Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.

Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose-dependent and -independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data.

[Limitations of blood pressure target in non-dialysis chronic kidney disease: a question of method?]. / Limiti del target pressorio nell'insufficienza renale cronica non-dialitica: una questione di metodo?

International guidelines recommend to reduce blood pressure (BP) levels below 130/80 mmHg in non-dialysis chronic kidney disease (CKD) patients. However, this BP target has not been validated by randomized controlled trials and is mainly driven by data obtained in observational and post-hoc analyses suggesting that it improves the renal and, to some extent, cardiovascular prognosis. The inconclusive results on the prognostic role of the BP target in patients with CKD might also relate to the limited ability of office BP readings to adequately stratify the global risk of this population. In fact, alterations of the pressure profile (such as white-coat hypertension) and nighttime hypertension are common in CKD patients. Recent studies have demonstrated that ambulatory blood pressure monitoring (ABPM) is superior to clinic BP measurements in predicting renal death and cardiovascular events. Therefore, while waiting for the results from the ongoing randomized Systolic Blood Pressure Intervention Trial (SPRINT) comparing the effect on cardiorenal prognosis of two BP target levels, the more widespread use of ABPM is desirable in CKD patients.

[Amino acid loss during dialysis treatment]. / Perdita di aminoacidi nel corso di terapia emodialitica extracorporea.

Protein-calorie malnutrition is a widespread complication in hemodialysis (HD) patients and is associated with increased mortality. The pathogenesis of malnutrition is multifactorial. Intradialytic amino acid (AA) loss is considered one of the cofactors in the complex mechanisms that lead to malnutrition in HD patients. It has been documented that in each dialysis session there is a 6-8 gram loss of AA into the dialysate, which worsens with the use of high-flux membranes. The intradialytic AA loss is variably compensated by reduction of liver synthesis and increased AA release from muscle stores. In malnourished HD patients the serum AA concentration, especially branched-chain AA (BCAA), is correlated with nutritional status and anorexia, whereas BCAA supplementation improves the nutritional parameters and increases appetite. Further studies are necessary to clarify the role of alterations of AA metabolism in the pathogenesis of malnutrition and the potential beneficial effects of BCAA supplementation or alternative treatments in malnourished patients.

[Role of paracalcitol in the management of non-dialysis CKD: state of art and... Unmet needs]. / Ruolo del paracalcitolo nella terapia conservativa della malattia renale cronica: stato dell'arte e... Unmet needs.

Chronic kidney disease (CKD) is associated with a high risk of cardiovascular morbidity and mortality due to the high prevalence of traditional risk factors and the presence of factors specific to CKD. Vitamin D deficiency and secondary hyperparathyroidism are the earliest complications in CKD, and observational data show that low plasma vitamin D is an independent predictor of death in patients with CKD. Oral supplementation with active oral vitamin D appears to be associated with greater survival but a significant improvement in renal outcome has not been demonstrated, probably because of its unwanted side effects (increase in plasma calcium and phosphate levels). Oral paracalcitol, a new vitamin D receptor activator, is now available for CKD patients not yet on dialysis. It suppresses PTH with a low incidence of increased serum calcium and phosphate levels in patients treated with dialysis and when high doses are administered. Furthermore, recent data show that paracalcitol treatment in CKD patients also results in a significant reduction of albuminuria, which is a major risk factor for cardiorenal outcome. The antiproteinuric effect of paracalcitol appears to be the result of intrarenal suppression of the renin-angiotensin system (RAS). Therefore, paracalcitol may be mostly effective in reducing albuminuria in patients already treated with RAS inhibitors who show compensatory increments of RAS components. Studies in large patients series and with adequate follow-up are needed to evaluate the effects of long-term paracalcitol treatment in CKD and its potential role in improving renal outcome in comparison not only with placebo but also other vitamin D metabolites and analogues.

[Iron deficiency in ND-CKD: from diagnosis to treatment]. / Deficit marziale nella Malattia Renale Cronica non dialitica: dalla diagnosi al trattamento.

In non-dialysis-chronic kidney disease (CKD), iron deficiency is a frequent nutritional disorder due to either the greater tendency to occult gastrointestinal bleeding or to the chronic inflammatory state resulting in a reduced intestinal iron reabsorption through an increased synthesis of hepcidin. These phenomenon are responsible for a negative iron balance that compromises erythropoiesis and contributes to the pathogenesis of anemia in CKD. Several laboratory tests are now available to allow an adequate diagnosis of iron deficiency. Among the new parameters, the percentage of hypochromic red cells (% HYPO) and the reticulocyte hemoglobin content (CHr) are now considered as the most specific markers for diagnosing iron-deficiency erythropoiesis. Unfortunately, their implementation in clinical practice is limited by the scarce availability. In non-dialyzed CKD , subjects intolerant or non-responsive to oral iron therapy, can be effectively treated with novel intravenous iron preparations, such as iron carboxymaltose, that allow a complete and rapid correction of iron deficient anemia. Furthermore, this iron compound is associated with lower rate of adverse effects since the carbohydrate shell (carboxymaltose) is more stable than gluconate and saccarate thus reducing the release of free iron in the bloodstream. Of note, the possibility of administering this drug at high doses and reduced frequency decreases the risk of infusion reactions. Finally, a substantial economic saving mainly dependent on a reduction in indirect costs represents a further advantage in the use of iron carboxymaltose in this population.

Nephroprotection with saxagliptin.

The nephroprotective effect of the new anti-diabetic drugs acting on incretin system is suggested by preclinical studies. However, no study evaluating kidney effects of these drugs as primary outcome on the long term has been conducted in patients followed in diabetes centers. We designed a pilot observational study involving two diabetes clinics to evaluate the effect of prolonged treatment with saxagliptin on renal function in type 2 diabetics. Patients were enrolled if treated for at least 12 months with saxagliptin without concurrent changes to anti-hypertensive and lipid-lowering therapy. Primary outcome was to evaluate the effect of saxagliptin on albuminuria and estimated glomerular filtration rate (eGFR). Secondary outcomes were the effects of treatment on common clinical and laboratory parameters. Sixty-three patients were enrolled. After 12 months of treatment with saxagliptin, albuminuria declined from a mean (95%CI) of 39 (25-52) to 22 (14-30) mg/l (P<0.001), and the prevalence of increased albuminuria (>20 mg/L) diminished by 27% versus baseline. The anti-albuminuric effect was independent of glycemic and blood pressure control. The eGFR remained unchanged after treatment in the presence of decreased glycated hemoglobin (from 7.1 to 6.7%). Therefore, this pilot study suggests that saxagliptin treatment in diabetic patients at high renal risk is associated with a reduction in albuminuria and GFR stability. Prospective trials are required to confirm the potential nephroprotective effects of saxagliptin.

Independent Role of Underlying Kidney Disease on Renal Prognosis of Patients with Chronic Kidney Disease under Nephrology Care.

Primary kidney disease is suggested to affect renal prognosis of CKD patients; however, whether nephrology care modifies this association is unknown. We studied patients with CKD stage I-IV treated in a renal clinic and with established diagnosis of CKD cause to evaluate whether the risk of renal event (composite of end-stage renal disease and eGFR decline ≥ 40%) linked to the specific diagnosis is modified by the achievement or maintenance in the first year of nephrology care of therapeutic goals for hypertension (BP ≤ 130/80 mmHg in patients with proteinuria ≥ 1 50 mg/24h and/or diabetes and ≤ 140/90 in those with proteinuria <150 mg/24h and without diabetes) anemia (hemoglobin, Hb ≥ 11 g/dL), and proteinuria (≤ 0.5 g/24h). Survival analysis started after first year of nephrology care. We studied 729 patients (age 64 ± 15 y; males 59.1%; diabetes 34.7%; cardiovascular disease (CVD) 44.9%; hypertensive nephropathy, HTN 53.8%; glomerulonephritis, GN 17.3%; diabetic nephropathy, DN 15.9%; tubule-interstitial nephropathy, TIN 9.5%; polycystic kidney disease, PKD 3.6%). During first year of Nephrology care, therapy was overall intensified in most patients and prevalence of main therapeutic goals generally improved. During subsequent follow up (median 3.3 years, IQR 1.9-5.1), 163 renal events occurred. Cox analysis disclosed a higher risk for PKD (Hazard Ratio 5.46, 95% Confidence Intervals 2.28-10.6) and DN (1.28,2.99-3.05), versus HTN (reference), independently of age, gender, CVD, BMI, eGFR or CKD stage, use of RAS inhibitors and achievement or maintenance in the first year of nephrology care of each of the three main therapeutic goals. No interaction was found on the risk of CKD progression between diagnostic categories and month-12 eGFR (P=0.737), as with control of BP (P=0.374), Hb (P=0.248) or proteinuria (P=0.590). Therefore, in CKD patients under nephrology care, diagnosis of kidney disease should be considered in conjunction with the main risk factors to refine renal risk stratification.

[Clinical experience with ferric carboxymaltose in non-dialysis chronic kidney disease]. / Ferro carbossimaltosio nella malattia renale cronica non dialitica: una iniziale esperienza clinica.

BACKGROUND: Patients with non-dialysis-dependent chronic kidney disease (ND-CKD) often show anemia and iron deficiency despite oral iron supplementation caused by poor iron absorption, intolerance and non-compliance. METHODS: We prospectively followed seven adult patients with ND-CKD (eGFR <60 ml/min/1.73m2), anemia (Hb<11 g/dl or treatment with ESA), iron deficiency (TSAT<20% and/or ferritin<100 ng/mL) and intolerant or non-responders to oral iron supplementation. Patients received ferric carboxymaltose (FCM) (single dose of 500 mg iv) eventually followed by further doses if iron deficiency persisted. Hemoglobin, ferritin, TSAT and ESA doses were recorded at baseline and after 2, 4, 8, 12, 16, 20 and 24 weeks. RESULTS: After 2 weeks of FCM, ferritin increased from 5348 to 222154 ng/mL (P<0.05) and remained steady thereafter. The increase of TSAT from baseline (115%) was more gradual being significant from week 4 (198%) up to week 24 (2412%). During the study, patients received on average 2.31.0 injections of FCM, to the amount of 1143440 mg. Hb levels remained stable throughout the study, despite a significant reduction of ESA dosage (from 3426 g/week at baseline to 1116 and 1710 g/week, after 4 and 24 weeks, respectively). On average, the ESA dose saving was 2024 g/week. Even considering the higher cost of FCM, ESA dose reduction allowed shortening overall costs by 673/patient during the 24 weeks of study. CONCLUSION: In ND-CKD patients, FCM is effective in correcting iron deficiency and associated with stable Hb levels and significant decrease of ESA dosage. This allows a marked reduction of costs for anemia correction.

[Prevention of diabetic nephropathy: from bench to bedside]. / Prevenzione della nefropatia diabetica: from bench to bedside.

The early phases of diabetic nephropathy are characterized by an increase of GFR that, according to the tubular hypothesis, is secondary to alterations of proximal tubules. Experimental studies have in fact shown that hyperglycemia induces an increase in proximal re-absorption due to hypertrophy of tubular cells with consequent increment of sodium-glucose co-transport. The increased re-absorption in turn causes a reduction of the distal delivery of solutes and, through activation of tubuloglomerular feedback, an increase in single- nephron GFR. The resulting hyper-filtration has been proposed as a main risk factor for progression of diabetic renal disease. Limiting this early alteration may therefore represent a useful strategy for the prevention of diabetic nephropathy, that represents the major cause of ESRD in the western world today. Dapagliflozin, a competitive and highly selective inhibitor of sodium-glucose co-transport, reduces proximal tubular glucose re-absorption, increases renal glucose excretion, and reduces hyperglycemia in a dose-dependent manner. This singular mechanism of action may also have a limiting effect on diabetic hyper-filtration. Clinical trials are therefore warranted to evaluate the reno-protective efficacy of this drug in the long term.

[Epidemiology and prognosis of chronic kidney disease in Italy]. / Epidemiologia e prognosi della malattia renale cronica in Italia.

Because chronic kidney disease (CKD) is a major public health issue, it is important to make the available epidemiological data widely known for a proper understanding of its social impact, and to identify risk factors that can influence the prognosis of the disease. The data from the CARHES study show in the general population of Italy a prevalence of CKD (stage 1-5) of 8%, less than in other countries, a higher prevalence of proteinuria at early stages (1-2), and a cardiovascular risk profile in CKD patients characterized by metabolic syndrome. The prognosis of CKD is an essential element in clinical practice as it allows to better define the severity of the disease and to determine the most appropriate therapeutic approach. The data from the TABLE study, performed in nephrology care, show that ESRD was more frequent than death before dialysis but not in stage 3; we note that advanced age reduces the progression of renal failure and that the most important among the modifiable risk factors is proteinuria, which has a negative predictive role in stage 3-4 but not stage 5 and which interacts specifically with advanced age. No predictive role was found for hypertension, but this is only apparently surprising; in fact, there is growing evidence of the superior effectiveness of ambulatory blood pressure measurement (ABPM) over office blood pressure measurement. These data, together with the results of some trials, show the need for the more extensive use of ABPM to identify subjects with white-coat hypertension and to better control the circadian blood pressure profile by administering antihypertensive drugs also in the evening.