Monogenic nephrolithiasis-collision of phenotypes, genotypes, and phenocopies

[Extract] Kidney stone disease is not uncommon in the general population and can be underpinned by multiple potential and predisposing underlying biochemical phenomena and phenotypes. The unraveling of these phenotypes and their potential monogenic and polygenic relationships is revealing a much more complex landscape than was previously appreciated. Even for the most significant of major underpinning urinary phenotypes, such as hypercalciuria, this is revealing complexity even though pathways toward precision medicine for affected individuals are being conceptualized

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

Purpose of review: This review will summarize and synthesize recent findings in regard to monogenic kidney disorders, including how that evidence is being translated into practice. It will add to existing key knowledge to provide context for clinicians in consolidating existing practice and approaches. Recent findings: Whilst there are long established factors, which indicate increased likelihood of identifying a monogenic cause for kidney disease, these can now be framed in terms of the identification of new genes, new indications for genomic testing and new evidence for clinical utility of genomic testing in nephrology. Further, inherent in the use of genomics in nephrology are key concepts including robust informed consent, variant interpretation and return of results. Recent findings of variants in genes related to complex or broader kidney phenotypes are emerging in addition to understanding of de novo variants. Phenocopy phenomena are indicating a more pragmatic use of broader gene panels whilst evidence is emerging of a role in unexplained kidney disease. Clinical utility is evolving but is being successfully demonstrated across multiple domains of outcome and practice. Summary: We provide an updated framework of evidence to guide application of genomic testing in chronic kidney disease (CKD), building upon existing principles and knowledge to indicate how the practice and implementation of this can be applied today. There are clearly established roles for genomic testing for some patients with CKD, largely those with suspected heritable forms, with these continuing to expand as new evidence emerges

A clinical approach to tubulopathies in children and young adults

Kidney tubules are responsible for the preservation of fluid, electrolyte and acid-base homeostasis via passive and active mechanisms. These physiological processes can be disrupted by inherited or acquired aetiologies. The net result is a tubulopathy. It is important to make a prompt and accurate diagnosis of tubulopathies in children and young adults. This allows timely and appropriate management, including disease-specific therapies, and avoids complications such as growth failure. Tubulopathies can present with a variety of non-specific clinical features which can be diagnostically challenging. In this review, we build from this common anatomical and physiological understanding to present a tangible appreciation of tubulopathies as they are likely to be clinically encountered among affected children and young adults

Diagnostic utility and outcomes of inpatient investigations for syncope in a regional setting

Background: Syncope is a common presentation to the emergency department with a wide spectrum of aetiology. The identification of the underlying cause can be diagnostically challenging, as are the choice of investigations and the decision for inpatient versus outpatient disposition. Aims: This study aimed to evaluate the aetiology of syncope as documented, the diagnostic yield of inpatient investigations and outcomes for adult patients admitted for syncope. Methods: A single-centred, retrospective cohort study was conducted in adult patients admitted for syncope within a 2-year period. A total of 386 patients were identified after exclusion. Information regarding syncope aetiology, investigations and outcomes were established via chart review of electronic records. Results: The most common cause of syncope was neural-mediated (43%), followed by orthostatic (36.5%) and cardiogenic (20.5%). The investigations performed in order of frequency included: telemetry electrocardiogram (ECG) (75.4%), computed tomography head non-contrast (58.8%), transthoracic echocardiogram (TTE) (20.2%), computed tomography pulmonary angiogram (CTPA) (6.5%), MR brain (3.9%), electroencephalogram (1.3%) and carotid ultrasound (0.3%). Telemetry ECG, TTE and CTPA led to the diagnosis of syncope in a minority of patients only. As a result, 17.5% of patients had a new intervention on discharge, 5.4% were readmitted for syncope and 9.6% of patients died. Conclusions: In the context of the inpatient evaluation of syncope, this study supports the use of telemetry ECG and TTE. Neuroimaging demonstrates a low diagnostic yield for the cause of syncope, but it may have a role to play in excluding other pathologies. Our study does not support the routine use of CTPA, EEG or carotid ultrasound in the evaluation of syncope

Characterising patients and clinician experiences in comprehensive conservative care for kidney failure in Northern Queensland

Background: Comprehensive conservative care (CCC) is an emerging treatment option in kidney failure (KF), but its implementation has been restricted by a limited understanding of KF populations, outcomes and clinician experiences. Aims: This pilot study aimed to investigate the characteristics of patients who are opting for (CCC) in North Queensland, Australia. It also aimed to highlight clinician factors impacting treatment discussions. Methods: It was an observational study facilitated through an online cross-sectional survey to nephrologists, nephrology advanced trainees and nurse practitioners working across North Queensland. Results: Study participants disagreed with the statement that patients commencing dialysis are more likely to have cardiac co-morbidities (46.7%), diabetes (40.0%), stroke (60.0%), liver disease (60.0%), chronic lung disease (53.3%), cognitive impairment (60.0%) and use of mobility aids (80.0%) than those commencing CCC. Conversely, they agreed that patients commencing dialysis are more likely to be independent (66.7%) and living in their private residence (40.0%). The median frailty score in patients choosing dialysis was 3.0 (interquartile range (IQR) 2.8–3.3), while that of patients selecting CCC was 4.5 (IQR 3.8–7.0). Our participants were aware of at least one clinical prognostication tool, and the one most frequently used was the ‘Surprise Question’ (46.2%, n = 6). Overall, our participants demonstrated low confidence (median 8.0%, IQR 6.0–8.0%) in facilitating CCC discussions. Conclusion: Patients who are highly co-morbid and frail and have functional impairment are suitable candidates for CCC. More focus needs to be placed on objective prognostication of patients and the upskilling of clinicians to advocate for, and deliver, CCC

Pharmacist-Led Education for Final Year Medical Students: A Pilot Study

Background: Prescribing is a core skillset for medical officers. Prescribing errors or deficiencies can lead to patient harm and increased healthcare costs. There is an undefined role for pharmacist-led education to final year medical students to improve prescribing skills. Aim: Assess if pharmacist-led education on prescription writing improves the quality and safety of final year medical students' prescribing skills. Method: Participants and Intervention: Final year medical students were randomised into tutorial (TG) or non-tutorial groups (NTG) and assessed pre- and post- intervention. TG received education by a clinical pharmacist and pharmacy educator using case-based learning. NTG received no additional training as per usual practice. Following the pre-test, all students completed a 3-week tertiary hospital medical ward placement. Students completed the post-test following placement and after the TG participated in the intervention. Student Assessment: Assessment included writing Schedule 4 (S4, prescription only), Schedule 8 (S8, controlled drug), S4 streamline (S4SL), and Mixed case (S4 and S8) prescriptions. Results: At baseline, there were no significant differences between TG and NTG for overall scores or proportion of passes. Post intervention scores significantly improved in TG (p = 0.012) whereas scores significantly decreased in the NTG (p = 0.004). The overall proportion of passes was significantly higher in the TG than NTG (p < 0.001). Conclusion: Education by a clinical pharmacist improved short-term prescribing skills of final year medical students in this study. Students learning primarily experientially from peers and rotational supervisors showed decreased prescribing skills. We propose pharmacist-led education on prescription writing should be further evaluated in larger studies across more student cohorts and for longer periods of follow up time to clarify whether such an educational model could be included in future medical school curricula

The Heritability of Kidney Function Using an Older Australian Twin Population

Introduction: Twin studies are unique population models which estimate observed rather than inferred genetic components of complex traits. Nonmonogenic chronic kidney disease (CKD) is a complex disease process with strong genetic and environmental influences, amenable to twin studies. We aimed to assess the heritability of CKD using twin analysis and modeling within Older Australian Twin Study (OATS) data. Methods: OATS had 109 dizygotic (DZ) and 126 monozygotic (MZ) twin pairs with paired serum creatinine levels. Heritability of kidney function as estimated glomerular filtration rate (eGFR CKD Epidemiology Collaboration [CKD-EPI]) was modeled using the ACE model to estimate additive heritability (A), common (C), and unique (E) environmental factors. Intratwin pair analysis using mixed effects logistic regression allowed analysis of variation in eGFR from established CKD risk factors. Results: The median age was 69.71 (interquartile range 78.4–83.0) years, with 65% female, and a mean CKD-EPI of 82.8 ml/min (SD 6.7). The unadjusted ACE model determined kidney function to be 33% genetically determined (A), 18% shared genetic-environmental (C), and 49% because of unique environment (E). This remained unchanged when adjusted for age, hypertension, and sex. Hypertension was associated with eGFR; however, intertwin variance in hypertension did not explain variance in eGFR. Two or more hypertension medications were associated with decreased eGFR (P = 0.009). Conclusion: This study estimates observed heritability at 33%, notably higher than inferred heritability in genome-wide association study (GWAS) (7.1%–18%). Epigenetics and other genomic phenomena may explain this heritability gap. Difference in antihypertension medications explains part of unique environmental exposures, though discordance in hypertension and diabetes does not

An audit of electron microscopy in the diagnosis of focal segmental glomerulosclerosis: are current pathological techniques missing important abnormalities in the glomerular basement membrane?

Background: There is an increasing appreciation that variants of the collagen IV genes may be associated with the development of focal segmental glomerulosclerosis (FSGS). On electron microscopy, such variants may produce characteristic changes within the glomerular basement membrane (GBM). These changes may be missed if glomerular lesions histologically diagnosed as FSGS on light microscopy are not subjected to electron microscopy. Methods: We conducted a retrospective cohort analysis of all patients presenting to two hospitals who received a primary histological diagnosis of FSGS to see if these samples underwent subsequent electron microscopy. Each such sample was also scrutinised for the presence of characteristic changes of an underlying collagen IV disorder. Results: A total of 43 patients were identified. Of these, only 30 underwent electron microscopy. In two samples there were histological changes detected that might have suggested the underlying presence of a collagen IV disorder. Around one in three biopsy samples that had a histological diagnosis of FSGS were not subjected to electron microscopy. Conclusion: Renal biopsy samples that have a histological diagnosis of primary FSGS not subjected to subsequent electron microscopy may potentially miss ultrastructural changes in the GBM that could signify an underlying collagen IV disorder as the patient’s underlying disease process. This could potentially affect both them and their families’ investigative and management decisions given potential for implications for transplant, heritability and different disease pathogenesis. This represents a gap in care which should be reflected upon and rectified via iterative standard care and unit-level quality assurance initiatives

Clinical versus research genomics in kidney disease

Key differences exist between clinical and research genomics. As genomic testing is adopted in nephrology clinical care, we propose focusing on clinical genomics approaches to obtain genetic diagnoses in order to ensure optimal use of resources and maximum patient benefit

Antenatally diagnosed ADPKD

[Extract] Advances in antenatal ultrasonographyhave substantially improved the counseling of pregnantwomen.1�4With this advancement comes a diagnosticdilemma in the approach to antenatal diagnoses of cystickidney disease. The differential diagnosis of enlargedcystic echogenic kidneys includes autosomal dominantpolycystic kidney disease (ADPKD), autosomal recessivepolycystic kidney disease, renal cysts and diabetessyndrome, and other syndromic disorders