Unsupervised Cluster Analysis in Patients with Cardiorenal Syndromes: Identifying Vascular Aspects.

Background/Objectives: Cardiorenal syndrome (CRS) is a disorder of the heart and kidneys, with one type of organ dysfunction affecting the other. The pathophysiology is complex, and its actual description has been questioned. We used clustering analysis to identify clinically relevant phenogroups among patients with CRS. Methods: Data for patients admitted from 1 January 2012 to 31 December 2012 were collected from the French national medico-administrative database. Patients with a diagnosis of heart failure and chronic kidney disease and at least 5 years of follow-up were included. Results: In total, 13,665 patients were included and four clusters were identified. Cluster 1 could be described as the vascular-diabetes cluster. It comprised 1930 patients (14.1%), among which 60% had diabetes, 94% had coronary artery disease (CAD), and 80% had peripheral artery disease (PAD). Cluster 2 could be described as the vascular cluster. It comprised 2487 patients (18.2%), among which 33% had diabetes, 85% had CAD, and 78% had PAD. Cluster 3 could be described as the metabolic cluster. It comprised 2163 patients (15.8%), among which 87% had diabetes, 67% dyslipidemia, and 62% obesity. Cluster 4 comprised 7085 patients (51.8%) and could be described as the low-vascular cluster. The vascular cluster was the only one associated with a higher risk of cardiovascular death (HR: 1.48 [1.32-1.66]). The metabolic cluster was associated with a higher risk of kidney replacement therapy (HR: 1.33 [1.17-1.51]). Conclusions: Our study supports a new classification of CRS based on the vascular aspect of pathophysiology differentiating microvascular or macrovascular lesions. These results could have an impact on patients' medical treatment.

Endocrine causes of hypertension: literature review and practical approach.

Hypertension (HTN) affects more than 30% of adults worldwide. It is the most frequent modifiable cardiovascular (CV) risk factor, and is responsible for more than 10 million death every year. Among patients with HTN, we usually distinguish secondary HTN, that is HTN due to an identified cause, and primary HTN, in which no underlying cause has been found. It is estimated that secondary hypertension represents between 5 and 15% of hypertensive patients [1]. Therefore, routine screening of patients for secondary HTN would be too costly and is not recommended. In addition to the presence of signs suggesting a specific secondary cause, screening is based on specific criteria. Identifying secondary HTN can be beneficial for patients in certain situations, because it may lead to specific treatments, and allow better control of blood pressure and sometimes even a cure. Besides, it is now known that secondary HTN are more associated with morbidity and mortality than primary HTN. The main causes of secondary HTN are endocrine and renovascular (mainly due to renal arteries abnormalities). The most frequent endocrine cause is primary aldosteronism, which diagnosis can lead to specific therapies. Pheochromocytoma and Cushing syndrome also are important causes, and can have serious complications. Other causes are less frequent and can be suspected on specific situations. In this article, we will describe the endocrine causes of HTN and discuss their treatments.

Blood pressure management and long-term outcomes in kidney transplantation: a holistic view over a 35-year period.

INTRODUCTION: Hypertension is a burden for most kidney transplant recipients. Whether respect of hypertension guidelines results in better outcomes is unknown. METHODS: In this multicenter study, office blood pressure at 12 months following transplantation (i.e., after > 20 outpatient visits), and survival were assessed over 35 years among 2004 consecutive kidney transplant recipients who received a first kidney graft from 1985 to 2019 (follow-up: 26,232 patient-years). RESULTS: Antihypertensive medications were used in 1763/2004 (88.0%) patients. Renin-angiotensin-system blockers were used in 35.6% (47.1% when proteinuria was > 0.5 g/day) and calcium-channel blockers were used in 6.0% of patients. Combined treatment including renin-angiotensin-system-blockers, calcium-channel blockers and diuretics was used in 15.4% of patients receiving ≥ 3 antihypertensive drugs. Blood pressure was controlled in 8.3%, 18.8% and 43.1%, respectively, depending on definition (BP < 120/80, < 130/80, < 140/90 mmHg, respectively) and has not improved since the year 2001. Two-thirds of patients with uncontrolled blood pressure received < 3 antihypertensive classes. Low sodium intake < 2 g/day (vs ≥ 2) was not associated with better blood pressure control. Uncontrolled blood pressure was associated with lower patient survival (in multivariable analyses) and graft survival (in univariate analyses) vs controlled hypertension or normotension. Low sodium intake and major antihypertensive classes had no influence on patient and graft survival. CONCLUSIONS: Pharmacological recommendations and sodium intake reduction are poorly respected, but even when respected, do not result in better blood pressure control, or patient or graft survival. Uncontrolled blood pressure, not the use of specific antihypertensive classes, is associated with reduced patient, and to a lesser extent, reduced graft survival, even using the 120/80 mmHg cut-off.

Characteristics and Prognosis of Patients With Hypertensive Encephalopathy: A French Nationwide Cohort Study.

BACKGROUND: Hypertensive encephalopathy (HE) constitutes a serious condition, usually observed in patients with long-lasting hypertension. Hypertension-associated HE is sometimes differentiated from the stroke-associated hypertensive emergency. Whether prognosis of hypertension-associated and stroke-associated HE is different is unclear. METHODS: Characteristics and prognosis of HE were assessed in this nationwide retrospective cohort study in all patients with an administrative code of HE compared with age-, sex- and year of inclusion-matched controls admitted to French hospitals during the 2014 to 2022 period. RESULTS: HE was identified in 7769 patients. Chronic kidney disease (19.3%), coronary artery disease (13.8%), diabetes (22.1%), and ischemic stroke (5.2%) were frequent but thrombotic microangiopathy, hemolytic-uremic syndrome, systemic sclerosis or renal infarction were <1%. HE prognosis was poor (death: 10.4%/y, heart failure: 8.6%/y, end-stage kidney disease: 9.0%/y, ischemic stroke: 3.6%/y, hemorrhagic stroke: 1.6%/y, dementia: 4.1%/y). The risk of death was increased to a similar extent in patients with HE, regardless of the presence of known hypertension or concomitant stroke (versus patients without HE). Among patients with HE, known hypertension was significantly associated with increased risks of ischemic stroke, hemorrhagic stroke, heart failure, vascular dementia, and all-cause dementia and to a lesser extent with chronic dialysis in multivariable analyses including adjustment on concomitant stroke. CONCLUSIONS: HE remains a considerable health burden and is associated with a poor prognosis. The distinction between hypertension- versus stroke-associated HE is relevant as these 2 situations convey different risks of stroke, heart failure, vascular dementia, and end-stage kidney disease.

A Universal Bleeding Risk Score in Native and Allograft Kidney Biopsies: A French Nationwide Cohort Study.

BACKGROUND: The risk of bleeding after percutaneous biopsy in kidney transplant recipients is usually low but may vary. A pre-procedure bleeding risk score in this population is lacking. METHODS: We assessed the major bleeding rate (transfusion, angiographic intervention, nephrectomy, hemorrhage/hematoma) at 8 days in 28,034 kidney transplant recipients with a kidney biopsy during the 2010-2019 period in France and compared them to 55,026 patients with a native kidney biopsy as controls. RESULTS: The rate of major bleeding was low (angiographic intervention: 0.2%, hemorrhage/hematoma: 0.4%, nephrectomy: 0.02%, blood transfusion: 4.0%). A new bleeding risk score was developed (anemia = 1, female gender = 1, heart failure = 1, acute kidney failure = 2 points). The rate of bleeding varied: 1.6%, 2.9%, 3.7%, 6.0%, 8.0%, and 9.2% for scores 0 to 5, respectively, in kidney transplant recipients. The ROC AUC was 0.649 (0.634-0.664) in kidney transplant recipients and 0.755 (0.746-0.763) in patients who had a native kidney biopsy (rate of bleeding: from 1.2% for score = 0 to 19.2% for score = 5). CONCLUSIONS: The risk of major bleeding is low in most patients but indeed variable. A new universal risk score can be helpful to guide the decision concerning kidney biopsy and the choice of inpatient vs. outpatient procedure both in native and allograft kidney recipients.

Type 2 diabetes and cardiorenal syndromes. A nationwide French hospital cohort study.

AIM: Type 2 diabetes mellitus (T2DM) is a risk factor for cardiac and renal complications; its effect on cardiorenal syndromes is unknown. METHODS: In a French nationwide cohort of 5,123,193 patients hospitalized in 2012 with ≥5 years of follow-up, we assessed the effect of T2DM on cardiorenal syndrome (CRS) (using cardiorenal, renocardiac, and simultaneous subtypes) incidence and outcomes using 1:1 propensity matching. RESULTS: Among 4,605,236 adults without cardiorenal syndrome, 380,581 (8.5%) with T2DM were matched to 380,581 adults without T2DM. During follow-up, CRS occurred in 104,788 patients: simultaneous n = 25,225 (24.0%); cardiorenal n = 51,745 (49.4%); renocardiac n = 27,818 (26.5%). T2DM doubled the risk of incident CRS (1.30% versus 0.65%/year; adjusted hazard ratio (HR) for any cardiorenal syndrome: 2.14 [95% confidence interval 2.10;2.19]; renocardiac: 2.43 [2.34;2.53]; cardiorenal: 2.09 [2.03;2.15]; simultaneous: 1.94 [1.86;2.03]. Among the 26,396 adults with CRS in 2012, 11,355 (43.0%) had T2DM and were younger than non-diabetic adults (77.4 ± 9.5 versus 82.3 ± 10.0); 8,314 patients with T2DM were matched to 8,314 patients without. T2DM increased risk of: end-stage kidney disease, adjusted HR 1.50 [1.39;1.62]; myocardial infarction 1.35 [1.19;1.53]; cardiovascular death 1.20 [1.13;1.27]; heart failure 1.17 [1.12;1.21]; and all-cause death 1.09 [1.06;1.13], but not ischemic stroke. CONCLUSION: Patients with T2DM represent almost half of patients with CRS and are younger than their non-diabetic counterparts. T2DM doubles the risk of CRS and increases the risk of death, cardiovascular outcome, and end-stage kidney disease but not ischemic stroke after CRS.

End-diastolic velocity mediates the relationship between renal resistive index and the risk of death.

OBJECTIVE: Renal resistive index predicts the risk of death in many populations but the mechanism linking renal resistive index and death remains elusive. Renal resistive index is derived from end-diastolic velocity (EDV) and peak systolic velocity (PSV). However, the predictive value of EDV or PSV considered alone is unknown. METHODS: We conducted a retrospective analysis of 2362 consecutive patients who received a kidney transplant from 1985 to 2017. EDV and PSV were measured at 3 months after transplantation, renal resistive index was calculated, and the risk of death was assessed [median follow-up: 6.25 years (0.25-29.15); total observation period: 13 201 patient-years]. RESULTS: Doppler indices were available in 1721 of 2362 (78.9%) patients (exclusions: 113 who died or returned to dialysis before, 427 with no Doppler studies, 27 with renal artery stenosis, 74 missing values). Among them, 279 (16.4%) had diabetes before transplantation. Mean age was 51.5 ±â€Š14.7, 1097 (63.7%) were male. During follow-up, 217 of 1721 (12.6%) patients died. Renal resistive index and EDV shared many determinants (notably systolic, diastolic and pulse pressure, recipient age and diabetes) unlike renal resistive index and PSV. EDV used as a binary [lowest tertile vs. higher values: (hazard ratio: 2.57 (1.96-3.36), P  < 0.001)] and as a continuous (the lower EDV, the greater the risk of death) variable was significantly associated with the risk of death. This finding was confirmed in multivariable analyses. Prediction of similar magnitude was found for renal resistive index. No association was found between PSV used as a binary or a continuous variable and the risk of death. CONCLUSION: Low EDV explains high renal resistive index, and the mechanism-linking renal resistive index to the risk of death is through low EDV.

Association of Lipoprotein(a) Levels With Incidence of Major Adverse Limb Events.

Importance: High lipoprotein(a) (Lp[a]) levels are involved in the development of cardiovascular events, particularly in myocardial infarction, stroke, and peripheral artery disease. Studies assessing the Lp(a) levels associated with adverse lower-limb events are lacking. Objective: To assess the association between Lp(a) levels and incidence of major adverse limb events in unselected hospitalized patients. Design, Setting, and Participants: This large retrospective monocentric cohort study was conducted from January 1, 2000, to December 31, 2020. Data were derived from the clinical information system of the Hôpital Européen Georges-Pompidou, a Paris-based university hospital. Patients who underwent at least 1 Lp(a) measurement at the center during the study period were included. Patients who had no follow-up data or who had the first Lp(a) measurement after the study outcome had occurred were excluded. Data analyses were performed from May 2021 to January 2022. Main Outcomes and Measures: The primary outcome was the first inpatient major adverse limb event, defined as a major amputation, peripheral endovascular revascularization, or peripheral surgical revascularization, during follow-up. Secondary outcomes included individual components of the primary outcome. Lipoprotein(a) levels were categorized as follows: normal (<50 mg/dL), high (50 to <134 mg/dL), and very high (≥134 mg/dL); to convert Lp(a) values to milligrams per liter, multiply by 0.1. Results: A total of 16 513 patients (median [IQR] age, 58.2 [49.0-66.7] years; 9774 men [59.2%]) were included in the cohort. The median (IQR) Lp(a) level was 24 (10.0-60.0) mg/dL. The 1-year incidence of major adverse limb event was 2.44% in the overall population and 4.54% among patients with very high Lp(a) levels. High (adjusted accelerated failure time [AFT] exponential estimate: 0.43; 95% CI, 0.24-0.78; Benjamini-Hochberg-corrected P = .01) and very high (adjusted AFT exponential estimate: 0.17; 95% CI, 0.07-0.40; Benjamini-Hochberg-corrected P < .001) Lp(a) levels were independently associated with an increased risk of major adverse limb event. Conclusions and Relevance: Results of this study showed that higher Lp(a) levels were independently associated with an increased risk of a major adverse limb event in hospitalized patients. The Lp(a) measurement needs to be taken into account to improve lower-limb vascular risk assessment.

Long-term impact of cardiorenal syndromes on major outcomes based on their chronology: a comprehensive French nationwide cohort study.

BACKGROUND: Cardiorenal syndromes (CRSs) are reputed to result in worse prognosis than isolated heart failure (HF) and chronic kidney disease (CKD). Whether it is true for all major outcomes over the long-term regardless of CRS chronology (simultaneous, cardiorenal and renocardiac CRS) is unknown. METHODS: The 5-year adjusted risk of major outcomes was assessed in this nationwide retrospective cohort study in all 385 687 with either CKD or HF (out of 5 123 193 patients who were admitted in a French hospital in 2012). RESULTS: Overall, 84.0% patients had HF and 8.9% had CKD (they had similar age, sex ratio, diabetes and hypertension prevalence), while 7.1% had CRS (cardiorenal: 44.6%, renocardiac: 14.5%, simultaneous CRS: 40.8%).The incidence of major outcomes was 57.3%, 53.0%, 79.2% for death; 18.8%, 10.9%, 27.5% for cardiovascular death; 52.6%, 34.7%, 64.3% for HF; 6.2%, 5.5%, 5.6% for myocardial infarction (MI); 6.1%, 5.8%, 5.3% for ischaemic stroke; and 23.1%, 4.8%, 16.1% for end-stage kidney disease (ESKD) for isolated CKD, isolated HF and CRS, respectively.As compared with isolated CKD or HF, the risk of death, cardiovascular death and HF was markedly increased in CRS, the worse phenotype being cardiorenal CRS, while the increased risk of MI and ischaemic stroke associated with CRS subtypes was statistically but not clinically significant. As compared with isolated CKD, the risk of ESKD was similar for cardiorenal CRS only and marginally increased for renocardiac and simultaneous CRS. We could not find a synergy between HF and CKD on major clinical outcomes in the whole population (n = 5 123 193 patients). CONCLUSIONS: The additional impact of CRS versus isolated HF or CKD on long-term kidney and cardiovascular risk is highly heterogenous, depending of the event considered and CRS chronology. No synergy between HF and CKD could be demonstrated.

Controversies about the systematic preoperative pharmacological treatment before pheochromocytoma or paraganglioma surgery.

The question of systematic use of a pharmacological treatment before surgery in patients diagnosed with pheochromocytoma and paraganglioma (PPGL) remains highly controversial. While recent guidelines suggest that this should be used in all patients, some experienced teams consider it unnecessary in some cases, provided the surgery is performed in a dedicated center that has expert endocrinologists, cardiologists, surgeons, and anesthetists. This controversy is aimed at shedding light on the potential benefits and risks of such a treatment, focusing specifically on alpha blockers which are considered as the first-line medical treatments in patients with PPGL. After discussing the rationale for alpha blockers, hemodynamic instability, tolerance, and acute cardiac complications will then be discussed in the first part of the manuscript, defending a systematic use. The second section will focus on blood pressure control, tolerance of alpha blockers, and also the management of normotensive PPGL, examining the daily risks of PPGL and arguing against the systematic use of a preoperative pharmacological treatment before surgery. Finally, we will discuss the concept of expert centers and define the patients in whom the risk/benefit profile would favor the use of this preoperative treatment.

How to Explore an Endocrine Cause of Hypertension.

Hypertension (HTN) is the most frequent modifiable risk factor in the world, affecting almost 30 to 40% of the adult population in the world. Among hypertensive patients, 10 to 15% have so-called "secondary" HTN, which means HTN due to an identified cause. The most frequent secondary causes of HTN are renal arteries abnormalities (renovascular HTN), kidney disease, and endocrine HTN, which are primarily due to adrenal causes. Knowing how to detect and explore endocrine causes of hypertension is particularly interesting because some causes have a cure or a specific treatment available. Moreover, the delayed diagnosis of secondary HTN is a major cause of uncontrolled blood pressure. Therefore, screening and exploration of patients at risk for secondary HTN should be a serious concern for every physician seeing patients with HTN. Regarding endocrine causes of HTN, the most frequent is primary aldosteronism (PA), which also is the most frequent cause of secondary HTN and could represent 10% of all HTN patients. Cushing syndrome and pheochromocytoma and paraganglioma (PPGL) are rarer (less than 0.5% of patients). In this review, among endocrine causes of HTN, we will mainly discuss explorations for PA and PPGL.

Early changes in renal resistive index and mortality in diabetic and nondiabetic kidney transplant recipients: a cohort study.

BACKGROUND: Renal resistive index (RI) predicts mortality in renal transplant recipients (RTR). However, its predictive value may be different according to the time of measurement. We analysed RI changes between 1 month and 3 months after transplantation and its predictive value for death with a functioning graft (DWFG). METHODS: We conducted a retrospective study in 1685 RTR between 1985 and 2017. The long-term predictive value of changes in RI value from 1 month to 3 months was assessed in diabetic and non-diabetic RTR. RESULTS: Best survival was observed in RTR with RI < 0.70 both at 1 and 3 months, and the worst survival was found in RTR with RI ≥ 0.70 both at 1 and 3 months (HR = 3.77, [2.71-5.24], p < 0.001). The risk of DWFG was intermediate when RI was < 0.70 at 1 month and ≥ 0.70 at 3 months (HR = 2.15 [1.29-3.60], p = 0.003) and when RI was ≥0.70 at 1 month and < 0.70 at 3 months (HR = 1.90 [1.20-3.03], p = 0.006). In diabetic RTR, RI was significantly associated with an increased risk of death only in those with RI < 0.70 at 1 month and ≥ 0.70 at 3 months (HR = 4.69 [1.07-20.52], p = 0.040). RI considered as a continuous variable at 1 and 3 months was significantly associated with the risk of DWFG in nondiabetic but not in diabetic RTR. CONCLUSION: RI changes overtime and this impacts differently diabetic and nondiabetic RTR. RI short-term changes have a strong prognosis value and refines the risk of DWFG associated with RI.

Lymphomas with kidney involvement: the French multicenter retrospective LyKID study.

The LyKID study is a nationwide survey in France of lymphoma patients with renal involvement based on biopsy and/or imaging, to evaluate its impact on disease outcome and renal function. A total of 87 adult cases of B or T-cell lymphomas were retrospectively analyzed. Interstitial topography was observed in most of the kidney biopsies (54/66; 80%). Kidney failure (glomerular filtration rate <60 mL/min/1.73 m2) was present in 47% of patients and was associated with non-significantly different outcome. After lymphoma treatment, 44% of patients had persistent chronic kidney failure (CKF); kidney failure at diagnosis was the only parameter associated with CKF in multivariate analysis. DLBCL (diffuse large B-cell lymphomas) represented half of the series, with noticeably CNS (central neurological system) relapse in 17% patients, while fewer than one of two patients had received CNS prophylaxis. To our knowledge, the LyKID study represents the largest published non-autopsy lymphoma series with renal involvement.

The association between renal resistive index and premature mortality after kidney transplantation is modified by pre-transplant diabetes status: a cohort study.

BACKGROUND: Renal resistive index (RI) predicts mortality in renal transplant recipients, but we do not know whether this is true in diabetic patients. The objective of this study was to analyse the long-term predictive value of RI for death with a functioning graft (DWFG) in renal transplant recipients with or without pre-transplant diabetes. METHODS: We conducted a retrospective study in 1800 renal transplant recipients between 1985 and 2017 who were followed for up to 30 years (total observation period: 14 202 patient years). Donor and recipient characteristics at time of transplantation and at 3 months were reviewed. The long-term predictive value of RI for DWFG and the age-RI and arterial pressure-RI relationships were assessed. RESULTS: A total of 284/1800 (15.7%) patients had diabetes mellitus before transplantation. RI was <0.75 in 1327/1800 patients (73.7%). High RI was associated with a higher risk of DWFG in non-diabetic patients [hazard ratio (HR) = 3.39, 95% confidence interval 2.50-4.61; P < 0.001], but not in patients with pre-transplant diabetes (HR = 1.25, 0.70-2.19; P = 0.39), even after multiple adjustments. There was no interaction between diabetes and age. In contrast, there was an interaction between RI and pulse pressure. CONCLUSION: Our study indicates that RI is not a predictor of DWFG in diabetic renal transplant recipients, in contrast to non-diabetic recipients. These findings could be due to a different age-RI or pulse pressure-RI relationship.

Impact on renal resistive index of diabetes in renal transplant donors and recipients: A retrospective analysis of 1827 kidney transplant recipients.

High renal resistive index (RI) is observed in diabetes and is associated with poor patient survival, but whether it is primarily due to renal vascular resistance or systemic vascular alterations is unclear. The respective impact of kidney transplant from diabetic donors or to diabetic recipients on RI would shed some light on this issue. The objective of the study was to analyze the impact of donor and recipient diabetes on RI in order to understand the respective impact of the kidney and the vascular environment. The authors conducted a retrospective study in 1827 renal transplant recipients who received a kidney between 1985 and 2017, and had Doppler measurements at 3 months after transplant. Donor and recipient characteristics at the time of transplant and at 3 months were reviewed. Both donor diabetes and recipient diabetes were associated with RI in univariate analysis, but only recipient diabetes remained significantly associated in stepwise multivariate analyses (effect estimate on RI: +0.03 ± 0.005, P < 0.001). These findings were confirmed when RI was expressed as a binary variable using a cutoff of 0.75 (OR = 2.50 [1.77, 3.54], P < 0.001). Other determinants of RI were recipient characteristics (age, sex, systolic and diastolic blood pressure, and duration of dialysis). Donor characteristics were not associated with RI. Our results suggest that high RI observed in diabetic recipients shortly after transplant is primarily due to the new vascular environment, rather than to characteristics of the transplanted kidney. Therefore, RI reflects systemic rather than intra-renal changes.