Sodium Zirconium Cyclosilicate in Chronic Kidney Disease, Hyperkalemia, and Metabolic Acidosis: NEUTRALIZE Randomized Study.

BACKGROUND: Metabolic acidosis and hyperkalemia are common in chronic kidney disease (CKD). A potential dual effect of sodium zirconium cyclosilicate (SZC), a selective binder of potassium in the gastrointestinal tract, on serum potassium (sK+) and serum bicarbonate (sHCO3-) was evaluated in patients with hyperkalemia and metabolic acidosis associated with CKD. METHODS: In the NEUTRALIZE study (NCT04727528), non-dialysis patients with stage 3-5 CKD, hyperkalemia (sK+ >5.0 to ≤5.9 mmol/l) and metabolic acidosis (sHCO3- 16-20 mmol/l) received open-label SZC 10 g three times daily for ≤48 hours. Patients achieving normokalemia (sK+ 3.5-5.0 mmol/l) were randomized 1:1 to SZC 10 g or placebo daily for 4 weeks. Primary endpoint was patients (%) maintaining normokalemia at end of treatment (EOT) without rescue. Secondary endpoints included mean change in sHCO3- at EOT (Day 29), and patients (%) normokalemic with a ≥3-mmol/l increase in sHCO3- without rescue. RESULTS: Of 229 patients screened, 37 were randomized (SZC, n = 17; placebo, n = 20). High screen failure led to early study termination. At EOT, 88.2% (SZC) versus 20.0% (placebo) of patients maintained normokalemia (odds ratio 56.2; P = 0.001). Low enrollment rendered secondary endpoint P-values nominal. SZC treatment provided nominally significant increases in sHCO3- versus placebo from Day 15 onwards. Patients who were normokalemic with a ≥3-mmol/l increase in sHCO3- without rescue were 35.3% (SZC) and 5.0% (placebo; P < 0.05). No new safety concerns were reported. CONCLUSIONS: SZC effectively lowered sK+ and maintained normokalemia, with nominally significant increases in sHCO3- observed for SZC versus placebo.

A Perfluorocarbon-Coated ZrP Cation Exchanger with Excellent Ammonium Selectivity and Chemical Stability: An Oral Sorbent for End-Stage Kidney Disease (ESKD).

An oral sorbent to remove NH4+ within the small intestine of end-stage kidney disease (ESKD) patients could reduce blood urea levels and diminish their dialysis treatment burden. But current sorbent materials like amorphous zirconium phosphate particles Zr(HPO4)2·H2O (ZrP) lack the selectivity to remove NH4+ in water solution with other competing ions. Our previous work found that a gas-permeable, hydrophobic polydimethylsiloxane (PDMS) coating on ZrP improved the material's selectivity for NH4+. However, a competing ion Ca2+ was still removed by PDMS-coated ZrP sorbent, and the permeability of the PDMS coating to Ca2+ was increased after low-pH stomach-like condition exposure. An alternative hydrophobic and gas permeable coating has been investigated─perfluorooctyltriethoxysilane (FOTS). The coating was attached in place of PDMS to a tetraethyl orthosilicate-coated ZrP surface. Surface atomic composition analysis and scanning electron microscopy observation verified the successful application of the FOTS coating. Water contact angle analysis validated the FOTS coating was hydrophobic (145.0 ± 3.2°). In vitro competing ion studies indicated the FOTS coating attached to ZrP increased NH4+ removal by 53% versus uncoated ZrP. FOTS offers complete selectivity for NH4+ over Ca2+ with similar NH4+ capacity as the previous PDMS coating. Moreover, FOTS-coated ZrP maintained NH4+ removal capacity and selectivity after the acid exposure study, indicating excellent acid resistance while NH4+ selectivity of ZrP-PDMS decreased by 72%. The results suggested that FOTS-coated ZrP is promising as an oral sorbent for ESKD patients.

Oral sorbents for small, charged uremic toxins, and carbon block for regeneration of dialysate: Fourth down and long.

Complexities of sorbent regeneration of dialysate led me to look at other ways to use sorbents to remove uremic toxins. An oral sorbent containing cation and anion exchangers showed effective binding of potassium, phosphate, sodium, hydrogen, and ammonium (from urea) in vitro. Animal studies are ongoing. Carbon block columns can effectively bind organic and middle molecules toxins from the dialysate. Together, these two technologies have the potential to greatly simplify dialysis for end-stage renal disease patients.

Wearable and implantable artificial kidney devices for end-stage kidney disease treatment: Current status and review.

BACKGROUND: Chronic kidney disease (CKD) is a major cause of early death worldwide. By 2030, 14.5 million people will have end-stage kidney disease (ESKD, or CKD stage 5), yet only 5.4 million will receive kidney replacement therapy (KRT) due to economic, social, and political factors. Even for those who are offered KRT by various means of dialysis, the life expectancy remains far too low. OBSERVATION: Researchers from different fields of artificial organs collaborate to overcome the challenges of creating products such as Wearable and/or Implantable Artificial Kidneys capable of providing long-term effective physiologic kidney functions such as removal of uremic toxins, electrolyte homeostasis, and fluid regulation. A focus should be to develop easily accessible, safe, and inexpensive KRT options that enable a good quality of life and will also be available for patients in less-developed regions of the world. CONCLUSIONS: Hence, it is required to discuss some of the limits and burdens of transplantation and different techniques of dialysis, including those performed at home. Furthermore, hurdles must be considered and overcome to develop wearable and implantable artificial kidney devices that can help to improve the quality of life and life expectancy of patients with CKD.

7% sodium citrate (with benzyl alcohol) as catheter lock: Dedication or obsession?

The standard heparin lock for dialysis catheters in US dialysis units is 1000 units/ml, though its use has significant limitations and problems. The alternative catheter lock of 4% sodium citrate is used in some patients, but a 7% solution would maintain catheter patency better than the 4% concentration. In spite of the failure of two prior catheter locks to become widely used in the US (highly concentrated citrate and Zuragen™), Ash Access worked with a compounding pharmacy to produce 7% sodium citrate with preservative in single-patient use frangible vials, at a reasonable cost to users. The product had early acceptance by a number of dialysis units and hospitals, but then follow-up orders were few. Where the project goes from here is unclear.

ZuraGard™: Being second with a better product.

In course of developing an anticoagulant and antibacterial catheter lock solution, we demonstrated that the components and alcohol formed an effective skin antiseptic. Ash Access formed a sister company to focus on development and clinical trials of this skin preparation and exchanged intellectual property for part ownership. Zurex Pharma now has Food and Drug Administration (FDA) approval on the new pre-operative skin preparation, ZuraGard™, and has made successful steps toward production and marketing of the product. The steps toward FDA approval, the size of the market, and user needs are clearer for a second product in the field than for the first.

Zuragen™ antiseptic catheter lock: A bridge too far?

When sodium citrate is used as an anticoagulant catheter lock the best concentration is 7%, since this provides a density approximately the same as blood. Our laboratory found that the addition of methylene blue and parabens greatly augmented antibacterial properties. Ash Access sponsored a randomized clinical trial in 400 dialysis patients with tunneled CVC, and this showed a significant decrease in incidence of catheter-related bloodstream infection (CRBSI) defined by stringent criteria. The FDA decided that the study missed its primary endpoint, and that the product was mis-classified, so they did not give approval to market. The licensee decided not to appeal to the decision to the physician panel and ended support of the project. Rights to market the catheter lock eventually returned to Ash Access.

Developing a Selective Zirconium Phosphate Cation Exchanger to Adsorb Ammonium: Effect of a Gas-Permeable and Hydrophobic Coating.

A sorbent with a high enough capacity for NH4+ could serve as an oral binder to lower urea levels in end-stage kidney disease (ESKD) patients. A hydrogen-loaded cation exchanger such as zirconium phosphate Zr(HPO4)2·H2O (ZrP) is a promising candidate for this application. However, the NH4+ binding selectivity versus other ions must be improved. Here, we have developed a gas-permeable and hydrophobic surface coating on an amorphous form of ZrP using tetraethyl orthosilicate and methoxy-terminated polydimethylsiloxane. The hydrophobic coating serves as a barrier to ions in water solution from reaching the ion-exchanger's surface. Meanwhile, its gas-permeable nature allows for gaseous ammonia transfer to the cation exchanger. In vitro studies were designed to replicate the small intestine's expected ion concentrations and exposure time to the sorbent. The effectiveness of the coating was measured with NH4+ and Ca2+ solutions and uncoated ZrP as the negative control. X-ray photoelectron spectroscopy and scanning electron microscopy measurements show that the coating successfully modifies the surface of the cation exchanger─ZrP. Water contact angle studies indicate that coated ZrP is hydrophobic with an angle of (149.8 ± 2.5°). Simulated small intestine solution studies show that the coated ZrP will bind 94% (±11%) more NH4+ than uncoated ZrP in the presence of Ca2+. Meanwhile, Ca2+ binding decreases by 64% (±6%). The nearly fourfold increase in NH4+ selectivity can be attributed to the gas-permeable and hydrophobic coating applied on the ZrP surface. This work suggests a novel pathway to develop a selective cation exchanger for treating ESKD patients.

Concentrated sodium citrate catheter lock: "The best laid schemes o' mice an' men ".

Our laboratory's in vitro studies showed that sodium citrate at concentrations from 23% to 47% is antibacterial, and a non-randomized clinical trial showed that its use as a lock solution in dialysis catheters greatly decreased the incidence of CRBSI. The licensee placed 30 ml bottles of 47% sodium citrate in kits containing the Ash Split Cath, with clear instructions to dilute the solution and inject only the catheter volume as a catheter lock. Gross misuse of the solution by one physician led to a serious adverse outcome. FDA instructed the company to remove the product from the market and issued a warning not to use concentrated citrate off-label. Sodium citrate at 23%-30% is widely used in Europe, without major complications or side effects. However, our EPO patent was contested by a Dutch company and they eventually prevailed.

The Ash Split Cath(TM) : The best inventions are simple.

Dual-lumen "acute" central venous catheters (CVC) for dialysis were developed in the 1970s and tunneled "chronic" CVC in the 1980s. Fibrous sheathing of these catheters diminished the patency after weeks to months of use. Double catheters like Canaud/Tesio worked better and longer than single body catheters but were tedious to place. I decided that the optimal CVC design would be a single body that split into two tips within the vena cava. The "Ash Split Cath(TM) " was developed in cooperation with a company focused on dialysis access catheters, and quickly became widely used around the world. However, the patent did not prevent other companies from marketing split-tip catheters. A disagreement on the terms of a royalty agreement further weakened the relationship between the marketing company and our R&D company.

Effect of Sodium Zirconium Cyclosilicate on Serum Potassium and Bicarbonate in Patients with Hyperkalemia and Metabolic Acidosis Associated with Chronic Kidney Disease: Rationale and Design of the NEUTRALIZE Study.

INTRODUCTION: Sodium zirconium cyclosilicate (SZC) is a selective potassium (K+) binder for hyperkalemia management that provides rapid and sustained correction of hyperkalemia. The NEUTRALIZE study is investigating whether SZC, in addition to correcting hyperkalemia and maintaining normal serum K+, can provide sustained increases in serum bicarbonate (HCO3-) in patients with hyperkalemia and metabolic acidosis associated with chronic kidney disease (CKD). METHODS: This is a prospective, randomized, double-blind, placebo-controlled phase 3b study of US adults with stage 3-5 CKD not on dialysis with hyperkalemia (K+ >5.0-≤5.9 mmol/L) and low-serum HCO3- (16-20 mmol/L). In the open-label correction phase, all eligible patients receive SZC 10 g three times daily for up to 48 h. Patients who achieve normokalemia (K+ ≥3.5-≤5.0 mmol/L) are then randomized 1:1 to once-daily SZC 10 g or placebo for a 4-week, double-blind, placebo-controlled maintenance phase. The primary endpoint is the proportion of patients with normokalemia at the end of treatment (EOT) without rescue therapy for hyperkalemia. Key secondary endpoints include mean change in serum HCO3-, the proportion of patients with an increase in serum HCO3- of ≥2 or ≥3 mmol/L without rescue therapy for metabolic acidosis, and the proportion of patients with serum HCO3- ≥22 mmol/L at EOT. CONCLUSIONS: NEUTRALIZE will establish whether SZC can provide sustained increases in serum HCO3- while lowering serum K+ in patients with hyperkalemia and CKD-associated metabolic acidosis and may provide insights on the mechanism(s) underlying the increased serum HCO3- with SZC treatment.

Zirconium cyclosilicate: An oral sorbent for potassium, four decades in the making.

HemoCleanse collaborated with Dr. John Sherman and Union Carbide in the 1980s to develop a cation exchanger with high selectivity for potassium and ammonium, for use in a wearable artificial kidney. Synthetic zeolites had unexpected solubility in this application but by 2000, UOP (a sister company of Union Carbide) had developed zirconium cyclosilicate (SZC). HemoCleanse performed early animal studies of SZC as an oral sorbent. These showed remarkable binding characteristics. HemoCleanse then obtained the license for SZC for medical applications, helped to form ZS Pharma, and collaborated in further animal studies and clinical trials. AstraZeneca purchased ZS Pharma in 2015, and SZC (Lokelma®) has now become an effective treatment for hyperkalemia in patients with kidney failure and cardiac conditions.

Allient™ hemodialysis machine: Sorbent-based, single-needle, UF-controlled dialysis reborn.

By the year 2000, there was rising interest in home hemodialysis in the United States. HemoCleanse decided to resurrect the BioLogic-HD machine, using updated components. A spin-off company Renal Solutions (RSI) created the Allient™, with sorbent regeneration of dialysate, hollow fiber dialyzer, pressure-controlled blood flow rate, controlled filtration, and single- or dual-needle access. RSI merged with Sorb Technology and the Allient™ was built, tested, and FDA-approved to market. In 2007 Fresenius Medical Corporation (FMC) bought RSI. FMC began an extensive re-design of the machine to fit the needs of both in-center and home dialysis. The redesigned machine never was marketed.

The BioLogic-DT™ and the saga of Liver Dialysis™.

Our small R&D company created a novel extracorporeal system for the treatment of hepatic coma and drug overdose, in which membrane motion in a screen-plate dialyzer served as a blood pump and also mixed dialysate containing powdered carbon. Early clinical trials of the Biologic-DT™ were successful in the treatment of patients with hepatic coma (especially from A-on-C liver failure) and FDA gave marketing approval. The BioLogic-DT™ was licensed to a venture capital-backed startup. It was marketed too widely and used in some patients without a chance for recovery or transplant. The licensing company failed, and the BioLogic-DT was not remarketed. The MARS™ device included albumin as a sorbent in dialysate, and clinical trials of this device also showed a benefit in the treatment of hepatic coma.

BioLogic-HD™ and the problem of being (way) too far ahead of the market.

In the 1980s, I led a team to build a hemodialysis machine with sorbent regeneration of dialysate, ultrafiltration control, and single-needle access. The BioLogic-HD™ was perfectly suited for home hemodialysis, but not for in-center or acute dialysis. The home dialysis market in the United States was decimated by HCFA's decision in 1987 to stop paying for home helpers. As a result, our Venture Capital partners stopped supporting our small company, and the BioLogic-HD was never marketed. There is criticism of nephrologists for the lack of innovation in dialysis, but the major problem has been the commercialization of new dialysis technology.

A lifelong quest to make home hemodialysis simple, safe, and effective: A review of outcomes of 12 major projects.

In the course of over four decades, I have worked with an R&D team on 12 major R&D projects, all with the goal of making hemodialysis simple, safe, effective, and suitable for use in the home. Our team has worked within a University and in private companies and has collaborated with major healthcare drug and device companies. As a practicing nephrologist, my definition of success is when I see the device or drug we helped to develop in widespread clinical use. By this measure, two of the projects were highly successful, but seven failed. Most failures were due to decisions made by various corporations, governmental agencies, and venture capital groups, out of the hands or control of the R&D company. Three projects are still ongoing. There is no shortage of creativity or new ideas in nephrology and in dialysis. The major challenge is in the commercialization of the products.

A Pilot Study on Automatic Three-Dimensional Quantification of Barrett's Esophagus for Risk Stratification and Therapy Monitoring.

BACKGROUND & AIMS: Barrett's epithelium measurement using widely accepted Prague C&M classification is highly operator dependent. We propose a novel methodology for measuring this risk score automatically. The method also enables quantification of the area of Barrett's epithelium (BEA) and islands, which was not possible before. Furthermore, it allows 3-dimensional (3D) reconstruction of the esophageal surface, enabling interactive 3D visualization. We aimed to assess the accuracy of the proposed artificial intelligence system on both phantom and endoscopic patient data. METHODS: Using advanced deep learning, a depth estimator network is used to predict endoscope camera distance from the gastric folds. By segmenting BEA and gastroesophageal junction and projecting them to the estimated mm distances, we measure C&M scores including the BEA. The derived endoscopy artificial intelligence system was tested on a purpose-built 3D printed esophagus phantom with varying BEAs and on 194 high-definition videos from 131 patients with C&M values scored by expert endoscopists. RESULTS: Endoscopic phantom video data demonstrated a 97.2% accuracy with a marginal ± 0.9 mm average deviation for C&M and island measurements, while for BEA we achieved 98.4% accuracy with only ±0.4 cm2 average deviation compared with ground-truth. On patient data, the C&M measurements provided by our system concurred with expert scores with marginal overall relative error (mean difference) of 8% (3.6 mm) and 7% (2.8 mm) for C and M scores, respectively. CONCLUSIONS: The proposed methodology automatically extracts Prague C&M scores with high accuracy. Quantification and 3D reconstruction of the entire Barrett's area provides new opportunities for risk stratification and assessment of therapy response.