Research Spotlight

House, A. A., C. Wanner, M. J. Sarnak, I. L. Pina, C. W. McIntyre, P. Komenda, B. L. Kasiske, A. Deswal, C. R. deFilippi, J. G. F. Cleland, S. D. Anker, C. A. Herzog, M. Cheung, D. C. Wheeler, W. C. Winkelmayer and P. A. McCullough (2019). “Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.” Kidney Int. Apr 30. [Epub ahead of print].

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The incidence and prevalence of heart failure (HF) and chronic kidney disease (CKD) are increasing, and as such a better understanding of the interface between both conditions is imperative for developing optimal strategies for their detection, prevention, diagnosis, and management. To this end, Kidney Disease: Improving Global Outcomes (KDIGO) convened an international, multidisciplinary Controversies Conference titled Heart Failure in CKD. Breakout group discussions included (i) HF with preserved ejection fraction (HFpEF) and nondialysis CKD, (ii) HF with reduced ejection fraction (HFrEF) and nondialysis CKD, (iii) HFpEF and dialysis-dependent CKD, (iv) HFrEF and dialysis-dependent CKD, and (v) HF in kidney transplant patients. The questions that formed the basis of discussions are available on the KDIGO website http://kdigo.org/conferences/heart-failure-in-ckd/, and the deliberations from the conference are summarized here.

Guo, L., D. R. Bertola, A. Takanohashi, A. Saito, Y. Segawa, T. Yokota, S. Ishibashi, Y. Nishida, G. L. Yamamoto, J. Franco, R. S. Honjo, C. A. Kim, C. M. Musso, M. Timmons, A. Pizzino, R. J. Taft, B. Lajoie, M. A. Knight, K. H. Fischbeck, A. B. Singleton, C. R. Ferreira, Z. Wang, L. Yan, J. Y. Garbern, P. O. Simsek-Kiper, H. Ohashi, P. G. Robey, A. Boyde, N. Matsumoto, N. Miyake, J. Spranger, R. Schiffmann, A. Vanderver, G. Nishimura, M. Passos-Bueno, C. Simons, K. Ishikawa and S. Ikegawa (2019). “Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation.” Am J Hum Genet 104(5): 925-935.

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Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

Goraya, N. and D. E. Wesson (2019). “Clinical evidence that treatment of metabolic acidosis slows the progression of chronic kidney disease.” Curr Opin Nephrol Hypertens 28(3): 267-277.

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PURPOSE OF REVIEW: We review the growing clinical evidence that metabolic acidosis mediates chronic kidney disease (CKD) progression and that treatment to increase the associated low serum bicarbonate (HCO3) in CKD is disease-modifying. RECENT FINDINGS: Seven prospective studies of patients with wide ranges of estimated glomerular filtration rates (eGFRs) and serum HCO3 examined the effect on CKD of increasing serum HCO3 using dietary acid reduction with either oral alkali (sodium bicarbonate or sodium citrate), a vegetarian diet very low in acid-producing protein (0.3 g/kg/day) supplemented with ketoanalogues or added base-producing fruits and vegetables. Clinical outcomes included slower kidney function decline (using eGFR measurements) and fewer patients progressing to end-stage kidney disease. Post hoc analyses demonstrated that: treatment of metabolic acidosis for 2 years decreased the number of patients with at least a 40% eGFR decline, a validated surrogate for progression to end-stage kidney disease and across four studies, treatment to increase serum HCO3 by 4-6.8 mEq/l in acidotic patients with CKD was associated with a approximately 4 ml/min/1.73 m reduction in the rate of eGFR decline over 6-24 months compared with controls. SUMMARY: Metabolic acidosis appears to enhance CKD progression and its treatment should be studied further as a potential disease-modifying intervention.

Goraya, N., J. Simoni, L. N. Sager, N. E. Madias and D. E. Wesson (2019). “Urine citrate excretion as a marker of acid retention in patients with chronic kidney disease without overt metabolic acidosis.” Kidney Int 95(5): 1190-1196.

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Acid (H(+)) retention appears to contribute to progressive decline in glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD), including some patients without metabolic acidosis. Identification of patients with H(+) retention but without metabolic acidosis could facilitate targeted alkali therapy; however, current methods to assess H(+) retention are invasive and have little clinical utility. We tested the hypothesis that urine excretion of the pH-sensitive metabolite citrate can identify H(+) retention in patients with reduced GFR but without overt metabolic acidosis. H(+) retention was assessed based on the difference between observed and expected plasma total CO2 after an oral sodium bicarbonate load. The association between H(+) retention and urine citrate excretion was evaluated in albuminuric CKD patients with eGFR 60-89 ml/min/1.73m(2) (CKD 2, n=40) or >90 ml/min/1.73m(2) (CKD 1, n = 26) before and after 30 days of base-producing fruits and vegetables. Baseline H(+) retention was higher in CKD 2, while baseline urine citrate excretion was lower in CKD 2 compared to CKD 1. Base-producing fruits and vegetables decreased H(+) retention in CKD 2 and increased urine citrate excretion in both groups. Thus, H(+) retention is associated with lower urine citrate excretion, and reduction of H(+) retention with a base-producing diet is associated with increased urine citrate excretion. These results support further exploration of the utility of urine citrate excretion to identify H(+) retention in CKD patients with reduced eGFR but without metabolic acidosis, to determine their candidacy for kidney protection with dietary H(+) reduction or alkali therapy.

Goraya, N., Y. Munoz-Maldonado, J. Simoni and D. E. Wesson (2019). “Fruit and Vegetable Treatment of Chronic Kidney Disease-Related Metabolic Acidosis Reduces Cardiovascular Risk Better than Sodium Bicarbonate.” Am J Nephrol 49(6): 438-448.

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BACKGROUND: Current guidelines recommend treatment of metabolic acidosis in chronic kidney disease (CKD) with sodium-based alkali. We tested the hypothesis that treatment with base-producing fruits and vegetables (F + V) better improves cardiovascular disease (CVD) risk indicators than oral sodium bicarbonate (NaHCO3). METHODS: We randomized 108 macroalbuminuric, matched, nondiabetic CKD patients with metabolic acidosis to F + V (n = 36) in amounts to reduce dietary acid by half, oral NaHCO3 (HCO3, n = 36) 0.3 mEq/kg bw/day, or to Usual Care (UC, n = 36) to assess the 5-year effect of these interventions on estimated glomerular filtration rate (eGFR) course as the primary analysis and on indicators of CVD risk as the secondary analysis. RESULTS: Five-year plasma total CO2 was higher in HCO3 and F + V than UC but was not different between HCO3 and F + V (difference p value < 0.01). Five-year net eGFR decrease was less in HCO3 (mean -12.3, 95% CI -12.9 to -11.7 mL/min/1.73 m2) and F + V (-10.0, 95% CI -10.6 to -9.4 mL/min/1.73 m2) than UC (-18.8, 95% CI -19.5 to -18.2 mL/min/1.73 m2; p value < 0.01) but was not different between HCO3 and F + V. Five-year systolic blood pressure was lower in F + V than UC and HCO3 (p value < 0.01). Despite similar baseline values, F + V had lower low-density lipoprotein, Lp(a), and higher serum vitamin K1 (low serum K1 is associated with coronary artery calcification) than HCO3 and UC at 5 years. CONCLUSION: Metabolic acidosis improvement and eGFR preservation were comparable in CKD patients treated with F + V or oral NaHCO3 but F + V better improved CVD risk indicators, making it a potentially better treatment option for reducing CVD risk.