Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials.

Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia. Methods: We selected phase 3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients. Efficacy outcomes were the changes from baseline of haemoglobin, iron parameters (hepcidin, serum iron, TIBC, TSAT, ferritin) and intravenous iron dose; as safety outcomes we considered cancer, adjudicated major adverse cardiovascular events (MACE), MACE+ (MACE plus hospitalization for hearth failure or unstable angina or thromboembolic event), thrombotic events (deep vein thrombosis, pulmonary embolism), arterovenous fistula (AVF) thrombosis and death. Results: We included 26 RCTs with 24 387 patients. Random effect meta-analysis of the unstandardized mean difference between HIF-PHIs and ESAs showed a significant change in haemoglobin levels from baseline of 0.10 g/dL (95% CI 0.02 to 0.17). Meta-regression analysis showed a significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21 g/dL, 95% CI 0.12 to 0.29 versus -0.01, 95% CI -0.09 to 0.07 in studies using long-acting ESA, P < .001). No significant effect on heterogeneity was found for type of HIF-PHIs. In comparison with ESAs, HIF-PHIs induced a significant decline in hepcidin and ferritin and a significant increase in serum iron and TIBC, while TSAT did not change; intravenous iron dose was lower with HIF-PHI (-3.1 mg/week, 95% CI -5.6 to -0.6, P = .020). Rate ratio of cancer (0.93, 95% CI 0.76 to 1.13), MACE (1.00, 95% CI 0.94 to 1.07), MACE+ (1.01, 95% CI 0.95 to 1.06), thrombotic events (1.08, 95% CI 0.84 to 1.38), AVF thrombosis (1.02, 95% CI 0.93 to 1.13) and death (1.02, 95% CI 0.95 to 1.13) did not differ between HIF-PHIs and ESAs. Conclusions: HIF-PHIs at the doses selected for the comparisons are effective in correcting anaemia in comparison with ESA therapy with a significant impact on iron metabolism without notable difference among various agents. No safety signals emerge with use of HIF-PHIs.

Secular Trend in GFR Decline in Non-Dialysis CKD Based on Observational Data From Standard of Care Arms of Trials.

RATIONALE & OBJECTIVE: The standard of care (SoC) group of randomized controlled trials (RCTs) is a useful setting to explore the secular trends in kidney disease progression because implementation of best clinical practices is pursued for all patients enrolled in trials. This meta-analysis evaluated the secular trend in the change of glomerular filtration rate (GFR) decline in the SoC arm of RCTs in chronic kidney disease (CKD) published in the last 30 years. STUDY DESIGN: Systematic review and meta-analysis of the SoC arms of RCTs analyzed as an observational study. SETTING & STUDY POPULATIONS: Adult patients with CKD enrolled in the SoC arm of RCTs. SELECTION CRITERIA FOR STUDIES: Phase 3 RCTs evaluating GFR decline as an outcome in SoC arms. DATA EXTRACTION: Two independent reviewers evaluated RCTs for eligibility and extracted relevant data. ANALYTICAL APPROACH: The mean of GFR declines extracted in the SoC arm of selected RCTs were pooled by using a random effects model. Meta-regression analyses were performed to identify factors that may explain heterogeneity. RESULTS: The SoC arms from 92 RCTs were included in the meta-analysis with a total of 32,202 patients. The overall mean GFR decline was-4.00 (95% CI, -4.55 to-3.44) mL/min/1.73m2 per year in the SoC arms with a high level of heterogeneity (I2, 98.4% [95% CI, 98.2-98.5], P<0.001). Meta-regression analysis showed an association between publication year (ß estimate, 0.09 [95% CI, 0.032-0.148], P=0.003) and reduction in GFR over time. When evaluating publication decade categorically, GFR decline was-5.44 (95% CI, -7.15 to-3.73), -3.92 (95% CI, -4.82 to-3.02), and -3.20 (95% CI, -3.75 to -2.64) mL/min/1.73m2 per year during 1991-2000, 2001-2010, and 2011-2023, respectively. Using meta-regression, the heterogeneity of GFR decline was mainly explained by age and proteinuria. LIMITATIONS: Different methods assessing GFR in selected trials and observational design of the study. CONCLUSIONS: In the last 3 decades, GFR decline has decreased over time in patients enrolled in RCTs who received the standard of care. TRIAL REGISTRATION: Registered at PROSPERO with record number CRD42022357704. PLAIN-LANGUAGE SUMMARY: This study evaluated the secular trend in the change in glomerular filtration rate (GFR) decline in the placebo arms of randomized controlled trials (RCTs) that were studying approaches to protect the kidneys in the setting of chronic kidney disease. The placebo groups of RCTs are useful for examining whether the rate of progression of kidney disease has changed over time. We found an improvement in the slope of change in GFR over time. These findings suggest that adherence to standards of kidney care as implemented in clinical trials may be associated with improved clinical outcomes, and these data may inform the design of future RCTs in nephrology.

Sustained Recovery of Kidney Function in Patients with ESKD under Chronic Dialysis Treatment: Systematic Review and Meta-Analysis.

The prevalence of recovery of kidney function (RKF) in patients under maintenance dialysis is poorly defined mainly because of different definitions of RKF. Therefore, to gain more insights into the epidemiology of RKF, we performed a systematic review and meta-analysis of studies addressing the prevalence of sustained (at least for 30 days) RKF in patients under maintenance dialysis. Acute kidney injury (AKI) and RKF in the first 90 days of dialysis were the main exclusion criteria. Overall, 7 studies (10 cohorts) including 2,444,943 chronic dialysis patients (range: 430-1,900,595 patients) were meta-analyzed. The period of observation ranged from 4 to 43 years. The prevalence of RKF was 1.49% (95% C.I.:1.05-2.11; p < 0.001] with high heterogeneity I2: 99.8%, p < 0.001. The weighted mean dialysis vintage before RKF was 294 ± 165 days; RKF persisted for a weighted mean of 27.5 months. The percentage of RKF was higher in studies from the U.S. (1.96% [95% C.I.: 1.24-3.07]) as compared to other countries (1.04% [95%C.I.: 0.66-1.62]; p = 0.049). In conclusion, sustained RKF unrelated to AKI occurs in about 1.5% of patients under maintenance dialysis. On average, RKF patients discontinue chronic dialysis about ten months after starting treatment and live free of dialysis for more than two years. The higher prevalence of RKF reported in the U.S. versus other countries suggests a major role of country-specific policies for dialysis start.

Sex difference in cardiovascular risk in patients with chronic kidney disease: pooled analysis of four cohort studies.

BACKGROUND: Progression of chronic kidney disease (CKD) has proven to be faster in men than in women. Whether the same holds true for cardiovascular risk remains ill-defined. METHODS: We conducted a pooled analysis of 4 cohort studies from 40 nephrology clinics in Italy including patients with CKD (estimated GFR<60 ml/min/1.73m2 or higher if proteinuria > 0.15 g/day). The aim was to compare multivariable-adjusted risk (Hazard Ratio, 95% Confidence Interval) of a composite cardiovascular endpoint (cardiovascular death and non-fatal myocardial infarction, congestive heart failure, stroke, revascularization, peripheral vascular disease, and non-traumatic amputation) in women (n = 1 192) versus men (n = 1 635). RESULTS: At baseline, women had slightly higher systolic blood pressure (SBP) as compared with men (139±19 vs 138±18 mmHg, P = 0.049), lower eGFR (33.4 vs 35.7 mL/min/1.73 m2, P = 0.001) and lower urine protein excretion (0.30 g/day vs 0.45 g/day in men, P < 0.001). Women did not differ from men in age and prevalence of diabetes while having a lower prevalence of cardiovascular disease, left ventricular hypertrophy and smoking habit. During a median follow-up of 4.0 years, 517 fatal and non-fatal cardiovascular events were registered (199 in women and 318 in men). The adjusted risk of cardiovascular events was lower in women (0.73, 0.60-0.89, P = 0.002) than in men; however, the cardiovascular risk advantage of women progressively diminished as SBP (as continuous variable) increased (P for interaction = 0.021). Similar results were obtained when considering SBP categories; when compared to men, women had lower cardiovascular risk for SBP <130 mmHg (0.50, 0.31-0.80; P = 0.004) and between 130-140 mmHg (0.72, 0.53-0.99; P = 0.038), while no difference was observed for SBP>140 mmHg (0.85, 0.64-1.11; P = 0.232). CONCLUSIONS: Higher BP levels abolish the cardiovascular protection seen in female vs male patients with overt CKD. This finding supports the need for higher awareness of hypertensive burden in women with CKD.

Dipping Status, Ambulatory Blood Pressure Control, Cardiovascular Disease, and Kidney Disease Progression: A Multicenter Cohort Study of CKD.

RATIONALE & OBJECTIVE: Ambulatory blood pressure (BP) monitoring allows concurrent evaluation of BP control and nocturnal BP dipping status, both related to adverse outcomes. However, few studies have assessed the prognostic role of combining information on dipping status and achieved ambulatory BP in patients with chronic kidney disease (CKD). STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 906 patients with hypertension and CKD attending 1 of 3 Italian nephrology clinics. EXPOSURE: Four groups were defined by simultaneously classifying systolic ambulatory BP levels as being at goal (daytime SBP <135 and nighttime SBP <120 mm Hg) or above goal, and the presence or absence of nocturnal dipping (nighttime to daytime SBP ratio of <0.9 versus ≥0.9). OUTCOME: The composite of time to initiation of maintenance dialysis or estimated glomerular filtration rate (eGFR) decline ≥50%, and the composite of fatal and nonfatal cardiovascular events. ANALYTICAL APPROACH: Multivariable Cox proportional hazards models were used to estimate risks of kidney disease progression and cardiovascular disease in the 4 exposure groups where nocturnal dipping with systolic ambulatory BP at goal was the reference group. RESULTS: The mean patient age was 63.8 years, 61% were male, and 26.4% had diabetes; eGFR was 41.1 ± 20.8 mL/min/1.73 m2. The dipping prevalence in each of the 4 groups was as follows: nocturnal dipping with ambulatory BP at goal, 18.6%; no nocturnal dipping with ambulatory BP at goal, 20.5%; nocturnal dipping with ambulatory BP above goal, 11.8%; and no nocturnal dipping with ambulatory BP above goal, 49.1%. Among patients with ambulatory BP above goal, the risk of cardiovascular events was greater in the absence (HR, 2.79 [95% CI, 1.64-4.75]) and presence (HR, 2.05 [95% CI, 1.10-3.84]) of nocturnal dipping. The same held true for risk of kidney disease progression (HRs of 2.40 [95% CI, 1.58-3.65] and 2.11 [95% CI, 1.28-3.48] in the absence and presence of nocturnal dipping, respectively). Patients at the ambulatory BP goal but who did not experience nocturnal dipping had an increased risk of the cardiovascular end point (HR, 2.06 [95% CI, 1.15-3.68]) and the kidney disease progression outcome (HR, 1.82 [95% CI, 1.17-2.82]). LIMITATIONS: Lack of a diverse cohort (all those enrolled were White). Residual uncontrolled confounding. CONCLUSIONS: Systolic ambulatory BP above goal or the absence of nocturnal dipping, regardless of ambulatory BP, is associated with higher risks of cardiovascular disease and kidney disease progression among patients with CKD. PLAIN-LANGUAGE SUMMARY: Among patients with chronic kidney disease (CKD), ambulatory blood pressure (BP) monitoring improves the identification of individuals at high risk of clinical disease outcomes. Those with uncontrolled ambulatory BP are known to have a higher risk of developing cardiovascular disease and kidney disease progression, particularly when their ambulatory BP does not decline by at least 10% at night. Whether this is also true for patients with presence of optimal ambulatory BP levels but a BP pattern of no nighttime decline is largely unknown. We measured ambulatory BP in 900 Italian patients with CKD and followed them for several years. We found that, independent of ambulatory BP level, the absence of nighttime reductions in BP was associated with worsening of CKD and more frequent cardiovascular events. The absence of nighttime declines in BP is an independent risk factor for adverse events among patients with CKD. Future studies are needed to examine whether treating the absence of nighttime declines in BP improves clinical outcomes.

New-onset anemia and associated risk of ESKD and death in non-dialysis CKD patients: a multicohort observational study.

Background: Anemia is a common complication of chronic kidney disease (CKD), but its incidence in nephrology settings is poorly investigated. Similarly, the risks of adverse outcomes associated with new-onset anemia are not known. Methods: We performed a pooled analysis of three observational cohort studies including 1031 non-anemic CKD patients with eGFR <60 mL/min/1.73 m2 regularly followed in renal clinics. We estimated the incidence of mild anemia (hemoglobin 11-12 g/dL in women and 11-13 g/dL in men) and severe anemia (hemoglobin <11 g/dL or use of erythropoiesis-stimulating agents) during a 3-year follow-up period. Thereafter we estimated the risk of end-stage kidney disease (ESKD) and all-cause death associated with new-onset mild and severe anemia. Results: The mean age was 63 ± 14 years, 60% were men and 20% had diabetes. The mean estimated glomerular filtration rate (eGFR) was 37 ± 13 mL/min/1.73 m2 and the median proteinuria was 0.4 g/day [interquartile range (IQR) 0.1-1.1]. The incidence of mild and severe anemia was 13.7/100 patients-year and 6.2/100 patients-year, respectively. Basal predictors of either mild or severe anemia were diabetes, lower hemoglobin, higher serum phosphate, eGFR <30 mL/min/1.73 m2 and proteinuria >0.50 g/day. Male sex, moderate CKD (eGFR 30-44 mL/min/1.73 m2) and moderate proteinuria (0.15-0.50 g/day) predicted only mild anemia. The incidence of anemia increased progressively with CKD stages (from 8.77 to 76.59/100 patients-year) and the proteinuria category (from 13.99 to 25.02/100 patients-year). During a median follow-up of 3.1 years, 232 patients reached ESKD and 135 died. Compared with non-anemic patients, mild anemia was associated with a higher adjusted risk of ESKD {hazard ratio [HR] 1.42 [95% confidence interval (CI) 1.02-1.98]} and all-cause death [HR 1.55 (95% CI 1.04-2.32)]. Severe anemia was associated with an even higher risk of ESKD [HR 1.73 (95% CI 1.20-2.51)] and death [HR 1.83 (95% CI 1.05-3.19)]. Conclusions: New-onset anemia is frequent, particularly in patients with more severe renal damage and in those with diabetes mellitus. The occurrence of anemia, even of a mild degree, is associated with mortality risk and faster progression towards ESKD.

Ferric Carboxymatose in Non-Hemodialysis CKD Patients: A Longitudinal Cohort Study.

No information is available on the efficacy of ferric carboxymaltose (FCM) in real-world CKD patients outside the hemodialysis setting. We prospectively followed 59 non-hemodialysis CKD patients with iron deficient anemia (IDA: hemoglobin <12.0/<13.5 g/dL in women/men and TSAT < 20% and/or ferritin < 100 ng/mL) who were intolerant or non-responders to oral iron. Patients received ferric carboxymaltose (FCM) (single dose of 500 mg) followed by additional doses if iron deficiency persisted. We evaluated efficacy of FCM in terms of increase of hemoglobin, ferritin, and TSAT levels. Direct and indirect costs of FCM were also analyzed in comparison with a hypothetical scenario where same amount of iron as ferric gluconate (FG) was administered intravenously. During the 24 weeks of study, 847 ± 428 mg of FCM per patient were administered. IDA improved after four weeks of FCM and remained stable thereafter. At week-24, mean change (95%CI) from baseline of hemoglobin, ferritin and TSAT were +1.16 g/dL (0.55-1.77), +104 ng/mL (40-168) and +9.5% (5.8-13.2), respectively. These changes were independent from ESA use and clinical setting (non-dialysis CKD, peritoneal dialysis and kidney transplant). Among ESA-treated patients (n = 24), ESA doses significantly decreased by 26% with treatment and stopped either temporarily or persistently in nine patients. FCM, compared to a FG-based scenario, was associated with a cost saving of 288 euros/patient/24 weeks. Saving was the same in ESA users/non-users. Therefore, in non-hemodialysis CKD patients, FCM effectively corrects IDA and allows remarkable cost savings in terms of societal, healthcare and patient perspective.

Sodium Intake and Chronic Kidney Disease.

In Chronic Kidney Disease (CKD) patients, elevated blood pressure (BP) is a frequent finding and is traditionally considered a direct consequence of their sodium sensitivity. Indeed, sodium and fluid retention, causing hypervolemia, leads to the development of hypertension in CKD. On the other hand, in non-dialysis CKD patients, salt restriction reduces BP levels and enhances anti-proteinuric effect of renin-angiotensin-aldosterone system inhibitors in non-dialysis CKD patients. However, studies on the long-term effect of low salt diet (LSD) on cardio-renal prognosis showed controversial findings. The negative results might be the consequence of measurement bias (spot urine and/or single measurement), reverse epidemiology, as well as poor adherence to diet. In end-stage kidney disease (ESKD), dialysis remains the only effective means to remove dietary sodium intake. The mismatch between intake and removal of sodium leads to fluid overload, hypertension and left ventricular hypertrophy, therefore worsening the prognosis of ESKD patients. This imposes the implementation of a LSD in these patients, irrespective of the lack of trials proving the efficacy of this measure in these patients. LSD is, therefore, a rational and basic tool to correct fluid overload and hypertension in all CKD stages. The implementation of LSD should be personalized, similarly to diuretic treatment, keeping into account the volume status and true burden of hypertension evaluated by ambulatory BP monitoring.

SGLT2 Inhibitors: Nephroprotective Efficacy and Side Effects.

The burden of diabetic kidney disease (DKD) has increased worldwide in the last two decades. Besides the growth of diabetic population, the main contributors to this phenomenon are the absence of novel nephroprotective drugs and the limited efficacy of those currently available, that is, the inhibitors of renin-angiotensin system. Nephroprotection in DKD therefore remains a major unmet need. Three recent trials testing effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) have produced great expectations on this therapy by consistently evidencing positive effects on hyperglycemia control, and more importantly, on the cardiovascular outcome of type 2 diabetes mellitus. Notably, these trials also disclosed nephroprotective effects when renal outcomes (glomerular filtration rate and albuminuria) were analyzed as secondary endpoints. On the other hand, the use of SGLT2-i can be potentially associated with some adverse effects. However, the balance between positive and negative effects is in favor of the former. The recent results of Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation Study and of other trials specifically testing these drugs in the population with chronic kidney disease, either diabetic or non-diabetic, do contribute to further improving our knowledge of these antihyperglycemic drugs. Here, we review the current state of the art of SGLT2-i by addressing all aspects of therapy, from the pathophysiological basis to clinical effectiveness.

High-flow arteriovenous fistula and heart failure: could the indexation of blood flow rate and echocardiography have a role in the identification of patients at higher risk?

BACKGROUND: Although only high-flow arteriovenous fistulas (AVFs) are postulated to cause high-output cardiac failure (HOCF), there are currently no universally accepted criteria defining a high-flow fistula. METHODS: To verify if vascular access blood flow (Qa) ≥ 2000 ml/min provides an accurate definition of high-flow fistula, we selected 29 consecutive patients with Qa ≥ 2000 ml/min at color-duplex ultrasound examination and assessed them for the presence of cardiac failure symptoms; transthoracic echocardiography was also performed. RESULTS: Nineteen patients (65%) had heart failure symptoms and were classified with HOCF. At receiver operating characteristic (ROC) curve analysis, Qa ml/min values did not identify patients with heart failure symptoms but when AVF blood flow was indexed for height2.7, Qa ≥ 603 ml/min/m2.7 detected the occurrence of HOCF with good accuracy (sensitivity 100%, specificity 60%, efficiency 86%, positive predictive value 83%, negative predictive value 100%, area under curve 0.75). At echocardiographic evaluation, patients with Qa ≥ 603 ml/min/m2.7 had a more severe increase of left ventricular mass (63 ± 18 vs. 47 ± 7 g/m2.7, p < 0.003), left ventricular diastolic volume (140 ± 42 vs. 109 ± 14 ml, p < 0.007), left atrial volume (53 ± 23 vs. 39 ± 5 ml/m2, p < 0.015), a higher incidence of diastolic dysfunction (70 vs. 17%, p < 0.019) and higher CO reduction after AVF manual compression (2151 ± 875 vs. 1292 ± 527 ml/min, p < 0.009) than patients with Qa < 603 ml/min/m2.7. CONCLUSIONS: Indexation of AVF blood flow should be considered in defining high-flow fistula because the effect of Qa may differ in individuals of different sizes. A Qa value ≥ 603 ml/min/m2.7 and its association with some echocardiographic alterations could identify patients at higher risk for HOCF.

Effect of post-nephrectomy acute kidney injury on renal outcome: a retrospective long-term study.

PURPOSE: The effects on renal prognosis of acute kidney injury after elective unilateral nephrectomy are ill-defined. We evaluated as whether post-operative acute kidney injury modifies renal outcome over the long term. METHODS: This is a retrospective study examining all consecutive adult patients referred to three Nephrology Units and that had previously undergone elective unilateral nephrectomy. We evaluated the association of post-nephrectomy acute kidney injury with the combined renal outcome of chronic dialysis requirement, ≥ 40% decline in glomerular filtration rate or new-onset severe proteinuria (> 500 mg/24 h). Clinical correlates of acute kidney injury and renal outcome were also examined. RESULTS: 106 patients were enrolled. 52 patients had post-operative acute kidney injury with a median increment of serum creatinine of 0.67 [0.48-0.86] mg/dl; in these patients, serum creatinine and urea increased from the first day post-nephrectomy while contraction of urinary output was found in 7 patients. Older age [OR: 1.72; 95% CI 1.05-2.82; P = 0.030] associated with post-operative acute kidney injury. Over a median follow-up of 8.9 [95% CI 3.1-24.2] years, the combined renal outcome occurred, respectively, in 28 (53.8%) and 14 (25.9%) patients with and without acute kidney injury (P = 0.003). Logistic regression analysis showed that acute kidney injury (OR: 3.22; 95% CI 1.35-7.66; P = 0.008) and male gender (OR: 2.72; 95% CI 1.08-6.85; P = 0.034) were associated with poor renal outcome after adjustment for main comorbidities. CONCLUSIONS: In our population of referred patients, acute kidney injury after unilateral nephrectomy was common and associated with progressive chronic kidney disease, especially in older males.

[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.

Stage 5-CKD under nephrology care: to dialyze or not to dialyze, that is the question.

Appropriate timing of starting chronic dialysis in patients with advanced chronic kidney disease (CKD) under nephrology care still is undefined. We systematically reviewed the most recent studies that have compared outcomes of stage 5-CKD under conservative versus substitutive treatment. Eleven studies, most in elderly patients, were identified. Results indicate no advantage of dialysis over conservative management in terms of survival, hospitalization or quality of life. This information is integrated with a case report on a middle-aged CKD patient followed in our clinic who has remained for 15 years in stage 5 despite severe disease. The patient is a diabetic woman who underwent right nephrectomy in 1994 because of renal tuberculosis. In 1999, she commenced regular nephrology care in our clinic and, since 2000, when she was 53 years old, her estimated glomerular filtration rate (eGFR) has been ≤15 ml/min/1.73 m(2). Over the last decade, despite, several episodes of acute kidney injury and placement of permanent percutaneous nephrostomy in 2001, renal function has remained remarkably stable, though severely impaired (eGFR 7.7-5.6 ml/min/1.73 m(2)). Our systematic analysis of the literature and this case report highlight the need for further studies, not limited exclusively to elderly patients, to verify the efficacy of non-dialysis treatment in stage 5-CKD patients. Meanwhile, nephrologists may consider that their intervention can safely prolong for several years the dialysis-free condition in ESRD independently of age.

[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.

Reassessment of Ambulatory Blood Pressure Improves Renal Risk Stratification in Nondialysis Chronic Kidney Disease: Long-Term Cohort Study.

In nondialysis chronic kidney disease, ambulatory blood pressure (ABP) performs better than clinic BP in predicting outcome, but whether repeated assessment of ABP further refines prognosis remains ill-defined. We recruited 182 consecutive hypertensive patients with nondialysis chronic kidney disease who underwent 2 ABPs 12 months apart to evaluate the enhancement in risk stratification provided by a second ABP obtained 1 year after baseline on the risk (hazard ratio and 95% confidence interval) of composite renal end point (death, chronic dialysis, and estimated glomerular filtration rate decline ≥40%). The difference in daytime and nighttime systolic BP between the 2 ABPs (daytime and nighttime bias) was added to a survival model including baseline ABP. Net reclassification improvement was also calculated. Age was 65.6±13.4 years; 36% had diabetes mellitus and 36% had previous cardiovascular event; estimated glomerular filtration rate was 42.2±19.6 mL/min per 1.73 m(2), and clinic BP was 145±18/80±11 mm Hg. Baseline ABP (daytime, 131±16/75±10 and nighttime, 122±18/66±10 mm Hg) and daytime/nighttime BP goals (58.2% and 43.4%) did not change at month 12. Besides baseline ABP values, bias for daytime and nighttime systolic BP linearly associated with renal outcome (1.12, 1.04-1.21 and 1.18, 1.08-1.29 for every 5-mm Hg increase, respectively). Classification of patients at risk improved when considering nighttime systolic level at second ABP (net reclassification improvement, 0.224; 95% confidence interval, 0.005-0.435). Patients with first and second ABPs above target showed greater renal risk (2.15, 1.29-3.59 and 1.71, 1.07-2.72, for daytime and nighttime, respectively). In nondialysis chronic kidney disease, reassessment of ABP at 1 year further refines renal prognosis; such reassessment should specifically be considered in patients with uncontrolled BP at baseline.

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.

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.

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.