Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging.
ABSTRACT: Interstitial fibrosis and hypoxia accelerate the progression of CKD, but clinical tools to quantitate these factors in patients are lacking. Here, we evaluated the use of two magnetic resonance imaging (MRI) techniques, diffusion-weighted (DW)-MRI and blood oxygen level-dependent (BOLD)-MRI, to assess kidney fibrosis and hypoxia of the cortex in 142 patients with either diabetic nephropathy (n = 43), CKD without diabetes (n = 76), or acute kidney injury (AKI) (n = 23). Apparent diffusion coefficient (ADC) values of DW-MRI correlated with estimated glomerular filtration rates (eGFR) in the diabetic nephropathy and CKD groups (r(2) = 0.56 and r(2) = 0.46, respectively). Although the T2* values of BOLD-MRI and eGFR displayed good correlation in the CKD group (r(2) = 0.38), we did not observe a significant correlation between these values in the diabetic nephropathy group, suggesting that factors other than tubulointerstitial alteration determine the degree of hypoxia in the renal cortex. In the AKI group, neither the T2* nor ADC values correlated with eGFR. Renal biopsies from patients with CKD demonstrated that the T2* and ADC MRI values correlated with renal pathology. Taken together, ADC and T2* values appear to serve as accurate indices for evaluating renal tubulointerstitial alterations and parenchymal hypoxia, respectively, in the cortex. Functional MRI can thus contribute to multilateral, noninvasive, in vivo assessment of kidney function.
Project description:OBJECTIVES:In human chronic kidney disease (CKD) the extent of renal tubulointerstitial fibrosis correlates with progressive loss of renal function. However, fibrosis can so far only be assessed by histology of kidney biopsies. Magnetic resonance imaging (MRI) can provide information about tissue architecture, but its potential to assess fibrosis and inflammation in diseased kidneys remains poorly defined. MATERIALS AND METHODS:We evaluated excised kidneys in a murine adenine-induced nephropathy model for CKD by MRI and correlated quantitative MRI parameters (T1, T2, and T2* relaxation times, apparent diffusion coefficient and fractional anisotropy) with histological hallmarks of progressive CKD, including renal fibrosis, inflammation, and microvascular rarefaction. Furthermore, we analyzed the effects of paraformaldehyde fixation on MRI parameters by comparing kidney samples before and after fixation with paraformaldehyde. RESULTS:In diseased kidneys T2 and T2* relaxation times, apparent diffusion coefficient and fractional anisotropy in the renal cortex and/or outer medulla were significantly different from those in control kidneys. In particular, T2 relaxation time was the best parameter to distinguish control and CKD groups and correlated very well with the extent of fibrosis, inflammatory infiltrates, tubular dilation, crystal deposition, and loss of peritubular capillaries and normal tubules in the renal cortex and outer medulla. Fixation with paraformaldehyde had no impact on T2 relaxation time and fractional anisotropy, whereas T1 times significantly decreased and T2* times and apparent diffusion coefficients increased in fixed kidney tissue. CONCLUSIONS:MRI parameters provide a promising approach to quantitatively assess renal fibrosis and inflammation in CKD. Especially T2 relaxation time correlates well with histological features of CKD and is not influenced by paraformaldehyde fixation of kidney samples. Thus, T2 relaxation time might be a candidate parameter for non-invasive assessment of renal fibrosis in human patients.
Project description:Tissue fibrosis is an important index of renal disease progression. Diffusion-weighted magnetic resonance imaging’s (DWI-MRI) apparent diffusion coefficient (ADC) reveals water diffusion is unobstructed by microstructural alterations like fibrosis. We hypothesized that ADC may indicate renal injury and response to therapy in patients with renovascular disease (RVD). RVD patients were treated with medical therapy (MT) and percutaneous transluminal renal angioplasty (MT?+?PTRA) (n?=?11, 3 bilaterally, n?=?14 kidneys) or MT (n?=?9). ADC and renal hypoxia (R2*) by blood-oxygen-level-dependent MRI were studied before (n?=?27) and 3 months after (n?=?20) treatment. Twelve patients underwent renal biopsies. Baseline ADC values were correlated with changes in eGFR, serum creatinine (SCr), systolic blood pressure (SBP), renal hypoxia, and renal vein levels of pro-inflammatory marker tumor necrosis-factor (TNF)-?. Renal oxygenation, eGFR, and SCr improved after MT?+?PTRA. ADC inversely correlated with the histological degree of renal fibrosis, but remained unchanged after MT or MT?+?PTRA. Basal ADC values correlated modestly with change in SBP, but not in renal hypoxia, TNF-? levels, or renal function. Lower ADC potentially reflects renal injury in RVD patients, but does not change in response to medical or interventional therapy over 3 months. Future studies need to pinpoint indices of kidney recovery potential.
Project description:Experimentally renal tissue hypoxia appears to play an important role in the pathogenesis of chronic kidney disease (CKD) and arterial hypertension (AHT). In this study we measured renal tissue oxygenation and its determinants in humans using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) under standardized hydration conditions. Four coronal slices were selected, and a multi gradient echo sequence was used to acquire T2* weighted images. The mean cortical and medullary R2* values (?=?1/T2*) were calculated before and after administration of IV furosemide, a low R2* indicating a high tissue oxygenation. We studied 195 subjects (95 CKD, 58 treated AHT, and 42 healthy controls). Mean cortical R2 and medullary R2* were not significantly different between the groups at baseline. In stimulated conditions (furosemide injection), the decrease in R2* was significantly blunted in patients with CKD and AHT. In multivariate linear regression analyses, neither cortical nor medullary R2* were associated with eGFR or blood pressure, but cortical R2* correlated positively with male gender, blood glucose and uric acid levels. In conclusion, our data show that kidney oxygenation is tightly regulated in CKD and hypertensive patients at rest. However, the metabolic response to acute changes in sodium transport is altered in CKD and in AHT, despite preserved renal function in the latter group. This suggests the presence of early renal metabolic alterations in hypertension. The correlations between cortical R2* values, male gender, glycemia and uric acid levels suggest that these factors interfere with the regulation of renal tissue oxygenation.
Project description:OBJECTIVE:Few studies with large sample populations concerning renal anaemia and IgA nephropathy have been reported worldwide. The purpose of this cross-sectional study was to examine the clinical and pathological characteristics and influencing factors associated with renal anaemia in patients with IgA nephropathy, which is the most common aetiology of chronic kidney disease. METHODS:A total of 462 hospitalised patients with IgA nephropathy confirmed by renal biopsy who met the inclusion criteria were consecutively recruited from January 2014 to January 2016. Their general information, routine blood test results, blood chemistries, estimated glomerular filtration rates (eGFRs) and renal pathologies were collected. The Oxford classification was used to characterise the renal pathologies. Univariable and multivariate logistic regression models were used to analyse the influencing factors of anaemia associated with IgA nephropathy. RESULTS:The incidence of renal anaemia was 28.5% (132/462 patients) in our study (21.3% in males and 38.9% in females). The anaemia type was primarily normocytic and normochromic. The rate of anaemia in patients with eGFR values of 30-59?mL/min/1.73?m2 was higher than that in patients with an eGFR >60?mL/min/1.73?m2 (42.9% vs 17.8%, p<0.001). Notably, in the group with eGFR values <15?mL/min/1.73?m2, the anaemia rate was 100%. Logistic regression analysis showed that factors affecting anaemia in patients with IgA nephropathy included being female (OR 3.02, 95% CI 1.76 to 5.17), low albumin levels (OR 0.87, 95% CI 0.82 to 0.93), reduced eGFR values (OR 0.98, 95% CI 0.97 to 0.99) and renal tubulointerstitial lesions >50% (OR 2.57, 95% CI 1.22 to 5.40). CONCLUSIONS:The female sex, hypoalbuminaemia, reduced eGFR levels and severe renal tubulointerstitial lesions were correlated with renal anaemia in patients with IgA nephropathy. These results provide new insight into our understanding of anaemia in IgA nephropathy and may improve the management and treatment of clinical renal anaemia.
Project description:The current clinical classification of chronic kidney disease (CKD) is not perfect and may be overestimating both the prevalence and the risk for progressive disease. Novel markers are being sought to identify those at risk of progression. This preliminary study evaluates the feasibility of magnetic resonance imaging based markers to identify early changes in CKD.Fifty-nine subjects (22 healthy, 7 anemics with no renal disease, 30 subjects with CKD) participated. Data using 3D volume imaging, blood oxygenation level dependent (BOLD) and Diffusion MRI was acquired. BOLD MRI acquisition was repeated after 20 mg of iv furosemide.Compared to healthy subjects, those with CKD have lower renal parenchymal volumes (329.6±66.4 vs. 257.1±87.0 ml, p<0.005), higher cortical R2* values (19.7±3.2 vs. 23.2±6.3 s(-1), p = 0.013) (suggesting higher levels of hypoxia) and lower response to furosemide on medullary R2* (6.9±3.3 vs. 3.1±7.5 s(-1), p = 0.02). All three parameters showed significant correlation with estimated glomerular filtration rate (eGFR). When the groups were matched for age and sex, cortical R2* and kidney volume still showed significant differences between CKD and healthy controls. The most interesting observation is that a small number of subjects (8 of 29) contributed to the increase in mean value observed in CKD. The difference in cortical R2* between these subjects compared to the rest were highly significant and had a large effect size (Cohen's d = 3.5). While highly suggestive, future studies may be necessary to verify if such higher levels of hypoxia are indicative of progressive disease. Diffusion MRI showed no differences between CKD and healthy controls.These data demonstrate that BOLD MRI can be used to identify enhanced hypoxia associated with CKD and the preliminary observations are consistent with the chronic hypoxia model for disease progression in CKD. Longitudinal studies are warranted to further verify these findings and assess their predictive value.
Project description:Tubulointerstitial fibrosis is recognized as a key determinant of progressive chronic kidney disease (CKD). Fucoidan, a sulphated polysaccharide extracted from brown seaweed, exerts beneficial effects in some nephropathy models. The present study evaluated the inhibitory effect of oligo-fucoidan (800?Da) on renal tubulointerstitial fibrosis. We established a mouse CKD model by right nephrectomy with transient ischemic injury to the left kidney. Six weeks after the surgery, we fed the CKD mice oligo-fucoidan at 10, 20, and 100?mg/kg/d for 6 weeks and found that the oligo-fucoidan doses less than 100?mg/kg/d improved renal function and reduced renal tubulointerstitial fibrosis in CKD mice. Oligo-fucoidan also inhibited pressure-induced fibrotic responses and the expression of CD44, ?-catenin, and TGF-? in rat renal tubular cells (NRK-52E). CD44 knockdown downregulated the expression of ?-catenin and TGF-? in pressure-treated cells. Additional ligands for CD44 reduced the anti-fibrotic effect of oligo-fucoidan in NRK-52E cells. These data suggest that oligo-fucoidan at the particular dose prevents renal tubulointerstitial fibrosis in a CKD model. The anti-fibrotic effect of oligo-fucoidan may result from interfering with the interaction between CD44 and its extracellular ligands.
Project description:BACKGROUND:Multi-parametric magnetic resonance imaging (MRI) provides the potential for a more comprehensive non-invasive assessment of organ structure and function than individual MRI measures, but has not previously been comprehensively evaluated in chronic kidney disease (CKD). METHODS:We performed multi-parametric renal MRI in persons with CKD (n?=?22, 61?±?24 years) who had a renal biopsy and measured glomerular filtration rate (mGFR), and matched healthy volunteers (HV) (n?=?22, 61?±?25 years). Longitudinal relaxation time (T1), diffusion-weighted imaging, renal blood flow (phase contrast MRI), cortical perfusion (arterial spin labelling) and blood-oxygen-level-dependent relaxation rate (R2*) were evaluated. RESULTS:MRI evidenced excellent reproducibility in CKD (coefficient of variation?<10%). Significant differences between CKD and HVs included cortical and corticomedullary difference (CMD) in T1, cortical and medullary apparent diffusion coefficient (ADC), renal artery blood flow and cortical perfusion. MRI measures correlated with kidney function in a combined CKD and HV analysis: estimated GFR correlated with cortical T1 (r = -0.68), T1 CMD (r = -0.62), cortical (r?=?0.54) and medullary ADC (r?=?0.49), renal artery flow (r?=?0.78) and cortical perfusion (r?=?0.81); log urine protein to creatinine ratio (UPCR) correlated with cortical T1 (r?=?0.61), T1 CMD (r?=?0.61), cortical (r = -0.45) and medullary ADC (r = -0.49), renal artery flow (r = -0.72) and cortical perfusion (r = -0.58). MRI measures (cortical T1 and ADC, T1 and ADC CMD, cortical perfusion) differed between low/high interstitial fibrosis groups at 30-40% fibrosis threshold. CONCLUSION:Comprehensive multi-parametric MRI is reproducible and correlates well with available measures of renal function and pathology. Larger longitudinal studies are warranted to evaluate its potential to stratify prognosis and response to therapy in CKD.
Project description:BACKGROUND:The individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia-derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss. METHODS:To investigate urinary DKK3's potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment. RESULTS:Median urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level >4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-to-creatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course. CONCLUSIONS:Urinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.
Project description:Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V2 receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration. Recurrent exposure to heat with limited water availability was performed in male mice over a 5-wk period, with one group receiving desmopressin two times daily and the other group receiving vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury were assessed. Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary neutrophil gelatinase-associated protein), glomerular changes (mesangiolysis, matrix expansion), and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes, and tubulointerstitial fibrosis in normal animals and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity. Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy and may be clinically relevant to the pathogenesis of Mesoamerican nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V2 receptor-dependent pathway.
Project description:Glomerulosclerosis and tubulointerstitial fibrosis are associated with lower renal parenchymal elasticity. This study was designed to evaluate the predictive ability of renal elasticity in patients with chronic kidney disease (CKD). 148 non-CKD patients and 227 patients with CKD were recruited. 145 (38.7%) were female, 166 (73.1%) had diabetes, the mean estimated glomerular filtration rate (eGFR) was 33.9?±?15.8?ml/min/1.73?m2 and the median urinary protein-to-creatinine ratio (UPCR) 502 (122-1491)?mg/g. Patients with later stages of CKD had lower renal elasticity values, indicating stiffer kidneys (p?<?0.001), and smaller kidney (p?<?0.001). Renal elasticity correlated with log-transformed UPCR (??=?-7.544, P?<?0.001). Renal length correlated with age (??=?-0.231, P?<?0.001), sex (??=?-3.730, P?<?0.001), serum albumin level (??=?-3.024, P?=?0.001), body mass index (??=?0.390, P?=?0.009) and eGFR (??=?0.146, P?<?0.001). In fully-adjusted logistic regression model, the odds ratio (OR) per 10 unit change in renal elasticity for rapid renal deterioration was 0.928 (95% CI, 0.864-0.997; P?=?0.042). The OR per 1?mm change in renal length for rapid renal deterioration was 1.022 (95% CI, 0.994-1.050; P?=?0.125). Renal elasticity is associated with proteinuria and rapid renal deterioration in patients with CKD.