Consensus commentary and position of the Italian Society of Nephrology on KDIGO controversies conference on novel anemia therapies in chronic kidney disease.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new drugs developed for the treatment of anemia associated with chronic kidney disease (CKD). This class of drugs stimulates endogenous erythropoietin production and, at the same time, improves iron absorption and mobilization of iron stores (less evident with daprodustat, vadadustat and enarodustat). Several studies have been published in the last few years showing that these agents are not inferior to standard therapy in correcting anemia associated with CKD. The efficacy of HIF-PHIs is coupled with a safety profile comparable to that of standard erythropoiesis stimulating agent (ESA) treatment. However, studies with HIF-PHIs were not long enough to definitively exclude the impact of new drugs on adverse events, such as cancer, death and possibly cardiovascular events, that usually occur after a long follow-up period. Kidney Disease: Improving Global Outcomes (KDIGO) recently reported the conclusions of the Controversies Conference on HIF-PHIs held in 2021. The goal of the present position paper endorsed by the Italian Society of Nephrology is to better adapt the conclusions of the latest KDIGO Conference on HIF-PHIs to the Italian context by reviewing the efficacy and safety of HIF-PHIs as well as their use in subpopulations of interest as emerged from more recent publications not discussed during the KDIGO Conference.

[The therapeutic management and economic burden of patients with chronic kidney disease non-dialysis-dependent with anemia and ESA treated: findings from a real-world study in Italy].

Background. This real-world study aimed to provide insights on the characteristics, drug utilization, and economic burden of chronic kidney disease non-dialysis-dependent (NDD-CKD) patients with anemia prescribed Erythropoiesis Stimulating Agents (ESA) in Italian clinical practice settings. Methods. A retrospective analysis was performed based on administrative and laboratory databases covering around 1.5 million subjects across Italy. Adult patients with a record for NDD-CKD stage 3a-5 and anemia during 2014-2016 were identified. Eligibility to ESA was defined as the presence of ≥ 2 records of Hb < 11 g/dL over 6 months, and patients eligible and currently treated with ESA were included. Results. Overall, 101,143 NDD-CKD patients were screened for inclusion, of which 40,020 were anemic. A total of 25,360 anemic patients were eligible to ESA treatment and 3,238 (12.8%) were prescribed ESA and included. The mean age was 76.9 years and 51.1% was male. More frequently observed comorbidities were hypertension (over 90% in each stage), followed by diabetes (37.8-43.2%) and cardiovascular condition (20.5-28.9%). Adherence to ESA was observed in 47.9% of patients, with a downward trend while progressing across stages (from 65.8% stage 3a to 35% stage 5). A consistent proportion of patients did not have nephrology visits during the 2 years of follow-up. Costs were mainly due to all drugs (€4,391) followed by all-cause hospitalization (€3,591) and laboratory tests (€1,460). Conclusions. Findings from the study highlight an under-use of ESA in the management of anemia in NDD-CKD as well as a sub-optimal adherence to ESA and showed a great economic burden for anemic NDD-CKD patients.

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism.

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis.

Prevalence and clinical correlates of hyperkalemia in stable kidney transplant recipients.

Although hyperkalemia (HK) is often associated with adverse clinical outcomes in renal patients, few studies are available in the setting of kidney transplantation. Therefore, we evaluated prevalence and clinical correlates of HK in stable kidney transplant recipients (KTRs) on standard of care immunosuppressive therapy. We studied 160 stable KTRs (post-transplant vintage 46.6 ± 16.6 months), most of whom (96.2%) on calcineurin inhibitor (CNI)-based immunosuppressive therapy. HK was defined as plasma potassium levels above 5 mEq/L, confirmed in two consecutive samples. Office blood pressure was measured, and renal graft function was expressed by estimated glomerular filtration rate (eGFR), calculated according to the CKD-EPI formula. HK prevalence was 8.8%, and plasma K above 5.5 mEq/L was found in 2.5% of all KTRs. In the univariate logistic regression analysis HK was significantly associated with serum urea concentration (OR 1.03, 95% CI 1.01-1.05 for each 1 mg/dL increase), tCO2 (OR 0.77, 95% CI 0.66-0.90 for each 1 mmol/L increase), the presence of arterial hypertension (OR 4.01, 95% CI 1.3-12.64), the use of RAAS inhibitors (OR 5.26, 95% CI 1.6-17.7), and eGFR less than 30 ml/min/1.73 m2 (OR 7.51, 95% CI 2.37-23.77). By multivariable backward stepwise regression analysis, the presence of metabolic acidosis (OR 0.83, 95% CI 0.69-0.99, P = 0.04), arterial hypertension (OR 4.65 95% CI 1.01-17.46 P = 0.03), and to be administered RAAS inhibitors (OR 6.11, 95% CI 1.03-25.96 P = 0.03) remained significantly associated with HK. We conclude that in stable KTRs the prevalence of HK is about 9%, slightly lower than previously reported. Moreover, it is not associated with eGFR, but with metabolic acidosis, arterial hypertension, and the use of RAAS inhibitors.

Everolimus for BKV nephropathy in kidney transplant recipients: a prospective, controlled study.

There is no specific therapy for polyoma BK virus nephropathy (BKVN) in kidney transplant recipients, a condition associated with poor outcomes. Everolimus showed promising antiviral effects, but data from prospective studies are limited. Therefore, we converted ten consecutive kidney transplant recipients with biopsy-proven BKVN from standard exposure Calcineurin inhibitors and Mycophenolate to Everolimus and reduced exposure Calcineurin inhibitors. Ten patients not administered Everolimus, on reduced exposure Calcineurin inhibitor and halved MPA doses served as controls. All kidney transplant recipients continued steroid therapy. Each patient underwent kidney graft biopsy, BKV replication by PCR, and de novo DSA determination. During a 3-year follow-up no graft loss occurred in kidney transplant recipients on Everolimus but it was observed in 5/10 controls (P = 0.032). eGFR improved on Everolimus and worsened in controls (between group difference + 25.6 ml/min/1.73 m2, 95% CI 10.5-40.7, P = 0.002). BKV replication declined in the Everolimus group alone (from 6.4 ± 0.8 to 3.6 ± 1.6 Log 10 genomic copies, P = 0.0001), and we found a significant inverse relationship between eGFR and BKV genomic copy changes (P = 0.022). Average Calcineurin inhibitors trough levels did not differ between the two study groups during follow-up. By multivariable Cox regression analysis, Everolimus treatment resulted the only significant predictor of survival free of a combined endpoint of graft loss and 57% eGFR reduction (P = 0.02). Kidney transplant recipients on Everolimus had a higher survival free of adverse graft outcome (log-rank test, P = 0.009). In conclusion an Everolimus-based immunosuppressive protocol with minimization of Calcineurin inhibitors and antimetabolite discontinuation effectively treated BKVN in kidney transplant recipients.

Vitamin K and Kidney Transplantation.

The assessment of the vitamin K status and its effects on clinical outcomes in kidney transplantation (KT) patients has sparked interest, but it is still largely unfulfilled. In part, this is due to difficulties in laboratory measurements of vitamin K, especially K2 vitamers. Vitamin K status is currently best assessed by measuring undercarboxylated vitamin-K-dependent proteins. The relative contribution of vitamin K1 and K2 to the health status of the general population and CKD (chronic kidney disease) patients, including KT patients, is also poorly studied. Through a complete and first review of the existing literature, we summarize the current knowledge of vitamin K pathophysiology and its potential role in preventing KT complications and improving organ survival. A specific focus is placed on cardiovascular complications, bone fractures, and the relationship between vitamin K and cancer. Vitamin K deficiency could determine adverse outcomes, and KT patients should be better studied for vitamin K assessment and modalities of effective therapeutic approaches.

Early interstitial macrophage infiltration with mild dysfunction is associated with subsequent kidney graft loss.

Macrophage infiltration is associated with unfavorable kidney graft outcome in protocol biopsies, but few studies have evaluated its impact on clinical practice. We therefore prospectively evaluated 37 kidney transplant recipients (KTRs) who underwent kidney biopsy due to slight increases in serum creatinine, or mild proteinuria (>0.3 g/24 hr), in the first post-transplant year. Banff score, CD68+ count (score 0-3) by immunohistochemistry, and 1-year DSA were assessed. DGF was reported in 10 (27%) patients, 6 (16%) had normal biopsy, 7 (19%) borderline lesions, 13 (35%) IFTA, and 11 (30%) other lesions. Fifteen KTRs had grade 3 CD68+ infiltration, and 47% developed de novo DSA. During a 6.2 ± 2.7 year follow-up, four patients (11%) suffered from biopsy-proven T-cell rejection, 17 KTRs (46%) lost their graft (12 in the grade 3 CD68+ group). Graft survival was lower in KTRs with grade 3 CD68+ infiltration (P = 0.0074; log-rank test). Grade 3 CD68+ infiltrate was an independent predictor of graft loss (HR 5.41, 95% CI 1.74-16.8; P = 0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57-16; P < 0.001). We conclude that grade 3 CD68+ interstitial infiltration is associated with increased risk of subsequent graft loss independent of other factors.

Cardiac valve calcification and use of anticoagulants: Preliminary observation of a potentially modifiable risk factor.

AIMS: Direct oral anticoagulant (DOAC) has been recently introduced in the clinical practice. Rather than interfering with vitamin K-dependent posttranscriptional modification of various proteins, DOACs selectively inhibit factors involved in the coagulation cascade. In particular, in contrast with Warfarin, Rivaroxabn does not interfere with activation of matrix Gla Protein (MGP), a potent vascular calcification Inhibitor. We herein sought to investigate the impact of Rivaroxaban and Warfarin on cardiac valve calcifications in a cohort of moderate-to advanced CKD patients. METHODS AND RESULTS: This is a multicenter, observational, retrospective, longitudinal study. Consecutive CKD stage 3b - 4 (according to KDIGO guidelines) patients from 8 cardiologic outpatient clinics were enrolled between May 2015 and October 2017. All patients received anticoagulation (100 Warfarin vs 247 Rivaroxaban) as part of their non-valvular atrial fibrillation management. Cardiac valve calcification was evaluated via standard trans-thoracic echocardiogram. 347 patients (mean age: 66 years; mean eGFR: 37 ml/min/1.73 m2) were studied. Over a mean follow-up period of 16 months, Rivaroxaban compared to Warfarin reduced both mitral and aortic valve calcifications (p < 0.001) independently of the degree of calcifications at baseline and potential confounders. Notably, Rivaroxaban use was also associated with a significant reduction in C reactive protein (CRP) (p < 0.001) during follow-up. CONCLUSION: This study generates the hypothesis that the use of Rivaroxaban associates with a reduction of cardiac valve calcification deposition and progression as compared to Warfarin, in a cohort of CKD stage 3b-4 patients. Future endeavors are needed to confirm and to establish the mechanisms responsible for these findings.

Controversial issues in CKD clinical practice: position statement of the CKD-treatment working group of the Italian Society of Nephrology.

This position paper of the study group "Conservative treatment of Chronic Kidney Disease-CKD" of the Italian Society of Nephrology addresses major practical, unresolved, issues related to the conservative treatment of chronic renal disease. Specifically, controversial topics from everyday clinical nephrology practice which cannot find a clear, definitive answer in the current literature or in nephrology guidelines are discussed. The paper reports the point of view of the study group. Concise and practical advice is given on several common issues: renal biopsy in diabetes; dual blockade of the renin-angiotensin-aldosterone system (RAAS); management of iron deficiency; low protein diet; dietary salt intake; bicarbonate supplementation; treatment of obesity; the choice of conservative therapy vs. dialysis. For each topic synthetic statements, guideline-style, are reported.

Optimizing global risk evaluation in primary hypertension: the role of microalbuminuria and cardiovascular ultrasonography.

OBJECTIVE: To assess the impact and cost-effectiveness of microalbuminuria and cardiovascular ultrasonography in evaluating the risk profile in primary hypertension. METHODS: Four hundred and five untreated patients with primary hypertension underwent a routine, traditional work-up plus evaluation of albuminuria and ultrasound (US) assessment of cardiac and vascular structures. Albuminuria was measured as the albumin to creatinine ratio in three non-consecutive first-morning urine samples. Left ventricular mass index was assessed by MB-mode echocardiography and carotid intima-media thickness by high-resolution US scan. The impact of these tests on patient risk classes, as indicated by European Society of Hypertension-European Society of Cardiology (ESH-ESC) guidelines, was assessed with respect to their cost and sensitivity. RESULTS: The prevalence of microalbuminuria, left ventricular hypertrophy and carotid intima-media thickening or carotid plaque was 13, 49 and 32%, respectively. The combined use of albuminuria, cardiac and vascular ultrasonography led to the detection of a significantly higher percentage of patients at high/very high risk. The three tests differ in sensitivity (albuminuria, 20%; echocardiography, 65%; and carotid ultrasound, 41%). The signs of target organ damage (TOD) only partly cluster within the same subgroup of patients and, thus, all three tests should be performed in order to maximize the sensitivity of the evaluation process. The diagnostic algorithm yielding the lowest cost per detected case of TOD is the search for microalbuminuria followed by cardiac and carotid ultrasound assessment. CONCLUSIONS: Ultrasonographic detection of TOD is a sensitive tool in the identification of high-risk patients, but should be preceded by a routine search for microalbuminuria in order to optimize the cost-effectiveness of the diagnostic work-up.

Mild renal dysfunction and subclinical cardiovascular damage in primary hypertension.

The presence of mild renal dysfunction is associated with high cardiovascular morbidity and mortality rates in patients with primary hypertension. The pathophysiological mechanisms underlying this association are currently unknown. We investigated the relation between mild renal dysfunction and subclinical cardiovascular organ damage in 358 never previously treated patients with primary hypertension. Mild renal dysfunction was defined as a creatinine clearance <60 mL/min and/or the presence of microalbuminuria. Left ventricular mass index and carotid intima-media thickness were assessed by ultrasound scan. The prevalence of mild renal dysfunction, left ventricular hypertrophy, and carotid plaque was 18%, 48%, and 28%, respectively. Mild renal dysfunction was related to the presence of several risk factors, such as older age, higher blood pressure levels and lipid status, and smoking habits. Patients with the highest left ventricular mass and carotid intima-media thickness (upper quartiles) showed a higher prevalence of mild renal dysfunction (P<0.0001). After adjusting for duration of hypertension, mean blood pressure, smoking habits, and age, we found that the risk of left ventricular hypertrophy and/or carotid atherosclerosis increased by 43% with each SD reduction in creatinine clearance, and by 89% with each SD increase in albuminuria. Mild renal dysfunction is associated with preclinical end-organ damage in patients with primary hypertension. These data may help explain the high cardiovascular mortality rates reported in patients with low glomerular filtration rate or with increased albuminuria. The evaluation of creatinine clearance and urinary albumin excretion could be useful for identifying subjects at higher cardiovascular risk.

Microalbuminuria and subclinical cerebrovascular damage in essential hypertension.

BACKGROUND: Microalbuminuria is a marker of hypertensive and atherosclerotic organ damage in essential hypertension and has powerful prognostic value for cerebral and cardiovascular morbidity and mortality. An association between carotid artery intima-media thickness (IMT) and increased urinary albumin excretion (UAE) has been reported in patients with essential hypertension, suggesting a link between microalbuminuria and atherosclerotic stroke mechanism(s). METHODS: We investigated the relationships between UAE, carotid artery changes, and asymptomatic cerebrovascular damage in two groups of untreated essential hypertensive patients, with (n=11) and without (n=11) microalbuminuria. The study groups, selected among participants in a large epidemiological trial, were carefully matched for several potential confounding variables such as sex, age, duration of hypertension, and body mass index. None had neurological abnormalities. Albuminuria was measured as albumin excretion rate (UAE) on three overnight collections; microalbuminuria was defined as between 20-200 microg/min. Carotid IMT was assessed by high resolution US scan, cerebral lacunar lesions by magnetic resonance imaging (MRI), and left ventricular mass index (LVMI) by M-B mode echocardiography. Office and 24-h ambulatory blood pressures (ABP, Takeda 2420) were also recorded. RESULTS: There were no differences between the two groups in office and ABP, lipid profile and smoking habits. Microalbuminuric patients had a higher prevalence of cerebral ischemic lacunae (82 vs 27%; P=0.03, OR=12, confidence interval - CI 1.6-91.1), and higher carotid IMT (0.94+/-0.05 vs 0.75+/-0.06 mm; P=0.03) than normoalbuminuric patients. No differences were found in LVMI and in the prevalence of Left Ventricular hypertrophy. Patients with ischemic lacunae showed a higher prevalence of microalbuminuria (75 vs 22%; P=0.03, OR=12, CI 1.0-13.5) and higher UAE (58.7+/-21.8 vs 9.4+/-3.7 mg/mmol, P=0.01) than to patients with normal MRI. CONCLUSIONS: Microalbuminuria is an early marker of preclinical brain damage in essential hypertension and may therefore be useful for identifying patients at higher risk of cerebral and cardiovascular events, for whom preventive therapeutic measures are advisable.