Non-steroidal anti-inflammatory drugs and risk of acute adverse renal outcomes in diabetes and diabetic kidney disease.

BACKGROUND: Individuals with diabetes mellitus (DM) may be susceptible to non-steroidal anti-inflammatory drug (NSAID)-induced acute kidney injury (AKI) but data on NSAID-related adverse renal events is sparse. OBJECTIVE: We aimed to evaluate the risk of acute kidney injury and/or hyperkalemia after systemic NSAID among individuals with DM and diabetic chronic kidney disease (CKD). METHODS: Retrospective cohort study of 3896 adults with DM with incident prescriptions between July 2015 and December 2017 from Singapore General Hospital and SingHealth Polyclinics. Laboratory, hospitalization and medication data were retrieved from electronic medical records. The primary outcome was the incidence of AKI and/ or hyperkalemia within 30 days after prescription. RESULTS: AKI and/or hyperkalemia occurred in 13.5% of all DM and 15.8% of diabetic CKD. The association between systemic NSAID >14 days and 30-day risk of AKI and/or hyperkalemia failed to reach statistical significance in unselected DM (adjusted OR 1.62, 95% CI 0.99-2.65, p = 0.05) and diabetic CKD (adjusted OR 0.64, 95% CI 0.15-2.82, p = 0.64), but the odds of AKI and/or hyperkalemia were markedly and significantly increased when NSAID was prescribed with renin-angiotensin-aldosterone system (RAAS) blocker (adjusted OR 4.17, 95% CI 1.74-9.98, p = 0.001) or diuretic (adjusted OR 3.31, 95% CI 1.09-10.08, p = 0.04) and in the absence of diabetic CKD (adjusted OR 1.98, 95% CI 1.16-3.36, p = 0.01). CONCLUSION: NSAID prescription >14 days in individuals with DM with concurrent RAAS blockers or diuretics was associated with higher 30-day risk of AKI and/or hyperkalemia.

Short-Course Systemic and Topical Non-Steroidal Anti-Inflammatory Drugs: Impact on Adverse Renal Events in Older Adults with Co-Morbid Disease.

BACKGROUND: Prolonged systemic non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with adverse renal outcomes among older adults. However, there is scant data regarding the renal safety of topical and short-course systemic NSAIDs. We aimed to evaluate the risk of acute adverse renal outcomes among older adults prescribed topical and short-term systemic NSAIDs. METHODS: We conducted a retrospective cohort study of all older adults, age 60 years and above, who received prescriptions between July 2015 and December 2017 from the largest tertiary hospital and a major public primary care institution in Singapore. Data from 6 months before until 30 days after the first prescription were retrieved from electronic medical records. The primary outcome was the incidence of acute kidney injury (serum creatinine increased >26.5 µmol/L or >50% from baseline) and/or hyperkalemia within 30 days. A multi-variate analysis taking into account age, sex, co-morbidities, baseline-estimated glomerular filtration rate and serum potassium, NSAID route of administration, and concurrent renin-angiotensin-aldosterone system blocker and diuretic prescription was performed to evaluate factors associated with the primary outcome. RESULTS: We identified 12,773 older adults with incident prescriptions: 3982 (31.2%) received short-course systemic NSAIDs, 3784 (29.6%) received topical NSAIDs, and 5007 (39.2%) did not receive any NSAID. Both short-course systemic NSAIDs (adjusted odds ratio [OR] 1.59, 95% confidence interval [CI] 1.41-1.80, p < 0.001) and topical NSAIDs (adjusted OR 1.48, 95% CI 1.31-1.67, p < 0.001), compared with the no-NSAID group, were independently associated with the primary outcome. Among older adults with co-morbid conditions and prescribed NSAIDs, topical NSAIDs had a reduced odds of 30-day incident acute kidney injury and/or hyperkalemia in diabetes mellitus (adjusted OR 0.78, 95% CI 0.65-1.06, p = 0.007), chronic kidney disease (adjusted OR 0.74, 95% CI 0.60-0.90, p = 0.003), and cardiovascular disease (adjusted OR 0.54, 95% CI 0.37-0.79, p < 0.001), compared with short-course systemic NSAIDs. CONCLUSIONS: NSAIDs increased the risk of acute adverse renal events. Topical NSAIDs, compared with short-course systemic NSAIDs, were associated with a reduced incidence of acute kidney injury and/or hyperkalemia among older adults with additional risk factors.

Managing a Renal Transplant Programme During the COVID-19 Pandemic: Practical Experience from a Singapore Transplant Centre.

INTRODUCTION: Coronavirus Disease 2019 (COVID-19) has significantly affected the way healthcare is delivered in Singapore. Healthcare services such as renal transplantation had to rapidly adjust and meet the needs to (1) protect patients and staff, (2) ramp up, conserve or redeploy resources while (3) ensuring that critical services remained operational. This paper aims to describe the experience of the renal transplant programme at the Singapore General Hospital (SGH) in responding to the risks and constraints posed by the pandemic. METHODS AND MATERIALS: This is a review and summary of the SGH renal transplant programme's policy and protocols that were either modified or developed in response to the COVID-19 Pandemic. RESULTS: A multi-pronged approach was adopted to respond to the challenges of COVID-19. These included ensuring business continuity by splitting the transplant team into different locations, adopting video and tele-consults to minimise potential patient exposure to COVID-19, streamlining work processes using electronic forms, ensuring safe paths for patients who needed to come to hospital, ring-fencing and testing new inpatients at risk for COVID-19, enhancing precautionary measures for transplant surgery, ensuring a stable supply chain of immunosuppression, and sustaining patient and staff education programmes via video conferencing. CONCLUSIONS: Though the COVID-19 pandemic has reduced access to kidney transplantation, opportunities arose to adopt telemedicine into mainstream transplant practice as well as use electronic platforms to streamline work processes. Screening protocols were established to ensure that transplantation could be performed safely, while webinars reached out to empower patients to take precautions against COVID-19.

Bleeding Complications and Adverse Events After Desmopressin Acetate for Percutaneous Renal Transplant Biopsy.

INTRODUCTION: Percutaneous renal biopsy remains critical for the workup of renal allograft dysfunction but is associated with the risk of bleeding. Prophylactic intravenous desmopressin has been proposed to reduce bleeding risk in native renal biopsies, but its efficacy in the renal transplant population is unclear and adverse events such as severe hyponatraemia have been reported. MATERIALS AND METHODS: We conducted a single-centre retrospective cohort study involving adult (≥21 years old) renal transplant recipients with impaired renal function (serum creatinine ≥150 µmol/L) who underwent ultrasound-guided renal allograft biopsies from 2011‒2015 to investigate the effect of prebiopsy desmopressin on the risk of bleeding and adverse events. RESULTS: Desmopressin was administered to 98 of 195 cases who had lower renal function, lower haemoglobin and more diuretic use. Postbiopsy bleeding was not significantly different between the 2 groups (adjusted odds ratio [OR] 0.79, 95% confidence interval [CI] 0.26‒2.43, P = 0.68) but desmopressin increased the risk of postbiopsy hyponatraemia (sodium [Na] <135 mmol/L) (adjusted OR 2.24, 95% CI 1.10‒4.59, P = 0.03). Seven cases of severe hyponatraemia (Na <125 mmol/L) developed in the desmopressin group, while none did in the non-desmopressin group. Amongst those who received desmopressin, risk of hyponatraemia was lower (OR 0.26, 95% CI 0.09‒0.72, P = 0.01) if fluid intake was <1 L on the day of biopsy. CONCLUSION: Prophylactic desmopressin for renal allograft biopsy may be associated with significant hyponatraemia but its effect on bleeding risk is unclear. Fluid restriction (where feasible) should be recommended when desmopressin is used during renal allograft biopsy. A randomised controlled trial is needed to clarify these outcomes.

Risk-stratified approach to anti-viral prophylaxis against cytomegalovirus disease in glomerulonephritis and renal vasculitis treated with potent immunosuppressants.

Aim: Cytomegalovirus (CMV) reactivation and disease in immunocompromised individuals is associated with significant morbidity and mortality. Preventive measures such as anti-viral prophylaxis or surveillance and pre-emptive therapy effectively reduced CMV disease in solid organ transplant but have not been evaluated among patients with glomerulonephritis at-risk for CMV disease after immunosuppressive therapy. We evaluated the utility and outcomes of a risk-stratified approach to anti-viral prophylaxis for adults with glomerulonephritis treated with potent immunosuppressants. Methods: Single-center retrospective cohort study of adults with glomerulonephritis and renal vasculitis prescribed methylprednisolone, cyclophosphamide or rituximab in a tertiary referral centre. A risk-stratified approach to CMV anti-viral prophylaxis was implemented in March 2015. We compared the incidence of CMV disease in the pre-implementation (January 2008-December 2014) and post-implementation (June 2015-June 2017) groups. Results: We studied 119 individuals: 85 in the pre-implementation group and 34 in the post-implementation group. The post-implementation group had worse kidney function, greater proteinuria, higher prednisolone dose and more received intravenous methylprednisolone and plasma exchanges but CMV disease within 6 months was similar to the pre-implementation group (2.9% vs. 3.5%, p = 1.00). Among individuals in the post-implementation group who satisfied criteria to receive anti-viral prophylaxis (n = 21), CMV disease was more frequent in the group not given prophylaxis compared to those given prophylaxis as recommended (8.3% versus 0%, p = 1.00). Adverse events related to anti-viral prophylaxis occurred in 40%. Conclusion: This study provided pilot data for future randomized controlled trials to evaluate CMV preventive strategies in selected high-risk patients with glomerulonephritis or renal vasculitis.

Desmopressin for the prevention of bleeding in percutaneous kidney biopsy: efficacy and hyponatremia.

BACKGROUND: Desmopressin is used to reduce bleeding complications for kidney biopsies with azotemia but little is known about desmopressin-induced hyponatremia in these individuals. We aimed to evaluate the impact of desmopressin prophylaxis on severe hyponatremia and bleeding after kidney biopsies in individuals with renal impairment. METHOD: This is a single-center retrospective cohort study of consecutive adults with serum creatinine ≥ 150 µmol/L and had ultrasound-guided percutaneous native or transplant kidney biopsies between June 2011 and July 2015. Data were retrieved from electronic medical records. Primary outcomes were the use of desmopressin prophylaxis and severe hyponatremia (serum sodium ≤ 125 mmol/L) within 7 days post-biopsy. Secondary outcome was post-biopsy bleeding. RESULTS: 240 native kidney and 196 allograft biopsies were performed. Median age was 51 (IQR 42.3, 60) years and eGFR was 21.9 (12.9, 30.1) ml/min/1.73 m2. Although patients prescribed desmopressin prophylaxis (n = 226) had higher serum creatinine [279 (201, 392) vs. 187 (160, 241), p < 0.001], bleeding (15.0% vs. 13.3%, p = 0.60) was not significantly different with and without desmopressin. Severe hyponatremia occurred in 30 biopsies (6.9%) with nadir serum sodium level of 122 (119, 124) mmol/L at 3 (2, 5) days after biopsy, more frequently among those with desmopressin prophylaxis (10.7% vs. 3.0%, p = 0.002). Multi-variate analysis found that pre-biopsy serum sodium level [adjusted OR 0.80 (95% CI 0.72, 0.90), p < 0.001] and desmopressin prophylaxis [adjusted OR 4.02 (95% CI 1.58, 10.21), p = 0.003] were independently associated with severe hyponatremia after kidney biopsy. CONCLUSION: Pre-biopsy desmopressin was associated with severe hyponatremia in individuals with renal impairment; hence, susceptible patients given desmopressin should be closely monitored.

Prevalence and risk factors for hypercalcemia among non-dialysis patients with chronic kidney disease-mineral and bone disorder.

PURPOSE: To examine the prevalence and risk factors for hypercalcemia among non-dialysis chronic kidney disease (CKD) patients with mineral and bone disorder (MBD). METHODS: A retrospective cohort study was conducted in Singapore General Hospital, involving all CKD stage 4 and 5 pre-dialysis patients who were on treatment for MBD in June 2016. Each patient was followed up for 1 year and screened for hypercalcemia episodes. Mild, moderate and severe hypercalcemia were defined as corrected calcium of 2.47-3.00, 3.01-3.50 and ≥ 3.51 mmol/l respectively. Patients who were on dialysis, post-renal transplant, post-parathyroidectomy or had no calcium levels taken during the study period were excluded. Details related to patients' clinical information and hypercalcemia episodes were collected. Multivariate logistic regression analysis was performed to evaluate risk factors for hypercalcemia. RESULTS: Of 557 patients, 75 (13.4%) patients developed hypercalcemia. There were 120 (97.6%) mild and 3 (2.4%) moderate hypercalcemia episodes. The daily elemental calcium intake from phosphate binders and usage of vitamin D analogues did not differ between patients with and without hypercalcemia (p > 0.05). After adjusting for covariates, lower baseline iPTH level [odds ratio (OR) 0.96, 95% CI 0.93-0.99], history of hypercalcemia in past 1 year (OR 11.11, 95% CI 3.36-36.75) and immobility (OR 3.34, 95% CI 1.34-8.40) were associated with increased hypercalcemia risk. CONCLUSION: Hypercalcemia affects a significant proportion of pre-dialysis patients with MBD. More studies should be undertaken to evaluate other risk factors associated with hypercalcemia.

Epidemiology and risk factors for cytomegalovirus infection in glomerular diseases treated with immunosuppressive therapy.

AIM: Cytomegalovirus (CMV) infections are associated with morbidity and mortality. We aimed to describe the epidemiology, risk factors and outcomes of CMV infection among patients with glomerulonephritis (GN) who received potent immunosuppressants (IS). METHODS: Single-centre retrospective study of adults with biopsy-proven GN prescribed methylprednisolone (MP), cyclophosphamide (CYC) or rituximab (RTX). Primary endpoint was CMV infection defined by significant CMV antigenaemia (>10 positive cells in 106 cells) or viraemia (>2000 copies/mL). Death was related to CMV if CMV infection occurred within the same hospitalization as death. RESULTS: Ninety-four patients were studied. CYC was prescribed in 65% and MP in 71% of the cohort. Only two patients received RTX and 15 patients received plasma exchanges (PEX). Median follow up was 31.9 (IQR: 13.7, 53.6) months. CMV infection occurred in 13 patients (13.8%) at 1.3 (0.6, 3.0) months from biopsy. Patients with CMV infection had higher serum creatinine [404 (272, 619) vs. 159 (93, 317) µmol/L, P < 0.001] and greater proteinuria [UPCR 7.5, (4.8, 11.8) vs. 4.2 (2.3, 8.4) g/g, P = 0.02] than those who did not have CMV infection. Also, more patients received CYC (92% vs. 60%, P = 0.03), RTX (15% vs. 0, P = 0.02) and PEX (38% vs. 12%, P = 0.01) than those who did not have CMV infection. Two patients had CMV-related deaths. CONCLUSION: Cytomegalovirus infection is common in GN patients receiving potent IS. Surveillance and possibly anti-viral prophylaxis should be considered for high-risk patients.

Genetic polymorphisms of MRP2 and UGT2B7 and gastrointestinal symptoms in renal transplant recipients taking mycophenolic acid.

The aim of this study was to determine the relationship between single nucleotide polymorphisms in multidrug resistance protein 2 (MRP2) and uridine diphosphate glucuronosyltransferase (UGT) 2B7 and the severity of gastrointestinal (GI) symptoms in patients receiving mycophenolic acid (MPA). A total of 67 renal transplant recipients taking MPA derivatives were included in the study. Genotypes for MRP2 C-24 T and UGT2B7 C802 T were determined. The incidence and severity of GI symptoms were assessed using the validated Gastrointestinal Symptom Rating Scale (GSRS) at baseline, 2 weeks, 3 months, and 6 months after transplantation. The mean overall GSRS score and the score on the subscale for diarrhea were compared using the Kruskal-Wallis test. The overall GSRS scores (23.5 +/- 4.5 vs. 26.7 +/- 9.9, P = 0.68) or diarrhea subscores (3.5 +/- 0.9 vs. 5.1 +/- 3.3, P = 0.08) were not significantly different among patients with the heterozygous variant MRP2 C-24 T and those with the homozygous wild type. For UGT2B7, the overall mean GSRS scores were significantly different between the homozygous wild type and the variant type (CC vs. CT + TT, 29.2 +/- 9.3 vs. 24.0 +/- 8.2, P = 0.009), although diarrhea subscale scores did not reach statistical significance (CC vs. CT + TT, 5.7 +/- 4.1 vs. 4.1 +/- 1.9, P = 0.13). When the genotypes for MRP2 and UGT2B7 were considered together, patients with the variant forms of MRP2 and UGT2B7 had significantly lower overall GSRS scores (CC-CC vs. CT-CT/TT, 22.5 +/- 4.3 vs. 30.1 +/- 10.1, P = 0.04) and diarrhea subscale scores compared to wild type (CC-CC vs. CT-CT/TT, 3.4 +/- 0.7 vs. 6.2 +/- 4.4, P = 0.03). However, there were no differences in GSRS scores between patients receiving either mycophenolic mofetil (MMF) or enteric-coated mycophenolic acid (EC-MPA) regardless of whether the patients were receiving different calcineurin inhibitors. In conclusion, this study suggests that among patients receiving MPA, those with UGT2B7 variant genotypes are protected from the GI side effects of MPA regardless of the formulation used or concurrent calcineurin inhibitors administered. MRP2 genotypes did not show significant differences in GI side effects among patients taking MPA therapy.