in the study of DKD, with the purpose of stimulating their clinical translation as possible tools for the diagnosis, follow-up, and monitoring of the clinical impacts of new DKD treatments.
Collapse
|
|
2
|
Vascular repair is vulnerable to renal regeneration in early stage of diabetic nephropathy. ASIAN BIOMED 2018. [DOI: 10.2478/abm-2010-0109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
3
|
Improved vascular repair is relevant to enhanced renal function with vasodilators in early stage of chronic kidney disease. ASIAN BIOMED 2018. [DOI: 10.2478/abm-2010-0018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Abstract
Background: Treatment with vasodilators can improve renal function in early stage of chronic kidney disease (CKD) patients. Objective: Study the mechanism of vascular repair in 20 CKD patients associated with actual creatinine clearance greater than 60 mL/min/1.73m2 (mean 84+24 mL/min/1.73m2) who had been under treatment with vasodilators. Results: Initial study on angiogenic factors revealed a low value of VEGF, no significant change in VEGF-R1, whereas antiangiogenic factors showed elevated angiopoietin-2 and no significant change in VEGF-R2. Initial actual creatinine clearance was significantly depleted and fractional excretion of magnesium (FE Mg) was elevated significantly. Follow-up study showed improved VEGF and a significant decline in angiopoietin-2. Such improved vascular repair coincided with enhanced creatinine clearance. Conclusion: Improved renal function can be achieved by vasodilators under environment favourable for adequate vascular repair.
Collapse
|
|
4
|
Abstract
Abstract
Background: Renal microvascular disease and reduction in peritubular capillary flow are generally observed in type 2 diabetic nephropathy (DN). Earlier therapeutic strategy with vasodilators has improved renal function in normo-albuminuric type 2 DN. Objective: Study the mechanism of vascular homeostasis in twenty patients associated with normo-albuminuric type 2 DN. Results: Angiogenic factors were observed in normo-albuminuric type 2 DN, where vascular endothelial growth factor (VEGF), was 420 ± 341 vs. 428±291 pg/mL (normal), and vascular endothelial growth factor - receptor 1 (VEGF-R1) was 60±12 vs. 49±5 ng/mL (normal), which were not significantly different from the controls. Anti-angiogenic factors were observed in normo-albuminuric type 2 DN, where angiopoietin-2, was 2309+1125 vs. 1671±835 pg/mL (normal), and vascular endothelial growth factor - receptor 2 (VEGF-R2) was 5715±1400 vs.6126 ±1060 ng/mL (normal), which were not significantly different from the controls. Conclusion: The mechanism of vascular homeostasis was adequately functional in normo-albuminuric type 2 DN. This mechanism may explain the positive response to vasodilators and improved renal function in early stage of type 2 DN following the vasodilator treatment.
Collapse
|
|
5
|
Futrakul N, Futrakul P. Biomarker for early renal microvascular and diabetic kidney diseases. Ren Fail 2017; 39:505-511. [PMID: 28494191 PMCID: PMC6014362 DOI: 10.1080/0886022x.2017.1323647] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/20/2017] [Accepted: 04/23/2017] [Indexed: 12/20/2022] Open
Abstract
Recognition of early stage of diabetic kidney disease, under common practice using biomarkers, namely microalbuminuria, serum creatinine level above 1 mg/dL and accepted definition of diabetic kidney disease associated with creatinine clearance value below 60 mL/min/1.73 m2, is unlikely. This would lead to delay treatment associated with therapeutic resistance to vasodilator due to a defective vascular homoeostasis. Other alternative biomarkers related to the state of microalbuminuria is not sensitive to screen for early diabetic kidney disease (stages I, II). In this regard, a better diagnostic markers to serve for this purpose are creatinine clearance, fractional excretion of magnesium (FE Mg), cystatin C. Recently, renal microvascular disease and renal ischemia have been demonstrated to correlate indirectly with the development of diabetic kidney disease and its function. Among these are angiogenic and anti-angiogenic factors, namely VEGF, VEGF receptors, angiopoietins and endostatin. With respect to therapeutic prevention, implementation of treatment at early stage of diabetic and nondiabetic kidney disease is able to restore renal perfusion and function.
Collapse
Affiliation(s)
- Narisa Futrakul
- Department of Physiology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand
| | - Prasit Futrakul
- Academy of Science, The Royal Institute of Thailand and Bhumirajanagarindra Kidney Institute, Bangkok, Thailand
| |
Collapse
|
|
6
|
Montanari A, Lazzeroni D, Pelà G, Crocamo A, Lytvyn Y, Musiari L, Cabassi A, Cherney DZI. Calcium channel blockade blunts the renal effects of acute nitric oxide synthase inhibition in healthy humans. Am J Physiol Renal Physiol 2017; 312:F870-F878. [DOI: 10.1152/ajprenal.00568.2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 02/01/2017] [Accepted: 02/06/2017] [Indexed: 01/25/2023] Open
Abstract
Our aim was to investigate whether blockade of calcium channels (CCs) or angiotensin II type 1 receptors (AT1R) modulates renal responses to nitric oxide synthesis inhibition (NOSI) in humans. Fourteen sodium-replete, healthy volunteers underwent 90-min infusions of 3.0 μg·kg−1·min−1 NG-nitro-l-arginine methyl ester (l-NAME) on 3 occasions, preceded by 3 days of either placebo (PL), 10 mg of manidipine (MANI), or 50 mg of losartan (LOS). At each phase, mean arterial pressure (MAP), glomerular filtration rate (GFR; inulin), renal blood flow (RBF; p-aminohippurate), urinary sodium (UNaV), and 8-isoprostane (U8-iso-PGF2αV; an oxidative stress marker) were measured. With PL + l -NAME, the following changes were observed: +6% MAP ( P < 0.005 vs. baseline), −10% GFR, −20% RBF, −49% UNaV ( P < 0.001), and +120% U8-iso-PGF2αV ( P < 0.01). In contrast, MAP did not increase during LOS + l-NAME or MANI + l-NAME ( P > 0.05 vs. baseline), whereas renal changes were the same during LOS + l-NAME vs. PL + l-NAME (ANOVA, P > 0.05). However, during MANI + l-NAME, changes vs. baseline in GFR (−6%), RBF (−12%), and UNaV (−34%) were blunted vs. PL + l-NAME and LOS + l-NAME ( P < 0.005), and the rise in U8-iso-PGF2αV was almost abolished (+37%, P > 0.05 vs. baseline; P < 0.01 vs. PL + l-NAME or LOS + l-NAME). We conclude that, since MANI blunted l-NAME-induced renal hemodynamic changes, CCs participate in the renal responses to NOSI in healthy, sodium-replete humans independent of changes in MAP and without the apparent contribution of the AT1R. Because the rise in U8-iso-PGF2αV was essentially prevented during MANI + l-NAME, CC blockade may oppose the renal effects of NOSI in part by counteracting oxidative stress responses to acutely impaired renal NO bioavailability.
Collapse
Affiliation(s)
- Alberto Montanari
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - Davide Lazzeroni
- Prevention and Rehabilitation Unit at the Don Gnocchi Foundation and Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy; and
| | - Giovanna Pelà
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - Antonio Crocamo
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - Yuliya Lytvyn
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Luisa Musiari
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - Aderville Cabassi
- Department of Clinical and Experimental Medicine, University of Parma Medical School, Parma, Italy
| | - David Z. I. Cherney
- Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
7
|
Wang J, Yang Q, Nie Y, Guo H, Zhang F, Zhou X, Yin X. Tetrahydrobiopterin contributes to the proliferation of mesangial cells and accumulation of extracellular matrix in early-stage diabetic nephropathy. J Pharm Pharmacol 2017; 69:182-190. [PMID: 28033650 DOI: 10.1111/jphp.12677] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 11/12/2016] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Nitric oxide (NO) plays an important role in the progression of early-stage diabetic nephropathy (DN), which is found to contribute to extracellular matrix (ECM) accumulation in mesangial cells (MCs). As a cofactor for NO production, tetrahydrobiopterin (BH4 ), a folacin analogue, may be responsible for the ECM accumulation and proliferation of MCs. This study was to investigate the effects of BH4 on glomerulosclerosis in early-stage DN. METHODS In in vitro studies with cultured mesangial cells and in vivo studies with streptozotocin-induced diabetic rats, BH4 levels were assayed by HPLC; NO was determined by Griess agents; laminin and collagen IV were determined by enzyme-linked immunosorbent assay; the inducible NO synthase protein was determined by immunofluorescence staining and Western blot; and mesangial matrix expansion and MC proliferation in the renal cortex were observed by periodic acid-schiff staining and transmission electron microscopy, respectively. KEY FINDINGS The in vivo and in vitro studies indicated that the increased BH4 resulted in the overproduction of NO, ECM accumulation and the proliferation of MCs in early-stage DN. CONCLUSIONS Our results suggest that inhibiting excessive BH4 may be a potential approach to prevent glomerulosclerosis in early-stage DN.
Collapse
Affiliation(s)
- Jianyun Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Qianqian Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yaxing Nie
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hao Guo
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Fan Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xueyan Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
| |
Collapse
|
|
8
|
Ott C, Kistner I, Keller M, Friedrich S, Willam C, Bramlage P, Schmieder RE. Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial. Diabetologia 2016; 59:2579-2587. [PMID: 27586249 DOI: 10.1007/s00125-016-4083-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 07/13/2016] [Indexed: 11/29/2022]
Abstract
AIMS/HYPOTHESIS Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature. METHODS In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion input-clearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS with N G-monomethyl-L-arginine (L-NMMA). RESULTS Treatment with linagliptin for 4 weeks reduced fasting, postprandial blood glucose and HbA1c, although not significantly; no change occurred with placebo. Renal plasma flow (RPF) did not change after linagliptin or placebo. After 4 weeks the absolute change in RPF due to L-NMMA was smaller in the linagliptin group than in the placebo group (-46.8 ± 34 vs -65.1 ± 36 ml/min, p = 0.045), indicating a lower basal NO activity after treatment with linagliptin. Consistently, the response of UACR to L-NMMA increased in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), pointing to an upregulation of NO activity in the placebo group. No clinically meaningful safety concerns were evident. CONCLUSIONS/INTERPRETATION Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT01835678 FUNDING: : This study was funded by Boehringer Ingelheim.
Collapse
Affiliation(s)
- Christian Ott
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Iris Kistner
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Mirjam Keller
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Stefanie Friedrich
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Carsten Willam
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany
| | - Peter Bramlage
- Institute for Pharmacology and Preventive Medicine, Mahlow, Germany
| | - Roland E Schmieder
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany.
| |
Collapse
|
|
9
|
Futrakul N, Chanakul A, Futrakul P, Deekajorndech T. Early stage of vascular disease and diabetic kidney disease: an under-recognized entity. Ren Fail 2015; 37:1243-6. [PMID: 26365595 DOI: 10.3109/0886022x.2015.1073054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Early stage of vascular disease and diabetic kidney disease (DKD stages 1 and 2) has been under-recognized, under common practice worldwide. The lack of sensitive diagnostic marker leads to late diagnosis and a progression of underlying vascular disease associated with chronic renal ischemia, which eventually intensifies the magnitude of DKD damage. Treatment at this late stage fails to correct the renal ischemia, or restore renal function, due to the altered vascular homeostasis associated with an impaired nitric oxide production. In contrast to the above information, early recognition of vascular disease and DKD with sensitive diagnostic markers would be able to implement an effective prevention of progression of vascular disease and DKD. Treatment at early stage under environment favorable for adequate vascular homeostasis is able to correct the renal ischemia and improve the renal function.
Collapse
Affiliation(s)
- Narisa Futrakul
- a Renal Microvascular Research Group, Department of Physiology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University , Bangkok , Thailand
| | - Ankanee Chanakul
- b Department of Pediatrics , King Chulalongkorn Memorial Hospital, Chulalongkorn University , Bangkok , Thailand , and
| | - Prasit Futrakul
- c Bhumirajanagarindra Kidney Institute, and Academy of Science, The Royal Institute of Thailand , Bangkok , Thailand
| | - Tawatchai Deekajorndech
- b Department of Pediatrics , King Chulalongkorn Memorial Hospital, Chulalongkorn University , Bangkok , Thailand , and
| |
Collapse
|
|
10
|
Theilade S, Lajer M, Hansen TW, Rossing P. Pulse wave reflection is associated with diabetes duration, albuminuria and cardiovascular disease in type 1 diabetes. Acta Diabetol 2014; 51:973-80. [PMID: 25274394 DOI: 10.1007/s00592-014-0651-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 09/08/2014] [Indexed: 10/24/2022]
Abstract
AIMS We investigate associations between the pulse-wave-derived measures augmentation pressure (AP) and augmentation index, and diabetic complications in type 1 diabetes. METHODS This cross-sectional study from 2009-2011 included 676 type 1 diabetes patients. SphygmoCor (Atcor Medical, Australia) measured AP and heart rate-adjusted augmentation index (AI75). Diabetic complications were micro- or macroalbuminuria [urinary albumin excretion rate (UAER) 30-299 or ≥300 mg/24-h], cardiovascular disease (CVD) (previous revascularization, myocardial infarction, peripheral arterial disease or stroke), autonomic dysfunction (heart rate variability <11 beats/min), or retinopathy (simple, proliferative or blindness). Adjustments included age, gender, diabetes duration, mean arterial pressure, heart rate, height, UAER, eGFR, HbA1c, total cholesterol, total daily insulin dose, antihypertensive medication, and smoking. RESULTS AP and AI75 measurements were available in 636 (94.1 %) patients and were 9.9 ± 7.6 mmHg and 16.9 ± 12.0, respectively. After adjustment, AP and AI75 were independently associated with diabetes duration and albuminuria (p ≤ 0.001). Furthermore, higher AP and AI75 were associated with previous CVD [adjusted odds ratios (95 % confidence interval) (per 1 SD increase) 1.9 (1.3-2.7) and 1.5 (1.0-2.2) (p ≤ 0.039)], but not with autonomic dysfunction or retinopathy (p ≥ 0.12). CONCLUSIONS In type 1 diabetes, augmentation pressure and heart rate-adjusted augmentation index were associated with diabetes duration, albuminuria, and CVD, independently of conventional risk factors. ClinicalTrials.gov:NCT01171248.
Collapse
Affiliation(s)
- Simone Theilade
- Steno Diabetes Center, Niels Steensens Vej 1, 2820, Gentofte, Denmark,
| | | | | | | |
Collapse
|
|
11
|
Effects of folic acid on renal endothelial function in patients with diabetic nephropathy: results from a randomized trial. Clin Sci (Lond) 2014; 127:499-505. [PMID: 24724807 DOI: 10.1042/cs20140111] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
UNLABELLED Endothelial dysfunction has been shown to promote podocyte injury and albuminuria in diabetes, highlighting the importance of the interaction between renal endothelial cells and podocytes. Folic acid (FA) improves nitric oxide synthase (NOS) function and reduces progression of diabetic nephropathy in animal models. We tested whether high-dose FA treatment improves renal endothelial function and albuminuria in human subjects with incipient diabetic nephropathy. Following a double-blind, randomized, cross-over design, 28 patients with Type 2 diabetes and albuminuria were allocated to 4 weeks' treatment with placebo and high-dose FA (5 mg/day). Renal nitric oxide (NO) production determined as the response of renal plasma flow (RPF) to NOS inhibition with NG-monomethyl-L-arginine (L-NMMA) (4.25 mg/kg intravenously), renal oxidant stress as response of RPF to vitamin C infusion (3 mg/kg) and albuminuria were determined after each treatment phase. Neither the reduction in RPF to L-NMMA nor the increase in RPF to vitamin C infusion differed between treatment phases (ΔRPF to L-NMMA -74±71 ml/min per m2 during placebo compared with -63±56 ml/min per m2 during FA, P=0.57; ΔRPF to vitamin C: +93±118 ml/min per m2 compared with +94±108 ml/min per m2; P=0.70). In line with the lack of effect on the renal endothelium, albuminuria was not affected by FA treatment (110±179 mg/day during placebo compared with 87±146 mg/day during FA; P=0.12). High-dose FA treatment does not improve renal endothelial function and fails to reduce albuminuria in human subjects with diabetic nephropathy. Novel treatment options for oxidant stress and endothelial dysfunction in patients with diabetes are urgently needed.
Collapse
|
|
12
|
Futrakul N, Futrakul P. Vascular response to vasodilator treatment in microalbuminuric diabetic kidney disease. World J Nephrol 2013; 2:125-128. [PMID: 24255895 PMCID: PMC3832868 DOI: 10.5527/wjn.v2.i4.125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 06/04/2013] [Accepted: 09/04/2013] [Indexed: 02/06/2023] Open
Abstract
Under common practice, the conventional diagnostic marker such as microalbuminuria determination does not recognized early stage of diabetic kidney disease (normoalbuminuria, chronic kidney disease stage 1, 2); due to the insensitiveness of the available marker. Treatment at later stage (microalbuminuria) simply slows the renal disease progression, but is rather difficult to restore the renal perfusion. Intrarenal hemodynamic study in these patients revealed an impaired renal perfusion and abnormally elevated renal arteriolar resistances. Treatment with vasodilators such as angiotensin converting enzyme inhibitor and angiotensin receptor blocker fails to correct the renal ischemia. Recent study on vascular homeostasis revealed a defective mechanism associated with an impaired nitric oxide production which would explain the therapeutic resistance to vasodilator treatment in microalbuminuric diabetic kidney disease. This study implies that the appropriate therapeutic strategy should be implemented at earlier stage before the appearance of microalbuminuria.
Collapse
|
|
13
|
Futrakul N, Futrakul P. Normalization of kidney dysfunction in normotensive, normo-albuminuric type 2 diabetes. Ren Fail 2013; 35:1058-9. [PMID: 23859540 DOI: 10.3109/0886022x.2013.810541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
|
|
14
|
Wacharasindhu S, Rugpolmuang R, Roonghiranwat T, Supornsilchai V, Sahakitrungruang T, Aroonparkmongkol S, Chaiwatanarat T. Preliminary study of renal hemodynamic alteration in early childhood diabetes mellitus. Ren Fail 2012; 35:98-100. [PMID: 23113652 DOI: 10.3109/0886022x.2012.736070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Renal hemodynamic study was performed in eight patients associated with type 1, early childhood diabetes mellitus (DM) and seven patients associated with type 2, early childhood DM. The results in both types of DM revealed a significant reduction in peritubular capillary flow and a high value of glomerular filtration rate (GFR) in the presence of reduced renal perfusion characteristic of glomerular hyperfiltration. These findings imply that renal ischemia has already developed in both types of early stage childhood DM and GFR is overestimated in DM, which may mislead to improper interpretation of renal function.
Collapse
Affiliation(s)
- Suttipong Wacharasindhu
- Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand.
| | | | | | | | | | | | | |
Collapse
|
|
15
|
Tousoulis D, Androulakis E, Papageorgiou N, Stefanadis C. Novel therapeutic strategies in the management of arterial hypertension. Pharmacol Ther 2012; 135:168-175. [PMID: 22609833 DOI: 10.1016/j.pharmthera.2012.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Accepted: 04/26/2012] [Indexed: 02/05/2023]
Abstract
Essential hypertension is a disease with a major impact on health worldwide, thus control of blood pressure seems to be a key component of cardiovascular disease prevention. Despite considerable advances in the treatment of hypertension, effective management remains poor and new strategies to control high blood pressure and cardiovascular risk reduction are required. These seem to be divided into two major categories: those seeking to advance blood pressure-lowering efficacy of already existing agents, and others related to novel approaches, both pharmacological and non-pharmacological. Moreover, numerous clinical trials have evaluated the use of nutritional supplements in the prevention of cardiovascular diseases and in achievement of optimal blood pressure control. Additionally, the advent of interventional techniques, such as carotid baroreceptor stimulation and renal ablation of sympathetic nerve activity, seems to be proved effective in cases where medical management and lifestyle modifications are insufficient. Genetic technology, which has advanced tremendously over the past few years, could assist novel treatment options in hypertensive patients, such as RNA interference targeting hypertension-related genes. However, continued efforts must progress in these areas and the effects of therapeutic strategies in hypertensive patients need to be further explored in larger trials over a longer period of time.
Collapse
Affiliation(s)
- Dimitris Tousoulis
- 1st Cardiology Unit, Hippokration Hospital, Athens University Medical School, Athens, Greece.
| | | | | | | |
Collapse
|
|
16
|
Ito H, Mifune M, Abe M, Oshikiri K, Antoku S, Takeuchi Y, Togane M, Ando S, Tsugami E. Hypertension resistant to antihypertensive agents commonly occurs with the progression of diabetic nephropathy in Japanese patients with type 2 diabetes mellitus: a prospective observational study. BMC Nephrol 2012; 13:48. [PMID: 22738384 PMCID: PMC3437202 DOI: 10.1186/1471-2369-13-48] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 06/27/2012] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND We investigated 1) the frequency of hypertension in patients with type 2 diabetes graded by the new classification of chronic kidney disease (CKD) reported by the Kidney Disease: Improving Global Outcomes (KDIGO) and 2) the number of antihypertensive agents needed to achieve treatment goals using a prospective observational study. METHODS A population of 2018 patients with type 2 diabetes mellitus was recruited for the study. The CKD stage was classified according to the eGFR and the urinary albumin excretion levels. RESULTS Hypertension was found in 1420 (70%) of the patients, and the proportion of subjects showing a blood pressure<130/80 mmHg was 31% at the baseline. Although the mean blood pressure was approximately 130/75 mmHg, the rate of patients with a blood pressure of <130/80 mmHg became limited to 41-50% during the observation period. The number of antihypertensive agents required for treatment was significantly higher at the endpoint (2.0±1.3) than at the baseline (1.6±1.2). Furthermore, it increased with the progression of the CKD stage at both the baseline and the endpoint of the observation. However, the frequency of subjects who did not achieve the blood pressure target was found to increase in the group demonstrating the later stage of CKD. CONCLUSIONS Hypertension resistant to antihypertensive agents was common in the patients with type 2 diabetes mellitus and increased with the progression of CKD. Although powerful combination therapy using antihypertensive agents is considered necessary for the strict control of blood pressure, this became difficult in individuals who were in advanced stages as graded based on the eGFR and the urinary albumin excretion levels.
Collapse
Affiliation(s)
- Hiroyuki Ito
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| | - Mizuo Mifune
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| | - Mariko Abe
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| | - Koshiro Oshikiri
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| | - Shinichi Antoku
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| | - Yuichiro Takeuchi
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| | - Michiko Togane
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| | - Shigenori Ando
- Pharmaceutical Department, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| | - Emiko Tsugami
- Pharmaceutical Department, Edogawa Hospital, 2-24-18, Higashi-Koiwa, Edogawa, Tokyo, 133-0052, Japan
| |
Collapse
|
|
17
|
Is Diabetic Nephropathy a Restorative Disease? Ren Fail 2012; 34:667-8. [DOI: 10.3109/0886022x.2012.664764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
|
|
18
|
Futrakul N, Futrakul P. A progression in peritubular capillary flow reduction and tubulointerstitial fibrosis reflected by FE Mg predict the decline in glomerular filtration rate. Kidney Int 2012; 81:707; author reply 707. [DOI: 10.1038/ki.2011.487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|
|
19
|
Hamilton SJ, Chew GT, Davis TME, Watts GF. Prevalence and predictors of abnormal arterial function in statin-treated type 2 diabetes mellitus patients. Metabolism 2012; 61:349-57. [PMID: 21944268 DOI: 10.1016/j.metabol.2011.07.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 06/26/2011] [Accepted: 07/18/2011] [Indexed: 11/18/2022]
Abstract
Arterial dysfunction (AD) in type 2 diabetes mellitus (T2DM) predicts cardiovascular events. The objective was to investigate the prevalence and predictors of AD in statin-treated T2DM patients. We measured flow-mediated (FMD) and nitrate-mediated (NMD) brachial artery dilatation in 86 statin-treated T2DM patients. Patients were classified into 2 groups: normal arterial function (FMD ≥3.7% with NMD ≥11.9%) or AD (FMD <3.7% with or without NMD <11.9%). Endothelial dysfunction without smooth muscle cell dysfunction (ED) was defined as FMD less than 3.7% with NMD of at least 11.9%, and endothelial dysfunction with smooth muscle cell dysfunction (ED/SMD) was defined as FMD less than 3.7% with NMD less than 11.9%. Predictors of arterial function were investigated using linear and logistic regression methods. The prevalence of AD was 33.7% (23.2% with ED and 10.5% with ED/SMD). In multivariate linear regression, history of hypertension (P < .01), statin dose (P < .05), and estimated glomerular filtration rate (eGFR) (P = .02) were significant predictors of FMD. Sex (P < .01) and creatinine (P = .03) or eGFR (P = .02) predicted NMD. In multivariate logistic regression, the independent predictors of AD were history of hypertension (odds ratio [OR], 8.79; 95% confidence interval, 2.14-36.12; P < .01), age (OR, 1.08; 1.01-1.17; P = .03), and statin dose (OR, 0.33; 0.12-0.87; P = .02). A history of hypertension (OR, 8.99; 1.87-43.26; P < .01) was the sole independent predictor of ED; eGFR (OR, 0.01; 0.00-0.26; P < .01) independently predicted ED/SMD. Our data suggest that one third of statin-treated diabetic patients have residual AD, mainly due to ED alone. Earlier identification and treatment of hypertension and renal impairment may improve AD and further decrease cardiovascular risk in such patients.
Collapse
Affiliation(s)
- Sandra J Hamilton
- School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia 6847, Australia
| | | | | | | |
Collapse
|
|
20
|
Futrakul N, Futrakul P. Renal Microvascular Disease Predicts Renal Function in Diabetes. Ren Fail 2011; 34:126-9. [DOI: 10.3109/0886022x.2011.623490] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
|
|
21
|
Futrakul N, Kulaputana O, Futrakul P, Chavanakul A, Deekajorndech T. Enhanced peritubular capillary flow and renal function can be accomplished in normoalbuminuric type 2 diabetic nephropathy. Ren Fail 2011; 33:312-5. [PMID: 21401356 DOI: 10.3109/0886022x.2011.560405] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Under common practice, treatment of diabetic nephropathy (DN) is usually initiated at late stage of CKD due to the insensitiveness of the available diagnostic markers. Such treatment fails to restore renal perfusion and function. This is due to the defective mechanism of vascular homeostasis and impaired nitric oxide production observed in late stage of DN. In contrast, the mechanism of vascular repair is adequately functional in early stage of DN (normoalbuminuria). In this study, we treated 50 normoalbuminuric diabetic patients with multidrug vasodilators, namely ACE inhibitor, angiotensin receptor blocker, ± calcium channel blocker in conjunction with correction of metabolic disorders for 24-36 months. Following the treatment, increment in peritubular capillary flow in response to vasodilators was observed, and thus supports the adequate role of vascular repair. In addition, increase in renal function documented in this study also implies that an effective preventive strategy to minimize end-stage renal disease can be accomplished in normoalbuminuric DN.
Collapse
Affiliation(s)
- N Futrakul
- Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
| | | | | | | | | |
Collapse
|
|
22
|
Vascular homeostasis and angiogenesis determine therapeutic effectiveness in type 2 diabetes. Int J Vasc Med 2011; 2011:971524. [PMID: 21748023 PMCID: PMC3124951 DOI: 10.1155/2011/971524] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2011] [Accepted: 03/27/2011] [Indexed: 12/11/2022] Open
Abstract
Under common practice, recognition and treatment of type 2 diabetic nephropathy (DN) are usually revealed at a rather late stage (CKD stages 3-5) due to the insensitiveness of available diagnostic markers. Accumulating data obtained from vascular homeostasis in late stage DN demonstrated (1) a defective angiogenesis and impaired NO production which explains the therapeutic resistance to vasodilators and the inability to correct chronic renal ischemia and (2) an abnormally elevated antiangiogenesis and a progressive vascular disease which correlates with the altered renal hemodynamics characterized by a progressive reduction in renal perfusion as the disease severity progressed. In contract, the vascular homeostasis is adequately functional in early stage DN. Thus, vasodilator treatment at early stage DN (CKD stages 1-2) can enhance renal perfusion, correct the renal ischemia, and restore renal function.
Collapse
|
|
23
|
Tousoulis D, Papageorgiou N, Androulakis E, Paroutoglou K, Stefanadis C. Novel therapeutic strategies targeting vascular endothelium in essential hypertension. Expert Opin Investig Drugs 2010; 19:1395-1412. [PMID: 20923260 DOI: 10.1517/13543784.2010.522989] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
IMPORTANCE OF THE FIELD Several studies have demonstrated the high prevalence of hypertension and the crucial role of the association between endothelial function and hypertension. Thus, in depth investigation of the pathophysiological mechanisms linking endothelial dysfunction and hypertension, as well as evaluation of the efficacy of therapeutic approaches targeting vascular endothelium in states of essential hypertension seems to be of great interest. AREAS COVERED IN THIS REVIEW The association of essential hypertension and endothelial function are discussed in depth. In addition to the classical anti-hypertensive agents, agents such as statins, tetrahydrobiopterin, l-arginine, antioxidants, sildenafil, third generation beta blockers and NO-release related agents have been found to be beneficial by improving endothelial dysfunction in essential hypertension. WHAT THE READER WILL GAIN Important aspects regarding the association of hypertension and endothelial dysfunction will be highlighted. In addition, classical and novel agents especially, will be reported thoroughly according to their effects on endothelial function in hypertension. TAKE HOME MESSAGE There is a strong bidirectional association between essential hypertension and endothelial dysfunction. Moreover, novel agents appear to be beneficial and promising in improving endothelial function in states of hypertension. However, more studies are required to evaluate their role, as the literature lacks large scale studies.
Collapse
Affiliation(s)
- Dimitris Tousoulis
- Athens University Medical School, Hippokration Hospital, First Cardiology Unit, Athens, Greece.
| | | | | | | | | |
Collapse
|
|
24
|
Ritt M, Janka R, Schneider MP, Martirosian P, Hornegger J, Bautz W, Uder M, Schmieder RE. Measurement of kidney perfusion by magnetic resonance imaging: comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome. Nephrol Dial Transplant 2009; 25:1126-33. [PMID: 19934080 DOI: 10.1093/ndt/gfp639] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Magnetic resonance imaging with arterial spin labeling (MRI-ASL) is a non-invasive approach to measure organ perfusion. We aimed to examine whether MRI-ASL kidney perfusion measurements are related to measurements of renal plasma flow (RPF) by para-aminohippuric acid (PAH) plasma clearance and whether changes of kidney perfusion in response to treatment with telmisartan can be detected by MRI-ASL. METHODS Twenty-four patients with metabolic syndrome and an estimated creatinine clearance according to Cockroft and Gault of > or =60 ml/min were included in the study. Kidney perfusion was assessed by MRI-ASL measurements of a single coronal kidney slice (with flow-sensitive alternating inversion recovery and true fast imaging with steady-state processing sequence) and by measurements of RPF using PAH plasma clearance before and after 2 weeks of treatment with the angiotensin receptor blocker telmisartan. All MRI-ASL examinations were performed on a 1.5 T scanner. RESULTS Two weeks of therapy with telmisartan led to a significant increase of RPF (from 313 +/- 47 to 348 +/- 69 ml/min/m, P = 0.007) and MRI-ASL kidney perfusion measurements (from 253 +/- 20 to 268 +/- 25 ml/min/100 g, P = 0.020). RPF measurements were related with MRI-ASL kidney perfusion measurements (r = 0.575, P < 0.001). Changes of RPF measurements and changes of MRI-ASL kidney perfusion measurements in response to treatment with telmisartan revealed a close relationship when expressed in absolute terms (r = 0.548, P = 0.015) and in percentage changes (r = 0.514, P = 0.025). CONCLUSIONS Perfusion measurement of a single coronal kidney slice by MRI-ASL is able to approximate kidney perfusion and to approximate changes in kidney perfusion due to pharmacological intervention.
Collapse
Affiliation(s)
- Martin Ritt
- Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Retinal arteriolar narrowing increases the likelihood of chronic kidney disease in hypertension. J Hypertens 2009; 27:2209-17. [DOI: 10.1097/hjh.0b013e328330141d] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
26
|
Futrakul N, Futrakul P. Adequate Vascular Repair is Relevant to Improving Renal Perfusion and Function Following Vasodilators in Normoalbuminuric Type 2 Diabetic Nephropathy. Am J Kidney Dis 2009; 54:583-4. [DOI: 10.1053/j.ajkd.2009.06.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2009] [Accepted: 06/22/2009] [Indexed: 11/11/2022]
|
|
27
|
Splenser AE, Fisher NDL, Danser AHJ, Hollenberg NK. Renal plasma flow: glomerular filtration rate relationships in man during direct renin inhibition with aliskiren. ACTA ACUST UNITED AC 2009; 3:315-20. [PMID: 20409974 DOI: 10.1016/j.jash.2009.06.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2009] [Revised: 06/11/2009] [Accepted: 06/29/2009] [Indexed: 11/28/2022]
Abstract
We examined the relation between change in renal plasma flow (RPF) and change in glomerular filtration rate (GFR) in healthy humans on a low-salt diet during direct renin inhibition with aliskiren. We measured the renal hemodynamic response to acute dosing of 300mg aliskiren by mouth to 19 healthy normotensive subjects (age, 33+/-3 years; baseline RPF, 575+/-23; GFR, 138+/-14mL/min/1.73m(2)) on a low-sodium diet (10mmol/day). GFR and RPF were measured by the clearance of inulin and para-aminohippurate. There was a marked increase in average RPF (169+/-24mL/min/1.73m(2)) and a small rise in average GFR (1.4+/-5mL/min/1.73m(2)) from baseline in response to aliskiren. There was a clear correlation between the change in RPF and the change in GFR between subjects (r=0.65; P < .003). A substantial increase in RPF was accompanied by a rise in GFR. Dependence of GFR on RPF was identified in healthy humans after RPF rose significantly with aliskiren. The responsible mechanism likely involves intravascular oncotic pressure along the glomerular capillary resulting in greater surface area available for filtration.
Collapse
Affiliation(s)
- Andres E Splenser
- Department of Radiology and Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | | | | | | |
Collapse
|