Associations Among Biomarkers of Inflammation, Tubular Injury and Lipid Metabolism With Gestational Diabetes Mellitus Status, Microalbuminuria and Retinopathy in the Microalbuminuria and Retinopathy in Gestational Diabetes Study.

OBJECTIVES: Pregnancy may be complicated by gestational diabetes mellitus (GDM) and/or microvascular complications like albuminuria, retinopathy and pre-eclampsia. In this study we aimed to identify whether mechanistic pathways associated with microvascular complications are active in pregnant women with GDM or microvascular disease. METHODS: Urinary albumin excretion and biomarkers of inflammation, lipoprotein metabolism and tubular injury were quantified in 355 pregnant women with and without GDM. Participants underwent fundus photography graded for retinopathy. Adjusted associations between individual biomarkers and each outcome variable of interest, including GDM status, albuminuria and retinopathy, were performed using logistic regression. RESULTS: After adjusting for age, systolic blood pressure, body mass index and ethnicity, significant associations between GDM status and apolipoprotein A1, interleukin (IL)-6, IL-8, soluble tumour necrosis factor receptor-I and -II (sTNFR-I and -II), vascular endothelial growth factor and von Willebrand factor were observed. Increased high-sensitivity C-reactive protein (hsCRP) and sTNFR-II were associated with higher levels of albuminuria. hsCRP and previous GDM were associated with retinopathy. CONCLUSION: Mechanistic pathways associated with microvascular complications appear to be active in pregnant women with GDM or microvascular disease.

Cancer Screening in Solid Organ Transplant Recipients: A Focus on Screening Liver, Lung, and Kidney Recipients for Cancers Related to the Transplanted Organ.

Over the last few decades, the life expectancy of solid organ transplant recipients (SOTRs) has improved significantly. With SOTRs living longer, more recipients are dying from cancer. There is a reported 2- to 3-fold increased risk of cancer-specific mortality in SOTRs compared with the general population. Cancer in an SOTR can be de novo, recurrent, or donor-derived. Cancer screening in this population is crucial, as early detection and treatment may improve outcomes. In the absence of randomized controlled trials dedicated to SOTRs, clinicians rely on clinical practice guidelines from regional and national transplant societies; however, these may vary considerably across jurisdictions and transplanted organ. At present, no widely accepted consensus exists for cancer screening protocols in SOTRs, particularly with regard to screening for malignancy related to transplanted organ. Some SOTRs may be at higher risk of malignancies within the allograft. This is particularly the case in lung and liver recipients, though less common in kidney recipients who are at increased risk of developing renal cell cancer in their native kidneys. This increased risk has not been uniformly incorporated into screening recommendations for SOTRs. In this review, we summarize the cancer screening recommendations for SOTRs from various transplant organizations based on transplanted organ. This review also discusses the complexity and controversies surrounding screening of cancer in the allograft and future avenues to improve cancer detection in this context. More studies specific to SOTRs are required to form generalizable and evidence-based cancer screening guidelines, particularly with respect to cancer screening in the allograft.

SGLT2 Inhibition in Patients With Type 2 Diabetes Mellitus Post-Nephrectomy: A Single-Center Case Series.

BACKGROUND: Nephrectomy is the mainstay of treatment for many kidney cancers, but has been correlated with increased incidence of acute kidney injury (AKI) and chronic kidney disease (CKD). Recently, sodium-glucose cotransporter-2 (SGLT2) inhibition has been shown to decrease the incidence of end-stage kidney disease and death in people with type 2 diabetes mellitus (T2D). However, at present, there has been no description of the use of SGLT2 inhibition in patients with T2D and solitary kidney despite the high risk of CKD progression. OBJECTIVE: To characterize the use of SGLT2 inhibition and kidney function in a series of patients with T2D with prior nephrectomy for renal cell carcinoma (RCC). DESIGN: Retrospective case series. SETTING: University hospital outpatient onco-nephrology clinic. PATIENTS: Patients post-nephrectomy for RCC with T2D who were prescribed an SGLT2 inhibitor. MEASUREMENTS: Serum creatinine, albumin to creatinine ratio (ACR), HgA1c, and blood pressure measurements. METHODS: Patients post-nephrectomy with incident use of SGLT2 inhibitor were identified from an existing registry of patients followed in the Onco-Nephrology Clinic at our institution from May 2019 to March 2021. Demographics, medication use, time since nephrectomy, cancer diagnosis, serum creatinine, ACR measurements, and blood pressure measurements were extracted from electronic medical records. RESULTS: Five patients were identified who had initiated SGLT2 inhibition post-nephrectomy. All patients were male, had T2D, and a prior history of hypertension. Renal cell carcinoma was the clinical indication for nephrectomy in all patients. None of patients were prescribed diuretics, and all were receiving renin-angiotensin system (RAS) inhibition therapies. The time from nephrectomy to SGLT2 inhibitor initiation ranged from 5 to 74 months. Baseline mean estimated glomerular filtration rate (eGFR) values were 49 mL/min/1.73 m2 (95% confidence interval [CI]: 31.5-66.5), and mean ACRs were 8.7 mg/mmol (95% CI: 0.6-16.9). After 6 months of SGLT2 inhibition, the mean eGFR and ACR values were 58 mL/min/1.73 m2 (95% CI: 29.7-86.2) and 23.8 mg/mmol (95% CI: 0-60), respectively. After 16 to 18 months of follow-up (4 patients), the mean eGFR was 56 mL/min/1.73 m2 (95% CI: 37.3-74.7), and mean ACR was 10.5 (95% CI: 0-30.5), similar to baseline values before SGTL2i therapy initiation. At baseline, mean systolic blood pressure was 128 mm Hg (95% CI: 118.3-140.9) and remained similar after 12 months of treatment (mean 131 mm Hg [95% CI: 112.3-149.7]). There were no adverse events related to AKI, electrolyte disturbances, ketoacidosis, or genitourinary infections during the 18-month follow-up period. LIMITATIONS: Small sample size, lack of a comparison group, and the variable timing of clinical data collection, including eGFR levels following initiation of SGLT2 inhibition. CONCLUSIONS: SGLT2 inhibition is becoming a standard component of nephrology care to reduce kidney function decline, cardiovascular risk, and mortality. To our knowledge, our report is the first to provide longitudinal data on SGLT2 inhibitor usage in patients with T2D and solitary kidneys post-nephrectomy. Larger prospective studies are needed to determine the efficacy and safety of SGLT2 inhibition strategies for kidney protection in patients post-nephrectomy.

CONTEXTE: La néphrectomie est le traitement de référence pour de nombreux cancers rénaux, mais elle est corrélée à une incidence accrue d'insuffisance rénale aiguë (IRA) et d'insuffisance rénale chronique (IRC). On a récemment montré que l'inhibition du cotransporteur sodium-glucose de type 2 (SGLT2) réduisait l'incidence de l'insuffisance rénale terminale et la mortalité chez les personnes atteintes de diabète de type 2 (DB2). À l'heure actuelle, malgré le risque élevé de progression vers l'IRC, il n'existe aucune description de l'utilisation des inhibiteurs du SGLT2 chez les patients DB2 ayant un seul rein. OBJECTIF: Caractériser la fonction rénale et l'utilisation des inhibiteurs du SGLT2 chez une série de patients atteints de DB2 ayant subi une néphrectomie pour traiter un carcinome rénal (CR). TYPE D'ÉTUDE: Série de cas rétrospective. CADRE: Clinique externe d'onconéphrologie d'un hôpital universitaire. SUJETS: Patients atteints de DB2 ayant subi une néphrectomie pour un CR et à qui on a prescrit un inhibiteur du SGLT2. MESURES: Créatinine sérique, rapport albumine/créatinine (RAC), HgA1c et mesures de la pression artérielle. MÉTHODOLOGIE: Les patients ayant subi une néphrectomie et ayant utilisé un inhibiteur du SGLT2 ont été identifiés dans le registre des patients suivis à la clinique d'onconéphrologie de notre établissement entre mai 2019 et mars 2021. Les données suivantes ont été extraites des dossiers médicaux : données démographiques, consommation de médicaments, temps écoulé depuis la néphrectomie, diagnostic du cancer, taux de créatinine sérique, mesures du RAC et de la pression artérielle. RÉSULTATS: Cinq patients avaient amorcé l'inhibition du SGLT2 après la néphrectomie. Tous les sujets étaient des hommes atteints de diabète de type 2 et présentant des antécédents d'hypertension. Le CR était dans tous les cas l'indication clinique pour la néphrectomie. Aucun des patients n'avait reçu une prescription de diurétiques et tous suivaient un traitement avec un inhibiteur du système rénine-angiotensine (SRA). Le délai entre la néphrectomie et l'amorce de l'inhibition du SGLT2 variait entre cinq et soixante-quatorze mois. Le DFGe initial moyen s'établissait à 49 ml/min/1,73 m2 (IC 95 % : 31,5-66,5) et le rapport albumine/créatinine moyen (RAC) à 8,7 mg/mmol (IC 95 % : 0,6-16,9). Après six mois d'inhibition du SGLT2, les valeurs moyennes de DFGe et de RAC s'établissaient respectivement à 58 ml/min/1,73 m2 (IC 95 % : 29,7-86,2) et à 23,8 mg/mmol (IC 95 % : 0-60). Après 16-18 mois de suivi (quatre patients), le DFGe moyen était de 56 ml/min/1,73 m2 (IC 95 % : 37,3-74,7) et le RAC moyen de 10,5 mg/mmol (IC 95 % : 0-30,5); des valeurs semblables aux valeurs mesurées avant le début du traitement par inhibiteur du SGTL2. La pression artérielle systolique (PAS) moyenne initiale était de 128 mmHg (IC 95 % : 118,3-140,9) et elle est demeurée quasi inchangée après douze mois de traitement (moyenne de 131 mmHg [IC 95 % : 112,3-149,7]). Aucun événement indésirable lié à l'insuffisance rénale aiguë, à des perturbations électrolytiques, à une acidocétose ou à des infections génito-urinaires n'a été observé au cours des 18 mois de suivi. LIMITES: Échantillon de petite taille, absence d'un groupe de comparaison et synchronisation variable de la collecte des données cliniques, notamment du DFGe, après le début de l'inhibition du SGLT2. CONCLUSION: L'inhibition du SGLT2 devient une partie intégrante des soins néphrologiques visant à réduire le déclin de la fonction rénale, les risques cardiovasculaires et la mortalité. À notre connaissance, notre rapport est le premier à fournir des données longitudinales sur l'utilisation des inhibiteurs du SGLT2 chez les patients atteints de diabète de type 2 ayant subi une néphrectomie. Des études prospectives de plus grande envergure sont nécessaires pour examiner l'efficacité et l'innocuité des stratégies d'inhibition du SGLT2 visant la protection rénale des patients post-néphrectomie.

Relationships between inflammation, hemodynamic function and RAAS in longstanding type 1 diabetes and diabetic kidney disease.

The renin angiotensin aldosterone system (RAAS) is associated with renal disease and inflammation in a diabetes setting, however, little is known about the implicated mechanisms in individuals with long standing diabetes. Accordingly, our aim was to perform an observational study to quantify urinary excretion of inflammatory biomarkers in participants with long standing type 1 diabetes (T1D) (with and without diabetic kidney disease [DKD]) and controls, at baseline and in response to RAAS activation. GFRINULIN, ERPFPAH, and 42 urine inflammatory biomarkers were measured in 74 participants with T1D for ≥50 years (21 with DKD and 44 without DKD [DKD resistors]) and 73 healthy controls. Additionally, inflammatory biomarkers were measured before and after an angiotensin II infusion (ANGII, 1 ng∙kg-1∙min-1). Significantly lower urinary excretion of cytokines (IL-18, IL-1RA, IL-8), chemokines (MCP1, RANTES) and growth factors (TGF-α, PDGFAA, PDGFBB, VEGF-A) was observed in participants with T1D at baseline compared to controls. Urinary IL-6 was higher in DKD than in DKD resistors in an exploratory analysis unadjusted for multiple comparisons. In T1D only, lower GFRINULIN correlated with greater excretion of proinflammatory biomarkers (IL-18, IP-10, & RANTES), growth factors (PDGF-AA & VEGFAA), and chemokines (eotaxin & MCP-1). ANGII increased 31 of 42 inflammatory biomarkers in T1D vs controls (p < 0.05), regardless of DKD resistor status. In conclusion, lower GFR and intra-renal RAAS activation were associated with increased inflammation even after longstanding T1D. The increased urinary IL-6 in patients with DKD requires further investigation to determine whether IL-6 is a candidate protective biomarker for prognostication or targeted therapy in DKD.

Making a case for the combined use of SGLT2 inhibitors and GLP1 receptor agonists for cardiorenal protection / Argumentando a favor do uso combinado de inibidores de SGLT2 e agonistas do receptor GLP1 para proteção cardiorrenal

ABSTRACT Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.

RESUMO Inibidores do cotransporter-2 de glicose sódica (SGLT2) e agonistas do receptor peptídeo-1 do tipo glucagon (GLP-1RA) foram inicialmente aprovados para melhorar o controle glicêmico no tratamento da diabetes tipo 2. Os ensaios clínicos também demonstraram efeitos benéficos em relação aos parâmetros cardiovasculares e renais. Além de melhorar o controle glicêmico, essas terapias promovem perda de peso e redução da pressão arterial quando usadas individualmente, e de forma aditiva quando usadas em conjunto. Consequentemente, tirar proveito de mecanismos de ação complementares com o uso combinado dessas duas classes de agentes para melhorar ainda mais os resultados cardiorrenais é conceitualmente atraente, mas ainda precisa ser explorado em detalhes em ensaios clínicos. Nesta revisão, discutimos os mecanismos propostos para proteção renal, benefícios clínicos e eventos adversos associados ao uso individual e combinado de inibidores de SGLT2 e GLP-1RA. O tratamento do diabetes tipo 2 mudou significativamente nos últimos anos, passando do controle exclusivamente glicêmico para o tratamento simultâneo de comorbidades associadas em uma população de pacientes com risco significativo de doença cardiovascular e progressão da doença renal crônica. É nessa perspectiva que procuramos delinear a justificativa para o uso sequencial e/ou combinado de inibidores de SGLT2 e GLP-1RA em pacientes com diabetes tipo 2.