Abstract Background and Aims Obesity is a modifiable risk factor for the development and progression of chronic kidney disease (CKD). Pathways through which obesity might cause renal disease are not ...completely understood, as not all obese subjects develop CKD. In terms of deepening the knowledge of the preliminary steps of obesity-related renal damage, our group has developed a diet-induced obese murine model with obesity related glomerulopathy (ORG). The objective of this study was to investigate ORG at a cellular, structural and transcriptomic level as a way to discover the triggering pathogenic phenomena of ORG and evaluate potential biomarkers. Method Thirty Wistar rats were randomized into two groups: control rats (n = 15), which were fed with standard diet (SD) and study rats (n = 15), which were fed with high-fat diet (HFD). After 10 weeks, weight, parameters of kidney function, renal histological features, transcriptomic changes, miRNA and mRNA isolation were compared. Results HFD gained significantly more weight (55.8%) than SD(29.2%), p = 0.001. Albuminuria was also significantly higher in HFD (10,384.04) compared with SD (5,845.45), p = 0.001. HFD rats showed typical lesions of early-stages of ORG, with a predominance of mesangial matrix increase (MMI) and podocyte hypertrophy (PH). All histologic lesions correlated with genes differentially expressed (DE) in kidneys of HFD group and, both MMI and PH, also correlated with specific miRNAs DE in the urine of HFD group. The functional analysis showed 4 miRNAs DE in the kidneys of HFD group that negatively regulates PTEN gene, which promotes podocyte endocytosis of lipids in ORG. The electronic microscope confirmed the spaces of lipid vacuoles in the podocytes of HFD rats. Between those 4 miRNAs DE, miR-205 was also found to be upregulated in the urine of HFD group. Conclusion Wistar rats fed with HFD for 10 weeks developed early-stages of ORG, with a specific targetome of miRNAs and gene expression. The upregulation of miR-205 in kidney and its isolation in urine is associated with lipid endocytosis of podocytes, which takes place in the early-stages of ORG and could become a plausible biomarker of early-stages of ORG and open new avenues for future therapeutics research.
The increasing prevalence of type 2 diabetes mellitus (T2DM) has influenced in an increasing prevalence of chronic kidney disease (CKD). Little is known about the influence of non-alcoholic fatty ...liver disease (NAFLD) on the progression of CKD. The aim of this study was to analyse the role of NAFLD and its severity in the progression of renal function in patients with T2DM.
We conducted a retrospective and observational study including patients with T2DM and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2. NAFLD was defined as the presence of compatible ultrasonography and/or the presence of fibrosis using the NAFLD score. Patients were classified into three groups according to the NAFLD score: Group 1: <-1.85; Group 2: -1.85-0.18 and Group 3: >0.18.
A total of 102 patients were included 67.6% males, median age 59 years interquartile range (IQR) 53-64), with a median time of T2DM evolution of 70 months (IQR 39-131). Group 3 had lower eGFR (84.8 ± 40.4 versus 71.4 ± 30.6 mL/min/1.73 m2; P = 0.03) and higher proteinuria at baseline (0.56 ± 0.77 versus 1.59 ± 2.70 g/24 h; P = 0.05). After a follow-up time of 75.8 ± 23.9 months, Group 3 had a significant decrease in eGFR (66.6 ± 33.3 versus 36.8 ± 23.1 mL/min/1.73 m2; P ≤ 0.01) and a higher risk of CKD progression odds ratio 7.50 (95% confidence interval 2.76-20.35); P ≤ 0.001 defined as a decrease in eGFR of >50%.
The presence of NAFLD with high-risk fibrosis confers higher risk of CKD progression in patients with T2DM. Therefore NAFLD should be a risk factor evaluated in these patients to optimize treatment.
There are no adequate studies that have formally tested the performance of different estimating formulas in patients with type 2 diabetes both with and without overt nephropathy. Here we evaluated ...the agreement between baseline GFRs, GFR changes at month 6, and long-term GFR decline measured by iohexol plasma clearance or estimated by 15 creatinine-based formulas in 600 type 2 diabetics followed for a median of 4.0 years. Ninety patients were hyperfiltering. The number of those identified by estimation formulas ranged from 0 to 24:58 were not identified by any formula. Baseline GFR was significantly underestimated and a 6-month GFR reduction was missed in hyperfiltering patients. Long-term GFR decline was also underestimated by all formulas in the whole study group and in hyper-, normo-, and hypofiltering patients considered separately. Five formulas generated positive slopes in hyperfiltering patients. Baseline concordance correlation coefficients and total deviation indexes ranged from 32.1% to 92.6% and from 0.21 to 0.53, respectively. Concordance correlation coefficients between estimated and measured long-term GFR decline ranged from -0.21 to 0.35. The agreement between estimated and measured values was also poor within each subgroup considered separately. Thus, our study questions the use of any estimation formula to identify hyperfiltering patients and monitor renal disease progression and response to treatment in type 2 diabetics without overt nephropathy.
Abstract
BACKGROUND AND AIMS
Klotho is a transmembrane protein expressed mainly in distal tubular epithelial cells of the kidneys. Its gene expression and soluble form levels play a crucial role in ...the interaction of the aging-inflammation binomial and act as a co-receptor for the phosphaturic fibroblast growth factor 23 (FGF-23). Klotho deficiency, which is the norm in chronic kidney disease (CKD), has been reported as an independent risk factor for cardiovascular disease and subclinical atherosclerosis 1, 2. This study investigates the evolution of Klotho and FGF-23 levels during the first 2 years after kidney transplantation and their variability depending on the glomerular filtration rate (GFR).
METHOD
Serum levels of Klotho and FGF-23 were determined in 42 patients right before kidney transplantation (KT) and at 3rd, 12th and 24th month after KT. The measurements were made by ELISA. The GFR of the kidney graft was performed by indirect methods (formula: MDRa and CKD-EPI) at each study visit. Variables were reported as mean ± SD, and a value of P < .05 was considered to be statistically significant for each test.
RESULTS
KT recipients were divided into two groups arbitrary: the first group with a GFR > 40 mL/min (n = 26) and the other one with a GFR ≤ 40 mL/min (n = 16). At the starting point, there was not found any statistical difference in Klotho and FGF-23 levels between groups (GFR > 40 mL/min: 462.65 ± 264.99 pg/mL and 786.84 ± 521.67 pg/mL, respectively; versus GFR ≤ 40 mL/min: 436.5 ± 189.33 and 779.02 ± 589.86).
Those with better kidney function after KT significantly increased Klotho levels on 12th and 24th month of follow-up (baseline 462.65 ± 264.99 versus 12th month 561.96 ± 314.68 and 24th month 581.15 ± 350.10; P = .001), whereas KT recipients with a GFR ≤ 40 mL/min only proved an increase in Klotho levels at 12th month after a non-significant initial decrease at 3rd month (462 ± 204.91 versus 356.96 ± 177.07, respectively; P = .028). This trend was not confirmed at the 24th month (397.12 ± 182.05). Klotho levels were found significantly different at the 24th month between groups (P = .031). See Fig. 1.
Figure 2 shows the changes in FGF-23 levels. There are significant differences in both groups from baseline to month 24. (P < .001 group GFR > 40 mL/min and P < .001 group GFR ≤ 40 mL/min). FGF-23 dropped significantly in both groups at the 3rd month (P = .018) and 12th months (P = .003).
CONCLUSION
Vascular disease and mineral metabolism malfunction are relevant abnormalities in patients with CKD as well as in KT recipients. This study shows that Klotho is increasingly produced after KT in those patients whose allografts achieve a better function. We failed to prove the same effect on those with a GFR < 40 mL/min. Nonetheless, FGF-23 production declines satisfactorily independently of GRF. These results suggest the promotion of cardiovascular health after KT, particularly in those with higher GFR. The clinical and prognostic value of these changes are yet to be determined.
Abstract Background and Aims ADPKD affects about 10% of the patients with CKD. In the disease the formation of cysts replace normal renal parenchyma leading to renal function loss. The evolution of ...the disease is irregular: some patients lose renal function very fast while others remain stable or have a slow loss. This may have consequences in clinical care. In day-to-day practice, GFR is evaluated by means of formulas, which are algorithms that use creatinine and others markers like age and gender to estimate GFR. However, the accuracy and precision of eGFR in reflecting real GFR in ADPKD is not clear, being this the objective of our study. Method To analyse the capacity of eGFR by creatinine-based formulas in predicting mGFR changes over time. We evaluated patients with ADPKD, who underwent mGFR and eGFR by a group 5 equations at baseline, month 6 and then annually. mGFR was evaluated by the clearance of iohexol using dried blood spots (iohexol-DBS) and eGFR with the following creatinine-based equations: Cockcroft-Gault, aMDRD, CKD-EPI, FAS and EKFC. We calculated renal function decline (GFR decline) using repeated measured with mGFR and eGFR. All subjects have at least 3 repeated evaluations of renal function. The agreement between mGFR and eGFR declines was analysed by the concordance correlation coefficient (CCC). Also, we evaluated the capacity of eGFR decline in detecting diverse degree of GFR decline (a) rapid progressors: mGFR of −5 ml/min/y; (b) moderate progressors: −2 to −5 ml/min/y; (c) stable: > −2 ml/min/y. Results We evaluated 111 (43; 37% men); age: 42 y ± 14, with a 5 ± 1 evaluations of GFR over time (mGFR and eGFR). The average GFR decline was: −2,8 ml/min/year (mGFR); −3,1 (Cockcroft-Gault), −2,9 (aMDRD), −3,0 (CKD-EPI), −2,8 (FAS) and −2,6 (EFKC) According with mGFR decline, 21 patients (19%) were rapid progressors; 46 (41%) moderate progressors and 44 (40%) stable. The agreement between eGFR decline and mGFR decline was poor, reflected by a low CCC: 0.37 (Cockcroft-Gault); 0.76 (aMDRD); 0.80 (CKD-EPI), 0.77 (FAS); 0.81 (EFKC). In general, eGFR decline failed to detect progression of renal function over time. On average, 43% of the rapid progressors, 53% of the moderate progressors and 54% of the stable patients were not detected by any formula, respectively. Finally, a total of 12% and 6% of those stable or moderate progressors were falsely classified as rapid progressors. Conclusion eGFR is not able to reflect properly renal function changes over time in patients with ADPKP in about half of the patients. A relevant number of cases are erroneously considered as rapid progressors or even stable patients. This may have clinical consequences. Whenever possible, mGFR could be considered in this population.
Abstract Background and Aims The influence of Renal Reserve (RR), i.e. its presence or absence, in post-transplant renal function both in living kidney donors and recipients is unknown. The presence ...of RR in donors may be beneficial in terms of better renal function both for the donor and recipient after transplantation. In the other hand, the absence of RR in donors might indicate a lower renal endowment and so predispose to lower GFR post-transplantation in donors and recipients. However, little evidence is available in this field. Method In a previous study (ERA Abstract 2023, #3737) we described in a group of 52 potential living kidney donors, the presence (24-46%), absence (13-25%) or use (15-29%) of RR before donation. The latter was defined as the lack of increase in GFR after stimulation in patients with basal GFR > 100 mL/min. GFR was measured before and after transplantation by the clearance of iohexol with dried blood spots. Presence of RR was defined as an increase >10% of basal GFR after IV amino acid infusion. GFR was unadjusted to body surface area (BSA). In this follow-up study we investigated the impact of the presence, absence or use of RR before donation in GFR 12 months after transplantation, both in donors and recipients. Results Of the 52 pairs of donors and recipients, renal transplantation was performed in 21 who also had 12 months of follow-up. Before transplantation 9 donors had RR, 4 did not and 8 had RR in use. Pre-transplant GFR was 95 ± 15 ml/min, 89 ± 6 ml/min and 127 ± 16 ml/min in donors with RR, without RR and with RR in use, respectively. At 12 months after kidney donation, GFR was higher in donors who had RR in use before donation: 79 ± 12 ml/min, compared with those with RR: 65 ± 9 ml/min (p = 0.048) and those without RR 59 ± 10 (p = 0.03). In recipients, GFR was comparable between those who had a donor with RR or RR in use: 72 ± 19 ml/min vs 68 ± 12 ml/min (p = ns), whereas both groups had higher GFR than those recipients whose donors had no RR before donation 53 ± 5 ml/min, although of borderline signification (p = 0.07). Non parametric tests were used. No major complications after transplantations such as rejections or surgical complications, etc, that could alter GFR were observed. Conclusion The presence or use of RR may determine a better renal function 12 months after donation both for donors and recipients. This is a preliminary study and we acknowledge that the low number of cases is a limitation and so, these results require further studies.
Renal function can be estimated with formulas, which are inaccurate, or measured with gold standard methods, which are reliable but unpractical. We propose to simplify the plasma clearance of ...iohexol, a gold standard method to measure renal function, by dried blood spot (DBS) testing.
We compared glomerular filtration rate (GFR) values assessed by DBS and the reference plasma analysis technique. We tested in vitro the agreement between non-volumetric and volumetric DBS with the reference technique. Then, we performed a clinical validation in vivo between volumetric DBS and plasma analysis in 203 patients. The agreement was evaluated with the concordance correlation coefficient (CCC), the total deviation index (TDI) and the coverage probability. We defined acceptable agreement as a TDI <10%.
In the in vitro studies, the non-volumetric DBS showed moderate agreement, TDI = 26.0%, while the volumetric method showed better but insufficient agreement, TDI = 13.0%, with the reference method in plasma. The non-volumetric DBS was rejected. To improve the agreement of the volumetric DBS, iopamidol was used as an internal standard. This method showed acceptable agreement, TDI = 9.0% with the analysis in plasma, and was selected as the definitive DBS method. In the in vivo studies, the agreement between the final DBS method and the reference technique was acceptable: TDI = 9.5%. This indicates that 90% of the GFR values ranged from -9.5% to + 9.5% compared with the reference method.
We simplified the plasma clearance of iohexol using DBS without losing accuracy and precision with respect to the reference technique. This may facilitate the use of a reliable determination of renal function to the medical community.
Abstract
Background and aims
Obesity and metabolic syndrome (MS) are risk factors for renal disease progression in patients with established chronic kidney disease (CKD). Although therapeutic ...exercise has a potential role to treat or ameliorate chronic diseases, the effect of this intervention on obesity/MS and major renal outcomes: proteinuria and/or glomerular filtration rate (GFR) in patients with CKD is scarcely known. In particular, the effect of exercise in short term changes in renal outcomes are unknown. So, the aim of the study is to evaluate the effect of therapeutic exercise on: (a) the amelioration of MS traits and (b) renal parameters, GFR and proteinuria, in patients with CKD and MS.
Method
This is a 6-month exploratory study that included clinically stable patients with CKD of different causes and MS with measured GFR of 30-90 ml/min/kg2. Patients were treated with an incremental protocol of exercise which was prescribed by a physiotherapist. Baseline treatment and increments in prescription were based on physical status and individual response on follow-up, treatment involved both aerobic and strength exercise. All patients start with aerobic exercise training 30-60 minutes and 5 times per week. Strength exercise was individualized and consisted of free weight exercises. The prescription was incremented every month. The following outcomes were considered: changes in GFR i.e., ≥ 7%, which is twice the variability of the method in our laboratory (https://lfr.ecihucan.es), and weight lost ≥ 5%, a change associated to lower cardiovascular risk. In parallel with exercise training, we designed a plan to evaluate and promote adherence using regular telephone calls, an activity tracker, and visits to the hospital. Measured glomerular filtration rate (iohexol-DBS), urine samples (albuminuria/proteinuria), anthropometric parameters and analytics were collected at baseline, 3 and 6 months. There is no evidence in the field to evaluate the sample size of the study. Then, we designed and explorative study including 40 cases.
Results
This is a preliminary analysis of 25 cases: 3 were lost of follow-up at 3 months, and so, we show data of 22 patients that finished the study. Mean age was 58 y ± 12 and 70% (N = 17) were male. All patients were obese or overweight and 17 (70%) were diabetic. The most frequent kidney diseases were glomerulonephritis (40%) and diabetic nephropathy (30%). Most patients were on ACE inhibitors/ARAs (96%) and lipid-lowering agents (52%). At 6 months, 5 (22%) patients did not have major changes in weight, which was attributed to low adherence to treatment, and so, were not considered for further analyses. Of the remaining cases (N = 17, 78%), all showed a reduction in weight: from 97 kg ± 18 to 87 ± 18, p˂0.001. These patients were then classified in 3 groups based on GFR changes: (A) decreased GFR (N = 6, 35%), with GFR changing from 54 ml/min ± 13 to 44 ± 14, p = 0.001; BMI decreasing from 33 kg/m2 ± 4 to 30 ± 5, p = 0.003 and TG from 211 mg/dL ± 98 to 127 ± 59, p = 0.026; (B) stable GFR (N = 7, 41%), GFR from 47 ml/min ± 22 to 46 ± 21, p = 0.2; BMI decreasing from 35 kg/m2 ± 3 to 31 ± 3, p = 0.002 and TG from 160 mg/dL ± 57 to 105 ± 29, p = 0.02; (C) increased GFR (N = 4, 24%), GFR increasing from 59 ml/min ± 16 to 66 ± 18; p = 0.015 and BMI decreasing from 39 kg/m2 ± 3 to 36.5 ± 2, p = 0.015. No significant changes were observed in albuminuria and other MS traits in the subgroups analyzed. No adverse events were found during follow-up.
Conclusion
exercise is an effective and safe intervention method to lose weight and improve dyslipidaemia in patients with MS and CKD. The effect of weight reduction on GFR is not universal. Some patients showed a reduction of GFR in line with the reduction of weight, which may reflect the correction of hyperfiltration related to obesity and MS. On the other hand, in some patients GFR remained stable or even increased after weight loss. The pathogenesis behind this aspect is clearly unexpected and unknown. The impact of GFR changes associated with weight and MS changes in CKD deserve detailed attention in ad hoc designed studies.
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