The Effects of Neprilysin Inhibition on GFR in CKD

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I always like to remind my cardiology colleagues that some of the most important drugs used in the cardiovascular arsenal, are in fact exerting their benefits through the kidneys. Case is point, drugs that target the renin-angiotensin-aldosterone system. I must admit that I envy how cardiology has come a long way, thanks in part to the number of randomized clinical trials (RCT) performed.

Nonetheless, nephrology is also moving at a steady pace especially in light of the recent positive findings of the CREDENCE trial. Take a look at the recent NephJC chat regarding the latest trends regarding research in nephrology.

Let’s take a look a recent RCT published in late 2018 in Circulation. The UK-HARP-III trial (United Kingdom Heart and Renal Protection-III) is a randomized double-blind trial of 414 participants randomly assigned to either sacubitril/valsartan 97/103 mg twice a day versus daily irbesartan 300 mg once daily.

In this study patients a total of 414 were randomized 1:1 to receive either sacubitril/valsartan or irbesartan at the end of the run-in period (207 participants in each group). Participants had to have and eGFR of ≥45 and <60 mL/min/1.73 m2 and a urine albumin:creatinine ratio (uACR) >177 mg/g, or an eGFR of ≥20 and <45 mL/min/1.73 m2 (regardless of uACR). In order to maximize blinding the authors used a method called the “double-dummy approach” in which patients received two bottles of medication, one containing sacubitril/valsartan 97/103 mg or placebo and the other bottle irbesartan 150 mg or placebo.

After two week of study patients double their dose of study medication; however only if no hyperkalemia or acute injury was recorded. During the next visits at 1, 3, 6, 9 and 12 months of study, several markers and relevant data were collected. The primary end point of the study was to assess their measured GFR at 12 months. A key strength of this paper was the use of measured glomerular filtration rate (mGFR) with either chromium-51 labeled ethylenediamine tetraacetic acid (Cr-EDTA), techicium-99 labeled diethylenetriaminepentaacetic acid (Tc-DTPA), or iohexol depending on local practice. The same technique used during baseline measurement was applied to the 12 month time point.

Results

No effect on kidney function was demonstrated in regards to change in mGFR (34 to 30 ml/min/1.73m2 in both groups) in the neprilysin group compared to the control group (both containing ARBs). Other results also demonstrated that there was no effect on estimated GFR (eGFR), or albuminuria. However, they did find that sacubitril/valsartan was well tolerated, and no major safety concerns identified. Interestingly, sacubitril/valsartan was found to reduce BP and cardiac biomarkers (troponin I and NT-proBNP) when compared with irbesartan. How these results translate to hard clinical outcomes is uncertain.

The pathophysiology of heart failure of decompensated heart failure is a complex process. While reduced heart function is the sine qua non. The kidneys play a critical role in this process as well. Several neurohumoral mechanisms are upregulated in heart failure to enhance sodium excretion. The natriuretic peptides (atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) both serve to induce natriuresis (a true cardio-renal integration).

Enter Sacubitril. Sacubitril is a prodrug that inhibits the enzyme neprilysin (a zinc metalloprotease), which is responsible for the degradation of several peptides including ANP and BNP (and angiotensin II itself and even beta amyloid). Hence, allowing for the prolonged effect of both ANP and BNP and potentially other peptides. But also important that an angiotensin receptor blocker (ARB) be added to the mix. The PARADIGM-HF trial (which made it to the 2nd round of the CardioRenal section NephMadness 2015) showed a favorable mortality benefit with the combination of a neprilysin inhibitor and an ARB. Importantly, the trial also hinted at a slower decline in kidney function. However, this was not a primary endpoint.

Thus, an important question to answer in the UK-HARP-III trial was if there was and effect on kidney outcomes (defined as mGFR achieved after twelve months). Unfortunately, in this short term trial, no apparent benefit was seen. Will the reduction seen in cardiac biomarkers provide a cardiovascular benefit in patients with CKD taking sacubitril/valsartan. Especially seeing that patients with CKD have such a profound risk of cardiovascular disease. We will have to see. Interestingly, this study paired two different ARBs head to head (in addition to sacubitril and placebo). Valsartan versus irbesartan. The dosing appeared to be equivalent (valsartan 103 BID versus irbesartan 300 mg daily). It is always interesting that they didn’t just use valsartan in both arms. But alas at least it is better than comparing the valsartan/sacubitril combination to the ACEi enalapril like was done in the PARADIGM-HF trial. Will be interested to see how kidney function in altered in patients with concomitant CKD and heart failure.

Xavier Vela
Mount Sinai West- St. Lukes, New York

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