Hemodynamic Maladjustment Research Articles

Urgent call for reconsideration of chronic kidney disease

free radicals, cytokines and metabolic products induce glomerular endothelial dysfunction, hemodynamic maladjustment and chronic ischemic state;this leads to tubulointerstitial fibrosis in chronic kidney disease (CKD). Altered vascular homeostasis observed in late stage CKD revealed defective angiogenesis and impaired nitric oxide production explaining therapeutic resistance to vasodilator treatment in late stage CKD. Under current practice, CKD patients are diagnosed and treated at a rather late stage due to the lack of sensitivity of the diagnostic markers available. This suggests the need for an alternative therapeutic strategy implementing the therapeutic approach at an early stage. This view is supported by the normal or mildly impaired vascular homeostasis observed in early stage CKD. Treatment at this early stage can potentially enhance renal perfusion, correct the renal ischemic state and restore renal function. Thus, this alternative therapeutic approach would effectively prevent end-stage renal disease.

Therapeutic strategy towards renal restoration in chronic kidney disease

Background: The population with end-stage renal disease is increasing. This continued growth is related to: i) diagnostic failure in screening for early chronic kidney disease (CKD) associated with tubulointerstitial fibrosis (TIF), ii) failure in preventing renal disease progression due to lack of understanding of the precise determinants that induce TIF, and iii) delayed treatment which simply slows renal disease progression, but is unable to restore renal function. Objective: To review therapeutic strategy to restore renal function in CKD stressing fractional excretion of magnesium (FE Mg) as a sensitive biomarker for screening early CKD associated with TIF. Results: There is much evidence to support the crucial role of renal microvascular disease as the determinant of TIF and disease progression. A unique pattern of hemodynamic maladjustment is characterized by a preferential constriction of the efferent arteriole that induces peritubular capillary flow reduction in CKDs. Conclusion: The present information leads to a therapeutic strategy to restore renal function in early CKD patients.

Altered Vascular Homeostasis in Type 2 Diabetic Nephropathy

Type 2 diabetic nephropathy is a primary cause of ESRD worldwide. Therapeutic strategy in patients with microalbuminuric or macroalbuminuric type 2 diabetic nephropathy usually fails to restore renal function but merely slows the renal disease progression. In contrast, a recent study implies that the restoration of renal function as well as renal perfusion can be accomplished in early stage of type 2 diabetic nephropathy (normoalbuminuria) by correcting the hemodynamic maladjustment in renal microcirculation with vasodilators. Therefore, we intend to study the mechanism of vascular homeostasis to explain why treatment in the late stage of diabetic nephropathy during microalbuminuria or macroalbuminuria fails to enhance renal perfusion or restore renal function. The results indicate that such therapeutic failure in late-stage type 2 diabetic nephropathy likely relates to multiple defects in vascular repair, namely deficiencies in angiogenic factors such as endothelial progenitor cell, angiopoietin-1, flt-1 receptor, as well as elevated levels of antiangiogenic factors such as angiopoietin-2 and KDR.

A combination of Chinese herbs, Astragalus membranaceus var. mongholicus and Angelica sinensis, enhanced nitric oxide production in obstructed rat kidney

Background The persistent renal hemodynamic maladjustment caused by imbalances between vasoactivators predisposes the kidney to tubulointerstitial injury and ultimate interstitial fibrosis. The decoction (A&A) of a combination of roots of two Chinese herbs, Astragalus membranaceus var. mongholicus and Angelica sinensis, has shown antifibrotic effects in rats with chronic kidney diseases and improvement of renal blood flow in rats with acute ischemic renal injury. In the present study, we investigated the effects and possible mechanisms of A&A on vasoactivators in the process of renal interstitial fibrosis. Methods Male Wistar rats were randomly divided into sham, unilateral ureteral obstruction (UUO) and UAA (UUO plus A&A administration) groups. After oral administration of A&A (14 g/kg/d) for 3, 7 and 10 days, morphological changes were evaluated by HE, Masson and Sirius red staining technique. The levels of Ang-II, ET-1, and the activities of different nitric oxide synthases (NOSs) in renal homogenate were measured by radioimmunoassay. The nitrite concentration as nitric oxide (NO) production was measured using the Griess reagent. Western blot analysis and immunohistochemical staining were performed to determine the expressions of eNOS, nNOS, and iNOS in the kidney. The ability of scavenging reactive oxygen species (ROS) was evaluated by spectrophotometry. Results Morphological analysis showed severe interstitial mononuclear cells infiltration, tubular atrophy, renal fibrosis and collagen expression in kidneys of UUO group, which reduced by A&A administration ( p < 0.05, UAA vs. UUO group). The levels of Ang-II and ET-I were increased in obstructed kidneys, but not significantly changed after A&A administration. NO production did not change in obstructed kidney at day 3 but increased in day 7 and day 10. Administering A&A progressively increased NO production by 2.2, 1.2, and 1.2 fold at days 3, 7 and 10, respectively. The activities of constitutive NOS and iNOS were comparable between UUO group and sham group. In contrast, the activity of constitutive NOS was much higher in UAA than that of UUO rats, which increased 78%, 68% and 78% at days 3, 7 and 10 respectively, although the protein expression of eNOS, nNOS and iNOS in renal tissue had no change in UAA rats. The activities of scavenging ROS in UUO group were not significantly different from the sham group at days 3 and 7, but increased at day 10 (24.1 ± 15.0 vs. 10.1 ± 0.8 U/min/mg protein, p < 0.05). After A&A administration, the activities of scavenging ROS were significantly increased at days 3 and 7 (51.5 ± 17.9 vs. 11.7 ± 7.4 U/min/mg protein, p < 0.05; and 16.1 ± 5.6 vs. 7.7 ± 1.4 U/min/mg protein, p < 0.05) respectively, comparing with the UUO group. Conclusion The anti-fibrosis effects of A&A might be associated with enhancing NO production via eNOS activation and scavenging ROS, and in turn might improve ischemic microvasculature and attenuate interstitial fibrosis.

Improvement of Renal Function in Type 2 Diabetic Nephropathy

Background. Therapeutic failure in preventing renal disease progression in type 2 diabetic nephropathy (DN) is due to a failure in the early detection of DN by microalbuminuria and the inappropriate correction of renal hemodynamic maladjustment secondary to glomerular endothelial dysfunction. Methods. Thirty patients associated with normoalbuminuric type 2 DN were subject to the following studies: tubular function by means of fractional excretion of magnesium (FE Mg), vascular function by means of determining the circulating endothelial cell, VEGF, VEGF/TGF B ratio, and intrarenal hemodynamic studies. Results. FE Mg, circulating endothelial cells, and TGF B were abnormally elevated, and VEGF/TGF B ratio was decreased in these normoalbuminuric patients. The intrarenal hemodynamic study revealed a hemodynamic maladjustment characterized by a preferential constriction at the efferent arteriole and a reduction in peritubular capillary flow. Following treatment with vasodilators, a decrease in efferent arteriolar resistance and increase in peritubular capillary flow as well as glomerular clearance were observed. Conclusion. FE Mg appears to be a more sensitive marker than microalbuminuria for the early detection of DN. Increased endothelial cell injury is reflected by enhanced circulating endothelial cell loss in conjunction with the increased TGF B and the decreased ratio between VEGF and TGF B. This is further supported by the dysfunctioning glomerular endothelium, which is characterized by hemodynamic maladjustment and a reduction in the peritubular capillary flow. A correction of such hemodynamic maladjustment by multidrug vasodilators effectively improves renal perfusion and restores renal function in type 2 DN.

Hemodynamic Maladjustment and Disease Progression in Nephrosis with FSGS

Idiopathic nephrotic syndrome (NS) associated with focal segmental glomerulosclerosis (FSGS) and severe renal function impairment is usually refractory to the conventional treatment and progresses to end‐stage renal disease. Herein, we reported 10 patients with NS‐FSGS who had initially had CCr 34 ± 12 mL/min/1.73m2 (normal 120 mL/min/1.73m2), FE Mg 7.8 ± 2.6% (normal 2.2%), 24‐h urinary protein 3.1 g (normal < 200 mg) and been followed up for over 10 years. The initial intrarenal hemodynamic study revealed a marked elevation of efferent arteriolar resistance (RE 17289 ± 8636 dyne.s.cm− 5; normal 3000 dyne.s.cm− 5), intraglomerular hypertension (PG 57 ± 1 mm Hg; normal 52 mm Hg), hyperfiltration (FF 0.24; normal 0.2), marked reductions in GFR 35 ± 17 mL/min/1.73m2, renal plasma flow (RPF 159 ± 61 mL/min/1.73m2; normal 600 mL/min/1.73m2) and peritubular capillary flow (PTCF 123 ± 57 mL/min/1.73m2; normal 480 mL/min/1.73m2). Such a hemodynamic alteration indicated a hemodynamic maladjustment with a preferential constriction at RE. Treatment consists of multidrugs, namely angiotensin converting enzyme inhibitor, calcium channel blocker, antiplatelet and anticoagulant, with or without angiotensin II receptor antagonist. Following the treatment, correction of hemodynamic maladjustment has been achieved which is characterized by reductions in RE 6046 ± 2191 dyne.s.cm− 5, PG 52 ± mm Hg, FF 0.19 ± 0.1 and increments in RPF 341 ± 118 mL/min/1.73m2, PTCF 280 ± 106 mL/min/1.73m2 and GFR 64 ± 17 mL/min/1.73m2. Coinciding with hemodynamic improvement, there has been a steadily increased creatinine clearance and improvement in FE Mg 4.3 ± 2.6% and suppression of proteinuria 0.29 ± 0.4g/24 h after the period of follow‐up of greater than 10 years.

Treatments of Hemodynamic Maladjustment and Oxidative Stress Prevent Renal Disease Progression in Chronically Severe Glomerulonephritides

Hemodynamic maladjustment is a unique observation in chronically severe glomerulonephritides. It is characterized by a markedly elevated efferent arteriolar resistance (RE), an elevated intraglomerular hydrostatic pressure (PG) and a markedly decreased renal plasma flow (RPF), and peritubular capillary flow (PTCF). A correction of such hemodynamic maladjustment can be accomplished by administering a combination of vasodilators (angiotensin receptor antagonist, angiotensin converting enzyme inhibitor, and calcium channel blocker) in 14 chronic glomerulonephritides with severe renal function impairment (mean serum creatinine 3.6 + 1.3 mg/dL). Doses titration aim for maximal renal perfusion effect (increased RPF, PTCF) or maximal renal function improvement (increased CCr, reduced FE Mg) usually higher than needed for maximal blood pressure reduction. Evidence of oxidative stress is also corrected with high doses of vitamins C and E. After a mean period of treatment for 13.5 months, improvements in CCr (pre Rx 22 ± 10 vs. post Rx 32 ± 13 mL/min/1.73 m2), and FE Mg (pre Rx 11.9 ± 4% vs. post Rx 10 ± 3%) were observed in conjunction with the improvement in intrarenal hemodynamics namely RPF (pre Rx 201 ± 71 vs. post Rx 288 ± 99 mL/min/1.73 m2), PTCF (pre Rx 161 ± 57 vs. post Rx 242 ± 90 mL/min/1.73 m2), PG (pre Rx 56.7 ± 0.5 vs. post Rx 51 ± 0.1 mm Hg), and RE (pre Rx 12085 ± 6503 vs. post Rx 6550 ± 1872 dyne.s.cm−5).

Glomerular Endothelial Dysfunction and Hemodynamic Maladjustment in Vesicoureteric Reflux

A structural defect of the non-vascular component of a nephron namely vesicoureteric reflex (VUR) can induce injury to the vascular component, which is reflected by the alteration in intrarenal hemodynamics. A mild alteration in intrarenal hemodynamics was observed in grades I–II VUR which revealed (a) mild reductions in renal plasma flow (RPF) 543 ± 104 mL/min/1.73 m2; in peritubular capillary flow (PTCF) 438 ± 103 mL/min/1.73 m2; in glomerular filtration rate (GFR) 105 ± 19 mL/min/1.73 m2 and in ultrafiltration coefficient (KFG) 0.04 ± 0.01 mL/s/mmHg; (b) normal values of filtration fraction (FF) 0.2 ± 0.04, of intraglomerular hydrostatic pressure (PG) 50 ± 0.3 mmHg, and of afferent arteriolar resistance (RA) 2261 ± 718 dyne s cm−5; and (c) a slight elevation of efferent arteriolar resistance (RE) 3914 ± 962 dyne s cm−5. In contrast, a moderately severe alteration in intrarenal hemodynamics was observed in severe VUR (grades III up) which revealed greater reductions in RPF 267 ± 114 mL/min/1.73 m2, in PTCF 195 ± 90 mL/min/1.73 m2, in GFR 72 ± 34 mL/min/1.73 m2 and in KFG 0.03 ± 0.01 mL/s/mmHg; and elevation of PG 53 ± 2 mmHg, of filtration fraction 0.27 ± 0.07, of RA 4557 ± 2340 dyne s cm−5 and of RE 9417 ± 4163 dyne s cm−5. Such an alteration in intrarenal hemodynamics observed in severe VUR induces both intraglomerular hypertension (elevated PG) and an exaggeratedly reduced PTCF. This intrarenal hemodynamic defect is due to the glomerular endothelial dysfunction and its hemodynamic maladjustment. In accordance with the preceding information, treatment to correct the hemodynamic maladjustment is likely to improve renal function and prevent renal disease progression.

OXIDATIVE STRESS AND HEMODYNAMIC MALADJUSTMENT IN CHRONIC RENAL DISEASE: A THERAPEUTIC IMPLICATION

Hemodynamic maladjustment with predominant constriction at the efferent arteriole has been encountered in a variety of clinical settings of glomerulonephropathy. In essence, it induces not only intraglomerular hypertension but also exaggeratedly reduces the peritubular capillary flow, which supplies the tubulointerstitial compartment. The hemodynamic maladjustment is believed to reflect a glomerular endothelial cell dysfunction. In this regard, oxidative stress and antioxidant defect are likely responsible for the glomerular endothelial dysfunction. Improvement in renal function was accomplished following the correction of oxidant and antioxidant imbalance with antioxidant therapy and vasodilators. Following such therapy, there was a correction in hemodynamic maladjustment with a decline in intraglomerular hydrostatic pressure and an increase in renal perfusion with a subsequent increase in renal functions namely creatinine clearance, glomerular filtration rate and a decline in FEMg.