A recent Nephrology digest,
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Study Type: Narrative review

Key Question: What is the role of mitochondrial dysfunction in CKD pathogenesis, and which diagnostic and therapeutic strategies targeting mitochondrial pathways show promise?

Key Findings:

• Mitochondrial remodelling — affecting bioenergetics, redox balance, dynamics, and biogenesis — is implicated in both diabetic and non-diabetic CKD progression
• Established agents (SGLT2 inhibitors, GLP-1 receptor agonists, non-steroidal MRAs) and emerging therapies (NAD⁺ boosters, CoQ10 derivatives, dual GIP/glucagon receptor agonists) may exert benefit partly via mitochondrial pathway modulation
• Multi-omics integration and spatial profiling are enabling development of mitochondrial health scores for precision phenotyping and individualised therapy

Clinical Relevance: With SGLT2 inhibitors and non-steroidal MRAs already embedded in NHS CKD management, understanding their mitochondrial mechanisms may inform future combination strategies and novel therapeutic targets.

Limitations: As a narrative review, conclusions are not derived from systematic evidence synthesis and are subject to selection bias.

Study Type: Educational review / core curriculum article (not original research)

Key Question: What are the distinct pathophysiological mechanisms underlying the various forms of ketoacidosis clinically encountered?

Key Findings:

• All forms share a reduced insulin-to-glucagon ratio driving lipolysis, hepatic β-oxidation, and ketone body accumulation, amplified by counterregulatory hormones (catecholamines, cortisol, growth hormone)
• Clinically distinct subtypes discussed include DKA, starvation ketosis, pregnancy-associated, alcoholic, salicylate-induced, SGLT2 inhibitor-induced, and euglycaemic ketoacidosis during continuous kidney replacement therapy (CKRT)
• Accurate subtype identification is emphasised as essential for targeted treatment, given differing triggers and metabolic contexts

Clinical Relevance: SGLT2 inhibitor-induced and CKRT-associated euglycaemic ketoacidosis are increasingly relevant to UK renal clinicians managing CKD, dialysis, and AKI patients where glucose levels may not signal the diagnosis.

Limitations: As a curriculum review, no original data are presented; recommendations reflect expert synthesis rather than primary evidence.

Study Type: Commentary / critical appraisal

Key Question: Are the 2024 KDIGO practice points on metabolic acidosis in CKD appropriately evidence-based, and do they risk undertreating patients?

Key Findings:

• KDIGO issued practice points (not formal recommendations) for metabolic acidosis in CKD, proposing treatment only when serum bicarbonate <18 mmol/L
• The authors argue this threshold is too restrictive and that the cited RCT evidence was potentially misinterpreted, leaving a significant proportion of CKD patients with untreated acidosis
• A revised evidence appraisal and future research agenda are proposed to better inform clinical practice

Clinical Relevance: UK nephrologists managing CKD patients with serum bicarbonate 18–22 mmol/L face genuine clinical uncertainty, as current KDIGO guidance may not support treatment in a group who could still benefit from alkali therapy to slow CKD progression.

Limitations: As a commentary, no new primary data are presented; conclusions rely on the authors' reinterpretation of existing evidence.

Study Type: Prospective cohort study

Key Question: Does pre-pandemic CKD stage predict risk of severe acute COVID-19, Long COVID, and post-vaccination antibody response?

Key Findings:

• Severe COVID-19 risk increased progressively with CKD stage: HR 1.27 (moderate), 2.33 (high), and 2.72 (very high) versus low-stage CKD
• Post-vaccination anti-Spike IgG levels were substantially lower with advancing CKD: –12% (moderate), –27% (high), and –49% (very high stage)
• Long COVID (LCRI score ≥11) was only significantly more prevalent in very high-stage CKD (OR 2.20; 95% CI 1.16–4.18); no consistent association in earlier stages

Clinical Relevance: These findings support prioritising enhanced vaccination strategies and clinical vigilance for severe infection in CKD patients across all stages, relevant to NHS renal and primary care COVID-19 management pathways.

Limitations: Several key outcomes relied on self-report, introducing potential misclassification bias.

Study Type: Narrative review / commentary

Key Question: Can a palliative, person-centred framework ("palliative dialysis") better align dialysis care with the goals and preferences of patients living with ESKD?

Key Findings:

• Current dialysis models prioritise longevity and transplantation, which may not reflect realistic or patient-preferred outcomes given high rates of comorbidity and frailty in this population
• "Palliative dialysis" is proposed as a framework integrating goals-of-care alignment, quality-of-life optimisation, and adaptive treatment across the disease trajectory
• Concurrent hospice and dialysis is highlighted as an innovative end-of-life model, alongside system- and policy-level changes needed for implementation

Clinical Relevance: Relevant to UK nephrology teams navigating conservative kidney management, dialysis withdrawal, and advance care planning within NHS renal services where person-centred care is a strategic priority.

Limitations: As a narrative review, no primary data are presented; recommendations lack empirical validation.

Study Type: Commentary / conceptual review

Key Question: Does sex-based dimorphism in renal potassium handling have clinically relevant implications for diuretic prescribing and electrolyte management?

Key Findings:

• Males exhibit an androgen-driven proximal-tubular-dominant pattern of sodium/K⁺ reabsorption; females rely on a distal-dominant strategy via upregulated thiazide-sensitive NCC, modulated by oestrogen and the WNK-SPAK kinase network
• This female-specific distal architecture resolves the aldosterone paradox during pregnancy but confers greater susceptibility to thiazide-induced hypokalaemia and hyponatraemia
• Post-menopausal loss of oestrogen removes the protective hormonal context, amplifying this vulnerability

Clinical Relevance: UK clinicians prescribing thiazides or thiazide-like diuretics (e.g., indapamide, bendroflumethiazide) should recognise that post-menopausal women represent a higher-risk group for electrolyte disturbance requiring closer monitoring.

Limitations: As a conceptual review drawing largely on animal and mechanistic data, direct clinical applicability to human prescribing practice remains inferential pending prospective human studies.

Study Type: Retrospective multicentre cohort study (real-world EHR data, PEDSnet network)

Key Question: What is the natural history and risk of kidney disease progression in children with C3G or IC-MPGN?

Key Findings:

• Of 204 children with MPGN identified, 159 were classifiable as C3G or IC-MPGN; baseline characteristics (eGFR, albumin, urine PCR, C3) did not differ significantly between groups.
• Rates of progression to the composite outcome (≥50% eGFR reduction, dialysis, or transplant) were similar between C3G and IC-MPGN.
• Low serum C3 at baseline was associated with reaching the composite kidney outcome.

Clinical Relevance: Emerging complement-targeted therapies (relevant to NHS prescribing decisions) may benefit both diagnostic subgroups equally, as clinical trajectories appear indistinguishable regardless of classification.

Limitations: Retrospective EHR-based design limits completeness of histopathological classification and follow-up data standardisation across institutions.

Study Type: Narrative review

Key Question: Do cardiovascular disease burden, phenotype, and outcomes differ across ethnic and regional CKD populations, and what drives these differences?

Key Findings:

• North American and European CKD cohorts (CRIC, GCKD, EQUAL) show greater atherosclerotic burden, coronary artery calcification, left ventricular hypertrophy, and cardiovascular-dominant clinical trajectories
• East Asian cohorts (CKD-JAC, C-STRIDE, KNOW-CKD) demonstrate fewer structural cardiac abnormalities and a kidney-dominant trajectory, with renal outcomes proportionally more prominent than cardiovascular events
• Observed differences appear driven by cardiometabolic risk profiles, inflammatory burden, environmental exposures, and healthcare access rather than race per se

Clinical Relevance: UK nephrology teams managing ethnically diverse CKD populations should consider phenotype- and exposure-informed CVD risk stratification — incorporating imaging, inflammatory biomarkers, and cardiometabolic profiling — rather than race-based assumptions.

Limitations: As a narrative review, it is subject to selective cohort inclusion and cannot establish causality between regional/ethnic factors and cardiorenal phenotype differences.