Renin-angiotensin system and cancer: epidemiology, cell signaling, genetics and epigenetics.

Day by day, the health and economical burden of cancer increases globally. Indeed it can be considered that there is ''cancer pandemic''. Blocking the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors (ACEI) or angiotensin-receptor blockers (ARB) are widely used measures to treat hypertension and heart failure. It has been recently suggested the activation and blocking of RAS has been associated with various types of cancer in epidemiological and experimental studies. Various studies have shown that RAS blockage is protective in some cancers. However, although fewer, contradictory data also showed that RAS blockage is either not related or adversely related to cancer. Although the reasons for these findings are not exactly known, different types of receptors and effectors in RAS may account for these findings. In the current review, we summarize the different RAS receptors and cancer development with regard to epidemiology, and pathogenesis including cell signaling pathways, apoptosis, genetic and epigenetic factors.

Body composition and circulating estradiol are the main bone density predictors in healthy young and middle-aged men.

PURPOSE: Current fracture risk assessment options in men call for improved evaluation strategies. Recent research directed towards non-classic bone mass determinants have often yielded scarce and conflicting results. We aimed at investigating the impact of novel potential bone mass regulators together with classic determinants of bone status in healthy young and middle-aged men. METHODS: Anthropometric measurements, all-site bone mineral density (BMD) and body composition parameters assessed by dual-energy X-ray absorptiometry and also serum concentrations of (1) the adipokines leptin and resistin, (2) vitamin D and parathormone (PTH), (3) sex hormone binding globulin (SHBG), total testosterone and estradiol (free testosterone was also calculated) and (4) C-terminal telopeptide of type I collagen (CTx) were obtained from 30 apparently healthy male volunteers aged 20-65 years enrolled in this cross-sectional study. RESULTS: Only lean mass (LM) and total estradiol independently predicted BMD in men in multiple regression analysis, together explaining 49% (p ≤ 0.001) of whole-body BMD variance. Hierarchical regression analysis with whole-body BMD as outcome variable demonstrated that the body mass index (BMI) beta coefficient became nonsignificant when LM was added to the model. Adipokines, fat parameters, testosterone (total and free), SHBG, PTH and vitamin D were not independently associated with BMD or CTx. CONCLUSIONS: The present study shows that LM and sex hormones-namely estradiol-are the main determinants of bone mass in young and middle-aged men. The effects of BMI upon BMD seem to be largely mediated by LM. Lifestyle interventions should focus on preserving LM in men for improved bone outcomes.

Kidney transplantation in Romania: two transplant centers experience.

PURPOSE: Kidney graft survival rates improved from decade to decade, but data about factors that affect patient and graft survival remain challenging and even controversial. METHODS: We analyzed retrospectively data from kidney transplanted patients followed in two Romanian transplant centers (Iasi and Bucharest)-new programmes specifically developed after 1989 to cover transplantation requirements for two-thirds of Romania. We used a composite survival outcome defined as 50% reduction in estimated glomerular filtration rate (eGFR), return to dialysis or death. Survival analysis was performed using uni- and multivariable Cox regression with baseline and time-updated covariates. RESULTS: From the entire cohort of 365 patients, 243 had the outcome of interest. In the univariable Cox survival analysis, age, hemoglobin, eGFR, cholesterol, AST and transplant center were associated with the outcome. The multivariable Cox analysis reveals that only cholesterol (HR 0.97, 95% CI 0.94-0.99 per 10 mg/dL increase) and transplant center (HR 3.64, 95% CI 2.67-4.97) remain associated. For the time-updated Cox survival analysis we found that eGFR (HR 0.91, 95% CI 0.87-0.96 per 10 ml/min/1.73 m2 increase) and cholesterol are associated with the outcome in the univariable analysis and only eGFR and transplant center in the multivariable Cox survival analysis. CONCLUSIONS: Our study reports data from two distinct transplant centers from a developing country. Our results are similar to the current literature data, but also reveal that the approach of a center to the transplantation management is an independent factor associated with graft survival.

Calibrating the impact of dual RAAS blockade on the heart and the kidney - balancing risks and benefits.

Overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of heart failure (HF) and chronic kidney disease (CKD). RAAS antagonists can significantly improve clinical outcomes, but monotherapy blocks but one step of the RAAS and can be bypassed through compensatory mechanisms. Providing more complete RAAS blockade by deploying drugs with complementary actions seemed logical - hence the practice of using dual (or triple) RAAS inhibitors. However, RAAS antagonists also exhibit dose-limiting side effects, including acute kidney injury, hyperkalaemia and hypotension, which blunt their overall effectiveness. Despite achieving better RAAS blockade, several trials failed to show clinical outcome improvements. Patients with concomitant CKD and HF (cardiorenal syndrome) are at the greatest risk of these adverse events and therefore the least able to benefit, yet they also have the worst prognosis. This paradox, where those most in need have fewest therapeutic options, poses three questions which are the focus of this review: whether (i) novel therapies that prevent adverse effects can restore therapeutic benefits to patients who would otherwise be RAAS-therapy intolerant, (ii) there are any validated alternatives to their use and (iii) newer approaches to the detection of fluid congestion are ready for implementation.

Diabetic nephropathy: What does the future hold?

The consensus management of diabetic nephropathy (DN) in 2015 involves good control of glycaemia, dyslipidaemia and blood pressure (BP). Blockade of the renin-angiotensin-aldosterone system using angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers or mineralocorticoid inhibitors are key therapeutic approaches, shown to be beneficial once overt nephropathy is manifest, as either, or both, of albuminuria and loss of glomerular filtration rate. Some significant additional clinical benefits in slowing the progression of DN was reported from the Remission clinic experience, where simultaneous intensive control of BP, tight glycaemic control, weight loss, exercise and smoking cessation were prioritised in the management of DN. This has not proved possible to translate to more conventional clinical settings. This review briefly looks over the history and limitations of current therapy from landmark papers and expert reviews, and following an extensive PubMed search identifies the most promising clinical biomarkers (both established and proposed). Many challenges need to be addressed urgently as in order to obtain novel therapies in the clinic; we also need to examine what we mean by remission, stability and progression of DN in the modern era.

POSTOPERATIVE ARTERIAL RELAXATION AND INTRAOPERATIVE VENOUS DILATION AS INTERCONNECTED PROGNOSTIC FACTORS FOR THE MATURATION OF ARTERIOVENOUS FISTULAS.

AIM: To investigate if immediate arterial distention can be used as a predictive factor for the development of a good fistula. MATERIAL AND METHODS: Over a 5-months period (January- May 2015) all the patients who underwent an arteriovenous fistula between the radial artery and the cephalic vein of the forearm at the Second Surgical Clinic of the Iasi Regional Cancer Institute and were willing to participate were enrolled in the study. The diameters of the vessels were measured 1 hour and 8 weeks after surgery. RESULTS: We found statistically significant differences for all measured diameter variations between the calcified artery and normal artery groups (p < 0.001 for the arterial distention at 1 hour and 8 weeks after surgery and p = 0.002 for the venous distention 8 weeks after surgery). A linear regression also showed that the degree of arterial distention immediately after surgery and the venous distention 8 weeks after surgery were statistically correlated. CONCLUSIONS: Arterial distention immediately after surgery and therefore the lack of it due to the presence of arterial calcifications can be used to predict whether or not a good fistula can be achieved at a 1% statistical significance level.

The EVOLVE study is negative, so what does this 'bitter pill' of disappointment mean now for renal patients?

The extremely high morbidity and mortality experienced by subjects with chronic kidney disease (CKD) has often been described and reviewed, but this familiarity should not breed indifference to the huge burden of premature cardiovascular disease ­ something which becomes more obvious, but increasingly challenging to treat, as GFR declines, or proteinuria increases. The health outcomes for a middle-aged person entering renal replacement therapy are as bad as those seen with a major solid organ malignancy; while there has been modest progress in improving outcomes over the last two decades, the diagnosis of significant or progressive CKD should and thus still does continue to cast a shadow over patients, carers and healthcare professionals alike.

Impact of gender and dialysis modality on early mortality risk in diabetic ESRD patients: data from a large single center cohort.

BACKGROUND: Diabetes mellitus (DM)-associated chronic kidney disease (diabetic renal disease) became the predominant etiology of the end-stage renal disease (ESRD) in the western countries and shows the same trend in the developing countries. Early mortality (EM) after the dialysis initiation, defined as death of all causes within the first 3 months after initiation of renal replacement therapy (RRT), is of concern especially for the high-risk renal patients including diabetics. The goal of the present study was to identify demographic and clinical risk factors associated with EM in a retrospective cohort of Romanian DM patients initiated on dialysis. METHODS: A retrospective case-control study was designed. Clinical recordings from all patients initiated on hemodialysis (HD) or peritoneal dialysis between January 1996 and December 2005 in the Dialysis Center of NIDNMD Paulescu, Bucharest, were collected and analyzed. Patients were classified accordingly in two groups: those who displayed EM formed the "cases" group, while the others were included in the "controls" group. Both univariate (subgroup analysis) and multivariate analyses (logistic regression, Cox regression) were used to analyze the impact of risk factors on EM outcome. RESULTS: Data from 788 patients were included in the analysis. The factors significantly associated with EM in the univariate analysis were female gender, late initiation (LI) of dialysis, old age and HD used as the first/only method. Applying the multivariate analysis, only the use of HD (OR = 4.20, p < 0.0001) and the LI of dialysis (p < 0.0001; 95 % CI 1.36-2.30) were associated with EM, while female gender showed only a trend to a higher EM (OR = 1.29, p = 0.052). CONCLUSIONS: Hemodialysis used as a first/single method for RRT and the LI of dialysis were independent predictors of EM in our ESRD diabetic patients. A possible explanation for the first factor could be our specific center procedure, which allows only the HD as rescue therapy method for the most severe cases, managed in the intensive care unit.

Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex.

PURPOSE: Tuberous sclerosis complex (TSC) is associated with hamartomatous growths including subependymal giant cell astrocytomas (SEGAs). Although, SEGAs are slow-growing glioneuronal tumors, they represent a significant cause of morbidity and mortality due to the risk of sudden death from acute hydrocephalus. Neurosurgical resection has been the mainstay of therapy, since radiotherapy and chemotherapy were proved inefficient in those tumors. Recent studies support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis and suggest it might represent a disease-modifying treatment for other aspects of tuberous sclerosis. METHODS: We describe the clinical and radiological progression of three pediatric patients with definitive diagnosis of TSC and SEGA, which have been treated with everolimus. RESULTS: Up to 34 % sustained SEGA decrease was observed in the three cases. All three patients have experienced seizure control and two of them have showed cognitive and behavioral improvement. Everolimus has been well tolerated by all. No severe adverse events have been observed to date. CONCLUSION: Everolimus offers significant promise in treating SEGAs. Studies are required to explore optimal therapy duration and management upon discontinuing therapy.

A cross-sectional study regarding the impact of end-stage renal disease on quality of life.

UNLABELLED: The number and severity of physical and psychological symptoms reported by chronic hemodialysis (HD) patients are significant and increasing; with a clear need to clarify which symptom intervention is the most needed. Measurements of quality of life (QoL) have shown, for many decades, an impairment of both physical and psychological aspects in both chronic kidney disease (CKD) pre-dialysis and in end stage renal disease (ESRD) patients. This cross-sectional study was conducted assess the quality of life of a Romanian hemodialysis population and the impact of several clinical and biochemical factors. MATERIAL AND METHODS: A total of 102 patients (41 males, 61 females) with a mean age of 52.5 +/- 12.0 years, who were treated with HD three times per week in our dialysis center were included in the study. All subjects completed the Short Form Health Survey Questionnaire (SF-36). Clinical and biochemical parameters were extracted from the EUCLID electronic database. RESULTS: Our measurement showed a deteriorated QoL in our population, all of the included subjects presenting with much lower scores in both physical and mental components than the reference values of SF-36. We did not found any statistic significant correlation between hemoglobin (Hgb) levels or dialysis adequacy and different domains of the SF-36. The only significant association was found between age and the physical component of the SF-36, implying that older patients perceive a more degraded quality of life. CONCLUSION: HD patients experience a great burden from physical and psychological symptoms of the disease, perceiving an important impairment in their quality of life, especially regarding the physical component.

Peri-aortic fat tissue and malnutrition-inflammation-atherosclerosis/calcification syndrome in end-stage renal disease patients.

PURPOSE: Thoracic peri-aortic fat tissue (PFT) is considered as a metabolically active organ in atherosclerosis. Malnutrition, inflammation and atherosclerosis/calcification (MIAC) are the most commonly encountered risk factors of cardiovascular disease in end-stage renal disease (ESRD) patients. Calcification of the aorta was found to be an important cardiovascular risk marker predicting future events, morbidity and mortality in this population. We aimed to investigate the relationship between PFT, MIAC syndrome and thoracic aortic calcification (TAC) in ESRD patients. METHODS: Seventy-nine ESRD patients receiving hemodialysis (HD) or peritoneal dialysis (PD) and 20 control subjects were enrolled in this cross-sectional study. PFT and TAC were assessed using a 64-MDCT scanner. Patients with serum albumin <3.5 g/dL were defined as patients with malnutrition; those with serum C-reactive protein level >10 mg/L had inflammation, and those with coronary artery calcification score (CACS) >10 had atherosclerosis/calcification. RESULTS: TAC and PFT were significantly higher in ESRD patients compared with control subjects. There was a statistically significant relationship between PFT and TAC in ESRD patients (r = 0.458, p < 0.0001). PFT was found to be significantly increased when the MIAC components increased. PFT was positively associated with age, BMI, uric acid, hemoglobin and CAC. The multivariate analysis revealed that age and uric acid were independent predictors of increased PFT. Twenty-four (30.4 %) patients had none, 30 (37.9 %) had one component, 17 (21.5 %) had two components, and 8 (10.2 %) had all MIAC components. PFT was highest among patients having all three components (28.6 cm(3)) and lowest among those who do not have the MIAC syndrome (8.54 cm(3)). TAC was highest among patients having all three components (179.2 HU) and lowest among those who do not have the MIAC syndrome (0 HU). CONCLUSIONS: We found a relationship between PFT and MIAC syndrome in ESRD patients.

Methods for estimating "dry weight" in hemodialysis patients.

The correct estimation on dry weight is very important in providing effective and safe hemodialysis to end stage renal disease patients. Optimal fluid removal with minimal adverse reactions from the treatment is one goal of hemodialysis treatment. The aim of this article is to discuss different methods of assessing dry weight and to determine their role in the complex fluid management of end-stage renal disease patient. Recent literature describes various methods of determining optimal hydration state, including clinical or paraclinical methods. Each of these methods has their benefits and limitations. Despite the large number of studies conducted on new technologies for determining dry weight, there is a lack of larger, randomized controlled trials to support these methods. Although the successful use of different methods of dry weight assessment is not supported yet by large clinical trials, some evidence is starting to link the use of some methods to improved outcomes (morbidity, mortality) in this population.

Surgical management of renal hyperparathyroidism: a preliminary series report.

BACKGROUND: Renal hyperparathyroidism (RHPT) is a frequent complication of uremic patients on hemodialysis and despite various advances in medical therapy parathyroidectomy is necessary in a semnificative number of cases. PATIENTS AND METHODS: We reviewed our experience (first in Romania) regarding fortythree patients with RHPT operated on in our clinic between 1994 and 2009 evaluating the diagnosis methods, surgical indications, techniques and results together with the evolution of our own therapeutical concept. The study included 22 men and 21 women of median age of 48 (range 15-67) years, performing hemodialysis (n=41) or peritoneal dialysis (n=2) from 7,7 (range 3-13) years respectively. Three patients received an unsuccessful renal graft. The diagnosis was established by anamnesis, clinical complaints (mainly osteoarticular pains, osteoporosis, fractures and skeletal deformities, muscle weakness, severe itching and mental troubles), completed by abnormal values of calcemia, phosphatemia alkaline phosphatasis and intact PTH. Ultrasonography and parathyroid scan were useful in "adenomised" parathyroids and coexistent thyroid pathology. RESULTS: All the patients were operated on. Twentyfour sub-total parathyroidectomies and 19 total parathyroidectomies (6 with autotransplantation), were performed (two video-assisted). There were no deaths and the operative morbidity was 20,9% (vocal cord hemiparesis and postoperative bleeding--each one case, mild transitory hypocalcemia three cases and recurrences four cases). Pathology revealed that RHTP was due to four gland diffuse hyperplasia (n = 23) or nodular hyperplasia (n = 19). One parathyroid carcinoma (in the fourth parathyroid gland), one thymoma and two papillary thyroid microcarcinoma was identified. Clinical and biochemical cure was achieved at median term control of 38 (range 6-165) months in 79.0% (n = 34) of cases. CONCLUSION: Parathyroidectomy is effective for long intervals as symptomatic therapy in cases of RHPT appearing in uremic patients on hemodialysis or after renal transplant but the optimal technique must be individualized on each case and still to be debated.

Burden of disease - prevalence and incidence of ESRD in selected European regions and populations.

Rates of renal replacement therapy (RRT) vary markedly between Eastern and Western European countries. This review aims to establish the characteristics of healthcare systems and renal services that are independently associated with rates of initiation of RRT in these countries. The incidence of RRT varied from 12 to 455 per million populations (pmp); the only general population indicator independently associated with RRT incidence was aged 65+. Economic and financial conditions could also play an important role. Gross Domestic Product (GDP) per capita and the proportion of GDP spent on healthcare independently predicted RRT incidence. Each increase in hemodialysis (HD) facilities and competition between providers is associated with higher RRT incidence. In this context, macroeconomic and potentially modifiable renal service organizational factors appear more important determinants of provision of RRT than measurable medical factors. The economic, financial or medical conditions could also play an important role in treatment strategy. The proportion of patients receiving HD, peritoneal dialysis (PD) or transplantation shows marked variation in Europe. The East Europeans use more HD and less RTx as compared to West Europeans; the use of PD is similar. Treatment of anemia and mineral metabolism disorders also varies from one region to another. The mean baseline hemoglobin level and the prevalence of patients reaching this value are higher in West Europeans. Regarding mineral metabolism, the percent of patients achieving all four parameters (Ca, P, CaxP and PTH) was also higher in Western Europe. The adherence to EBPG (European Best Practice Guidelines) was also higher in these countries.

Association of +35A/C (intron3/exon3) polymorphism in SOD1-gene with diabetic nephropathy in type 1 diabetes.

Diabetic nephropathy is a major complication of type 1 diabetes whose pathogenesis is insufficiently known, but oxidative stress and genetic susceptibility seem to be involved. The purpose of this study is to assess the possible association of +35A/C (rs2234694) polymorphism in SOD1-gene with advanced stages of diabetic nephropathy in patients with type 1 diabetes in Romania. There have been enrolled 238 unrelated patients, having type 1 diabetes, divided into group A (106 patients) with diabetic nephropathy - macroalbuminuria or ESRD (End Stage Renal Disease) and group B (132 patients) without diabetic nephropathy. The genomic DNA was extracted from the peripheral venous blood and the genotyping of +35A/C (rs2234694) polymorphism has been made using the PCR-RFLP technique. The statistical analysis has been made using De Finetti's program. There has not been a significant deviation from the Hardy-Weinberg equilibrium for any group (p=0.229 and p=0.894, respectively). The data analysis revealed that the presence of a C-allele confers a significant risk (p=0.008) for the advanced diabetes nephropathy (OR=4.940, 95% C.I.=1.341-18.198), and the CA-genotype (p=0.015) confers a little lower risk (OR=4.491, 95% C.I.=1.203-16.766). This study shows the association of a mutant C-allele of rs2234694 polymorphism in SOD1-gene with the advanced stages of diabetic nephropathy in patients with type 1 diabetes in Romania, suggesting the involvement of the defense against oxidative stress, as an important link in the pathogeny of diabetic nephropathy.

[Acute renal failure--the present and perspectives]. / Insuficienta renala acuta--prezent si perspective.

Acute kidney injury is a common complication in hospitalized patients, and its incidence has risen significantly in the past 15 yr. Despite significant technical advances in therapeutics, the mortality and morbidity rates associated with acute kidney injury remain dismally high and have not appreciably improved during the past four decades. An ideal biomarker for acute kidney injury would help clinicians and scientists diagnose the most common form of acute kidney injury, acute tubular necrosis, early and accurately and may aid to risk stratify patients with acute kidney injury by predicting the need for renal replacement therapy, the duration of acute kidney injury, the length of stay, and mortality. The major types of urinary biomarkers fall into three classes: 1) inflammatory; 2) renal tubular proteins that are excreted into the urine after injury; 3) surrogate markers of tubular injury. There has been increasing interest in the identification and validation of novel biomarkers of acute kidney injury that permit earlier and more accurate diagnosis.

[Clinical epidemiologic assessment of the incidence of chronic kidney diseases registered in Romania, Iasi County, in the years of 2004-2008]. / Evaluari clinico-epidemiologice asupra incidentei unor boli cronice de rinichi, inregistrate in România si judetul Iasi, in perioada 2004-2008.

UNLABELLED: Authors present the results of a study carried out in Iasi County and Romania, comparatively, between 2004-2008, in order to know the incidence of the main chronic kidney diseases (CKDs) (nephritic syndrome and nephrosis, chronic renal failure, kidney and urinary lithiasis) and those with a major role in their etiology (essential arterial hypertension--EAHT and diabetes mellitus--DM). RESULTS: The distribution of cases at the county and national level was assessed both for CKDs and EAHT and DM, respectively, by area, sex and age groups. Clinical epidemiological research highlighted high values of CKDs incidence, taking into account a defficiency in standardized data collecting, processing, and interpretation to allow a database useful for elaboration and implementation of prevention programmes.

Hemoglobin normalization trials in chronic kidney disease: what should we learn about quality of life as an end point?

This editorial review takes an in-depth look to the effect of hemoglobin (Hb) normalization with erythropoietin on quality of life (QoL) in chronic kidney disease (CKD). The analysis of the current available data shows major inhomogeneities in the tools used for assessment of QoL and in data reporting. Furthermore, the major trials on Hb normalization were generally not primarily designed to analyze QoL as a specific end-point. However, current data suggest that only partial correction of anemia with EPO may improve QoL, whereas correction of Hb to above 12 g/dL does not exert any positive effect. Finally, the authors provide recommendations on a more rigorous assessment of QoL in future trials in CKD patients.

ORAMA: a study to investigate EBPG impact on renal anaemia - design and baseline data.

BACKGROUND: It is of paramount importance not only to publish anaemia management guidelines for chronic kidney disease (CKD) but also to verify their implementation in clinical practice. The Optimal Renal Anaemia Management Assessment (ORAMA) is the first European study investigating the impact of adherence to the 2004 revised European Best Practice Guidelines (EBPG) and its impact on patient outcomes. METHODS: Participating centres were randomised into 2 groups: group A with, and group B without, access to an EBPG-based computerised clinical decision support (CDS) system after baseline. Patients with stage 2-5 CKD either anaemic (haemoglobin [Hb] <11 g/dL) or treated with erythropoiesis-stimulating agents (ESAs) and/or iron supplementation were enrolled. Primary end points are based on achievement of anaemia-related guideline targets. Here, baseline data are reported descriptively. RESULTS: Fifty-three centres in 8 countries included 739 patients, 81% of whom have received dialysis. Mean baseline Hb was 11.2 g/dL, and 52% of all patients met the EBPG target of >11 g/dL Hb at baseline. However, only 37% of patients had their Hb values >11 g/dL throughout a 3-month prestudy period. Serum ferritin and transferrin saturation were above the guideline target in circa 80% of patients. The vast majority of patients (96%) received ESA therapy at baseline. CONCLUSIONS: In line with findings from previous studies ORAMA baseline data show that achievement of EBPG is suboptimal across European countries. Final results promise an insight into the impact of guideline-based CDS tools on clinical practice and target attainment.

[The management in chronic kidney disease (CKD)]. / Noi strategii terapeutice in boala cronica de rinichi.

Renal fibrosis is the principal process underlying the progression of chronic kidney disease (CKD) to end stage renal disease (ESRD). It is a relatively uniform response involving glomerulosclerosis, tubulointerstitial fibrosis and changes in renal vasculature. Direct or indirect tubulointerstitial injury via oxidative stress and various effector molecules trigger cellular responses like tubular epithelial cell (TEC) apoptosis, activation of fibroblasts and their phenotypic switch to myofibroblasts, proliferation of macrophages, fibrocytes, fibroblasts as well as epithelial to mesenchimal transition of TEC. In this review we explore the potential of experimental therapeutic strategies, based on preventing or reversing the pathophysiologic steps of kidney remodeling that lead to fibrosis.