Siderosis

In this column, we cite a large body of our previously published histopathologic and biochemical findings (1-14) concerning renal insufficiency to provide a framework of reference for presenting the dysox model of renal insufficiency, including: (1) histopathologic and biochemical studies of renal diseases; (2) autopsy findings of tissues in subjects on chronic hemodialysis; (3) microscopic and biochemical observations concerning oxygen homeostasis and dysoxygenosis (dysox) that led to the development of the dysox models of atherogenesis in general and of renal vascular pathology specifically; and (4) limited data concerning improved renal function with oxystatic therapies. We follow that up with: (1) a brief review of the efficacy of EDTA chelation therapies for renal insufficiency by others; (2) profiles of recovery from chronic renal failure of several of our patients; (3) brief comments about the enormous potential of oxystatic therapies for obviating the need for chronic dialysis and renal transplants; and (4) financial data showing potential for enormous savings with oxystatic and chelation therapies of empirically established efficacy.

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Histopathologic Studies in Chronic Renal Failure

In 1982, in The Pathology of Maintenance Hemodialysis, (1) two of the authors (MA & AOF) summarized a large body of their biochemical and pathologic observations on patients receiving chronic hemodialysis. Of great significance to the subject of this column among those studies were the histopathologic abnormalities observed in the vasculature, especially arterionephrosclerosis and arteriolonephrosclerosis. (5) In addition to the renal consequences of those vascular changes, we also delineated patterns of cellular injury in other sites, including: (1) cardiac myocytolysis at autopsy (the degree of which correlated well with reduction in the ventricular ejection fraction before the death of patients) (6); (2) cerebral arteriosclerosis associated with cerebral and cerebellar cortical atrophy (7); (3) pulmonary interstitial changes associated with interstitial edema and fibrosis (8); (4) hepatosplenic and adrenal siderosis (9); (5) systemic oxalosis (10); (6) parathyroid hyperplasia (11); malignant neoplasms (12); and (7) structural abnormalities in other tissues. (13) Our main conclusion drawn from those studies was that progressive renal perfusion deficit caused by accelerated arterionephrosclerosis and arteriolonephrosclerosis was the primary pathologic mechanism responsible for perpetuation and progression of renal insufficiency. Furthermore, all biochemical and histopathologic abnormalities encountered in patients on dialysis during life and at autopsy could be explained on the basis of perfusion deficits in the kidneys and other tissues.

The Dysox Model of Atherogenesis

During the last two decades, the focus at the Institute of Integrative Medicine has been on the clinical aspects of derangements of oxygen homeostasis, redox equilibrium, and acid-base balance. Derangements of those primary homeostatic mechanisms set the stage for abnormalities of the autonomic, inflammatory and autoimmune responses in patients with chronic disorders, including neoplastic disorders. (15-24) Specifically, morphologic changes of oxidative coagulopathy, (15) patterns of oxidative regression to primordial cellular ecology, (20) and biochemical profiles of dysoxygenosis (dysox) (21) including respiratory-to-fermentative shifts were described. That body of work led to the putting forth of the hypothesis of the oxidative-dysoxygenative model of coronary artery disease (ODCAD) (25) and later the dysox model of atherosclerosis, (26) which has the following three core tenets:

* The first essential energetic-molecular lesion in atherogenesis is oxidative dysautonomia, primarily related to issues of spiritual dysequilibrium (unrelenting anger and a persistent sense of being a victim);

* The second essential molecular lesion in atherogenesis is oxidative coagulopathy involving oxidative injury to all plasma and cellular components of the circulating blood, primarily related to issues of nutrition and environment; and

* The secondary lesions are intimal, medial, and thrombotic-occlusive phenomena that are the consequences of those two primary lesions, and essentially represent disturbed oxygen homeostasis with mitochondrial uncoupling of respiration and oxidative phosphorylation in those tissues.

The dysox model of atherogenesis in general and the dysox model of vascular pathology specifically in the present context, reach far beyond the prevailing cholesterol and inflammatory theories of arteriosclerosis. In 1997, one of the authors (MA), with his colleague Omar Ali, described the morphologic features of oxidative coagulopathy and marshaled thirteen lines of evidence for our view that cholesterol is not a major factor in the pathogenesis of atherosclerosis. (15) In that article, we asserted that the inflammatory response in atheroma as the basis of the inflammatory theory of arteriosclerosis, occurs as a consequence of oxidosis in the circulating blood, with subsequent regional intimal and medial injury. Since then, several lines of direct and incontrovertible experimental evidence for the dysox model of atherogenesis and of arterionephrosclerosis and arteriolonephrosclerosis in the current context have been developed. For instance, in mice most atherosclerosis loci recognized so far have not been associated with systemic risk factors associated with atherosclerosis. (27) For those reasons, in the clinical application of the dysox model of arteriosclerosis, we have emphasized the need for focusing on oxygen homeostasis in the vascular wall in the reversal of cardiovascular disease.

The Dysox Model of Renal Vascular Pathology and Renal Insufficiency

Seen in light of the morphologic observations in patients with renal failure and evidence of the pathogenetic role of dysoxygenosis in atherogenesis cited above, perpetuation and progression of chronic renal insufficiency can be seen essentially as renal dysoxygenosis. The primary strength of the dysox model of progressive renal insufficiency is twofold: (1) It brings into sharp focus the significance of pathophysiologic disruptions in body organs other than the kidneys--especially in the bowel, blood, and liver ecosystems that profoundly affect renal functional status; and (2) It requires that all elements that threaten oxygen homeostasis anywhere in the body, as well as those related to lifestyle stresses, be considered in designing integrative management plans for reversing renal failure. In order to underscore the crucial importance of those two considerations, below we present some aspects of cellular energetics that are fundamental for understanding the dysox model of renal vascular pathology.

The vascular wall regularly undergoes regional disturbances of molecular energetics (27-30) including the uncoupling of respiration and oxidative phosphorylation as components of physiologic inflammatory response discussed in a previous (May 2005) column. It has been shown that such uncoupling occurs to some extent in all cells, and to a greater degree in blood vessels that are predisposed to the development of atherosclerosis. (27-30) Those earlier findings have been fully validated by recent studies with mice generated to exhibit doxycycline-inducible expression of uncoupling protein 1 (UCP1) in the artery wall. (27) In such mice, UCP1 expression in aortic smooth muscle cells causes hypertension and increases dietary atherosclerosis without affecting cholesterol levels. Furthermore, UCP1 expression regionally increases superoxide production and decreases the availability of nitric oxide--the two clear markers of local oxidosis. Some recent advances in the understanding of mitochondrial pathophysiology provide further evidence for the dysox model of renal insufficiency. For readers with special interest in the subject, additional comments on this crucial subject are included in a later section.

The dysox model of renal insufficiency is of crucial importance, both for understanding the nature of the processes that perpetuate renal failure and for designing scientifically sound strategies for reversal of renal failure. In that light, the dysox model of chronic renal insufficiency is seen as a unifying model with a strong explanatory power for therapies that have been empirically shown to be effective for restoring renal function.

EDTA Nephrotoxicity

Much has been written and spoken about nephrotoxic effects of ethylenediaminetetraacetic acid (EDTA). In our view, following are the important aspects of this subject:

* Under experimental conditions, EDTA is known to cause acute tubular necrosis and glomerular filtration dysfunction. (31-34)

* During the early years of EDTA chelation therapy, EDTA nephrotoxicity and rising serum creatinine levels, in most cases was seen when large doses were administered rapidly. (35-37)

* EDTA does not cause renal dysfunction in individuals without pre-existing renal damage when infused slowly in doses of 1 to 1.5 grams over a period of ninety minutes or more. (38)

* EDTA chelation therapy can be administered safely with concurrent use of most commonly prescribed agents for cardiovascular disorders (unpublished observations made at the Institute).

* Safety and efficacy of EDTA infusions for improving renal function have been recognized by many groups of clinicians. (39-47)

* Nearly all patients with renal insufficiency can tolerate modest doses of EDTA (100 to 250 mg) when administered slowly (90 to 120 minutes) to well-hydrated individuals after an initial period of restoration of bowel, blood, and liver ecologies.

For safe EDTA chelation therapy, the last consideration is the most crucial. It is our practice not to initiate EDTA chelation therapy for our patients with renal insufficiency until the bowel, blood, and liver issues have been effectively addressed and some direct oxystatic therapies--intravenous hydrogen peroxide and ozone infusions, singlet oxygen therapy, and others have been administered. The theoretical and clinical aspects of EDTA and hydrogen peroxide have been described in detail in Dysoxygenosis and Oxystatic Therapies, the third volume of The Principles and Practice of Integrative Medicine. (48)

Integrated EDTA/[H.sub.2][O.sub.2] Regimens

In our experience, a weekly combination of EDTA and hydrogen peroxide infusions proved more effective than EDTA infusions alone for patients with serum creatinine levels between 1.2 to 2.5 mg/dL. For individuals with creatinine levels above that range, we generally prefer hydrogen peroxide infusions to EDTA infusions. Initially, we use modest doses of EDTA ranging from 100 to 250 mg. EDTA infusion therapy requires close monitoring with serum creatinine measurements, usually before each infusion during the first five to six periods of therapy. Needless to say, such infusions are administered as components of an integrated treatment plan with robust nutrient and herbal therapies. (See Integrative Nutritional Medicine, the fifth volume of The Principles and Practice of Integrative Medicine (49) for details.)

Brief Review of EDTA Chelation Therapy for Improving Renal Function

The names of Sidbury, (31) Meltzer, (43,44) Soffer, (32) Schwartz, (33-35) Stamp, (36) and Stankovic (37) stand out among the earlier investigators of EDTA chelation therapies. In 1975, Morgan reviewed the subject of EDTA chelation for lead nephropathy, with focus on issues of safe dosage and clinical efficacy of EDTA therapy, and presented his experience with seventeen patients. (39) (The term 'lead nephropathy' may be reassuring for some, but clearly the mere coexistence of nephropathy and increased body lead burden are not sufficient to exclude the presence of other factors of importance in the dysox model of renal insufficiency.) McDonagh, Rudolph, and Cheraskin stand out among those who documented the efficacy of EDTA for improving renal functions during the 1980s. (40-42)

Although chelation treatment for childhood lead poisoning and for industrial lead exposure has been well defined, the issue of renal insufficiency associated with heavy metal body burden has not been addressed effectively. Nephrologists generally recommend 'watchful waiting' for patients with renal insufficiency (except for prescribing ACE inhibitors) until the time comes for dialysis or kidney transplant. In that context, we were elated to see a 2003 report in The New England Journal of Medicine including the following in the conclusion section of the abstract: "Low-level environmental lead exposure may accelerate progressive renal insufficiency in patients without diabetes who have chronic renal disease. Repeated chelation therapy may improve renal function and slow the progression of renal insufficiency." (55)

It seemed to us then that the day of EDTA chelation for reversing renal insufficiency, at least in persons with documented increased body lead burden, had arrived. Alas! That did not turn out to be the case. Individuals with renal insufficiency continue to be neglected with the regrettable 'watchful waiting' strategy. Indeed, an editorial accompanying that article was entitled "Increased Body Lead Burden--Cause or Consequence of Chronic Renal Insufficiency?" (51) It is needless to point out the subliminal message of doubt in the choice of words for the title.

Toxic Metal Nephropathy and Its Reversal

Two hundred two patients with chronic renal insufficiency (indicated by a serum creatinine level between 1.5 mg per deciliter and 3.9 mg per deciliter) who had a normal totalbody lead burden and no history of exposure to lead were observed for 24 months. The New England Journal of Medicine. (50)

Who had a normal total-body lead burden! A normal total body lead burden? What might that be? This is a crucial point. Any and all amounts of toxic metals without any known physiologic roles and with well-established toxicity to oxygen homeostasis and redox equilibrium must be deemed a health hazard and a target for safe chelation therapies. Lead toxicity in children is a more compelling problem than in adults with equivalent body lead burden by weight. Thus, the recommendation that lead poisoning should be accepted only when the blood lead level is higher than 10 [degrees]g per deciliter is simply not acceptable. Fortunately, it is being recognized that there is no threshold blood level at which lead has no adverse effect on health. (52-55)

As for the renal function, it has been estimated that each increase of 100 [micro]g (0.5 [micro]mol) in the body lead burden is associated with a decrease in the glomerular filtration rate of 0.3 ml per minute per 1.73 [m.sup.2] of body-surface area, after adjustment for other factors (P<0.001). (50) However, the blood lead level, in general, is a poor measure of the long-term exposure to lead and the actual total body lead burden. It is now widely recognized that the red cell level of lead reflects only recent exposure. It has also been estimated that approximately 90 to 95% of the lead is stored in calcium-dependent skeletal pools with slow turnover. The best measure of body lead burden, in our view, is with measurements of 24-hour urinary elimination of heavy metals after a combined EDTA and DMSA challenge (see Heavy Metal Load and Toxicity, the seventh volume of The Principles and Practice of Integrative Medicine, www.majidali.com).

Oxystatic Integrative Protocols for Improving Renal Function

The sun-soil model for restoring oxygen homeostasis, redox equilibrium, and acid-base balance has been described at length in Integrative Nutritional Medicine. (49) In that model, the pathogenetic mechanisms causing acquired chronic disorders are related to spiritual disequilibrium symbolized by sun--issues of unremitting anger, sense of being a victim, forgiveness issues, and others and altered states of bowel, blood, and liver ecosystems that are metaphorically equated with the soil-roots unit of the plant. Thus, the protocols employed at the Institute for improving renal function are heavily focused on those two aspects of the sun-soil model. Among direct oxystatic therapies found to be of critical value, as mentioned earlier, are hydrogen peroxide, ozone, and EDTA chelation infusions. The theoretical and practical aspects of those therapies have been presented in detail in Dysoxygenosis and Oxystatic Therapies. (48)

Case Studies of Improved Renal Function

The reversal of chronic renal failure with integrative treatment plans, including EDTA chelation therapy, has been documented in several reports. (31-37,39-44) As for the deteriorating renal function in patients with arteriosclerosis, autoimmune disorders, and heavy metal toxicity, during the last two decades we had also clinically validated the observations of those earlier works. Some of our limited observations were included in Oxygen and Aging (www.Canary21.com.) In this column, we include several case studies that illustrate patterns of improved renal function, as assessed with serial measurements of serum creatinine levels, over periods of several months (Figure 1). It is important to point out that results shown were achieved with integrated management protocols that included robust nutrient, herbal, and self-regulatory measures. Underscoring the inter-relationships between inflammation, renal perfusion, and renal sufficiency, Table 1 presents data correlating changes in the serum creatinine levels with those in the blood levels of C-reactive protein, and blood pressure observed in a 49-year-old man with atrial fibrillation.

Improved Renal Function Without EDTA Chelation

Following the dysox model of renal insufficiency presented above, improvement of renal function should be achievable without chelation therapies if other issues can be vigorously addressed. That, indeed, is the case. The following illustrative case study documents an example. In April 2005, we saw a 49-year-old engineer with hypertension, inhalant allergy, and renal insufficiency with a serum creatinine level of 1.6 mg/dL. His creatinine level was 1.5 mg/dL in April of 2001. He had worked in the World Trade Center area in New York City and was heavily affected by the events related to the collapse of the Towers. His health steadily deteriorated during the following months, with rising blood pressure and worsening of allergic symptoms.

Some months later, his serum creatinine level was found to be 1.6 mg/dL. However, he was not offered any treatment plan to reverse renal failure. The creatinine levels stayed at about 1.6 during the next three years. We gave him detailed explanation of the nature of his kidney disorder and its relationship with hypertension and renal insufficiency. As a part of our integrative oxystatic management plan, we prescribed self-regulatory breathing methods, exercise, nutrient and herbal protocols, and hydrogen peroxide infusions and EDTA chelation with a dose of 250 mg. (See Dysoxygenosis and Oxystatic Therapies (48) for details.) He received only one EDTA infusion and could not continue infusion therapies for reasons of cost. Four weeks later, his creatinine level was 1.2, a value lower than 1.6, for the first time in four years. It was our clinical sense that what contributed most to the drop in creatinine level was the time spent on giving him a clear view of the problem and our plan of corrective action, as well as his self-regulatory work (generalized vasodilatation with consequent improved renal perfusion), since we have never seen such rapid improvement in that short a period of time with nutrient and herbal programs alone in any of our other cases.

Cost Savings of Integrated Oxystatic Plans Including EDTA Chelation

The dialysis and kidney transplant industry has mushroomed during the last three decades with no sign of letup. To give some sense of the financial scale, Medicare's portion of the End Stage Renal Disease (ESRD) program grew from $5.8 billion in 1991 to $17.0 billion in 2002, representing 6.7% of the total Medicare budget. (56) That is only the Medicare side of the dialysis industry picture, and essentially represents the cost of dialysis for those over 65 years of age. To that must be added another $5 billion or so for the Americans under the age of 65.

The yearly cost of dialysis per patient is approximately $65,000 for Medicare and $100,000 for non-Medicare patients. For Medicare beneficiaries, this breaks down as follows: The Medicare cost per member per year (PMPY) is about $53,000. It is estimated that coinsurers add another $10,000 to the bill, raising the total to approximately $65,000 per year. To make matters worse, the annual increases in the dialysis costs are estimated to continue to grow by about 10%, as has been the case for recent years. The annual cost of an integrative plan (including oxystatic infusions and EDTA therapy) at the Institute is less than $8,000 for the first year and $5-6,000 a year after that. We need not belabor the point. Those numbers speak eloquently. What those numbers are silent about is the enormous biologic cost of receiving dialysis therapy for years and decades or the broad range of nonrenal benefits that accrue from successful reversal of chronic renal insufficiency.

Mitochondrial Energetics of Significance to the Dysox Model of Renal Insufficiency

In this section, we present some information about cellular energetics to shed more light on the dysox model of renal insufficiency. In human biology, mitochondrial respiration energetics generate ATP from ADP phosphorylation, and the electron transport in that process accounts for most reactive oxygen species (ROS) production. (57) ROS generation begins with molecular oxygen picking up electrons to produce superoxide at complex I and III. (58) Located at the inner mitochondrial membrane are anion transporters called uncoupling proteins (UCP1, UCP2, and UCP3), which permit proton leakage back into the mitochondrial matrix, two consequences of which are a decrease in the potential energy available for ADP phosphorylation and a reduction in ROS generation. UCPs also increase respiration, which accelerates superoxide production in the setting of low proton motive force. (59) Superoxide, in turn, activates uncoupling protein. (60,61) Thus a valuable contrariety in free radical homeostasis at one of the most fundamental levels of molecular energetics of human biology is established.

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In the vascular wall, smooth muscle cells are the principal source of ROS. (57) In order to study the effects of uncoupling respiration and oxidative phosphorylation, mice with doxycycline-inducible expression of UCP1 restricted to aortic smooth muscle cells were generated. In such mice given doxycycline (2 mg/ ml in sucrose-containing drinking water), aortic UCP1 messenger RNA expression was induced by nearly 12-fold compared with the control wild-type mice drinking sucrose-containing water alone. (27) Transgenic mice carrying the reverse tetracycline transactivator driven by the -441 SM22 promoter were mated with mice transgenic for a tetracycline responsive element (TRE)-UCP1 minigene yielding UCP1 mice. There was no doxycycline-dependent induction of UCP1 gene expression in the aorta of SM22-rtTA mice (lacking a TRE target) or TRE-UCP1 mice (lacking an antibiotic-inducible transactivator).

Doxycycline induction of aortic UCP1 expression significantly increases both systolic and diastolic blood pressure. That hypertensive effect was abrogated ten days after removing doxycycline from the drinking water. Plasma renin activity also increases significantly--up to three-fold--in doxycycline-treated mice. Concomitantly, urinary sodium excretion decreases in the presence of doxycycline, suggesting activation of the renin-angiotensin-aldosterone system. By contrast, urinary excretion of norepinephrine, a marker of sympathetic activation, is not altered by UCP1 induction.

The relevance of oxygen-driven and redox-related events in the matrix to the oxidative-dysoxygenative model of tissue injury has been underscored. (62) While the electron transfer events in human cellular energetics have been well delineated, the subject of electron transfer in matrix has received little attention so far. Among microbial species, organisms that can transfer electrons to extracellular electron acceptors Fe(iii) oxides and others are of crucial importance to microbial organic matter degradation and nutrient cycling. Recent studies with a pilus-deficient mutant of Geobacter sulfurreducens revealed that the microbial species was unable to reduce Fe(iii) oxides, but was able to attach to them. Work with conducting-probe atomic force microscopy showed that the pili were highly conductive of electrons. It appeared that the pili of G. sulfurreducens served as biological nanowires, transferring electrons from the cell surface to the surface of Fe(iii) oxides. Such electron transfer through pili indicated that there might exist yet other unique cell-surface and cell-cell interactions. It seems likely that similar electron transfer nanowires might also exist in the matrix of human tissues. What might be the clinical significance of derangements involving these nanowires in human illness and renal insufficiency in the present context remains to be elucidated.

The Core Message

The single most important message of this column is this: In the vast majority of patients, renal insufficiency can be successfully managed, renal failure reversed, and dialysis avoided, with well-considered and well-executed integrated oxystatic protocols that correct the cellular energetic dysfunction in renal microvasculature and nephrons. None of the patients seen at the Institute with initial serum creatinine levels of less than 4 mg / dL, who were able to follow the program for more than six months, went on to receive dialysis treatment or kidney transplants during the periods of ongoing treatment. In Figure 1, the data for falling serum creatinine levels in several patients with renal insufficiency managed with oxystatic protocols, including EDTA and hydrogen peroxide infusions, are displayed. We end this column with the following quote from the 1982 preface written for The Pathology of Maintenance Hemodialysis (1):

Notwithstanding the success achieved in the man-machine interaction, and the assumption of renal excretory function by the dialysis process, the fundamental derangements in chronic renal failure have come into sharper focus with growing experience with MHD [maintenance hemodialysis]; the dialytic therapy, as we know it today, is unable to reverse the uremic milieu.

We believe that statement is as true today as it was in 1982. However, our understanding of the disruptions in oxygen homeostasis, redox equilibrium, and acidbase balance in renal failure has vastly improved. And so have the opportunities for the integrative physician to improve renal function and obviate the need for chronic dialysis and renal transplantation.

References

1. Ali M, Fayemi AO. Pathology of Maintenance Hemodialysis. 1982. Springfield, CC Thomas.

2. Ali M, Rigolosi R, Fayemi AO, Braun EV, Frascino J, Singer R. Failure of serum ferritin levels to predict bone marrow iron content after intravenous iron-dextran therapy. Lancet 1982;i:651-655.

3. Ali M, Fayemi AO, Rigolosi R, Frascino J, Marsden T, Malcolm D: Hemosidero-sis in hemodialysis patients: an autopsy study of 50 cases. JAMA 1980;244:343-345.

4. Fayemi AO, Ali M. The pathology of end-stage renal disease in hemodialysis patients. Israel J Med Sci 1979;15:901-909.

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6. Ali M, Prasad PV, Rigolosi R, Braun EV, Frascino J, Singer R, Fayemi AO, Angeli R, Haft J. Cardiac myocytolysis: pathologic basis of cardiomyopathy in dialysis patients (abstract). Kidney Int 1982;21:161.

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by Majid Ali, MD

Director, The Institute of Integrative Medicine

Director, Certification Program in Nutrition of The American Academy of Integrative Medicine

www.intmed4.com

with Alfred O. Fayemi, MD, Judy Juco, MD, and Shara Fischer, BS

212-873-2444 * 973-586-4111 * Majidalimd@aol.com * www.majidali.com

COPYRIGHT 2005 The Townsend Letter Group
COPYRIGHT 2005 Gale Group