Improving Detection Rates for Primary Aldosteronism.

Primary aldosteronism (PA), once considered a rare disease, is being increasingly recognized as an important cause of hypertension. It is associated with higher rates of cardiovascular complications compared to blood pressure-matched essential hypertension. Targeted treatments are available which can mitigate the excess cardiovascular risks and, in some cases, cure hypertension. Making a timely diagnosis of PA is, therefore, highly beneficial for patients. Furthermore, numerous studies from different parts of the world have found PA to be a relatively common disease that can affect patients in any stage of hypertension, regardless of their age or potassium levels. Despite this well-established data, the current rate of PA detection is appallingly low, much below its actual prevalence. This review explores the challenges that clinicians often face in diagnosing PA and offers strategies that may improve the detection of this potentially curable form of hypertension.

Screening for primary aldosteronism in the diabetic population: a cohort study.

BACKGROUND: Primary aldosteronism (PA) is the most common endocrine cause of hypertension. It is associated with higher cardio-metabolic risk than essential hypertension. Hypertension is common in patients with type 2 diabetes who carry increased cardiovascular risk; however, it is unknown how frequently they are tested for PA. AIM: To assess the extent to which the Endocrine Society's 2016 PA screening guidelines have been applied in a tertiary diabetes care setting and evaluate the demographic, clinical and biochemical characteristics of patients who met screening criteria compared with those who did not. METHODS: This is a retrospective cohort study. Data were collected from 272 patients who attended tertiary diabetes clinics and had two or more blood pressure measurements from January to December 2018. RESULTS: Of 272 patients, 60 (22.1%) had indication(s) for PA screening, but only 14 (23.3%) of 60 were screened using the aldosterone-to-renin ratio (ARR). Five patients who did not meet screening criteria were screened. Only one of 19 patients screened had an abnormal ARR; however, 16 were taking medications known to affect aldosterone and/or renin production. CONCLUSIONS: In a tertiary diabetes outpatient setting, only a minority of patients who fulfilled the Endocrine Society criteria for PA screening were actually screened. Appropriate screening for PA in the diabetic hypertensive population is necessary for the diagnosis and targeted treatment of a highly modifiable cardiovascular risk factor. Further studies are needed to develop feasible strategies to identify patients with PA in this population.

Risky business: a single-centre cross-sectional analysis of calculated cardiovascular risk in patients with primary aldosteronism and essential hypertension.

OBJECTIVES: Primary aldosteronism (PA), the most common endocrine cause of hypertension, is associated with a higher risk of cardiovascular disease (CVD) than blood pressure (BP)-matched essential hypertension (EH). We aimed to compare the calculated risks of CVD in patients who had hypertension with PA or EH using CVD risk calculators, hypothesising that they will fail to recognise the increased CVD risk in PA. DESIGN: Cross-sectional analysis. SETTING: An endocrine hypertension service in Victoria, Australia. PARTICIPANTS: Patients who had hypertension without CVD referred for the investigation of hypertension. OUTCOME MEASURES: Calculated 5-year or 10-year CVD risk as predicted by the National Vascular Disease Prevention Alliance (NVDPA) algorithm, Framingham Risk Score, Pooled Cohort Equations and QRISK3. RESULTS: Those with PA (n=128) and EH (n=133), did not differ significantly in their calculated CVD risks with the NVDPA algorithm (moderate-to-high 5-year risk 36/100 vs 45/99, p=0.17); the Framingham Risk Score (median 10-year risk 7.72% (4.43%-12.95%) vs 6.84% (3.85%-10.50%), p=0.14); the Pooled Cohort Equations (median 10-year risk 9.45% (4.36%-15.37%) vs 7.90% (2.09%-14.73%), p=0.07); and QRISK3 (median 10-year risk 11.31% (7.22%-20.29%) vs 12.47% (5.10%-19.93%), p=0.51). Similarities persisted on regression analyses accounting for systolic BP. CONCLUSIONS: CVD risk algorithms do not reflect the increased risk of CVD in patients with PA, and likely underestimate the true risk of CVD among those with PA. Screening for PA, in addition to using the CVD risk algorithm in patients who had hypertension, may facilitate the targeted treatment of PA and minimisation of cardiovascular risk in affected individuals.

Impact of dedicated multidisciplinary service on patient selection and outcomes for surgical treatment of primary aldosteronism.

BACKGROUND: Primary aldosteronism is the most common surgically curable cause of endocrine hypertension. Management of the unilateral subtype of primary aldosteronism with adrenalectomy requires multidisciplinary input. It is unclear if a dedicated endocrine hypertension service confers better outcomes compared to standard care offered by individual clinicians. METHODS: In this retrospective study, patients from the Monash University Endocrine Surgery Database were divided into either the endocrine hypertension service group, where patients were managed by a dedicated multidisciplinary team, or the standard group, where patients were managed by individual clinicians. The comparisons included patient selection for surgery, perioperative blood pressure control, and surgical cure rate. RESULTS: Despite similar perioperative blood pressure, patients in the endocrine hypertension service group (n = 41) were on fewer antihypertensive medications (1 vs 2, P = .011) compared to the standard group (n = 55). A larger proportion of patients in the endocrine hypertension service group had either bilateral adrenal nodules or no adrenal lesions on computed tomography (41% vs 18%, P = .013). Patients in the standard group had larger adrenal lesions on computed tomography (median 15 mm vs 10 mm, P = .032). Postoperatively, the biochemical cure rate was higher in the endocrine hypertension service group at 6 to 12 months (97% vs 76%, P = .021). CONCLUSION: Patients managed by endocrine hypertension service were more likely to be diagnosed with surgically curable primary aldosteronism without a unilateral adrenal adenoma on imaging, required fewer medications for perioperative blood pressure control, and experienced superior postoperative outcomes. Referral to a dedicated endocrine hypertension service is recommended for patients with primary aldosteronism who wish to pursue a surgical cure.

Aldosterone, Renin, and Aldosterone-to-Renin Ratio Variability in Screening for Primary Aldosteronism.

CONTEXT: The plasma aldosterone concentration (PAC), renin, and aldosterone-to-renin ratio (ARR) are used to screen for primary aldosteronism (PA). Substantial intra-individual variability of PAC and ARR using plasma renin activity in the context of usual antihypertensive therapy has been described, but there is no data on ARR variability calculated using direct renin concentration (DRC). OBJECTIVE: To describe the intra-individual variability of PAC, DRC, and ARR in the absence of interfering medications in patients with and without PA. DESIGN: Retrospective cohort study. PATIENTS: Hypertensive patients referred for investigation of PA, with at least 2 ARR measurements while off interfering medications. SETTING: Endocrine hypertension service of a tertiary center, from May 2017 to July 2021. MAIN OUTCOME MEASURES: PAC, DRC, and ARR variability was calculated as coefficient of variation (CV) and percent difference (PD). RESULTS: Analysis of 223 patients (55% female, median age 52 years), including 162 with confirmed PA, demonstrated high variability with a sample CV of 22-25% in the PAC and sample CV of 41% to 42% in the DRC and ARR in both the PA and non-PA groups. The degree of variability was substantially higher than the assays' analytical CV. Sixty-two patients (38%) with PA had at least one ARR below 70 pmol/L:mU/L (2.4 ng/dL:mU/L), a cut-off for first-line screening of PA. CONCLUSIONS: Significant intra-individual variability in PAC, DRC, and hence ARR occurs in a large proportion of patients being investigated for PA. These findings support the need for at least 2 ARR before PA is excluded or further investigated.

Impact of Intraprocedural Sedation on Adrenal Vein Sampling without Corticotropin Stimulation.

See also the editorial by Georgiades in this issue.

Screening for primary aldosteronism is underutilised in patients with chronic kidney disease.

BACKGROUND: Primary aldosteronism (PA) is the most common and potentially curable endocrine cause of secondary hypertension, and carries a worse prognosis than essential hypertension. Despite the high prevalence of hypertension in patients with chronic kidney disease (CKD), the screening rates for primary aldosteronism in CKD are unknown. METHODS: In this study, we retrospectively reviewed medical records of 1627 adults who presented to the nephrology clinics of 2 tertiary hospitals in Melbourne, Australia, between 2014 and 2019. In addition to assessing the pattern of screening, we also evaluated patient-specific factors associated with the decision to test for primary aldosteronism. Patients were excluded from the final analysis if they did not have CKD, had an organ transplant, had end stage renal failure, or had insufficient data or follow-up. RESULTS: Of the 600 patients included in the analysis, 234 (39%) had an indication for screening for primary aldosteronism based on recommendations made by the Endocrine Society. However, only 33 (14%) were tested. They were younger, had a higher mean systolic blood pressure, better renal function, and lower mean serum potassium than those who were indicated but not screened. Of the 33 screened patients, an elevated aldosterone-to-renin ratio was noted in 8 patients and a diagnosis of primary aldosteronism was made in 4 patients. CONCLUSIONS: The screening rate for primary aldosteronism is low in a CKD population, especially in patients who are older, have a lower eGFR and normal serum potassium. The consequences of undiagnosed primary aldosteronism in this select population may be substantial due to the cardiovascular and renal sequelae associated with untreated disease.

Detecting primary aldosteronism in Australian primary care: a prospective study.

OBJECTIVE: To assess the identification of primary aldosteronism (PA) in newly diagnosed, treatment-naïve patients with hypertension by screening in primary care. DESIGN: Prospective study. SETTING: General practices in the South Eastern Melbourne Primary Health Network with at least three general practitioners and general practices elsewhere in Victoria that had referred patients to the Endocrine Hypertension Clinic at Monash Health, 2017-2020. PARTICIPANTS: Adults (18-80 years) with newly diagnosed hypertension (measurements of systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg on at least two occasions) and not taking antihypertensive medications were screened for PA by assessing their aldosterone-to-renin ratio (ARR). Participants with two ARR values exceeding 70 pmol/mU underwent saline suppression testing at the Endocrine Hypertension Service (Monash Health) to confirm the diagnosis of PA. MAIN OUTCOME MEASURES: Prevalence of PA (number of patients with confirmed PA divided by number screened). RESULTS: Sixty-two of 247 screened participants had elevated ARR values on screening (25%); for 35 people (14%; 95% CI, 10-19%), PA was confirmed by saline suppression testing. Baseline characteristics (mean age, sex distribution, median baseline blood pressure levels, and serum potassium concentration) were similar for people with or without PA. CONCLUSION: PA was diagnosed in 14% of patients with newly diagnosed hypertension screened by GPs, indicating a potential role for GPs in the early detection of an important form of secondary hypertension for which specific therapies are available.

Preoperative mineralocorticoid receptor antagonist reduces postoperative hyperkalaemia in patients with Conn syndrome.

BACKGROUND: The preoperative use of mineralocorticoid receptor antagonists (MRA) in patients with unilateral forms of primary aldosteronism (PA) is not standardized. The current Endocrine Society Guidelines do not specifically recommend MRA treatment before surgery. It is unclear whether preoperative MRA can optimize perioperative blood pressure and potassium control, and reduce the incidence of postoperative hyperkalaemia. OBJECTIVE: This study aimed to investigate the effect of MRA on the incidence of postoperative hyperkalaemia in addition to perioperative blood pressure and potassium concentration in patients undergoing unilateral adrenalectomy for the treatment of PA. DESIGN: Retrospective cohort study. SETTING: Tertiary referral centres, Victoria, Australia. PATIENTS: A total of 96 patients who were diagnosed with unilateral forms of PA: 73 patients ('MRA' group) received preoperative MRA while 23 patients ('No-MRA' group) did not. RESULTS: The prevalence of postoperative hyperkalaemia was significantly higher in the 'No-MRA' group at 2-4 weeks after surgery, compared to the 'MRA' group (35% vs. 11%, p = .014). In a logistic regression, the use of MRA significantly predicted a lower incidence of postoperative hyperkalaemia after adjusting for age, sex, baseline aldosterone-to-renin ratio, potassium and preoperative eGFR. Before surgery, patients in the 'MRA' group had normalized blood pressure and potassium concentration requiring fewer antihypertensive medications and no potassium supplements. CONCLUSION: Preoperative MRA use was associated with optimal perioperative blood pressure and normalized serum potassium in addition to a lower incidence of postoperative hyperkalaemia. MRA should be considered standard treatment for patients awaiting surgery for PA.

Prospective Screening for Primary Aldosteronism in Patients With Suspected Obstructive Sleep Apnea.

[Figure: see text].

Adrenal disease: An update.

BACKGROUND: Diseases of the adrenal gland occur rather more frequently than is appreciated and provide a series of challenges for the treating practitioner. OBJECTIVE: The aim of this article is to provide a practical approach to common adrenal disorders encountered in general practice, including adrenal incidentalomas, primary aldosteronism and adrenal insufficiency. DISCUSSION: Adrenal incidentalomas are adrenal mass lesions >1 cm in diameter serendipitously discovered by radiological examination. They require structural assessment to distinguish common benign pathologies from the rare malignant ones, and biochemistry to exclude hypersecretion syndromes resulting from excess cortisol, aldosterone or catecholamines. Primary aldosteronism represents >5% of hypertension and may be cured or specifically treated, yet is rarely screened for in primary care. Low cortisol levels may reflect adrenal insufficiency due to either adrenal failure, where adrenocorticotropic hormone levels will be elevated, or secondary to hypothalamic-pituitary dysfunction resulting from structural lesions or, increasingly, prescribed exogenous synthetic glucocorticoids and nonconventional therapies.

Impact of Victoria's first dedicated endocrine hypertension service on the pattern of primary aldosteronism diagnoses.

BACKGROUND: Primary aldosteronism (PA) accounts for 3.2-12.7% of hypertension in primary care but is often diagnosed late, if at all. A delayed or missed diagnosis leads to poor blood pressure control and greater cardiovascular risk. AIMS: To analyse the impact of Victoria's first dedicated endocrine hypertension service (EHS) on the pattern of PA diagnosis. METHODS: Socio-demographic and clinical data from all patients who attended the EHS since July 2016 (n = 267) was collected prospectively. Patients were divided into Year 1 (Y1), Year 2 (Y2) and Year 3 (Y3), based on their first visit. RESULTS: The proportion of primary care referrals increased (20% in Y1, 47% in Y2, 52% in Y3) with more referrals being made for treatment-naive hypertension (3% in Y1, 14% in Y2, 19% in Y3). Among PA patients, the median duration of hypertension prior to their first visit decreased (11 years in Y1, 10 years in Y2, 7 years in Y3), and the prevalence of end-organ damage decreased (44% in Y1, 42% in Y2, 33% in Y3). Targeted management of PA improved clinical and biochemical outcomes. The average blood pressure reduction following targeted management increased from 16/12 mmHg in Y1 to 23/12 mmHg in Y3. CONCLUSION: The EHS, with its strong component of general practitioner engagement, led to increased primary care referrals and PA detection earlier in the course of hypertension. Referred patients were on fewer antihypertensives and had less end-organ damage which simplified the diagnostic process, allowing targeted treatment to be commenced earlier and patient outcomes optimised.

Comparison of ambulatory blood pressure between patients with primary aldosteronism and other forms of hypertension.

OBJECTIVE: Primary aldosteronism (PA) is a potentially curable cause of hypertension associated with worse cardiovascular prognosis than blood pressure-matched essential hypertension (EH). Effective targeted treatment for PA is available with the greatest benefit seen if treatment is started early, prior to the development of end-organ damage. However, PA is currently substantially under-diagnosed. The standard screening test for PA, the aldosterone-to-renin ratio (ARR), is performed infrequently in both primary and tertiary care. In contrast, ambulatory blood pressure monitoring (ABPM) is frequently utilized in the assessment of hypertension. The aim of this study was to compare ABPM parameters in hypertensive patients with and without PA, in order to identify features of ABPM associated with PA that can prompt screening. STUDY DESIGN: Patients with PA (n = 55) were identified from a tertiary clinic specializing in the management of endocrine causes of hypertension whilst the controls (n = 389) were consecutive patients with hypertension but without a known diagnosis of PA who were referred for ABPM. RESULTS: In this study, PA patients were younger and had higher 24-h, day, and night-time blood pressure compared with controls despite similar number of antihypertensive medications. However, there was no significant difference in nocturnal dipping or day-night blood pressure variability between the two groups. CONCLUSIONS: An elevated ambulatory blood pressure in patients on multiple antihypertensives could suggest underlying PA but in the absence of other distinguishing features, ABPM could not reliably differentiate PA from other forms of hypertension. Routine biochemical screening for PA remained the most reliable way of detecting this treatable secondary cause of hypertension.

A Multicenter Study of Neutrophil-to-Lymphocyte Ratio in Primary Aldosteronism.

BACKGROUND: Hypertensive patients with primary aldosteronism (PA) have a higher risk of cardiovascular complications than those with blood pressure-matched essential hypertension. The excess cardiovascular consequences of PA can be attributed to the proinflammatory effect of excessive aldosterone and mineralocorticoid receptor activation in a range of peripheral tissues and cell types. The neutrophil-to-lymphocyte ratio (NLR) is a widely available marker of inflammation which has been shown to predict cardiovascular outcome in the general population. This study aims to evaluate the use of NLR as a potential biomarker of PA and PA severity. METHODS: Patients with PA (n = 355) were identified from 2 large PA databases in Australia and China, while controls (n = 222) were patients with hypertension who were referred for assessment but did not meet the diagnostic criteria for PA. The NLR was retrospectively collected from routine full blood examination, prior to commencement of targeted treatment for PA. RESULTS: The NLR did not differ between PA patients and hypertensive controls (median 2.3 and 2.4, P = 0.563). However, among patients with PA, the NLR was positively correlated with baseline and post-saline aldosterone levels (r = 0.22 and P < 0.001 for both) and negatively correlated with serum potassium (r = -0.15, P = 0.006). Furthermore, in a logistic regression analysis of data from patients with PA, the NLR predicted the presence of comorbid chronic kidney disease (CKD) (defined as estimated glomerular filtration rate <60 mL/min/1.73m2) with an odds ratio of 1.5 (P = 0.003). CONCLUSION: While the NLR did not distinguish PA from controls, it was a marker of PA severity, being associated with aldosterone concentration as well as the presence of CKD. A prospective study is needed to further clarify the role of NLR in predicting end-organ damage associated with PA.

Utility of adrenocorticotropic hormone in adrenal vein sampling despite the occurrence of discordant lateralization.

BACKGROUND: Adrenal vein sampling (AVS) is crucial for accurate lateralization of aldosterone excess but it is technically challenging due to the difficulty of adrenal vein cannulation. The use of adrenocorticotropic hormone (ACTH) to improve cannulation success is controversial and can lead to discordant lateralization outcomes. OBJECTIVE: To evaluate the utility of ACTH in two centres with different levels of AVS expertise and formulate a strategy for interpreting discordant results. DESIGN: A retrospective cross-sectional analysis of AVS results and postoperative patient outcomes. SETTING: Two large tertiary hospitals with harmonized AVS protocols where adrenal venous samples are collected both before and after ACTH stimulation. MEASUREMENTS: Cannulation success (measured by selectivity index, SI), lateralization (measured by lateralization index, LI) and postoperative biochemical cure. RESULTS: Number of AVS procedures judged to have successful bilateral adrenal vein cannulation increased from 53% pre- to 73% post-ACTH. The increase in cannulation success was significantly higher in centre where AVS was performed by multiple radiologists with a lower basal success rate. In both centres, the proportion of cases deemed to display lateralization significantly decreased with the use of ACTH (70% pre- to 52% post-ACTH). Based on postoperative outcomes of patients with discordant results who underwent unilateral adrenalectomy, the combination of LI >3 pre-ACTH and LI >2 post-ACTH was predictive of a biochemical cure. CONCLUSION: Adrenocorticotropic hormone can increase the rate of cannulation success during AVS at the expense of reduced lateralization. The criteria for lateralization should be carefully determined based on local data when ACTH is used.

Primary aldosteronism is a public health issue: challenges and opportunities.

A significant proportion of hypertension (potentially more than 5% in the general population) is due to primary aldosteronism (PA) which carries a worse prognosis when compared with blood pressure-matched essential hypertension. Effective targeted treatments are available which mitigate many of the cardiovascular complications of untreated PA. Despite this, the detection rate of PA in primary care is sub-optimal. In this review, we explore the challenges contributing to the under-diagnosis of PA in the community, including uncertainties regarding its actual prevalence. In order to detect PA early and offer targeted treatment before adverse cardiovascular consequences develop, routine screening for PA at the time of a diagnosis of hypertension would seem desirable. However, this is limited by a lack of studies to establish whether routine screening in primary care is cost-effective. Newer techniques are also being developed which could lessen the complexity of diagnosing PA. Most importantly, a dramatic increase in awareness of PA, as a treatable cause of hypertension, is needed amongst clinicians who manage hypertension.

Advances in type 2 diabetes therapy: a focus on cardiovascular and renal outcomes.

Treatment options for type 2 diabetes have expanded. While metformin remains the first line treatment in most cases, choices for second line treatment now extend beyond sulfonylureas and include the sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors. SGLT2 inhibitors are recommended for people with atherosclerotic cardiovascular disease, heart failure or kidney disease. Diabetic ketoacidosis is an uncommon but important side effect; its occurrence can be minimised with appropriate patient education and management, especially during perioperative periods and times of illness. GLP1 receptor agonists are recommended for people with atherosclerotic cardiovascular disease. Gastrointestinal side effects are common but are less prominent with the longer acting agents and can be minimised with slow titration of the shorter acting agents. DPP4 inhibitors are generally well tolerated, but alogliptin and saxagliptin should be used with caution in people with risk factors for heart failure. To optimise the management of type 2 diabetes, clinicians need to be aware of the pharmacological characteristics of each class of blood glucose-lowering medications and of the effect on cardiovascular health and renal function, balanced by potential adverse effects. Medications that have cardiovascular or renal benefits should be prescribed for patients with these comorbidities, and this is reflected in recent international guidelines.

Effect of angiotensin II receptor blocker and salt supplementation on short-term blood pressure variability in type 2 diabetes.

High blood pressure variability (BPV) has been associated with increased cardiovascular (CV) risk. The effect of dietary salt and renin-angiotensin-aldosterone system (RAAS) activity on short-term BPV in type 2 diabetes mellitus (T2DM) is not well characterised. We aimed to determine the effect of dietary salt (sodium chloride, NaCl) supplementation on 24-h mean arterial BPV (24hBPV) during angiotensin II receptor blocker (telmisartan) use and to evaluate the effects of age, sex, plasma renin activity (PRA) and serum aldosterone on 24hBPV. In a randomised, double-blind, crossover study, patients with T2DM (n = 28), treated with telmisartan received NaCl (100 mmol/24 h) or placebo capsules during 2 weeks of telmisartan. Following a 6-week washout, the protocol was repeated in reverse. 24hBPV was evaluated as a co-efficient of variation [CV (%) = mean/standard deviation] × 100). Twenty-four hour urinary sodium excretion, ambulatory BP and biochemical tests were performed at each phase. Results were analysed using a linear mixed model to generate predicted values for 24hBPV. Predicted 24hBPV was higher with telmisartan vs baseline (p = 0.01), with a trend towards reduced 24hBPV with salt (p = 0.052). Predicted 24hBPV was lower in females (p = 0.017), increasing age (p = 0.001) and increasing PRA (p = 0.011). In patients with T2DM, predicted 24hBPV increased from baseline with telmisartan, but there was no additional increase in predicted 24hBPV with salt supplementation. This suggests that in the short-term, salt supplementation has no apparent deleterious effects on 24hBPV. Long-term studies are required to evaluate the effect of 24hBPV on CV outcomes in patients with T2DM.

Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility.

The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.