Metadichol® and Red Cell Distribution Width (RDW) in CKD patients

Abstract

Red blood cells originate in the bone marrow. Red cell distribution width (RDW) show sizes of circulating erythrocytes (RBC) and has been explored in several large clinical databases to be a robust marker of adverse clinical outcomes in patients. The prognostic value of RDW is seen in other conditions with end-organ dysfunction such as renal failure or. Elevated RDW levels are of significance in diseases such as kidney diseases. The high RDW levels are an indication of increased oxidative stress and closely related to the presence and poor prognosis of the disease.
No known therapy exists that can normalize RDW levels. In this paper, we present here case studies using Metadichol® [1] that leads to normal RDW levels in patients with CKD and PKD.

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Volume 7 • Issue 7 • 1000392
J Stem Cell Res Ther, an open access journal
ISSN: 2157-7633
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ISSN: 2157-7633
Raghavan, J Stem Cell Res Ther 2017, 7:7
DOI: 10.4172/2157-7633.1000392
Abstract
Red blood cells originate in the bone marrow. Red cell distribution width (RDW) show sizes of circulating
erythrocytes (RBC) and has been explored in several large clinical databases to be a robust marker of adverse clinical
outcomes in patients. The prognostic value of RDW is seen in other conditions with end-organ dysfunction such as
renal failure or. Elevated RDW levels are of signicance in diseases such as kidney diseases. The high RDW levels
are an indication of increased oxidative stress and closely related to the presence and poor prognosis of the disease.
No known therapy exists that can normalize RDW levels. In this paper, we present here case studies using
Metadichol® [1] that leads to normal RDW levels in patients with CKD and PKD.
Metadichol® and Red Cell Distribution Width (RDW) in CKD patients
Raghavan PR
Nanorx Inc., New York, USA
*Corresponding author: Raghavan PR, Nanorx Inc., PO Box 131, Chappaqua, NY
10514, USA, Tel: +1-914-671-0224; E-mail: raghavan@nanorxinc.com
Received June 27, 2017; Accepted June 30, 2017; Published July 06, 2017
Citation: Raghavan PR (2017) Metadichol® and Red Cell Distribution Width (RDW)
in CKD patients. J Stem Cell Res Ther 7: 392. doi: 10.4172/2157-7633.1000392
Copyright: © 2017 Raghavan PR. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Keywords: Red Cell Distribution Width; RDW; Metadichol; Bone
marrow; Hematopoietic stem cells; Red blood cell; Erythropoietin;
EPO; CKD; Peritoneal dialysis; Hemodialysis; EPO; TNF-alpha;
Vitamin D; VDR; Inverse/protean agonist; Creatinine; eGFR; Iron and
Iron saturation
Introduction
In the 21st-century Chronic Kidney Disease (CKD) is becoming a
worldwide health issue [2]. RDW elevation is seen in patients with CKD
[3], Peritoneal Dialysis (PD) or Hemodialysis [4] which is a standard
therapy for patients reaching End-Stage Renal Disease (ESRD). RDW
has potential use as a biomarker in estimating the risk of mortality. A
higher RDW is an independent risk factor for overall and CVD-related
mortality in patients undergoing dialysis, and that its value was superior
to others biomarkers of anaemia [5].
Although mechanisms are unknown, evidence suggests an
independent relationship between RDW and clinical outcomes in many
human diseases [6]. A high RDW Level indicates heterogeneity in RBC
size (anisocytosis). Also, accelerating RBC destruction and ineective
erythropoiesis, are common in patients undergoing dialysis, and bone
marrow dysfunction which leads to a high RDW level.
Bone marrow-derived mesenchymal stem cells have been reported
to play a crucial role in the restoration of many injured vital organs [7].
us, hematopoiesis in dialysis patients leads to mortality associated
with a high RDW.
Inammation, which is prevalent in CKD patients, has been
closely linked to RDW in many patient populations. Pro-inammatory
cytokines like TNF-alpha are well known to inhibit, induced RBC
maturation and proliferation [8].
Malnutrition and protein-energy wasting, which is common in
dialysis patients, increases RDW and is inversely related to nutritional
index in a broad range of medical conditions [9].
e residual renal function was greater in the low RDW group than
that in the high RDW group. e residual renal function has a benecial
eect on patient survival [10].
High RDW levels are associated with an increased risk of adverse
outcomes in the general population and in patients with severe sepsis,
heart failure, coronary artery disease, stroke, and acute kidney injury
that required renal replacement therapy and kidney transplant [11].
High level of RDW impairs iron metabolism, and the resulting
inammation disrupts the process of erythropoiesis [12].
Cytokines are released when there is inammatory stress and can
inhibit erythrocyte maturation. ese cytokines like TNF-alpha block
the activity of erythropoietin inhibit erythrocyte maturation, and this
results in the production of ineective red blood cells and elevated
RDW [13].
Given the importance of RDW in mitigating disease outcomes [14],
there is only one reported study by Fici et al. [15] that evaluated the
eects of nebivolol and metoprolol on RDW in hypertensive patients
(Table1). Nebivolol decreased RDW marginally by about 4%. ere are
no known drugs available to treat this dysfunction today.
Metadichol (16 ), as we have shown earlier, binds to VDR and is
also a TNF-alpha (1) inhibitor and also demonstrated that it increased
platelets in Dengue patients [16]. Platelets result from hematopoietic
stem cells which also is the pathway to normal erythropoiesis and
normal RDW. We treated three patients with CKD and high RDW
levels using Metadichol. In addition to improvement in RDW, other
improvements in Creatinine, Iron, PTH is seen and a feeling of well-
being [17].
Case Presentation 1
70 years old male has been on Hemodialysis 3 days a week for ve
years. Treated with Metadichol at 10 mg per day. e patient is also on
statins, phosphate binders and Vitamin D. He reports improved energy
RDW Nebivolol (n=37) Metroprolol (n=35) P*
Before 15.75 ± 1.49 15.68 ± 1.60 0.85
After 15.07 ± 1.26 15.62 ± 1.59 0.11
P† <0.001 0.35
Table 1: Effects of nebivolol and metoprolol on RDW in hypertensive patients.

Citation: Raghavan PR (2017) Metadichol® and Red Cell Distribution Width (RDW) in CKD patients. J Stem Cell Res Ther 7: 392. doi: 10.4172/2157-
7633.1000392
Page 2 of 4
Volume 7 • Issue 7 • 1000392
J Stem Cell Res Ther, an open access journal
ISSN: 2157-7633
well as a general feeling of wellness. All the three patients have shown
improvements in various biomarkers like Creatinine, PTH, and ferritin
and will be reported in due course. No adverse side eects have since
Metadichol® is a natural food-based product that is completely safe (18-20).
Figure 1: Representation of case 1.
and no sudden drops in pressure during dialysis (Figure 1).
Case Presentation 2
62 years old male patient with CKD for four years. He is obese,
diabetic and hypertensive and has been on hemodialysis three days
a week. Treated with Metadichol® 10 mg per day. e p a tient w a s
on hypertension drugs, insulin and metformin. Also, he had an
accumulation of water retention in legs and was on diuretics as well. e
patient lost 22 lb aer starting with Metadichol®, his swelling is gone,
and blood sugar has normalized. He is o insulin and metformin but
still on hypertensive drugs (Figure 2).
Case Presentation 3
A 65 years old female patient diagnosed with Polycystic Kidney
disease on dialysis for seven years before she had a kidney transplant.
Undergoes infusion once a month for anti-rejection therapy but is not
on dialysis. A year aer the transplant she still did not feel completely
normal. She had a lot of water retention and weight increase. Aer using
Metadichol® at 5 mg per day, she feels much improved and energetic.
She also lost 15 lb in weight, mostly water, and is feeling very energetic
(Figure 3).
Discussion
e results show that all three patients have experienced a decrease
in their RDW. Also, all of them showed improvement in RBC and
Hemoglobin levels. Statistical Analysis of Variance one way was carried
out using JMP software from SAS showed that the following RBC
were significant at p = 0.0023, but Hemoglobin was not significant
with a p = 0.21
Case 1 patient’s Hemoglobin and RBC are heading in the direction
of normality though at a slower pace compared to the other two cases
presented. Also improvements in other parameters such as Creatinine,
Iron, and Iron saturation, and loss of weight and increased energy as
Figure 2: Representation of case 2.
Figure 3: Representation of case 3.

Citation: Raghavan PR (2017) Metadichol® and Red Cell Distribution Width (RDW) in CKD patients. J Stem Cell Res Ther 7: 392. doi: 10.4172/2157-
7633.1000392
Page 3 of 4
Volume 7 • Issue 7 • 1000392
J Stem Cell Res Ther, an open access journal
ISSN: 2157-7633
consumed on a daily basis and with no toxicity seen even with doses of
up to 5000 mg/kg (18-20). Metadichol could be used as a nutritional
supplement in renal and hematological diseases as a cheaper alternative.
It can prevent complications from existing therapies that add to health
care costs.
References
1. Raghavan PR. US Patents 8,722,093 (2014), 9,034,383 (2015), 9,006,292
(2015).
2. Glassock RJ, Warnock DG, Delanaye P (2017) The global burden of chronic
kidney disease: estimates, variability, and pitfalls. Nat Rev Nephrol 13: 104-114.
[PubMed]
3. Solak Y, Yilmaz MI, Saglam M, Caglar K, Verim S, et al. (2014) Red cell
distribution width is independently related to endothelial dysfunction in patients
with chronic kidney disease. Am J Med Sci 347: 118-124. [PubMed]
4. The National Forum of ESRD Networks.
5. Allen LA, Felker GM, Mehra MR, Chiong JR, Dunlap SH, et al. (2010) Validation
and Potential Mechanisms of Red Cell DistributionWidth as a Prognostic Marker
in Heart Failure. J Card Fail Vol 16: 230-238. [PubMed]
6. Salvagno GL Sanchis-Gomar F, Picanza A, Lippi G (2015) Red blood cell
distribution width: A simple parameter with multiple clinical applications. Crit Rev
Clin Lab Sci. 52: 86-105. [PubMed]
7. Li M, Ikehara S (2013) Bone-marrow-derived mesenchymal stem cells for organ
repair. Stem Cells Int 2013: 132642. [PubMed]
8. Macdougall IC, Cooper AC (2002) Erythropoietin resistance: the role of
inammation and pro-inammatory cytokines. Nephrol Dial Transplant 17: 39-
43. [PubMed]
9. Forhecz Z, Gombos T, Borgulya G, Pozsonyi Z, Prohászka Z, et al. (2009) Red
cell distribution width in heart failure: Prediction of clinical events and relationship
of with markers of ineffective erythropoiesis, inammation, renal function, and
nutritional state. Am Heart J 158: 659-666. [PubMed]
10. Wang AY, Sea MM, Ho ZS, Lui SF, Li PK, Et al. (2005) Evaluation of handgrip
strength as a nutritional marker and prognostic indicator in peritoneal dialysis
patients. Am J Clin Nutr 81: 79-86. [PubMed]
11. Sun OI, Chung BH, Yoon HJ, Kim JH, Choi BS, et al. (2016) Clinical signicance
of red blood cell distribution width in the prediction of mortality in patients on
peritoneal dialysis In Kidney Res Clin Pract 35, 114-118. [PubMed]
12. Chiari MM, Bagnoli R, De Luca PD, Monti M, Rampoldi E, et al. (1995) Inuence
of acute inammation on iron and nutritional status Indexes in older inpatients.
J Am Geriatr Soc 43: 767-771. [PubMed]
13. Pierce CN, Larson DF (2005) Inammatory cytokine inhibition of erythropoiesis
in patients implanted with a mechanical circulatory assist device. Perfusion
20:8i-90. [PubMed]
14. Bujak K, Wasilewski J, Osadnik T, Jonczyk S, Kołodziejska A, et al. (2015)
The Prognostic Role of Red Blood Cell Distribution Width in Coronary Artery
Disease, A Review of the Pathophysiology. Disease Markers 2015: 824624.
15. Fici F, Celik T, Balta S, Iyisoy A, Unlu M, et al. (2013) Comparative Effects
of Nebivolol and Metoprolol on Red Cell Distribution Width and Neutrophil/
Lymphocyte Ratio in Patients With Newly Diagnosed Essential Hypertension. J
Cardiovasc Pharmacol 62: 388-393. [PubMed]
16. Raghavan PR (2016) Inhibition of Dengue and other enveloped viruses by
Metadichol®, a Novel Nanoemulsion Lipid. JSCHO 8: 19-25.
17. Raghavan PR, unpublished results of the ongoing study.
18. Alemán CL, Más R, Hernández C, Rodeiro I, Cerejido E, et al. (1994) A
12-month study of policosanol oral toxicity in Sprague Dawley rats. Toxicol Lett
70: 77-87. [PubMed]
19. Alemán, CL, Más Ferreiro R, Noa Puig M, Rodeiro Guerra I, Hernández Ortega
C, et al. Carcinogenicity of policosanol in Sprague-Dawley rats: A 24-month
study. Teratog Carcinog Mutagen 14: 239-249; [PubMed]
20. Aleman, CL, Puig MN, Elías EC, Ortega CH, Guerra IR, et al. Carcinogenicity
of policosanol in mice: An 18-month study. Food Chem Toxicol: 1995; 33: 573-
578. [PubMed]
Inammation induced by cytokines like TNF-alpha, IL-1B, Il-6, etc.
can have a suppressing eect on Erythropoietin (EPO) thus erythrocyte
maturation, leading to the production of ineective red blood cells and
elevated RDW hemoglobin synthesis and cause chronic inammatory
anemia (21). us a simple explanation of the mechanism of action
of Metadichol® that as a TNF-alpha inhibitor [1] it could reduce
inammatory cytokines and bring about the normalization of RDW,
RBC, and HGB levels.
Previous studies have shown that Tumor Necrosis Factor alpha
(TNF-alpha) as a therapeutic target in many human immune disorders,
including inammatory diseases, ischemia-reperfusion injury as well
as trauma (22)]. Also, it might plays an essential role in rapid necrotic
regression of certain forms of tumors [23]. erefore, it is crucial to
understand the potential mechanisms that involved in the regulation
of TNF-alpha in normal and disease-related cells. Recent observation
indicated that histone methyltransferase G9a and heterochromatin-
associated protein HP1 is essential for the silencing of TNF-alpha [24].
Epigenetically, G9a functions as the H3K9me1/2 writer whereas HP1
binds and maintains H3K9me3 at heterochromatin loci [25] suggesting
that methylation of histone H3 lysine nine residues is critical for the
regulation of TNF-alpha. Additionally, as G9a also interacts with
DNA methyltransferase (DNMTs) and maintains DNA methylation
at particular loci [26] the presence of DNA methylation might also
aect the expression of TNF-alpha. Taken together, investigation of the
H3K9me, as well as the DNA methylation patterns, might create a new
direction for revealing the mechanisms that involved in the regulation
of TNF-alpha.
Another explanation is the role of Vitamin D in the hematopoietic
process. Suppression of erythropoiesis occurs in bone marrow by
inammatory cytokine due to blockage of erythroid progenitor cell
proliferation and pro-erythroblast maturation. e inammatory
cytokine modulation on bone marrow erythroid progenitors
desensitizes the cells to EPO, which blocks its anti-apoptotic and pro-
maturation eects (27-28).
Vitamin D range of biological eects involve not just calcium and
Phosphorus homeostasis, but it is also an immune modulator. is
property allows it to modulate dysfunctional hematopoietic and this
can aect in hematologic disorders. (29-30). Immune cells express
Vitamin D receptor (VDR) which are well known to modulate innate
and adaptive immunity. VDR activation can inhibit production of
inammatory cytokines up-regulates interleukin-10 (IL-10) exerting
both anti-inammatory activity and proliferative eects on erythroid
progenitors. In CKD patients, vitamin D deciency stimulates
immune cells within the bone marrow to produce cytokines, leading
to dysfunctional erythropoiesis. Kiss et.al. have shown that there is an
inverse association between vitamin D levels and EPO CKD patients
[25]. Vitamin D supplementation and Paricalcitol therapy have been
shown to lead to improvement in biomarkers of inammation (31-33).
Metadichol is a TNF-alpha inhibitor and also it binds to VDR,
and hence it could be working through more than one pathway in
modulating RDW and normalizing RBC and Hemoglobin levels.
We have previously shown how Metadichol works on other diseases
through the Vitamin D receptor as an inverse/protean agonist and
other nuclear receptors (34-42). e results of this study demonstrate
that Metadichol is safe and eective as evidenced by the improvement
of various biomarkers such as RDW that lead to improved RBC and
Hemoglobin levels in CKD patients. Metadichol has the potential to be
an anti-inammatory molecule with a broad spectrum of activity. Its
constituents (long-chain lipid alcohols) are present in foods commonly

Citation: Raghavan PR (2017) Metadichol® and Red Cell Distribution Width (RDW) in CKD patients. J Stem Cell Res Ther 7: 392. doi: 10.4172/2157-
7633.1000392
Page 4 of 4
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J Stem Cell Res Ther, an open access journal
ISSN: 2157-7633
21. Cetian M, Kocaman SA, Bostan M, Çanga A, Çiçek Y, et al. (2012) Red Blood
Cell Distribution Width (RDW) and its Association with Coronary Atherosclerotic
Burden in Patients with Stable Angina Pectoris. Eur J Gen Med 9: 7-13.
22. Esposito E, Cuzzocrea S (2009) TNF-alpha as a therapeutic target in
inammatory diseases, ischemia-reperfusion injury, and trauma. Curr Med
Chem 16: 3152-3167. [PubMed]
23. Idriss HT, Naismith JH (2000) TNF-alpha and the TNF receptor superfamily:
structure-function relationship(s). Microsc Res Tech 50: 184-195. [PubMed]
24. El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, et al. (2008) G9a and HP1
couple histone and DNA methylation to TNFalpha transcription silencing during
endotoxin J Biol Chem 283: 32198-32208. [PubMed]
25. Shinkai Y, Tachibana M (2011) H3K9, methyl-transferase G9a, and the related
molecule GLP.Genes Dev 25: 781-788: [PubMed]
26. Muramatsu D, Kimura H, Kotoshiba K, Tachibana M, Shinkai Y, et al. (2016)
Pericentric H3K9me3 Formation by HP1 Interaction-defective Histone Methyl-
transferase Suv39h1.Cell Struct Funct 41: 145-152. [PubMed]
27. Zhang T, Termanis A, Özkan B, Bao XX, Culley J, et al. (2016) G9a/GLP
Complex Maintains Imprinted DNA Methylation in Embryonic Stem Cells. Cell
Reports 15: 77-85. [PubMed]
28. Hellwig-Burgel T, Rutkowski K, Metzen E, Fandrey J, Jelkmann W (1999)
Interleukin-1 beta and tumor necrosis factor-alpha stimulate DNA binding of
hypoxia inducible factor-1. Blood 94: 1561-1567 [PubMed]
29. Lacombe C, Mayeux P (1999) The Molecular biology of erythropoietin. Nephrol
Dial Transplant 14: 22-28. [PubMed]
30. Macdougall IC, Cooper A (2012) The inammatory response and Epoetin
sensitivity. Nephrol Dial Transplant 17: 48-52. [PubMed]
31. Hall AC, Juckett MB (2013) The Role of Vitamin D in Hematologic Disease and
Stem Cell Transplantation. Nutrients 5: 2206-2221. [PubMed]
32. Kiss Z, Ambrus C, Almasi C, Berta K, Deak G, et al. (2011) Serum 25(OH)-
cholecalciferol concentration is associated with hemoglobin level and
erythropoietin resistance in patients on maintenance hemodialysis. Nephron
Clin Pract 117: c373-c378. [PubMed]
33. Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, et al. (2008) Paricalcitol
reduces albuminuria and inammation in chronic kidney disease: a randomized,
double-blind pilot trial. Hypertension 52: 249-255. [PubMed]
34. Raghavan PR (2017) Rheumatoid Arthritis and Osteoporosis: A Case Study. J
Arthritis 6: 240.
35. Raghavan PR (2017) Systolic, and Diastolic BP Control in Metabolic Syndrome
Patients with Metadichol® a Novel Nano Emulsion Lipid. J Cardiol & Cardiovasc
Ther 5: 555660.
36. Raghavan PR (2017) Metadichol® A Novel Nano Lipid; GPR 120 Agonist. Int J
Diabetes Complications 1-3
37. Raghavan PR (2017) Metadichol® and MRSA Infections: A Case Report. J
Infect Dis Ther 5: 100317.
38. Raghavan PR (2017) Improving Longevity with Metadichol ® by inhibiting Bcat-1
Gene. J Aging Sci 5: 1.
39. Raghavan PR (2016) In vitro Inhibition of Zika Virus by Metadichol®. A Novel
Nano Emulsion Lipid. J Immunol Tech Infect Dis 5: 4.
40. Raghavan PR (2016) Inhibition of Dengue and other enveloped viruses by
Metadichol®, a Novel Nanoemulsion Lipid. Journal of the Science of Healing
Outcomes 8: 19-25.
41. Raghavan PR (2016) Metadichol and Type 2 Diabetes A case report. J Sci
Healing Outcomes 8: 5-10.
42. Raghavan PR (2010) Case Report of Type1. Diabetes. Journal of the Science
of Healing Outcomes 2: 8-9.
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Citation: Raghavan PR (2017) Metadichol® and Red Cell Distribution Width
(RDW) in CKD patients. J Stem Cell Res Ther 7: 392. doi: 10.4172/2157-
7633.1000392