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Background. While dysmetabolism is common in patients with chronic kidney disease (CKD) and associated with mortality, the mechanisms mediating these changes are unclear. New data implicate fibroblast growth factor (FGF)-19 as a possible entero-hepatic modulator of lipid metabolism. Methods. Using samples previously gathered as part of a randomized placebo-controlled study of antioxidative therapy for postprandial dysmetabolism, we investigated short-term (4 h) postprandial changes in circulating FGF-19 (ELISA) and the relationship to metabolic markers in six haemodialysis (HD) patients and nine matched healthy subjects (HS), with each participant assessed on four separate occasions. Results. The postprandial FGF-19 response was blunted in patients [maximum change +34.63 (0.24–186) pg/mL] versus controls [maximum change +150.3 (31.2–378.7) pg/mL; P < 0.0001], and the area under the curve (AUC; pg × min × mL �1 )w as also significantly lower 18 019 (12 513–44 387) versus 38 517 (19 775–72 816; P < 0.01). In patients, we found univariate correlations between AUC FGF-19 with AUC C-peptide (rho = 0.71; P = 0.001), AUC insulin (rho = 0.63; P = 0.001), but not with AUCs for triglycerides (TG) or glucose. Finally, treatment with the antioxidative compounds N-acetyl cysteine or MP865, but not with placebo, was associated with higher plasma FGF-19 (NAC and MP865 coefficients �0.28 and �0.23, P < 0.05, respectively). Conclusion. In advanced CKD, the postprandial FGF-19 response appears to be blunted, with partial normalization following antioxidative treatments. A blunted FGF-19 response was associated with impaired insulin and C-peptide signalling.

BACKGROUND Previous research suggest that repeated lead-chelation therapy decelerates progression of renal insufficiency in non-diabetic (non-DM) patients with high-normal body lead burden (BLB). Study findings are limited by relatively short-term follow-up and small sample size. METHODS A total of 116 non-DM patients with chronic kidney diseases (serum creatinine level of 1.5-3.9 mg/dl), high-normal BLB (>60 microg and

UNLABELLED: The severity and dynamics of renal tissue damage in chronic kidney disease (CKD) may be reflected by the urinary excretion of vasoactive and growth factors released by the damaged kidney. Urinary excretion of ET-1, TGF-beta1 and VEGF(165) was evaluated in 303 children with CKD stage II-IV (GFR 48 +/- 22 ml/min/1.73 m(2)) and 81 age-matched healthy controls. Major renal disease groups were hypo-/dysplastic kidney disease (N = 183), obstructive uropathies (N = 47), glomerulopathies (N = 34), nephronophthisis (N = 19) and polycystic kidney disease (N = 20). RESULTS: The mean urinary excretion rates of each of the three putative biomarkers were significantly elevated in CKD patients compared to controls: 965 +/- 2042 vs 216 +/- 335 fmol/g creatinine for ET-1; 252 +/- 338 vs 155 +/- 158 ng/g for VEGF; 31.6 +/- 37.0 vs 10.9 +/- 9.8 ng/g for TGF-beta1 (each P < 0.0001). The excretion of ET-1 and TGF-beta1 was highest in patients with obstructive uropathies. In the patients, ET-1, TGF-beta1 and VEGF excretion rates were inversely correlated with age (r = -0.22, -0.32 and -0.17, all P < 0.005) and renal function (r = -0.21, -0.13 and -0.15; P < 0.001; < 0.05; < 0.01; respectively) VEGF and TGF-beta1 excretion rates were positively correlated both in patients and controls. CONCLUSIONS: Children with CKD exhibit significantly elevated urinary excretion of ET-1, TGF-beta1 and VEGF(165) in comparison to healthy children. Urinary excretion of these biomarkers was most enhanced in patients with obstructive uropathies. A positive correlation between urinary TGF-beta1 and VEGF(165) excretion, shown both in patients and healthy controls, indicates an interdependent nature of their generation.

The current therapeutic strategy for the treatment of chronic kidney diseases only ameliorates disease progression. During renal injury, developmental genes are re-expressed and could be potential therapeutic targets. Among those genes reactivated in the adult damaged kidney, Gremlin is of particular relevance since recent data suggest that it could be a mediator of diabetic nephropathy and other progressive renal diseases. Earlier studies have shown that Gremlin is upregulated in trans-differentiated renal proximal tubular cells and in several chronic kidney diseases associated with fibrosis. However, not much was known about the mechanisms by which Gremlin acts in renal pathophysiology. The role of Gremlin as a bone morphogenetic protein antagonist has clearly been demonstrated in organogenesis and in fibrotic-related disorders. Gremlin binds to vascular endothelial growth factor receptor 2 (VEGFR2) in endothelial and tubular epithelial cells. Activation of the Gremlin-VEGFR2 axis was found in several human nephropathies. We have recently described that Gremlin activates the VEGFR2 signaling pathway in the kidney, eliciting a downstream mechanism linked to renal inflammatory response. Gremlin deletion improves experimental renal damage, diminishing fibrosis. Overall, the available data identify the Gremlin-VEGFR2 axis as a novel therapeutic target for kidney inflammation and fibrosis and provide a rationale for unveiling new concepts to investigate in several clinical conditions.

Epidemiological studies support a strong link between organ fibrosis and epithelial cancers. Moreover, clinical and experimental investigations consistently indicate that these diseases intertwine and share strikingly overlapping features. As a deregulated response to injury occurring in all body tissues, fibrosis is characterized by activation of fibroblasts and immune cells, contributing to progressive deposition of extracellular matrix (ECM) and inflammation. Cancers are driven by genetic alterations resulting in dysregulated cell survival, proliferation and dissemination. However, non-cancerous components of tumour tissues including fibroblasts, inflammatory cells and ECM play key roles in oncogenesis and cancer progression by providing a pro-mutagenic environment where cancer cells can develop, favouring their survival, expansion and invasiveness. Additional commonalities of fibrosis and cancer are also represented by overproduction of growth factors, like transforming growth factor β, epithelial-to-mesenchymal transition, high oxidative stress, Hippo pathway dysfunctions and enhanced cellular senescence. Here, we review advances in the analysis of cellular and molecular mechanisms involved in the pathogenesis of both organ fibrosis and cancer, with particular reference to chronic kidney diseases and renal cell cancers. Most importantly, improved understanding of common features is contributing to the development of innovative treatment strategies targeting shared mechanisms.

Background Bariatric surgery has been widely indicated for the management of obesity and related comorbidities. However, there are uncertainties pertaining to the risks of post-bariatric severe hypoglycaemia (SH), cardiovascular diseases (CVDs), end-stage kidney diseases (ESKDs) and all-cause mortality in obese patients with Type 2 diabetes mellitus (T2DM), especially among Asian populations. Methods A retrospective population-based cohort of 1702 obese T2DM patients who were free of CVD and ESKD were assembled based on the 2006–17 Hospital Authority database. One-to-five propensity-score matching was used to balance baseline covariates between patients in bariatric surgery and control groups. Incidence rates (IRs) of SH, CVD, Stage 4/5 chronic kidney diseases (CKD), ESKD and all-cause mortality events for two groups were calculated. Hazard ratios (HR) for SH, CVD and Stage 4/5 CKD events were assessed using Cox-proportional hazard models. Changes in estimated glomerular filtration rate (eGFR) and urine albumin–creatinine ratio (UACR) were measured up to 60 months. Results Over a mean follow-up period of 32 months with 5725 person-years, cumulative incidences of mortality, CVD, Stage 4/5 CKD, ESKD and SH were 0, 0.036, 0.050, 0.017 and 0.020, respectively. The surgery group had a significant reduction in risk of CVD events (HR = 0.464, P = 0.015) and no occurrence of mortality events. However, there were no significant differences in risks of SH [HR = 0.469, 95% confidence interval (CI): 0.204–1.081], Stage 4/5 CKD (HR =0.896, 95% CI: 0.519–1.545) and ESKD (HR = 0.666, 95% CI: 0.264–1.683) between two groups, although IRs were lower in the surgery group. Surgical patients had significantly higher eGFR within 12 months and had significantly lower UACR until 48 months. Conclusions Among obese T2DM patients, bariatric surgery lowered the risk of CVD and mortality, and was beneficial towards the kidney outcomes.

The heparin-binding protein midkine is a potent growth factor with emerging roles in numerous inflammatory diseases. Beyond its characterization in embryogenesis and organ development, ample insights into its function have been collected from experimental disease models using knockout animals or knockdown intervention strategies. Here a comprehensive overview on midkine and its functions in atherogenesis and kidney diseases is provided. Molecular clues to key signalling pathways (Akt, ERK, HIF1α) and key events in atherosclerotic vessels link midkine expression with vascular smooth muscle proliferation and (neo)angiogenesis. In acute and chronic kidney diseases, midkine expression is upregulated in tubular as well as endothelial cells. Experimental disease models that mimic diabetic nephropathy and/or immunologic glomerular damage indicate dichotomous midkine activities, with cytoprotective as well as injurious effects. This review also pinpoints the commonalities of the disease models. An understanding of the underlying molecular events will be required in order to design a targeted intervention into cardiovascular or renal diseases as well as inflammatory processes.

The occupants of our globe, on average, are steadily growing older consequent to lower birth rates and longer life expectancy. While the actual tempo of this global aging process varies from region to region, due to the impact of epidemics of disease (e.g. AIDS), reduced infant mortality, hygiene, malnutrition and violence, there is little doubt that the aging of society as a whole will have profound effects on healthcare systems and clinical practice. The discipline of nephrology is not exempt from these events, indeed it has already been and is continuing to be impacted by the aging of society, particularly in income-rich countries. The prevalence of acute and chronic kidney diseases is expected to increase significantly in the next few decades, largely in the older adult population. The specific causes or nature of these diseases are quite heterogeneous and often difficult to categorize on clinical grounds alone. Renal biopsy has been and continues to be a powerful tool to add precision to diagnosis. Many surveys of renal pathology, as it exists in a given population and how it changes over time, have been published, mostly collected in regional renal biopsy registries, but relatively few have focused mainly on the older and elder adult, conventionally defined as having attained the age of 65 years or more [1–3]. The survey by Jin et al. [4] from Jinling Hospital and the Nanjing University School of Medicine in Nanjing, China, published in this issue of Nephrology Dialysis Transplantation is a good example of this kind of morphological/epidemiological investigation. Remarkably, over 29 000 renal biopsies were performed in adults (age 18–81 years) at a single center over a 10-year period, of which ∼850 (2.9%) were performed in older or elder adults. These older subjects had a variety of clinical presentations and indications for performance of renal biopsy, but the actual rate of renal biopsy performance is not precisely known, but a rate of ∼2900 renal biopsies per year would be high by any standard. Undoubtedly, selection pressures such as the referral nature of and the cachement areas sub-served by the center play large roles in the epidemiological observations reported. Not surprisingly, proteinuria (including nephrotic syndrome; NS) with or without hematuria or acute kidney injury (AKI) was commonly the reason for performance of renal biopsy—observed in almost two-thirds of the subjects. Glomerular or vasculitic diseases predominated— slightly over 70% of all biopsies showed lesion of membranous nephropathy (MN), IgA nephropathy (IgA N), minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), small vessel vasculitis (SVV), diabetic nephropathy (DN) or amyloidosis (AM). DN is likely under-represented (at 9.75%) in this series, compared with its actual prevalence in the population as a whole—even though in this series renal biopsies were performed in diabetic subjects with renal involvement and without biopsy ‘contraindications’. It is not clear if the extent of ‘atypical’ characteristics at presentation influenced the decision to perform renal biopsy in diabetic subjects. Among elderly subjects presenting with NS, four lesions (MN, AM, MCD and IgA N) accounted for 80% of those observed. The distribution of these lesions in the elderly is strikingly different from that observed in the ‘control’ younger population. It is also noteworthy that the most common lesion in the very old (>75 years) was MN. Of great interest is the low prevalence of lesions of FSGS in both the young and old subjects alike (5.8 and 4.7%, respectively). Among older patients presenting with NS (with or without AKI) on only 28/851 (3.3%) demonstrated FSGS on renal biopsy. The frequency of FSGS in this and other studies in Asians is much different that seen in non-Asian populations, especially in subjects of African ancestry [5]. This difference is likely explained on a genetic basis (lack of APOL1 risk alleles in Asians), but environmental influences cannot be excluded [6]. The relative rarity of ‘primary’ or ‘idiopathic’membrano-proliferative glomerulonephritis (MPGN) in the elderly is notable (only 7 in 851 cases; 0.82%). These data support the contemporary view that IN F O C U S

Aliskiren is a relatively new oral direct renin inhibitor (DRI) that has been increasingly used for the treatment of diabetic nephropathy and hypertension. Its potential efficacy in nondiabetic chronic kidney diseases that are driven by renin-angiotensin system activation remains to be explored.From a teaching and regional hospital in Hong Kong between July 2009 and March 2010, patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in whom the ratio of protein to creatinine, as measured in early morning urine samples, remained113 mg/mmol (1000 mg/g), despite receiving the maximum recommended dose of losartan (100 mg daily) were recruited to receive additional DRI treatment. They were followed prospectively for 12 months with changes in proteinuria as the main outcome measure.Twenty-five consecutive patients were enrolled. Treatment with aliskiren for 12 months reduced the mean urinary protein-to-creatinine ratio by 26.3% (95% confidence interval, 20.1-43.6; P = 0.001 versus baseline), with a reduction of ≥ 50% in 24% of patients. There were significant reductions in plasma renin activity (P0.0001) and serum interleukin-6 (P0.05) and transforming growth factor-β (P = 0.01) levels, compared with baseline. Two patients (8%) developed mild allergic reactions and six (24%) had transient hyperkalemia (K5.5 mmol/L) during the study.Aliskiren confers an antiproteinuric effect in IgAN patients with significant residual proteinuria, despite receiving the recommended renoprotective treatment. Further prospective randomized trials are warranted to examine its long-term renoprotective potential. This trial is registered with the ClinicalTrials.gov number NCT00922311.

Background. Peroxisome proliferator-activated receptor gamma (PPARc) agonists have beneficial effects on renal structure and function in models of diabetes and chronic kidney diseases. However, the increased incidence of weight gain and edema potentially limits their usefulness. We studied an acute minimal-change disease-like nephrotic syndrome model to assess effects of PPARc agonist on acute podocyte injury and effects on fluid homeostasis. Methods. Acute podocyte injury and nephrotic syndrome were induced by puromycin aminonucleoside (PAN) injection in rats. Results. PPARc agonist, given at the time or after, but not before PAN, reduced proteinuria, restored synaptopodin, decreased desmin and trended to improve foot process effacement. There was no significant difference in glomerular filtration, effective circulating volume, blood pressure or fractional sodium excretion. PAN-injured podocytes had decreased PPARc, less nephrin and a-actinin-4, more apoptosis and reduced phosphorylated Akt. In PAN-injured cultured podocytes, PPARc agonist also reversed abnormalities only when given simultaneously or after injury. Conclusions. These results show that PPARc agonist has protective effects on podocytes in acute nephrotic syndrome without deleterious effects on fluid homeostasis. PPARc agonist-induced decrease in proteinuria in acute nephrotic syndrome is dependent at least partially on regulation of peroxisome proliferator-response element-sensitive gene expression such as a-actinin-4 and nephrin and the restoration of podocyte structure.

Background. Chronic kidney diseases (CKD) tend to progress to end-stage renal failure (ESRF). As it has been demonstrated that angiotensin-converting enzyme inhibitors (ACEi) have a renoprotective effect in adults with proteinuric disease and may be effective in reducing hyperfiltration and proteinuria, they are also frequently used as anti-progression agents in paediatric patients with CKD despite the lack of data confirming their role in the nephropathies peculiar to children. The aim of this study was to investigate whether patients with hypodysplastic CKD (the most common cause of ESRF in children) treated with ACEi show a significantly slower decline in creatinine clearance (Ccr). Methods. The analysis was based on the information available in the database of the ItalKid Project, a nationwide, population-based registry of chronic renal insufficiency (CRI) in children in Italy. Of the 822 patients with CRI due to hypodysplasia, we selected those who had been continuously treated with ACEi; the control patients were identified from the same diagnostic group and matched for gender, age and baseline Ccr. Results. Progression was analysed as the slope of Ccr in a total of 164 patients: 41 cases and 123 matched controls. There were no significant between-group differences in blood pressure, duration of follow-up or pre-study slope of Ccr (� 0.31 � 2.26 vs � 0.33 � 3.58 ml/min/1.73m 2 /year; P ¼ NS). After an average of 4.9 � 2.3 years, the mean slope of Ccr was 40% lower in the ACEi-treated cases in comparison to controls (� 1.08 � 2.08 vs � 1.80 � 4.42 ml/min/1.73 m 2 / year), however, this difference was not statistically significant (P ¼ 0.31). Conclusions. We conclude that ACEi treatment does not significantly modify the naturally progressive course of hypodysplastic nephropathy in children and further studies are necessary before such treatment is routinely proposed for anti-progression purposes in children with CKD.

Background. Renin–angiotensin system (RAS) blockades, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are well accepted for the cardiorenal-protective benefits added to antihypertensive effects in chronic kidney diseases (CKD), but associated with an increased risk of hyperkalaemia. However, few studies have investigated the effect of RAS blockades on serum potassium in dialysis patients. Methods. Hyperkalaemia associated with RAS blockades by ACEI and/or ARB was evaluated in 69 patients on maintenance haemodialysis, who underwent a three-period crossover study in four groups (no exposure to RAS blockades, ACEI or ARB alone and ACEI plus ARB treatments), lasting one month in each period. Results. Sixty-two patients completed this prospective 3-month study, and no one stopped the study because of the development of hyperkalaemia and/or complications. Mean serum K was similar among the four periods (no exposure, 5.54 � 0.67 mmol/l; ACEI alone, 5.54 � 0.75 mmol/l; ARB alone, 5.50 � 0.66 mmol/l; ACEI þ ARB combination, 5.42 � 0.66 mmol/l) and was also equal when compared between the two groups with and without exposure to RAS blockades (5.48 � 0.68 vs 5.54 � 0.67 mmol/l, P ¼ NS). The incidence of severe hyperkalaemic episodes (>6.0 mmol/l) upon monthly predialysis serum K determination was 25.8% with no exposure to RAS blockades, 29.8% for ACEI alone, 19.6% for ARB alone and 17.7% for ACEI þ ARB combination without statistically significant differences among the four periods (P ¼ NS). Among covariables, the degree of Kt/V, intakes of other medications interfering with potassium homeostasis and diabetes mellitus did not result in any significant hyperkalaemic changes during the 3-month study period except anuric patients compared with non-anuric patients (5.58 � 0.69 vs 5.19 � 0.65 mmol/l, P < 0.001). Conclusion. Neither monotherapy (ACEI or ARB) nor combination therapy (ACEI plus ARB) is associated with the additional risk of hyperkalaemia in patients on maintenance haemodialysis. However, those patients with anuria on RAS blockades warrant the cautious monitoring of serum K to prevent hyperkalaemia.