Peter A. McCullough M.D.

McCullough, P.A. (2021). “Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality.” Cardiorenal Med 11(3): 123-132.

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BACKGROUND: Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. SUMMARY: Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to <5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels <5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. Key Messages: Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.

Swolinsky, J.S., Nerger, N.P., Leistner, D.M., Edelmann, F., Knebel, F., Tuvshinbat, E., Lemke, C., Roehle, R., Haase, M., Costanzo, M.R., Rauch, G., Mitrovic, V., Gasanin, E., Meier, D., McCullough, P.A., Eckardt, K.U., Molitoris, B.A. and Schmidt-Ott, K.M. (2021). “Serum creatinine and cystatin C-based estimates of glomerular filtration rate are misleading in acute heart failure.” ESC Heart Fail May 6. [Epub ahead of print].

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AIMS: We aimed to test whether the endogenous filtration markers serum creatinine or cystatin C and equation-based estimates of glomerular filtration rate (GFR) based on these markers appropriately reflect changes of measured GFR in patients with acute heart failure. METHODS: In this prospective cohort study of 50 hospitalized acute heart failure patients undergoing decongestive therapy, we applied an intravenous visible fluorescent injectate (VFI), consisting of a low molecular weight component to measure GFR and a high molecular weight component to correct for measured plasma volume. Thirty-eight patients had two sequential GFR measurements 48 h apart. The co-primary endpoints of the study were safety of VFI and plasma stability of the high molecular weight component. A key secondary endpoint was to compare changes in measured GFR (mGFR) to changes of serum creatinine, cystatin C and estimated GFR. RESULTS: VFI-based GFR measurements were safe and consistent with plasma stability of the high molecular weight component and glomerular filtration of the low molecular weight component. Filtration marker-based point estimates of GFR, when compared with mGFR, provided only moderate correlation (Pearson’s r, range 0.80-0.88, depending on equation used), precision (r(2) , range 0.65-0.78) and accuracy (56%-74% of estimates scored within 30% of mGFR). Correlations of 48-h changes GFR estimates and changes of mGFR were significant (P < 0.05) but weak (Pearson's r, range 0.35-0.39). Observed decreases of eGFR by more than 15% had a low sensitivity (range 38%-46%, depending on equation used) in detecting true worsening mGFR, defined by a >15% decrease in mGFR. CONCLUSIONS: In patients hospitalized for acute heart failure, serum creatinine- and cystatin C-based predictions performed poorly in detecting actual changes of GFR. These data challenge current clinical strategies to evaluate dynamics of kidney function in acute heart failure.

Palazzuoli, A., Tecson, K.M., Ronco, C. and McCullough, P.A. (2021). “Nomenclature for Kidney Function from KDIGO: Shortcomings of Terminology Oversimplification.” Cardiorenal Med Jun 4;1-4. [Epub ahead of print].

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The recent Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference proposed a universal nomenclature calling for “Kidney Disease” (KD) to be applied to every form of kidney dysfunction, regardless of etiology. We recognize that the estimated glomerular filtration rate and urine albumin:creatinine ratio are limited in their application to the broad spectrum of KD. However, there are additional in vitro and advanced diagnostic options that can help identify the underlying cause of KD and inform about prognosis and management. While the overarching benefit of generalizing KD as a medical problem lies with screening and detection, the downsides attributable to a nonexact diagnosis (i.e., unclear prognosis and management strategy) are considerable. Finally, the terms “acute kidney injury” and “worsening renal function” are currently used interchangeably by nephrologists and cardiologists alike, and a universal adoption of one term will likely be a sizeable challenge. To be of greater benefit, we propose KD be used as a starting point and that the etiology and other epigenetic determinants of illness continue to be evaluated and characterized.

McCullough, P.A. and Vijay, K. (2021). “SARS-CoV-2 infection and the COVID-19 pandemic: a call to action for therapy and interventions to resolve the crisis of hospitalization, death, and handle the aftermath.” Rev Cardiovasc Med 22(1): 9-10.

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In this bold issue of Reviews in Cardiovascular Medicine, we present the most comprehensive and scalable early ambulatory treatment program for high-risk patients who have contracted SARS-CoV-2. No such published regimen has received so much acclaim and the concepts embodied in this paper have been responsible for saving hundreds of thousands of lives and sparing millions of hospitalization. Since it took months for the large body of information to congeal on the pathophysiology and rationale for treatment, we cannot go back in time and estimate avoidable losses [6]. Going forward, available sources of data from Zelenko and Procter, suggest available drugs used in combination can reduce hospitalizations and death by 85% and that no high-risk patient with COVID-19 should go untreated at home. Lack of home treatment can only lead to long durations of illness, more intense symptoms, and increases the risk of hospitalization, death, and potentially post-COVID-19 syndromes. At this point in time, there is no justification in any part of the world for denial of available, appropriately prescribed off label intracellular anti-infectives, corticosteroids/colchicine, and antithrombotics. [No abstract; excerpt from article].

McCullough, P.A., Rahimi, G. and Tecson, K.M. (2021). “Ambulatory Worsening of Renal Function in Heart Failure With Preserved Ejection Fraction.” J Am Coll Cardiol 77(9): 1222-1224.

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The emergence of new pharmacological therapies for heart failure (HF) patients, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and angiotensin receptor–neprilysin inhibitors, has improved the life expectancy of those living with this disease markedly. [No abstract; excerpt from article].