PYROXD1-associated myopathy.

PYROXD1-associated myopathy is a rare genetic form of limb-girdle muscular dystrophy (LGMD) with only 23 previous cases having been reported in the literature. The exact role of PYROXD1 in the pathophysiology of LGMD remains unclear. We describe two brothers who presented to the neuromuscular clinic with progressive weakness of their upper and lower limbs over the preceding decades. Our case highlights how recent advancements in genetic sequencing have revolutionised the diagnostic classification process for LGMD and provided opportunities to establish diagnoses for previously unclassified myopathies. We also illustrate how the increased adoption of muscle MRI to identify disease and target muscle biopsy can provide better quality and more informative samples for classification. Finally, our report details the clinical and histopathological findings found in both cases adding valuable data to the currently limited information published on PYROXD1-associated myopathy.

Analyzing COVID-19 Vaccine Responses in Transplant Recipients.

COVID-19 vaccination has significantly impacted the global pandemic by reducing the severity of infection, lowering rates of hospitalization, and reducing morbidity/mortality in healthy individuals. However, the degree of vaccine-induced protection afforded to renal transplant recipients who receive forms of maintenance immunosuppression remains poorly defined. This is particularly important when we factor in the emergence of SARS-CoV-2 variants of concern (VOCs) that have defined mutations that reduce the effectiveness of Ab responses targeting the Spike Ags from the ancestral Wuhan-Hu-1 variants employed in the most widely used vaccine formats. In this study, we describe a qualitative, longitudinal analysis of neutralizing Ab responses against multiple SARS-CoV-2 VOCs in 129 renal transplant recipients who have received three doses of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2). Our results reveal a qualitative and quantitative reduction in the vaccine-induced serological response in transplant recipients versus healthy controls where only 51.9% (67 of 129) made a measurable vaccine-induced IgG response and 41.1% (53 of 129) exhibited a significant neutralizing Ab titer (based on a pseudovirus neutralization test value >50%). Analysis on the VOCs revealed strongest binding toward the wild-type Wuhan-Hu-1 and Delta variants but none with both of the Omicron variants tested (BA1 and BA2). Moreover, older transplant recipients and those who are on mycophenolic acid as part of their maintenance therapy exhibited a profound reduction in all of the analyzed vaccine-induced immune correlates. These data have important implications for how we monitor and manage transplant patients in the future as COVID-19 becomes endemic in our populations.

Nuclear Magnetic Resonance Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls.

BACKGROUND: The urine metabolites and chemistries that contribute to kidney stone formation are not fully understood. This study examined differences between the urine metabolic and chemistries profiles of first-time stone formers and controls. METHODS: High-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was performed in 24-hour urine samples from a prospective cohort of 418 first-time symptomatic kidney stone formers and 440 controls. In total, 48 NMR-quantified metabolites in addition to 12 standard urine chemistries were assayed. Analysis of covariance was used to determine the association of stone former status with urine metabolites or chemistries after adjusting for age and sex and correcting for the false discovery rate. Gradient-boosted machine methods with nested cross-validation were applied to predict stone former status. RESULTS: Among the standard urine chemistries, stone formers had lower urine oxalate and potassium and higher urine calcium, phosphate, and creatinine. Among NMR urine metabolites, stone formers had lower hippuric acid, trigonelline, 2-furoylglycine, imidazole, and citrate and higher creatine and alanine. A cross-validated model using urine chemistries, age, and sex yielded a mean AUC of 0.76 (95% CI, 0.73 to 0.79). A cross-validated model using urine chemistries, NMR-quantified metabolites, age, and sex did not meaningfully improve the discrimination (mean AUC, 0.78; 95% CI, 0.75 to 0.81). In this combined model, among the top ten discriminating features, four were urine chemistries and six NMR-quantified metabolites. CONCLUSIONS: Although NMR-quantified metabolites did not improve discrimination, several urine metabolic profiles were identified that may improve understanding of kidney stone pathogenesis.

The Barriers and Facilitators to the Use of Lifestyle Apps: A Systematic Review of Qualitative Studies.

BACKGROUND: Mobile-health applications are revolutionising the way healthcare is being delivered. However, current research focusses on apps aimed at monitoring of conditions rather than the prevention of disease. Healthcare apps that prevent disease can be classified as lifestyle apps (LAs) and encompass mindfulness, exercise, and diet apps. In order for widespread implementation of these apps, perspectives of the user must be taken into consideration. Therefore, this systematic literature review identifies the barriers and facilitators to the use of LAs from a user's perspective. OBJECTIVE: To both identify the facilitators to the use of LAs from a user perspective as well as identify the barriers to the use of LAs from a user perspective. METHODS: A systematic literature review was conducted following PRISMA guidelines. Qualitative articles focussed on a healthy non-diseased population were obtained. Two independent researchers coded the articles, and themes were identified. RESULTS: Our results found that there were five barriers and five facilitators to app use. The facilitators included (1) motivational aspects to the user, (2) effective marketing and communication, (3) user-centred design and content, (4) humanising technology, and (5) accessibility. The five barriers identified were (1) a non-conducive, (2) poor marketing and branding, (3) controlling and invasive, (4) disengaging content, and (5) inaccessibility. CONCLUSIONS: By overcoming the barriers of LAs and encouraging the facilitators found, users are more likely to engage with this method of health promotion. Future research must be conducted on the barriers and facilitators to development and distribution of apps in order for LAs to be implemented in widespread healthcare practice.

Death With Function and Graft Failure After Kidney Transplantation: Risk Factors at Baseline Suggest New Approaches to Management.

BACKGROUND: Improving both patient and graft survival after kidney transplantation are major unmet needs. The goal of this study was to assess risk factors for specific causes of graft loss to determine to what extent patients who develop either death with a functioning graft (DWFG) or graft failure (GF) have similar baseline risk factors for graft loss. METHODS: We retrospectively studied all solitary renal transplants performed between January 1, 2006, and December 31, 2018, at 3 centers and determined the specific causes of DWFG and GF. We examined outcomes in different subgroups using competing risk estimates and cause-specific Cox models. RESULTS: Of the 5752 kidney transplants, graft loss occurred in 21.6% (1244) patients, including 12.0% (691) DWFG and 9.6% (553) GF. DWFG was most commonly due to malignancy (20.0%), infection (19.7%), cardiac disease (12.6%) with risk factors of older age and pretransplant dialysis, and diabetes as the cause of renal failure. For GF, alloimmunity (38.7%), glomerular diseases (18.6%), and tubular injury (13.9%) were the major causes. Competing risk incidence models identified diabetes and older recipients with higher rates of both DWFG and nonalloimmune GF. CONCLUSIONS: These data suggest that at baseline, 2 distinct populations can be identified who are at high risk for renal allograft loss: a younger, nondiabetic patient group who develops GF due to alloimmunity and an older, more commonly diabetic population who develops DWFG and GF due to a mixture of causes-many nonalloimmune. Individualized management is needed to improve long-term renal allograft survival in the latter group.

Microsporidium Infection-Associated Acute Kidney Injury in a Patient With HIV.

Patients infected with HIV (human immunodeficiency virus) are at an increased risk of developing acute kidney injury (AKI) compared with patients without HIV infection. We report a rare case of disseminated Microsporidium infection-associated AKI affecting the native kidneys in a 30-year-old Asian woman with HIV infection. She initially presented to an outside institution with AKI after completing treatment with trimethoprim-sulfamethoxazole (Bactrim [Hoffmann-La Roche]) and prednisone for Pneumocystis pneumonia. She was empirically treated with prednisone for presumed acute interstitial nephritis due to Bactrim, and her serum creatinine concentration improved from 3.0 mg/dL to 1.8 mg/dL. She was subsequently initiated on antiretroviral therapy and was also treated with ganciclovir for cytomegalovirus viremia. Because of persistent fever, she was transferred to our institution and was diagnosed with a disseminated Mycobacterium avium complex infection and a disseminated Microsporidium infection. Her serum creatinine concentration increased to 4.2 mg/dL. A kidney biopsy was performed because of her worsening kidney function, which revealed plasma cell-rich acute interstitial nephritis associated with disseminated Microsporidium infection. She was maintained on antiretroviral therapy and was treated with albendazole. This case highlights the fact that there are various etiologies and kidney manifestations of AKI in patients infected with HIV with equally various implications for management; thus, performing a kidney biopsy is often crucial to help elucidate the underlying pathology and guide management.

Clinical and Kidney Structural Characteristics of Living Kidney Donors With Nephrolithiasis and Their Long-term Outcomes.

BACKGROUND: Nephrolithiasis in living kidney donors is concerning due to the potential impact on long-term postdonation kidney function. METHODS: We performed a cohort study of living kidney donors from 2 centers with a baseline computed tomography scan and implantation renal biopsy. Donors (>5 y since donation) completed a follow-up survey or underwent chart review to assess eGFR and incident hypertension. Stone formers were classified as symptomatic if they had a past symptomatic episode or asymptomatic if only incidental radiographic kidney stones were identified during donor evaluation. We compared baseline clinical, imaging, and biopsy characteristics by stone former status including review of metabolic evaluations in stone formers. Long-term risks of renal complications (low eGFR and hypertension) by stone former status were evaluated. RESULTS: There were 12 symptomatic and 76 asymptomatic stone formers among 866 donors. Overall, baseline clinical characteristics and implantation biopsy findings were similar between stone formers and non-stone formers. After a median follow-up of 10 y, stone former status was not associated with eGFR <60 mL/min/1.73 m2, eGFR <45 mL/min/1.73 m2, or hypertension. CONCLUSIONS: Both asymptomatic and symptomatic SF have favorable histology findings at baseline. Long-term kidney outcomes were favorable in select stone formers with no evident increased long-term risk for decreased kidney function or hypertension after donation.

Renal function outcomes and kidney biopsy features of living kidney donors with hypertension.

BACKGROUND: The medium- to long-term outcomes of living kidney donors with hypertension compared to normotensive donors are not well understood, especially with the recent changes in hypertension guidelines. METHODS: We studied a cohort of 950 living kidney donors using different definitions of hypertension based on either ≥140/90 or ≥130/80 mmHg thresholds and based on either office or ambulatory blood pressure readings. Microstructural features on kidney biopsy at the time of donation were compared using different definitions of hypertension. RESULTS: After adjusting for years of follow-up, age, sex, and baseline eGFR, hypertension (by any definition) did not significantly predict an eGFR < 45 ml/min/1.73 m2 at a median follow-up of 10 years postdonation, though there was a borderline association with ambulatory blood pressure ≥ 130/80 mmHg predicting a 40% decline in eGFR (OR = 1.53, 1.00-2.36; p = .051). Proteinuria was predicted by office blood pressure ≥ 140/90 mmHg and by nondipper profile on nocturnal ambulatory blood pressure measurements. At the time of donation, larger glomeruli and arterial hyalinosis on biopsy were associated with hypertension defined by either ≥140/90 or ≥130/80 mmHg (by office or ambulatory measurements). Nocturnal nondipper status was associated with larger glomeruli size but not arteriolar hyalinosis when compared to dippers. CONCLUSIONS: In programs that accept donors with controlled hypertension, various definitions of hypertension are associated with histological findings in the donated kidney, but none predict a clinically significant decline in kidney function 10 years after donation. These data support allowing healthy individuals with controlled hypertension to donate a kidney. However, donors with office hypertension (≥140/90 mmHg) and nondippers (regardless of hypertension status) are at greater long-term risk for proteinuria, and particularly for these donors, longer follow-up is warranted.

Subsequent urinary stone events are predicted by the magnitude of urinary oxalate excretion in enteric hyperoxaluria.

Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. Therefore, we assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. Mean ± standard deviation age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6-73.0) mg/24 h and 81 patients had one or more stone event during a median follow-up time of 4.9 (2.8-7.8) years. Higher UOx was associated with a higher probability of developing a stone event (P < 0.01) and predicted an increased annual risk of kidney stones (P = 0.001). Estimates derived from these analyses suggest that a 20% decrease in UOx is associated with 25% reduction in the annual odds of a future stone event. Thus, these data demonstrate an association between baseline UOx and stone events in EH patients and highlight the potential benefit of strategies to reduce UOx in this patient group. BACKGROUND: Data directly demonstrating the relationship between urinary oxalate (UOx) excretion and stone events in those with enteric hyperoxaluria (EH) are limited. METHODS: We assessed the relationship between UOx excretion and risk of kidney stone events in a retrospective population-based EH cohort. In all, 297 patients from Olmsted County, Minnesota were identified with EH based upon having a 24-h UOx ≥40 mg/24 h preceded by a diagnosis or procedure associated with malabsorption. Diagnostic codes and urologic procedures consistent with kidney stones during follow-up after baseline UOx were considered a new stone event. Logistic regression and accelerated failure time modeling were performed as a function of UOx excretion to predict the probability of new stone event and the annual rate of stone events, respectively, with adjustment for urine calcium and citrate. RESULTS: Mean ± SD age was 51.4 ± 11.4 years and 68% were female. Median (interquartile range) UOx was 55.4 (46.6-73.0) mg/24 h and 81 patients had ≥1 stone event during a median follow-up time of 4.9 (2.8-7.8) years. Higher UOx was associated with a higher probability of developing a stone event (P < 0.01) and predicted an increased annual risk of kidney stones (P = 0.001). Estimates derived from these analyses suggest that a 20% decrease in UOx is associated with 25% reduction in the annual odds of a future stone event. CONCLUSIONS: These data demonstrate an association between baseline UOx and stone events in EH patients and highlight the potential benefit of strategies to reduce UOx in this patient group.

Mesangial expansion at 5 years predicts death and death-censored graft loss after renal transplantation.

Death with a functioning graft and death-censored renal allograft failure remain major problems for which effective preventative protocols are lacking. The retrospective cohort study aimed to determine whether histologic changes on a 5-year surveillance kidney biopsy predict adverse outcomes after transplantation in recipients who had: both Type 2 diabetes (T2DM) and obesity (BMI ≥ 30 kg/m2 ) at the time of transplantation (T2DM/Obesity, n = 75); neither (No T2DM/No obesity, n = 78); No T2DM/Obesity (n = 41), and T2DM/No obesity (n = 47). On 5-year biopsies, moderate-to-severe mesangial expansion was more common in the T2DM/Obesity group (Banff mm score ≥2 = 49.3%; Tervaert classification MS ≥ 2b = 26.7%) compared to the other groups (p < .001 for both scores). Risk factors included older age, higher BMI, HbA1C, and triglycerides at 1-year post-transplant. Moderate-to-severe mesangial expansion correlated with death with function (HR 1.74 (1.01, 2.98), p = .045 Banff and 1.89 (1.01, 3.51) p = .045 Tervaert) and with death-censored graft loss (HR 3.2 (1.2, 8.8), p = .02 Banff and HR 3.8 (1.3, 11.5), p = .01 Tervaert) over a mean of 11.6 years of recipient follow-up post-transplant. These data suggest that mesangial expansion in recipients with T2DM and obesity may reflect systemic vascular injury and might be a novel biomarker to predict adverse outcomes post renal transplant.

Chronic Histologic Changes Are Present Regardless of HLA Mismatches: Evidence from HLA-Identical Living Donor Kidney Transplants.

BACKGROUND: At 5 and 10 y after kidney transplantation, chronic histologic changes such as arteriolar hyalinosis and mesangial expansion are common; however, determining cause is difficult. We compared surveillance biopsies in living donor kidney transplants (LDKTx) from HLA-matched siblings (termed HLA-identical [HLA-ID]) with HLA non-ID to investigate which histologic changes were likely due to alloimmune injury and which were due to nonalloimmune injury. METHODS: We performed a retrospective, cohort study comparing HLA-ID sibling LDKTx (n = 175) with HLA non-ID LDKTx (n = 175; matched for age, sex, and year of transplant ±2 y) performed at a single institution from March 1999 to November 2018. RESULTS: Baseline characteristics and maintenance immunosuppression were similar. Mortality rates were similar, but in the HLA-ID group, 10-y death-censored graft survival was higher (93.8% versus 80.9% HLA non-ID LDKTx; P < 0.001), rejection rates were lower (after 1 y 9.6% versus 27.1%; P < 0.001), and Banff inflammation scores including glomerulitis and peritubular capillaritis were lower on surveillance biopsies at 1, 5, and 10 y. In contrast, chronic Banff scores (interstitial fibrosis, arteriolar hyalinosis, mesangial expansion, etc) were similar in prevalence and severity on surveillance biopsies at 1, 5, and 10 y. CONCLUSIONS: HLA-ID LDKTx have less inflammation and less transplant glomerulopathy, but most chronic histologic changes were similar to less well-matched LDKTx. We conclude that these types of chronic changes are not associated with HLA mismatches and may be due to nonimmunologic causes (hypertension, obesity, etc), suggesting that new management approaches to prevent these lesions may be needed.

The role of kidney biopsy in diagnosis of preeclampsia in kidney transplant patients.

OBJECTIVE: The aim of this report is to review two patients who developed proteinuria in pregnancy after kidney transplant in order to highlight the importance of maintaining a broad differential and the diagnostic utility of kidney biopsy in this clinical scenario. METHODS: Two cases of women with kidney transplants who presented with proteinuria in pregnancy are described and the literature is reviewed. RESULTS: In both cases, a kidney biopsy allowed for prompt diagnosis and treatment. CONCLUSION: Kidney biopsy should be considered an important diagnostic tool in this clinical scenario. ABBREVIATIONS: ACE: angiotensin-converting enzyme; ESKD: end-stage kidney disease; FSGS: focal segmental glomerulosclerosis; RAAS: renin aldosterone angiotensin system.

The Use of GLP1R Agonists for the Treatment of Type 2 Diabetes in Kidney Transplant Recipients.

Glucagon-like peptide-1 receptor agonists (GLP1RA) have been shown to improve glucose control and diabetes-related comorbidities in patients without solid organ transplants. The effectiveness, safety, and tolerability of GLP1RA after kidney transplantation have not been adequately studied. METHODS: We retrospectively reviewed data on kidney transplant recipients performed in our institution, who were initiated on GLP1RA either for the treatment of type 2 diabetes diagnosed before transplantation or posttransplant diabetes. We analyzed efficacy, safety, and the effect on kidney allograft function. RESULTS: Seventeen kidney transplant recipients were initiated on GLP1RA therapy, 14 of which remained on the medication for at least 12 months. The use of GLP1RA had no significant impact on weight loss, but was associated with a significant reduction in the total daily insulin dose, from the median of 63 [interquartile range 43-113] IU to 44 [interquartile range 25-88] and reduction in the risk of hypoglycemia in patients who were on therapy for at least approximately 12 months. Kidney function remained stable and none of the recipients experienced acute rejection. Tacrolimus dose was not significantly changed. Five patients (29%) discontinued GLP1RA therapy-4 due to side effects and 1 due to uncontrolled hyperglycemia. CONCLUSIONS: GLP1RA may be a relatively safe and effective treatment for kidney transplant recipients with type 2 diabetes that allows for a reduction in insulin requirements. More studies are needed to determine whether the use of these agents will translate into an improvement in allograft and patient survival.

Symptomatic and Radiographic Manifestations of Kidney Stone Recurrence and Their Prediction by Risk Factors: A Prospective Cohort Study.

BACKGROUND: Meaningful interpretation of changes in radiographic kidney stone burden requires understanding how radiographic recurrence relates to symptomatic recurrence and how established risk factors predict these different manifestations of recurrence. METHODS: We recruited first-time symptomatic stone formers from the general community in Minnesota and Florida. Baseline and 5-year follow-up study visits included computed tomography scans, surveys, and medical record review. We noted symptomatic recurrence detected by clinical care (through chart review) or self-report, and radiographic recurrence of any new stone, stone growth, or stone passage (comparing baseline and follow-up scans). To assess the prediction of different manifestations of recurrence, we used the Recurrence of Kidney Stone (ROKS) score, which sums multiple baseline risk factors. RESULTS: Among 175 stone formers, 19% had symptomatic recurrence detected by clinical care and 25% detected by self-report; radiographic recurrence manifested as a new stone in 35%, stone growth in 24%, and stone passage in 27%. Among those with a baseline asymptomatic stone (54%), at 5 years, 51% had radiographic evidence of stone passage (accompanied by symptoms in only 52%). Imaging evidence of a new stone or stone passage more strongly associated with symptomatic recurrence detected by clinical care than by self-report. The ROKS score weakly predicted one manifestation-symptomatic recurrence resulting in clinical care (c-statistic, 0.63; 95% confidence interval, 0.52 to 0.73)-but strongly predicted any manifestation of symptomatic or radiographic recurrence (5-year rate, 67%; c-statistic, 0.79; 95% confidence interval, 0.72 to 0.86). CONCLUSIONS: Recurrence after the first stone episode is both more common and more predictable when all manifestations of recurrence (symptomatic and radiographic) are considered.