Gary C.W. Chan

Diabetic nephropathy: landmark clinical trials and tribulations

Diabetic nephropathy remains the most common cause of end-stage renal disease worldwide. The current standard of therapy for diabetic nephropathy involves stringent blood pressure control via blockade of the renin-angiotensin system and control of hyperglycemia. Despite these strategies, diabetic nephropathy is still seen to progress relentlessly. A pressing need for novel therapeutic agents has fueled endless basic science research projects and clinical trials in the quest for a more specific therapy. Throughout the process, only a handful of ancillary agents have shown experimental promise and even fewer have demonstrated an impact in human trials. This review article aims to summarize the available data from landmark studies for the main therapeutic approaches investigated.

Cancer Incidence and Mortality in Chronic Dialysis Population: A Multicenter Cohort Study

Background: Different studies in the past have shown that the risk of cancer development is increased in chronic dialysis patients. However, data concerning the cancer risk in Asian dialysis patients was scarce. More importantly, there was lack of information about the cancer-specific mortality in dialysis patients. Methods: A multicenter retrospective cohort study of 6,254 patients who started either chronic peritoneal dialysis or hemodialysis between 1994 and 2014 in 4 renal units in Hong Kong. Patterns of cancer incidence and mortality in our dialysis patients were compared with those of the general population using standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) respectively. Results: With 14,887 person-years of follow-up, 220 cancers were recorded. The SIR of all cancers was 1.44 (95% CI 1.26-1.65). A trend of an increased SIR was observed in young patients and within the first year of dialysis. Colorectum was the most common site of cancer (20%) while kidney cancer carried the highest risk (SIR 12.28, 95% CI 8.44-17.08). The SMR of all cancers was 0.91 (95% CI 0.72-1.13) and only kidney cancer had higher cancer mortality risk (SMR 4.92, 95% CI 1.80-10.70). SMR was highest in young patients and then decreased with age. Conclusions: The incidence of cancers in our chronic dialysis patients was elevated. Our findings of substantially increased risks in young patients, particularly in relation to kidney cancer, suggest that we can adopt a more individualized approach to cancer screening in chronic dialysis patients.

Recent advances in managing and understanding diabetic nephropathy

Diabetic nephropathy is the commonest cause of end-stage renal disease in most developed economies. Current standard of care for diabetic nephropathy embraces stringent blood pressure control via blockade of the renin-angiotensin-aldosterone system and glycemia control. Recent understanding of the pathophysiology of diabetic nephropathy has led to the development of novel therapeutic options. This review article focuses on available data from landmark studies on the main therapeutic approaches and highlights some novel management strategies.

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.

N-Acetyl-seryl-aspartyl-lysyl-proline Alleviates Renal Fibrosis Induced by Unilateral Ureteric Obstruction in BALB/C Mice

To expand the armamentarium of treatment for chronic kidney disease (CKD), we explored the utility of boosting endogenously synthesized N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is augmented by inhibition of the angiotensin converting enzyme. Male BALB/c mice underwent unilateral ureteral ligation (UUO) or sham operation and received exogenously administered Ac-SDKP delivered via a subcutaneous osmotic minipump or Captopril treatment by oral gavage. Seven days after UUO, there were significant reductions in the expression of both collagen 1 and collagen 3 in kidneys treated with Ac-SDKP or Captopril, and there was a trend towards reductions in collagen IV, α-SMA, and MCP-1 versus control. However, no significant attenuation of interstitial injury or macrophage infiltration was observed. These findings are in contrary to observations in other models and underscore the fact that a longer treatment time frame may be required to yield anti-inflammatory effects in BALB/c mice treated with Ac-SDKP compared to untreated mice. Finding an effective treatment regimen for CKD requires fine-tuning of pharmacologic protocols.

Quantification of BK viral load in asymptomatic renal allograft recipients

Introduction: Polyoma BK virus (BKV) has recently been identified to cause renal allograft dysfunction, which manifests as polyomavirus-associated nephropathy (PVAN). However, the presence and level of BKV DNA in renal allograft patients with good and stable renal function have remained undetermined. Methods: In this prospective study, serum samples were collected from a total of 45 renal allograft recipients with serum creatinine <155 μmol/L. In 17 patients, whose duration of transplantation was under 2 years, samples were collected at 3–4-month intervals for up to 2 years after transplantation. BK viral load was quantified using quantitative polymerase chain reaction (Q-PCR). Results: The BK viral load in asymptomatic renal allograft recipients was independent of the duration of transplantation and did not correlate with allograft function. The mean (± SD) level of viremia was 552.80 ± 1931.00 genome copies/mL, with 92.9% of patients having low levels of viremia corresponding to <1 × 103 copies/mL. In contrast, patients with proven PVAN had levels in the range of 106 copies/mL. Conclusions: The prevailing BK viral load in asymptomatic renal allograft patients is quantifiably low. Our findings may guide optimal immunosuppressive modulation in PVAN cases, where judicious manipulation of immunosuppression is required without inciting allograft rejection.

Proteinuria is associated with sleep apnea in chronic kidney disease

BACKGROUND The prevalence and severity of sleep apnea (SA) in the chronic kidney disease (CKD) population is not well characterized. Recent studies have yielded highly variable prevalence rates due to cohort heterogeneity and interstudy inconsistencies in defining SA. This study sought to determine the association of SA with CKD by recruiting a uniform cohort to undertake overnight polysomnography (PSG). METHODS A total of 141 male Chinese CKD patients, ages 40-60 years, underwent overnight PSG to delineate the prevalence and severity of SA and nocturnal hypoxemia (NH). Body mass index (BMI), neck girth, estimated glomerular filtration rate, urinary protein excretion and Epworth sleepiness scale (ESS) score were collected at baseline to determine associative factors. RESULTS The prevalence rates of SA and NH were 35.5 and 10.6%, respectively, in this study population [mean (±SD) age 51.44 ± 6.05 years; BMI 26.05 ± 4.22 kg/m(2)]. The adjusted odds ratios (ORs) for SA by BMI and proteinuria were 1.18 [95% confidence interval (CI) 1.02, 1.37; P ≤ 0.05] and 1.57 (95% CI 1.12, 2.46; P ≤ 0.05), respectively. The adjusted ORs for the median cohort oxygen desaturation index (ODI) by BMI and proteinuria were 1.23 (95% CI 1.05, 1.45; P ≤ 0.05) and 1.75 (95% CI 1.12, 2.76; P ≤ 0.05). However, no significant correlation between the prevalence and severity of SA and NH with progressive renal deterioration was observed. Furthermore, no significant mean difference in the apnea-hypopnea index and ODI was observed for an ESS above and below 10. CONCLUSIONS SA is prevalent in CKD patients and strongly correlated with BMI and proteinuria, but not with renal function. The ESS is an investigative tool that lacks discriminatory power in patients with renal insufficiency. Therefore clinical vigilance for SA is paramount when attending to CKD patients with significant proteinuria.

Serum and urinary biomarkers that predict hepatorenal syndrome in patients with advanced cirrhosis

BACKGROUND Prediction of hepatorenal syndrome (HRS) remains difficult in advanced cirrhotic patients. AIMS To evaluate use of serum and urine biomarkers to predict HRS. METHODS We prospectively recruited Childs B or C cirrhotic patients with normal serum creatinine, and followed them for 12 weeks for the development of HRS. Serum Cystatin C (CysC), serum and urine Neutrophil Gelatinase-Associated Lipocalin (NGAL), serum and urine IL-18, serum N-acetyl-β-d glucosaminidase (NAG), urine kidney injury molecule-1 (KIM-1) and urine liver-type fatty acid binding protein (LFABP) were measured at recruitment (baseline), and their relationship with subsequent HRS investigated. RESULTS 43 patients were included. 12 (27.9%) developed HRS at 7.3±5.1 weeks from baseline. Logistic regression analysis showed that baseline urinary NGAL and urinary KIM-1 were significantly associated with the development of HRS (RR 1.007, 95% CI 1.001-1.012, p=0.014; RR 1.973, 95% CI 1.002-3.886, p=0.049). The cut-off values for NGAL and KIM-1 to predict HRS were 18.72ng/mL and 1.499ng/mL respectively (AUCs 0.84, p=0.005; and 0.78, p=0.008). CONCLUSION Urinary NGAL and KIM-1 could serve as biomarkers to predict HRS in advanced cirrhotic patients.

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.

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.