Lorraine P.Y. Kwan

Long-term data on tacrolimus treatment in lupus nephritis

OBJECTIVE Calcineurin inhibitors are effective immunosuppressants. They also reduce proteinuria in glomerular diseases but are potentially nephrotoxic. Short-term data suggest that tacrolimus (TAC) combined with corticosteroids is effective in LN, but long-term data are lacking. This study examined the long-term outcomes and tolerability of TAC for the treatment of LN. METHODS We retrospectively reviewed 29 LN patients who received TAC treatment for 46.9 months (s.d. 37.9). RESULTS In 17 patients with class III/IV or V LN and persistent proteinuria >2 g/day despite induction immunosuppression, response rates after 12 and 24 months of add-on TAC treatment were 66.7% and 80.0%, respectively. In 10 patients with nephrotic syndrome due to class V LN who were given prednisolone and TAC as initial treatment, the response rate was 60.0% and 90.0% after 12 and 24 months, respectively. TAC facilitated steroid minimization in two patients with lupus podocytopathy. As a group, proteinuria decreased from 3.6 g/day (s.d. 2.6) to 1.0 (s.d. 1.1) (P < 0.05). Four patients developed end-stage renal failure, with 3-, 5- and 8-year renal survival rates of 93%, 83% and 83%, respectively. In the remaining patients, serum creatinine and estimated GFR remained stable after 36 months. One patient with pre-existing chronic renal failure developed TAC nephrotoxicity. Four renal flares occurred, all associated with low TAC blood levels. Six patients (20.1%) had deterioration of hypertension and one patient (3.4%) had new-onset diabetes mellitus. Six patients (20.1%) had infections that required hospitalization. Two deaths occurred: one due to pneumonia and one to breast cancer. CONCLUSION The results suggest efficacy of TAC in LN, especially in reducing proteinuria, and its role as a long-term maintenance agent warrants further investigation.

Entecavir Treatment in Kidney Transplant Recipients Infected with Hepatitis B

Although nucleotide/side analogs improve the clinical outcome of hepatitis B surface antigen‐positive (HBsAg+) kidney transplant recipients (KTR), a significant proportion of subjects have developed resistance to lamivudine (LAM). We retrospectively analyzed the efficacy and tolerability of entecavir (ETV) in HBsAg+ KTR at Queen Mary Hospital during 2005–2013. Twenty‐one patients (10 treatment‐naïve, 11 with LAM resistance) were included (duration of ETV treatment 34.7 ± 22.9 months, range 6–75 months). ETV treatment led to a decline of hepatitis B virus (HBV) DNA titer compared to baseline and is more significant in the treatment‐naïve group (treatment‐naïve: p = 0.028, <0.001 and <0.001; LAM‐resistant p = 0.273, 0.180, and 0.109 after 12, 24, and 36 months). The cumulative rate of HBV DNA undetectability at 12, 24, and 36 months was 60%, 100%, and 100% for treatment‐naïve group, and 27%, 45%, and 45% for LAM‐resistant group, respectively. Time‐to‐HBV DNA undetectability and time‐to‐alanine transaminase (ALT) normalization were 15.7 ± 4.6 and 12.6 ± 3.7 months for treatment‐naïve patients, and 24.5 ± 4.2 and 28.2 ± 3.5 months for those with LAM resistance. Genotypic resistance to ETV emerged after 20.0 ± 3.5 months with increase in ALT and HBV DNA in two patients with LAM resistance, but was not observed in the treatment‐naïve group. Allograft dysfunction, de novo cirrhosis, or hepatocellular carcinoma did not occur during follow‐up.

Significant reduction of Tacrolimus trough level after conversion from twice daily Prograf to once daily Advagraf in Chinese renal transplant recipients with or without concomitant diltiazem treatment.

Abstract A dose ratio of 1:1 was recommended for the conversion from Standard-release Tacrolimus (Prograf) to Prolonged-release Tacrolimus (Advagraf). We investigated the trough tacrolimus blood level in Chinese kidney transplant recipients after conversion, including subjects receiving concomitant treatment with diltiazem. Eighteen stable renal allograft recipients were followed prospectively for 12 weeks after conversion from Prograf to Advagraf at the same daily dose. Tacrolimus blood trough level decreased significantly within 8 weeks after conversion (p < 0.01). Twelve patients required escalation of the Advagraf dose by 1.10 ± 0.36 mg. For the whole group the daily tacrolimus dose was increased from 0.057 ± 0.032 mg/kg to 0.068 ± 0.033 mg/kg (p < 0.0001). At week 12 the daily dose of Advagraf was 127 ± 32% of the original daily dose of Prograf. In the subgroup of patients receiving diltiazem, their tacrolimus trough level decreased significantly after conversion (p = 0.001), and the daily tacrolimus dose was increased from 0.060 ± 0.036 mg/kg to 0.073 ± 0.036 mg/kg (p < 0.0001). At week 12, their daily dose of Advagraf was 131 ± 34% of the original daily dose before conversion. To conclude, conversion from Prograf to Advagraf in renal allograft recipients with or without diltiazem co-treatment necessitated an increase in the daily dose by approximately 30% to maintain the target blood trough level unchanged.

Longterm Data on Disease Flares in Patients with Proliferative Lupus Nephritis in Recent Years

Objective. To examine the disease flare rate in lupus nephritis (LN), focusing on renal flares, and the factors associated with relapse risk in recent years. Methods. We analyzed data on 139 Chinese patients with class III/IV ± V LN diagnosed from January 1983 to December 2013. We also compared data before and after 1998, when maintenance immunosuppression was changed from azathioprine (AZA) to mycophenolic acid (MPA). Results. Over 112.5 ± 88.4 months, 135 episodes of renal flare occurred, giving a flare rate of 0.108 episodes per patient-year. The renal relapse-free survival rate was 96%, 90%, 86%, 80%, 69%, and 57% after 1, 2, 3, 4, 5, and 10 years, respectively, calculated from the start of induction treatment. Reduced risk of flare was associated with MPA maintenance (OR 0.314, 95% CI 0.099–0.994, p = 0.049), complete remission after induction immunosuppression (OR 0.329, 95% CI 0.133–0.810, p = 0.016), and diagnosis after 1998 (OR 0.305, 95% CI 0.133–0.700, p = 0.005). Relapse-free survival was significantly better in patients treated with prednisolone and MPA as maintenance immunosuppression (91% after 5 yrs and 83% after 10 yrs, respectively) compared with prednisolone and AZA (70% and 52%, respectively, p = 0.044). LN diagnosed in 1998–2013 showed 5-year and 10-year relapse-free survival rates of 93% and 86%, respectively, compared with 81% and 66%, respectively (p = 0.017) for LN that presented in 1983–1997. Conclusion. Our data show a relatively low flare rate for LN in the more recent era, attributed to effective induction of immunosuppression and MPA as maintenance treatment.

Non‐invasive assessment of kidney allograft fibrosis with shear wave elastography: A radiological‐pathological correlation analysis

To evaluate the use of shear wave elastography in assessment of kidney allograft tubulointerstitial fibrosis.

Cortical necrosis in a kidney transplant recipient due to leptospirosis

A 64-year-old woman suffered from end-stage renal failure due to unknown cause. She received kidney transplantation in 2003 and her maintenance immunosuppression comprised corticosteroids, cyclosporine A and azathioprine. She presented with fever, graft pain and reduced urine output in May 2013. Her serum creatinine level rose from 82 μmol/L to 279 μmol/L, and then rapidly deteriorated into oliguric renal failure. Complete blood picture revealed leukocytosis (13.3 × 10/L; neutrophil predominant) and concomitant liver derangement (aspartate aminotransferase, 724 U/L; alanine aminotransferase, 288 U/L; total bilirubin, 33 μmol/L; lactate dehydrogenase, 2183 U/L). The haemoglobin level, platelet counts, clotting profiles and urinalysis were unremarkable. Blood film showed no fragmented red cells and lupus anticoagulant was negative. Ultrasound did not demonstrate vascular thrombosis or obstruction and renal isotope scan only showed mildly impaired perfusion. Allograft biopsy revealed extensive cortical necrosis involving both glomeruli and tubules, with thrombi within the glomeruli (Fig. 1A) and fibrinoid necrosis of arterioles but no evidence of rejection (Fig. 1B). The Panbio Leptospira IgM ELISA (Standard Diagnostic, Gyeonggi-Do, Korea) was repeatedly positive. In retrospect, the patient volunteered that she had experienced occupational exposure to sewage water. Her urine output returned to normal after 2 weeks of temporary haemodialysis and i.v. meropenem. Her serum creatinine was 324 μmol/L 6 months after her initial presentation. Leptospirosis is a zoonotic disease caused by the spirochete Leptospira spp. Classical renal histological changes of leptospirosis include tubulointerstitial nephritis and acute tubular necrosis, while extensive cortical necrosis has not been reported previously. As the Doppler ultrasound and renal isotope scan did not reveal significant abnormalities, we postulate that the extensive renal necrosis in this case might have been related to thrombosis and fibrinoid necrosis of small intrarenal vasculatures triggered by severe Leptospira infection. Indeed, cerebral venous thrombosis due to severe vasculitis has previously been reported in leptospirosis. Data regarding leptospirosis in renal transplant recipients are limited but these immunocompromised subjects can develop fulminant leptospirosis and succumb to multi-organ failure. Another reason for the poor outcomes is due to the diagnostic difficulty of leptospirosis in renal transplant recipients as it may mimic more common conditions such as graft pyelonephritis or acute rejection, and serological confirmation is often delayed. Therefore, one should initiate empirical antibiotics with activity against leptospirosis given a compatible clinical context and history of exposure, as this will significantly improve patient outcomes.

Longterm Data on Sirolimus Treatment in Patients with Lupus Nephritis

Objective. To expand the limited longterm data on sirolimus treatment in patients with lupus nephritis (LN). Our pilot short-term data suggested efficacy of sirolimus treatment in these patients. Methods. We retrospectively reviewed 16 class III/IV/V patients with LN who have received prednisolone (PSL) and sirolimus either as initial or maintenance treatment. Results. Sixteen patients received sirolimus treatment (9 because of intolerance to standard immunosuppressants and 7 because of a history of malignancy) for 45.3 ± 36.5 months. In 5 patients, sirolimus and PSL were given as induction for active nephritis, and they showed improvements in proteinuria (2.8 ± 1.9 g/day at baseline, 0.1 ± 0.1 g/day after 36 mos, p = 0.011), anti-dsDNA (107.7 ± 91.9 IU/ml and 37.0 ± 55.4 IU/ml, respectively, p = 0.178), and C3 (54.8 ± 26.1 mg/dl and 86.3 ± 18.6 mg/dl, respectively, p = 0.081). Eleven patients received sirolimus and low-dose PSL as longterm maintenance, and they showed continued improvement in C3 (90.4 ± 18.1 mg/dl and 117.7 ± 25.1 mg/dl at commencement and after 36 mos, respectively, p = 0.025), stable renal function (estimated glomerular filtration rate 58.6 ± 25.8 ml/min and 63.0 ± 29.6 ml/min, respectively, p = 0.239), and proteinuria (0.8 ± 0.7 g/day and 0.7 ± 0.7 g/day respectively, p = 0.252). Renal flare occurred in 1 patient, and another patient who had stage 4 chronic kidney disease when sirolimus was started developed endstage renal failure after 27 months. Sirolimus was discontinued in 5 patients, in 4 cases related to drug side effects. Deterioration of dyslipidemia occurred in 4 patients, but was adequately controlled with statin therapy. Conclusion. The preliminary evidence suggests that sirolimus may serve as an alternative treatment for patients with LN who do not tolerate standard treatment or who had a history of malignancy, and it has an acceptable longterm safety profile.

A LONGITUDINAL STUDY ON THE PREVALENCE AND RISK FACTORS FOR DEPRESSION AND ANXIETY, QUALITY OF LIFE, AND CLINICAL OUTCOMES IN INCIDENT PERITONEAL DIALYSIS PATIENTS

Background: Starting dialysis is an important life event. The prevalence and evolution of psychological symptoms at commencement of long-term dialysis is unclear. We examined the prevalence of and risk factors for depression and anxiety, and the quality of life (QOL) of incident peritoneal dialysis (PD) patients, and also the change of these parameters in the first year of PD in relation to clinical outcomes under the PD-first policy. Methods: All patients commencing long-term PD from March 2011 to April 2015 were asked to complete the Hospital Anxiety and Depression Scale (HADS), World Health Organization Quality of Life-BREF and the Kidney Disease Quality of Life Instrument Short Form questionnaire. Patient demographics and the incidence of hospitalization, peritonitis, exit-site infection, and all-cause mortality were studied. The HADS was repeated after 9 – 12 months. Results: A high depression score was present in 39.6% of 191 patients at commencement of PD and was more common in diabetes patients (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.09 – 3.81). A high anxiety score was present in 23.6%, and the risk factors included younger age (OR 0.96 per year, 95% CI 0.94 – 0.99) and diabetes (OR 2.59, 95% CI 1.20 – 5.57). Both high depression and anxiety scores were associated with an inferior QOL, overall and across most QOL domains. Depression and anxiety symptoms did not change in the first year of PD and were not associated with short-term clinical outcomes. Conclusions: High depression and anxiety scores were prevalent in incident PD patients where PD-first policy is adopted and were associated with inferior QOL. There was no improvement after 1 year of PD. The impact of strategic interventions targeting patient groups at risk such as those with diabetes or of younger age warrants further investigation.

Preemptive immunosuppressive treatment for asymptomatic serological reactivation may reduce renal flares in patients with lupus nephritis: a cohort study

BACKGROUND Serological activity may precede clinical flares of lupus nephritis (LN) but the management of asymptomatic serological reactivation (ASR) remains undefined. METHODS We conducted a retrospective analysis of 138 episodes of ASR, which included 53 episodes in which immunosuppression was increased preemptively and 85 episodes in which treatment was unaltered. Preemptive immunosuppressive treatment comprised increasing the dose of prednisolone to ∼0.5 mg/kg/day, and in patients already on mycophenolate mofetil (MMF) or azathioprine (AZA), increasing the dose to 1.5 g/day and 100 mg/day, respectively. RESULTS Thirty-four episodes of renal flare occurred during follow-up (88.8 ± 77.3 and 82.8 ± 89.7 months in the preemptive group and controls, respectively), following 5 (9.4%) of preemptively treated ASR and 27 (31.8%) of untreated ASR [hazard ratio 0.3 (confidence interval 0.1-0.7), P = 0.012]. Preemptive treatment was associated with superior survival free of renal relapse (99, 92 and 90% at 6, 12 and 24 month, respectively, compared with 94, 69 and 64% in controls; P = 0.011), whereas survival rate free of extrarenal relapse was similar in the two groups. Preemptively treated patients who did not develop renal flares showed better renal function preservation (estimated glomerular filtration rate slope +0.54 ± 0.43 mL/min/1.73 m2/year, compared with -2.11 ± 0.50 and -1.00 ± 0.33 mL/min/1.73 m2/year, respectively, in controls who did and did not develop subsequent renal flares; P = 0.001 and 0.012, respectively). Preemptive treatment was associated with an increased incidence of gastrointestinal side effects attributed to MMF (P = 0.031), whereas infection rate did not differ between the two groups. CONCLUSION A preemptive moderate increase of immunosuppression for ASR in LN patients may reduce renal flares and confer benefit to long-term renal function.

A Rare Case of Famotidine-Induced Delirium in a Peritoneal Dialysis Patient

H2 receptor antagonists are commonly employed to manage gastro-esophageal reflux and peptic ulcer diseases with a very low incidence of side effects. Herein, we report an extremely rare incidence of famotidine-induced acute confusion in a patient with end-stage renal failure. We also discuss the pharmacokinetic properties of famotidine and its interplay with compromised renal function to result in neuropsychiatric manifestations, highlighting the importance of dosage ad ustment in individuals with renal insufficiency.