Parminder K. Judge

Neprilysin inhibition in chronic kidney disease

Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin–angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population.

The 2014 International Workshop on Alport Syndrome.

Alport syndrome, historically referred to as hereditary glomerulonephritis with sensorineural deafness and anterior lenticonus, is a genetic disease of collagen α3α4α5(IV) resulting in renal failure. The collagen α3α4α5(IV) heterotrimer forms a network that is a major component of the kidney glomerular basement membrane (GBM) and basement membranes in the cochlea and eye. Alport syndrome, estimated to affect 1 in 5000–10,000 individuals, is caused by mutations in any one of the three genes that encode the α chain components of the collagen α3α4α5(IV) heterotrimer: COL4A3, COL4A4, and COL4A5. Although angiotensin-converting enzyme inhibition is effective in Alport syndrome patients for slowing progression to end-stage renal disease, it is neither a cure nor an adequate long-term protector. The 2014 International Workshop on Alport Syndrome, held in Oxford, UK, from January 3–5, was organized by individuals and families living with Alport syndrome, in concert with international experts in the clinical, genetic, and basic science aspects of the disease. Stakeholders from diverse communities—patient families, physicians, geneticists, researchers, Pharma, and funding organizations—were brought together so that they could meet and learn from each other and establish strategies and collaborations for the future, with the overall aim of discovering much needed new treatments to prolong kidney function.

Evidence for Reverse Causality in the Association Between Blood Pressure and Cardiovascular Risk in Patients With Chronic Kidney Disease

Among those with moderate-to-advanced chronic kidney disease, the relationship between blood pressure (BP) and cardiovascular disease seems U shaped but is loglinear in apparently healthy adults. The SHARP (Study of Heart and Renal Protection) randomized 9270 patients with chronic kidney disease to ezetimibe/simvastatin versus matching placebo and measured BP at each follow-up visit. Cox regression was used to assess the association between BP and risk of cardiovascular disease among (1) those with a self-reported history of cardiovascular disease and (2) those with no such history and, based on plasma troponin-I concentration, a low probability of subclinical cardiac disease. A total of 8666 participants had a valid baseline BP and troponin-I measurement, and 2188 had at least 1 cardiovascular event during follow-up. After adjustment for relevant confounders, the association between systolic BP and cardiovascular events was U shaped, but among participants without evidence of previous cardiovascular disease, there was a positive loglinear association throughout the range of values studied. Among those with the lowest probability of subclinical cardiac disease, each 10 mm Hg higher systolic BP corresponded to a 27% increased risk of cardiovascular disease (hazard ratio, 1.27; 95% confidence interval, 1.11–1.44). In contrast, the relationship between diastolic BP and cardiovascular risk remained U shaped irrespective of cardiovascular disease history or risk of subclinical disease. In conclusion, the lack of a clear association between systolic BP and cardiovascular risk in this population seems attributable to confounding, suggesting that more intensive systolic BP reduction may be beneficial in such patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00125593.

Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome.

Abstract Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including ‘repurposing’) therapies on an international basis.

Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III—rationale, trial design and baseline data

Abstract Background Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. Methods UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor–neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m2 and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m2 (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin–angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. Results Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m2 and the median uACR was 58.5 mg/mmol. Conclusions UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD.

Use of Causal Diagrams to Inform the Design and Interpretation of Observational Studies: An Example from the Study of Heart and Renal Protection (SHARP)

Observational studies often seek to estimate the causal relevance of an exposure to an outcome of interest. However, many possible biases can arise when estimating such relationships, in particular bias because of confounding. To control for confounding properly, careful consideration of the nature of the assumed relationships between the exposure, the outcome, and other characteristics is required. Causal diagrams provide a simple graphic means of displaying such relationships, describing the assumptions made, and allowing for the identification of a set of characteristics that should be taken into account (i.e., adjusted for) in any analysis. Furthermore, causal diagrams can be used to identify other possible sources of bias (such as selection bias), which if understood from the outset, can inform the planning of appropriate analyses. In this article, we review the basic theory of causal diagrams and describe some of the methods available to identify which characteristics need to be taken into account when estimating the total effect of an exposure on an outcome. In doing so, we review the concept of collider bias and show how it is inappropriate to adjust for characteristics that may be influenced, directly or indirectly, by both the exposure and the outcome of interest. A motivating example is taken from the Study of Heart and Renal Protection, in which the relevance of smoking to progression to ESRD is considered.

Effect of Processing Delay and Storage Conditions on Urine Albumin-to-Creatinine Ratio

BACKGROUND AND OBJECTIVES Because there is substantial biologic intraindividual variation in albumin excretion, randomized trials of albuminuria-reducing therapies may need multiple urine samples to estimate daily urinary albumin excretion. Mailing spot urine samples could offer a convenient and cost-effective method to collect multiple samples, but urine albumin-to-creatinine ratio stability in samples stored at ambient temperatures for several days is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients with kidney disease provided fresh urine samples in two tubes (with and without boric acid preservative). Reference aliquots from each participant were analyzed immediately, whereas remaining aliquots were subject to different handling/storage conditions before analysis, including delayed processing for up to 7 days at three different storage temperatures (4°C, 18°C, and 30°C), multiple freeze-thaw cycles, and long-term frozen storage at -80°C, -40°C, and -20°C. We calculated the mean percentage change in urine albumin-to-creatinine ratio for each condition, and we considered samples stable if the 95% confidence interval was within a ±5% threshold. RESULTS Ninety-three patients provided samples with detectable albuminuria in the reference aliquot. Median (interquartile range) urine albumin-to-creatinine ratio was 87 (20-499) mg/g. The inclusion of preservative had minimal effect on fresh urine albumin-to-creatinine ratio measurements but reduced the changes in albumin and creatinine in samples subject to processing delay and storage conditions. The urine albumin-to-creatinine ratio was stable for 7 days in samples containing preservative at 4°C and 18°C and 2 days when stored at 30°C. It was also stable in samples with preservative after three freeze-thaw cycles and in frozen storage for 6 months at -80°C or -40°C but not at -20°C. CONCLUSIONS Mailed urine samples collected with preservative and received within 7 days if ambient temperature is ≤18°C, or within 2 days if the temperature is higher but does not exceed 30°C, are suitable for the measurement of urine albumin-to-creatinine ratio in randomized trials. Preserved samples frozen to -40°C or -80°C for 6 months before analysis also seem suitable.

Biliary Tract and Liver Complications in Polycystic Kidney Disease

Polycystic liver disease is a well described manifestation of autosomal dominant polycystic kidney disease (ADPKD). Biliary tract complications are less well recognized. We report a 50-year single-center experience of 1007 patients, which raised a hypothesis that ADPKD is associated with biliary tract disease. We tested this hypothesis using all England Hospital Episode Statistics data (1998-2012), within which we identified 23,454 people with ADPKD and 6,412,754 hospital controls. Hospitalization rates for biliary tract disease, serious liver complications, and a range of other known ADPKD manifestations were adjusted for potential confounders. Compared with non-ADPKD hospital controls, those with ADPKD had higher rates of admission for biliary tract disease (rate ratio [RR], 2.24; 95% confidence interval [95% CI], 2.16 to 2.33) and serious liver complications (RR, 4.67; 95% CI, 4.35 to 5.02). In analyses restricted to those on maintenance dialysis or with a kidney transplant, RRs attenuated substantially, but ADPKD remained associated with biliary tract disease (RR, 1.19; 95% CI, 1.08 to 1.31) and perhaps with serious liver complications (RR, 1.15; 95% CI, 0.98 to 1.33). The ADPKD versus non-ADPKD RRs for biliary tract disease were larger for men than women (heterogeneity P<0.001), but RRs for serious liver complications appeared higher in women (heterogeneity P<0.001). Absolute excess risk of biliary tract disease associated with ADPKD was larger than that for serious liver disease, cerebral aneurysms, and inguinal hernias but less than that for urinary tract infections. Overall, biliary tract disease seems to be a distinct and important extrarenal complication of ADPKD.

Outcomes of Elderly Patients with Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis Treated with Immunosuppressive Therapy

Background/Aims: Anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is a cause of biopsy-proven acute kidney injury, more common in the elderly. Treatment requires immunosuppression, which can have significant toxic effects. The aim of this study was to assess whether morbidity and mortality that are associated with immunosuppression for AAV varied with age. Methods: A retrospective review of 232 patients given induction therapy with prednisolone and cyclophosphamide was conducted. Information was collected on baseline characteristics (including requirement for dialysis at presentation) and the occurrence of leukopenia, infection, end-stage renal disease and death during follow-up. Results: Median follow-up was 51 months. Older patients (aged ≥70 years) were treated with lower total cyclophosphamide doses than those aged <70 years (mean 7.3 g (SD 4.4) vs. 10.7 g (SD 7.4), respectively). Increasing age was associated with an increased risk of leukopenia (odds ratio (OR) 1.50; 95% confidence interval (CI) 1.20-1.86; p < 0.001), and older patients were more likely to develop infections in the first year (OR 1.87; 95% CI 1.1-3.2). Older patients were also significantly more likely to require dialysis at presentation (OR 1.66; 95% CI 1.13-2.5) and longer term. After multivariable adjustment, age and requirement for dialysis at presentation were significant predictors of death (hazard ratio (HR) per year of age 1.07; 95% CI 1.03-1.11; p < 0.001 and HR 2.2; 95% CI 1.10-4.38; p = 0.03, respectively). Conclusions: Among patients treated with prednisolone and cyclophosphamide, increasing age and dialysis dependency were associated with worse survival. Older patients were more likely to develop treatment-related complications despite lower cumulative doses of immunosuppression. Morbidity and mortality associated with treatment must therefore be carefully balanced against that associated with the disease process itself.