THE PATH AHEAD
The Kidney Dysfunction Epidemic, Part 2: Intervention Joseph Pizzorno, ND, Editor in Chief
I
n my last editorial, “The Kidney Dysfunction Epidemic: Part 1, Causes,” I reviewed the key environmental, dietary, and endogenous toxins that appear to be the primary causes of the epidemic of kidney dysfunction and failure. Heavy metals (cadmium and mercury); persistent organic pollutants (halogenated hydrocarbons—especially those that are fluorinated and released when nonstick pans are heated to typical cooking temperatures—glyphosates, etc); smoking; nonsteroidal anti-inflammatory drugs (especially acetaminophen); lipopolysaccharides from a leaky, toxic gut; and excessive dietary salt and phosphates all add up to a heavy and damaging load on the kidneys. The scope of kidney failure was really brought home to me while I was writing this editorial. I met with an insurance broker interested in natural/integrative medicine solutions for her client corporations. Her story of why she was interested was quite illustrative of the problem. Fifteen years ago, when she first started working in health care insurance, she was seeing approximately 1 new claim per year for dialysis. When after a dozen years it had burgeoned to 10 per month, she realized something was wrong. She then started seeking solutions, as the conventional interventions not only were very expensive, but did not seem to be dealing with the underlying causes of the epidemic. As we were talking in a Starbucks near my home, I looked thoughtfully at the kidney dialysis center across the street. When it opened 5 years ago, I simply thought, “How nice, now kidney failure patients no longer have to drive downtown to ‘pill hill’ to get treated.” Hmmm. An Internet search quickly showed more than 10 centers within 3 miles of my home. Sure makes this real. Protecting and Regenerating the Kidneys First, of course, we need to advise our patients on the causes of their kidney damage. Basically, inadequate blood supply to the kidneys, inadequate water consumption, and excessive toxic load. Almost all the causes of kidney damage can be controlled by helping our patients make better choices. Keys for the most immediate benefit are decreasing obvious toxins of choice, such as excessive dietary salt and phosphates, and drugs such as the NSAIDS. Foundational to kidney function is simply the quantity of their blood supply. Much of the loss of glomerular filtration rate (GFR) is determined by the loss in quality and quantity of the microcirculation of the kidneys.
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Integrative Medicine • Vol. 15, No. 1 • February 2016
Interestingly, many of the factors known to increase risk of most chronic diseases have as part of the mechanism damage to the microcirculation. Obvious examples include smoking, poor blood sugar control (loss of microcirculation underlies the serious sequelae of diabetes such as loss of vision, loss of toes, and, appropriately, accelerated decline in kidney function), elevated blood pressure, oxidative stress, elevated homocysteine, obesity, and even high-fat meals (which increase absorption of endotoxins from the gut). Some research suggests that impaired microcirculation in the kidneys, not only glomerular damage, may be the primary reason function declines with aging, as well as the factors mentioned above.1 A significant number of the elderly have enough atherosclerosis in the arteries leading to the kidneys to cause measureable loss of kidney function. Catherization to remove the blockage significantly increases kidney function strongly supporting the concept that the glomerular dysfunction may be as much due to poor blood flow as cellular death.2 This decreased circulation also facilitates the accumulation of extracellular matrix around the kidney, which not only causes a buildup of scar tissue, but also impairs vascular endothelial growth factor (VEGF) from helping restore blood flow. This is modeled in Figure 1. Figure 1. Model for the Development of Kidney Fibrosis1 Renal MV endothelial dysfunction Vasoconstriction Mild tissue ischemia
TGF-β CTGF MMPs HGF
ECM accumulation Fibrosis MV repair and proliferation
VEGF TSP, Angio
MV remodeling, damage, and loss Severe tissue ischemia Progressive renal injury
Pizzorno—The Path Ahead
1. Decrease total toxic load on the kidneys. 2. Aggressively reduce exposure to nephrotoxins. 3. Increase microcirculation of kidneys. 4. Protect the kidneys from oxidative stress. Decrease Total Toxic Load Exogenous toxins, endogenous toxins, and toxins of choice have been discussed in many of my editorials and articles I have recruited for IMCJ. Mercury, persistent organic pollutants, excessive salt and phosphates—the list is long. No, I am not saying we need to give up on our more comfortable industrialized life, but we most certainly need to stop being so cavalier about letting all these undesirable elements and molecules into our food, water, and air. Aggressively Decrease Exposure to Nephrotoxins The key nephrotoxic agents were discussed in “The Kidney Dysfunction Epidemic: Part 1, Causes.” By far the worst is cadmium. Although some chemicals are more toxic, we are exposed to a lot more cadmium, especially those who smoke or eat conventionally grown foods. With a half-life of 10 years and 50% of total body load in the kidneys, the challenge presented by cadmium is serious. I will write an editorial on cadmium in the future. In the meantime, I think the work of Stephen Genuis, MD, in Edmonton, Alberta, Canada, is very encouraging. Specifically, he has shown that sweating helps excrete cadmium through the skin. Improve Microcirculation of Kidneys Beetroot Juice Increases Blood Flow to the Kidneys Increasing blood flow to the kidneys has a huge impact on improving detoxification and decreasing oxidative stress. The research process looking at the benefits of foods and nutrients that increase production of nitrogen oxides in dilating peripheral blood vessels to increase blood flow to the tissues is in the early stages, but encouraging. A study in rats showed an impressive, dose-dependent increase in blood flow to the kidneys up to 26% as shown in Table 1.3 There is growing research on the health benefits of beetroot juice for humans, although I could not find any that specifically looked at effects on kidney function. A relevant study in adults with peripheral vascular disease found, as shown in Figure 2, that beetroot juice clearly improved microcirculation resulting in improved walking distance. This 18% increase in walking time certainly supports a significant improvement in blood flow. Table 1. Beetroot Juice Increases Blood Flow to Kidneys Control BRLD BRHD BF 447 ± 32 521 ± 32 Kidney 414 ± 29 Abbreviations: BF, blood flow; BRLD, beetroot low dose; BRHD, beetroot high dose.
Pizzorno—The Path Ahead
Figure 2. Beetroot Juice Improves Peripheral Blood Supply4 425
Claudication Onset Time (s)
This all leads me to recommend the following foundational strategies:
350 250 225
a
200 175 150 125 100 75
Beetroot Juice a Significantly different from placebo group, P ≤ .01. Placebo
Centella asiatica Improves Blood Flow to the Kidneys Traditional Chinese medicine has used Gotu kola (Centella asiatica) to treat kidney diseases for centuries. Asiaticoside has been shown to improve in microcirculation and reverse fibrosis in humans with varicose veins. Its direct benefits for the kidneys have only been shown in animals but are encouraging. One found Gotu kola very effectively protected rats from adriamycin-induced nephropathy resulting in dramatically improved kidney function compared with the untreated rats.5 Another study combined Gotu kola in conjunction with naringenin and showed decreased fibrosis formation in the kidneys.6 Chocolate Improves Blood Flow to Kidneys Dark chocolate consumption improves oxygenation of the kidneys, even in healthy people. The benefit is directly proportional to catechin levels.7 Animal research has shown that these substances also protect the kidneys from oxidative stress from toxic drugs such as cyclosporine,8 which is a good segue into our final strategy. Protect the Kidneys From Oxidative Stress Blueberries Protect the Kidneys From Oxidative Stress Every time I write about the remarkable health benefits of blueberries, I think of insightful researcher and compelling lecturer, James Joseph, PhD. I vividly remember the first time we spoke at the same conference some 15 years ago and being so impressed by his deep understanding of the healing effects of colorful foods. His untimely death in 2010 was a shock and undoubtedly slowed discovery in this important field. Integrative Medicine • Vol. 15, No. 1 • February 2016
9
Figure 3. Blueberries Protect the Kidneys from Gutderived Toxins9 GFR
mL/min/g kidney wt
2.0 1.5 1.0 0.5 0
SAL
BB
SAL
Control
BB LPS
Abbreviations: GFR, glomerular filtration rate; SAL, saline; BB, blueberries; LPS, lipopolysaccharide. A benefit that surprised me was that blueberry anthocyanins specifically protect the kidneys from bowelderived entoxins. This is well demonstrated in Figure 3, which shows how blueberries increase GFR in normal kidneys (but the increase is not statistically significant) but far more importantly completely protects the kidneys from the dramatic lowering of GFR caused by gut toxins in those with impaired function.
improved kidney blood flow and function in hypertensive rats.11 The protective effects of Ginkgo have been shown in many tissues. One especially relevant study found that Ginkgo protects the kidneys from glyphosate.12 Other animal studies have shown protection of the kidneys from mercury, uranium, naphthalene, and many other toxins.13,14,15 Ginkgo also protects the kidneys from gut-derived endotoxins.16 Ginger Protects Kidney Function Although human studies have not caught up with the animal studies on the kidneys, there is now enough animal research showing that Zingiber officinale not only improves kidney function but is especially beneficial protecting the kidney from cadmium. The primary mechanism of protection appears to be ginger’s ability to decrease inflammation and oxidative damage to kidney tissue exposed to a wide variety of toxins. The anti-inflammatory benefits of ginger in the kidney are due to not only its antioxidant properties, but epigenetic downregulation of proinflammatory genes.17 (On a side note, I am beginning to wonder what proportion of the beneficial effects of botanical medicine is due their epigenetic effects. Which then brings up the question of why. Why does consumption of herbs result so often in desirable epigenetic effects? I wonder if this is in response to potentially toxic constituents in herbs [and foods] that we evolved mechanisms to detoxify, which then has unexpected benefits elsewhere.) One study, as shown in Table 4, found that ginger specifically increases activity of kidney antioxidant enzymes in obese and diabetic rats.18 Seems especially relevant considering that one-third of our population is obese and if not already diabetic are well on their way.
Curcumin (Turmeric) Protects the Kidneys Seems whenever I write an editorial like this, curcumin shows up. Curcumin has shown renoprotective benefit in diabetic nephropathy, chronic renal failure, ischemia, and nephrotoxicity induced by cadmium, gentamicin, adriamycin, chloroquine, iron nitrilotriacetate, sodium fluoride, Table 4. Ginger Increases Production of Kidney Antioxidant Enzymes hexavalent chromium, and cisplatin.10 In fact, it not only protects from damage but SOD GPx (mM/ CAT (mM/ also maintains GFR despite the toxins. (U/mg min/mg min/mg I am especially intrigued by its protective Parameters protein) protein) protein) effects against cadmium. a a 18.5 ± 0.1a Group 1: Negative control 58.70 ± 2.2 69.0 ± 2.1 Ginkgo biloba Improves Kidney Function This will come as no surprise considering how most of us prescribe this ancient herbal medicine to improve circulation in many chronic diseases. Ginkgo has been shown to improve blood supply to the brain and in other critical tissues. Also of great importance is its ability to protect against numerous mitochondrial toxins. As discussed in my last editorial, mitochondrial damage in the kidneys mediate much of the nephrotoxicity. I could not find human studies on Ginkgo specifically for the kidneys, but one animal study showed 10
Integrative Medicine • Vol. 15, No. 1 • February 2016
Group 2: Positive control
36.50 ± 2.3d 38.0 ± 1.4d
Group 3: CAE (200 mg/kg) 47.24 ± 3.4
13.8 ± 0.2d
b
22.0 ± 1.3
14.5 ± 0.1b
Group 4: CAE (400 mg/kg) 48.15 ± 2.5c 23.0 ± 2.1b
15.8 ± 0.1b
Group 5: GAE (200 mg/kg) 55.15 ± 2.6b 0.49 ± 1.5c
17.5 ± 0.2c
Group 6: GAE (400 mg/kg) 57.17 ± 2.3b 0.47 ± 1.6c
17.8 ± 0.2c
c
Note: Means ± SE with different letter superscripts (a, b, c, d) in the same column are significant at P < .05 using 1-way ANOVA test. Unit of GPx = mM of GSH utilized/min/mg protein. Unit of CAT = mM of H2O2 utilized/min/mg protein. Abbreviations: CAE, cinnamon aqueous extract; GAE, ginger aqueous extract; SOD, superoxide dismutase; GPx, glutathione peroxidase; CAT, catalase; SE, standard error; ANOVA, analysis of variance. Pizzorno—The Path Ahead
Blood Urea (mg/dL)
Figure 5. Ginger Partially Restores Kidney Function in Diabetic Rats 55 50 45 40 35 30 25 20 15 10 5 0
Control
Diabetic Diabetic Untreated + Free
Diabetic Diabetic + + Bound Glubenclamide
Note: Values are mean ± SEM of 8 rats per group. All values are significantly different (P < .05). Abbreviation: Free, free phenolic extract; Bound, bound phenolic extract; SEM, standard error of the mean. Several animal studies have also shown that ginger can protect kidneys from cadmium. One study found that the anti-inflammatory effects of ginger were so strong it was able to prevent most of the kidney damage from cadmium.19 Another found almost no histological kidney damage when ginger was fed along with cadmium.20 This makes sense as much of the damage from cadmium is caused by increased oxidation. Animal research has also shown kidney protection from alcohol, malathion, carbon tetrachloride, chromates, fructose, gentamycin, ischemia, lead, cancer drugs, etc.21,22 Another study found that in a rat model of rheumatoid arthritis induced by injection of Complete Freund’s adjuvant that ginger prevented damage to the kidneys.23 One especially encouraging animal study showed restoration of kidney function in rats that already had diabetes as shown in Figure 4.24 Summary Loss of kidney function and outright failure are an expensive and progressively more common problem. The causes are clear: toxins from the environment, from within, and by choice. Fortunately, several of our core nutritional and botanical medicines have been shown in animal and ever more human studies to not only help protect the kidneys from damage but to actually improve microcirculation and at least partially restore function. I would like to acknowledge and thank Australian master Pizzorno—The Path Ahead
herbalist Kerry Bone for many of the kidney function restoration ideas in this editorial.) In This Issue Associate editor, Jeffery Bland, PhD, leads this issue from his remarkable perspective of decades of deep study of nutrition research and biochemical individuality. I think his discussion is important to better understand the clinical implications of phenotypes existing in not only severe but also mild and moderate forms. Although the severely dysfunctional phenotypes are well recognized by conventional medicine, we clinicians must deal regularly with the much more common milder forms that are not nearly as well studied. Associate editor, David S. Riley, MD, leads a team of integrative medicine doctors—Robert Anderson, MD; Jennifer C. Blair, LAc, MaOM; Seroya Crouch, ND; William Meeker, DC, MPH; Scott Shannon, MD, ABIHM; Nancy Sudak, MD, ABIHM; Lucia Thornton, RN, MSN, AHN-BC; and Tieraona Low Dog, MD—who have worked together to compile the history of integrative medicine. I find quite fascinating how so many different areas of the country and diverse health professions seem to be arriving at similar perspectives on the causes of the health care crisis and best practices for restoring health. I also have come to wonder why orthomolecular medicine, which seems to be the first organization to apply rigorous science to this way of thinking about patients, did not evolve further. As usual, John Weeks keeps us apprised of the evolving political, economic, and structural environment in which we practice our patient-centered curative medicine. I have often thought that the key reason the many efforts for health care reform have been almost universally disappointing is that the core practitioners in the various settings did not have the right training. No, I am not saying diagnosis and treatment of disease are not important, but rather the disease treatment model that has dominated the past century fundamentally fails at core primary care. Very encouraging to see emerging demonstration models with our doctors at the core now showing what a real HEALTH CARE system looks like. We welcome with this issue a new associate editor, Tim Birdsall, ND. Most of IMCJ’s readers will be aware of his excellent research and leadership in integrative cancer care. As this is a challenge frequently facing most integrative medicine practitioners, I am very excited he is bringing us his welcome expertise. For his first commentary, he addresses the recently widely publicized reports downplaying the role of diet and lifestyle as causes of cancer. I am very pleased that we are able to publish abstracts from the Academy of Integrative Health & Medicine (AIHM) 2015 annual conference. Reviewing the summaries of these many dedicated researchers and clinicians, I am starting to see us build the necessary infrastructure of understanding and rigor necessary for this field to advance. Integrative Medicine • Vol. 15, No. 1 • February 2016
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My dear spouse Lara Pizzorno, MDiv, MA, LMT, provides us a 2-part series on the many underrecognized nutritional problems caused by bariatric surgery. As the population becomes ever-more obese, we will see more and more patients trying to deal with the aftermath of these procedures. As Lara and I reviewed the research, we were both quite surprised by how little awareness most clinicians have about how this procedure disrupts nutritional status and the dearth of studies on how to take care of these patients. I very much appreciate the rigorous case histories associate editor, David Riley, MD, has brought to IMCJ. Elliot T. Taxman, BA; Erin D. Conlon, BS; Alex Speers, BA; Kristin L. Dismuke, BS; Tonya S. Heyman, MD, FACOG; and Thomas L. Taxman, MD, FAAP, point out that one-half of cancer patients use integrative medicine, whether or not their oncologist is aware of their … dallying. Clearly, this is an area where astute and comprehensive integration and communication are critical for these patients—as well demonstrated by these expert clinicians. BTW, love the timeline, David. I don’t think we can adequately recognize and honor pioneer William Rea, MD, for his seminal work in environmental toxicity. He will be a keynote speaker on endocrine disrupting toxins at the upcoming Environmental Health Symposium, March 4 through 6, 2016, in San Diego, California. Managing editor, Craig Gustafson, interviewed him for this issue. This month, our clinician interview is with Karen Mercereau, RN. I was quite intrigued when I met her and learned of the network of nurses she and her team have created to provide greatly needed guidance for patients. I have always thought nurses with their extensive training are seriously underutilized. I think you will find this interview by Craig Gustafson quite encouraging. Associate editor, Bill Benda, MD, channels the famous philosopher, Pogo. In response, I assert, “Laughter is the best medicine,” the origin of which is apparently Proverbs 17:22: “A merry heart doeth good like a medicine: But a broken spirit drieth the bones.”
4. Kenjale AA, Ham KL, Stabler T, et al. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol. 2011;110(6):1582-1591. 5. Wang Z, Liu J, Sun W. Effects of asiaticoside on levels of podocyte cytoskeletal proteins and renal slit diaphragm proteins in adriamycininduced rat nephropathy. Life Sci. 2013;93(8):352-358. 6. Meng XM, Zhang Y, Huang XR, et al. Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 2015;6(35):36984-36997. 7. Pruijm M, Hofmann L, Charollais-Thoenig J, et al. Effect of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy volunteers. Clin Nephrol. 2013;80(3):211-217. 8. Al-Malki AL, Moselhy SS. The protective effect of epicatchin against oxidative stress and nephrotoxicity in rats induced by cyclosporine. Hum Exp Toxicol. 2011;30(2):145-151. 9. Nair AR, Masson GS, Ebenezer PJ, et al. Role of TLR4 in lipopolysaccharideinduced acute kidney injury: protection by blueberry. Free Radic Biol Med. June 2014;71:16-25. 10. Trujillo J, Chirino YI, Molina-Jijón E, et al. Renoprotective effect of the antioxidant curcumin: Recent findings. Redox Biol. September 2013;1:448-456. 11. Mansour SM, Bahgat AK, El-Khatib AS, Khayyal MT. Ginkgo biloba extract (EGb 761) normalizes hypertension in 2K, 1C hypertensive rats: role of antioxidant mechanisms, ACE inhibiting activity and improvement of endothelial dysfunction. Phytomedicine. 2011;18(8-9):641-647. 12. Cavuşoğlu K, Yapar K, Oruç E, Yalçın E. Protective effect of Ginkgo biloba L. leaf extract against glyphosate toxicity in Swiss albino mice. J Med Food. 2011;14(10):1263-1272. 13. Sener G, Sehirli O, Tozan A, et al. Ginkgo biloba extract protects against mercury(II)-induced oxidative tissue damage in rats. Food Chem Toxicol. 2007;45(4):543-550. 14. Yapar K, Cavuşoğlu K, Oruç E, Yalçin E. Protective role of Ginkgo biloba against hepatotoxicity and nephrotoxicity in uranium-treated mice. J Med Food. 2010;13(1):179-188. 15. Tozan A, Sehirli O, Omurtag GZ, et al. Ginkgo biloba extract reduces naphthalene-induced oxidative damage in mice. Phytother Res. 2007;21(1):72-77. 16. Coskun O, Armutcu F, Kanter M, Kuzey GM. Protection of endotoxininduced oxidative renal tissue damage of rats by vitamin E or/and EGb 761 treatment. J Appl Toxicol. 2005;25(1):8-12. 17. Kim MK, Chung SW, Kim DH, et al. Modulation of age-related NF-kappaB a c t i v at i on by d i e t ar y z i nge ron e v i a M A P K p at hw ay. E x p Gerontol. 2010;45(6):419-426. 18. Shalaby MA, Saifan HY. Some pharmacological effects of cinnamon and ginger herbs in obese diabetic rats. J Intercult Ethnopharmacol. 2014;3(4):144-149. 19. Onwuka FC, Erhabor O, Eteng MU, Umoh IB. Protective effects of ginger toward cadmium-induced testes and kidney lipid peroxidation and hematological impairment in albino rats. J Med Food. 2011;14(7-8):817-821. 20. Baiomy AA, Mansour AA. Genetic and histopathological responses to cadmium toxicity in rabbit’s kidney and liver: Protection by ginger (Zingiber officinale). Biol Trace Elem Res. September 2015. [Epub ahead of print.] 21. Shanmugam KR, Ramakrishna CH, Mallikarjuna K, Reddy KS. Protective effect of ginger against alcohol-induced renal damage and antioxidant enzymes in male albino rats. Indian J Exp Biol. 2010;48(2):143-149. 22. Baiomy AA, Attia HF, Soliman MM, Makrum O. Protective effect of ginger and zinc chloride mixture on the liver and kidney alterations induced by malathion toxicity. Int J Immunopathol Pharmacol. 2015;28(1):122-128. 23. Ramadan G, El-Menshawy O. Protective effects of ginger-turmeric rhizomes mixture on joint inflammation, atherogenesis, kidneydysfunction and other complications in a rat model of human rheumatoid arthritis. Int J Rheum Dis. 2013;16(2):219-229. 24. Kazeem MI, Akanji MA, Yakubu MT. Amelioration of pancreatic and renal derangements in streptozotocin-induced diabetic rats by polyphenol extracts of Ginger (Zingiber officinale) rhizome. Pathophysiology. 2015;22(4):203-209.
Joseph Pizzorno, ND, Editor in Chief [email protected] http://twitter.com/drpizzorno References
1. Chade AR. Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis. Am J Physiol Regul Integr Comp Physiol. 2011;300(4):R783-R790. 2. White CJ. Catheter-based therapy for atherosclerotic renal artery stenosis. Circulation. 2006;113:1464-1473. 3. Ferguson SK, Hirai DM, Copp SW, et al. Dose dependent effects of nitrate supplementation on cardiovascular control and microvascular oxygenation dynamics in healthy rats. Nitric Oxide. May 2014;39:51-58.
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Integrative Medicine • Vol. 15, No. 1 • February 2016
Pizzorno—The Path Ahead
The Kidney Dysfunction Epidemic, Part 2: Intervention Joseph Pizzorno, ND, Editor in Chief
I
n my last editorial, “The Kidney Dysfunction Epidemic: Part 1, Causes,” I reviewed the key environmental, dietary, and endogenous toxins that appear to be the primary causes of the epidemic of kidney dysfunction and failure. Heavy metals (cadmium and mercury); persistent organic pollutants (halogenated hydrocarbons—especially those that are fluorinated and released when nonstick pans are heated to typical cooking temperatures—glyphosates, etc); smoking; nonsteroidal anti-inflammatory drugs (especially acetaminophen); lipopolysaccharides from a leaky, toxic gut; and excessive dietary salt and phosphates all add up to a heavy and damaging load on the kidneys. The scope of kidney failure was really brought home to me while I was writing this editorial. I met with an insurance broker interested in natural/integrative medicine solutions for her client corporations. Her story of why she was interested was quite illustrative of the problem. Fifteen years ago, when she first started working in health care insurance, she was seeing approximately 1 new claim per year for dialysis. When after a dozen years it had burgeoned to 10 per month, she realized something was wrong. She then started seeking solutions, as the conventional interventions not only were very expensive, but did not seem to be dealing with the underlying causes of the epidemic. As we were talking in a Starbucks near my home, I looked thoughtfully at the kidney dialysis center across the street. When it opened 5 years ago, I simply thought, “How nice, now kidney failure patients no longer have to drive downtown to ‘pill hill’ to get treated.” Hmmm. An Internet search quickly showed more than 10 centers within 3 miles of my home. Sure makes this real. Protecting and Regenerating the Kidneys First, of course, we need to advise our patients on the causes of their kidney damage. Basically, inadequate blood supply to the kidneys, inadequate water consumption, and excessive toxic load. Almost all the causes of kidney damage can be controlled by helping our patients make better choices. Keys for the most immediate benefit are decreasing obvious toxins of choice, such as excessive dietary salt and phosphates, and drugs such as the NSAIDS. Foundational to kidney function is simply the quantity of their blood supply. Much of the loss of glomerular filtration rate (GFR) is determined by the loss in quality and quantity of the microcirculation of the kidneys.
8
Integrative Medicine • Vol. 15, No. 1 • February 2016
Interestingly, many of the factors known to increase risk of most chronic diseases have as part of the mechanism damage to the microcirculation. Obvious examples include smoking, poor blood sugar control (loss of microcirculation underlies the serious sequelae of diabetes such as loss of vision, loss of toes, and, appropriately, accelerated decline in kidney function), elevated blood pressure, oxidative stress, elevated homocysteine, obesity, and even high-fat meals (which increase absorption of endotoxins from the gut). Some research suggests that impaired microcirculation in the kidneys, not only glomerular damage, may be the primary reason function declines with aging, as well as the factors mentioned above.1 A significant number of the elderly have enough atherosclerosis in the arteries leading to the kidneys to cause measureable loss of kidney function. Catherization to remove the blockage significantly increases kidney function strongly supporting the concept that the glomerular dysfunction may be as much due to poor blood flow as cellular death.2 This decreased circulation also facilitates the accumulation of extracellular matrix around the kidney, which not only causes a buildup of scar tissue, but also impairs vascular endothelial growth factor (VEGF) from helping restore blood flow. This is modeled in Figure 1. Figure 1. Model for the Development of Kidney Fibrosis1 Renal MV endothelial dysfunction Vasoconstriction Mild tissue ischemia
TGF-β CTGF MMPs HGF
ECM accumulation Fibrosis MV repair and proliferation
VEGF TSP, Angio
MV remodeling, damage, and loss Severe tissue ischemia Progressive renal injury
Pizzorno—The Path Ahead
1. Decrease total toxic load on the kidneys. 2. Aggressively reduce exposure to nephrotoxins. 3. Increase microcirculation of kidneys. 4. Protect the kidneys from oxidative stress. Decrease Total Toxic Load Exogenous toxins, endogenous toxins, and toxins of choice have been discussed in many of my editorials and articles I have recruited for IMCJ. Mercury, persistent organic pollutants, excessive salt and phosphates—the list is long. No, I am not saying we need to give up on our more comfortable industrialized life, but we most certainly need to stop being so cavalier about letting all these undesirable elements and molecules into our food, water, and air. Aggressively Decrease Exposure to Nephrotoxins The key nephrotoxic agents were discussed in “The Kidney Dysfunction Epidemic: Part 1, Causes.” By far the worst is cadmium. Although some chemicals are more toxic, we are exposed to a lot more cadmium, especially those who smoke or eat conventionally grown foods. With a half-life of 10 years and 50% of total body load in the kidneys, the challenge presented by cadmium is serious. I will write an editorial on cadmium in the future. In the meantime, I think the work of Stephen Genuis, MD, in Edmonton, Alberta, Canada, is very encouraging. Specifically, he has shown that sweating helps excrete cadmium through the skin. Improve Microcirculation of Kidneys Beetroot Juice Increases Blood Flow to the Kidneys Increasing blood flow to the kidneys has a huge impact on improving detoxification and decreasing oxidative stress. The research process looking at the benefits of foods and nutrients that increase production of nitrogen oxides in dilating peripheral blood vessels to increase blood flow to the tissues is in the early stages, but encouraging. A study in rats showed an impressive, dose-dependent increase in blood flow to the kidneys up to 26% as shown in Table 1.3 There is growing research on the health benefits of beetroot juice for humans, although I could not find any that specifically looked at effects on kidney function. A relevant study in adults with peripheral vascular disease found, as shown in Figure 2, that beetroot juice clearly improved microcirculation resulting in improved walking distance. This 18% increase in walking time certainly supports a significant improvement in blood flow. Table 1. Beetroot Juice Increases Blood Flow to Kidneys Control BRLD BRHD BF 447 ± 32 521 ± 32 Kidney 414 ± 29 Abbreviations: BF, blood flow; BRLD, beetroot low dose; BRHD, beetroot high dose.
Pizzorno—The Path Ahead
Figure 2. Beetroot Juice Improves Peripheral Blood Supply4 425
Claudication Onset Time (s)
This all leads me to recommend the following foundational strategies:
350 250 225
a
200 175 150 125 100 75
Beetroot Juice a Significantly different from placebo group, P ≤ .01. Placebo
Centella asiatica Improves Blood Flow to the Kidneys Traditional Chinese medicine has used Gotu kola (Centella asiatica) to treat kidney diseases for centuries. Asiaticoside has been shown to improve in microcirculation and reverse fibrosis in humans with varicose veins. Its direct benefits for the kidneys have only been shown in animals but are encouraging. One found Gotu kola very effectively protected rats from adriamycin-induced nephropathy resulting in dramatically improved kidney function compared with the untreated rats.5 Another study combined Gotu kola in conjunction with naringenin and showed decreased fibrosis formation in the kidneys.6 Chocolate Improves Blood Flow to Kidneys Dark chocolate consumption improves oxygenation of the kidneys, even in healthy people. The benefit is directly proportional to catechin levels.7 Animal research has shown that these substances also protect the kidneys from oxidative stress from toxic drugs such as cyclosporine,8 which is a good segue into our final strategy. Protect the Kidneys From Oxidative Stress Blueberries Protect the Kidneys From Oxidative Stress Every time I write about the remarkable health benefits of blueberries, I think of insightful researcher and compelling lecturer, James Joseph, PhD. I vividly remember the first time we spoke at the same conference some 15 years ago and being so impressed by his deep understanding of the healing effects of colorful foods. His untimely death in 2010 was a shock and undoubtedly slowed discovery in this important field. Integrative Medicine • Vol. 15, No. 1 • February 2016
9
Figure 3. Blueberries Protect the Kidneys from Gutderived Toxins9 GFR
mL/min/g kidney wt
2.0 1.5 1.0 0.5 0
SAL
BB
SAL
Control
BB LPS
Abbreviations: GFR, glomerular filtration rate; SAL, saline; BB, blueberries; LPS, lipopolysaccharide. A benefit that surprised me was that blueberry anthocyanins specifically protect the kidneys from bowelderived entoxins. This is well demonstrated in Figure 3, which shows how blueberries increase GFR in normal kidneys (but the increase is not statistically significant) but far more importantly completely protects the kidneys from the dramatic lowering of GFR caused by gut toxins in those with impaired function.
improved kidney blood flow and function in hypertensive rats.11 The protective effects of Ginkgo have been shown in many tissues. One especially relevant study found that Ginkgo protects the kidneys from glyphosate.12 Other animal studies have shown protection of the kidneys from mercury, uranium, naphthalene, and many other toxins.13,14,15 Ginkgo also protects the kidneys from gut-derived endotoxins.16 Ginger Protects Kidney Function Although human studies have not caught up with the animal studies on the kidneys, there is now enough animal research showing that Zingiber officinale not only improves kidney function but is especially beneficial protecting the kidney from cadmium. The primary mechanism of protection appears to be ginger’s ability to decrease inflammation and oxidative damage to kidney tissue exposed to a wide variety of toxins. The anti-inflammatory benefits of ginger in the kidney are due to not only its antioxidant properties, but epigenetic downregulation of proinflammatory genes.17 (On a side note, I am beginning to wonder what proportion of the beneficial effects of botanical medicine is due their epigenetic effects. Which then brings up the question of why. Why does consumption of herbs result so often in desirable epigenetic effects? I wonder if this is in response to potentially toxic constituents in herbs [and foods] that we evolved mechanisms to detoxify, which then has unexpected benefits elsewhere.) One study, as shown in Table 4, found that ginger specifically increases activity of kidney antioxidant enzymes in obese and diabetic rats.18 Seems especially relevant considering that one-third of our population is obese and if not already diabetic are well on their way.
Curcumin (Turmeric) Protects the Kidneys Seems whenever I write an editorial like this, curcumin shows up. Curcumin has shown renoprotective benefit in diabetic nephropathy, chronic renal failure, ischemia, and nephrotoxicity induced by cadmium, gentamicin, adriamycin, chloroquine, iron nitrilotriacetate, sodium fluoride, Table 4. Ginger Increases Production of Kidney Antioxidant Enzymes hexavalent chromium, and cisplatin.10 In fact, it not only protects from damage but SOD GPx (mM/ CAT (mM/ also maintains GFR despite the toxins. (U/mg min/mg min/mg I am especially intrigued by its protective Parameters protein) protein) protein) effects against cadmium. a a 18.5 ± 0.1a Group 1: Negative control 58.70 ± 2.2 69.0 ± 2.1 Ginkgo biloba Improves Kidney Function This will come as no surprise considering how most of us prescribe this ancient herbal medicine to improve circulation in many chronic diseases. Ginkgo has been shown to improve blood supply to the brain and in other critical tissues. Also of great importance is its ability to protect against numerous mitochondrial toxins. As discussed in my last editorial, mitochondrial damage in the kidneys mediate much of the nephrotoxicity. I could not find human studies on Ginkgo specifically for the kidneys, but one animal study showed 10
Integrative Medicine • Vol. 15, No. 1 • February 2016
Group 2: Positive control
36.50 ± 2.3d 38.0 ± 1.4d
Group 3: CAE (200 mg/kg) 47.24 ± 3.4
13.8 ± 0.2d
b
22.0 ± 1.3
14.5 ± 0.1b
Group 4: CAE (400 mg/kg) 48.15 ± 2.5c 23.0 ± 2.1b
15.8 ± 0.1b
Group 5: GAE (200 mg/kg) 55.15 ± 2.6b 0.49 ± 1.5c
17.5 ± 0.2c
Group 6: GAE (400 mg/kg) 57.17 ± 2.3b 0.47 ± 1.6c
17.8 ± 0.2c
c
Note: Means ± SE with different letter superscripts (a, b, c, d) in the same column are significant at P < .05 using 1-way ANOVA test. Unit of GPx = mM of GSH utilized/min/mg protein. Unit of CAT = mM of H2O2 utilized/min/mg protein. Abbreviations: CAE, cinnamon aqueous extract; GAE, ginger aqueous extract; SOD, superoxide dismutase; GPx, glutathione peroxidase; CAT, catalase; SE, standard error; ANOVA, analysis of variance. Pizzorno—The Path Ahead
Blood Urea (mg/dL)
Figure 5. Ginger Partially Restores Kidney Function in Diabetic Rats 55 50 45 40 35 30 25 20 15 10 5 0
Control
Diabetic Diabetic Untreated + Free
Diabetic Diabetic + + Bound Glubenclamide
Note: Values are mean ± SEM of 8 rats per group. All values are significantly different (P < .05). Abbreviation: Free, free phenolic extract; Bound, bound phenolic extract; SEM, standard error of the mean. Several animal studies have also shown that ginger can protect kidneys from cadmium. One study found that the anti-inflammatory effects of ginger were so strong it was able to prevent most of the kidney damage from cadmium.19 Another found almost no histological kidney damage when ginger was fed along with cadmium.20 This makes sense as much of the damage from cadmium is caused by increased oxidation. Animal research has also shown kidney protection from alcohol, malathion, carbon tetrachloride, chromates, fructose, gentamycin, ischemia, lead, cancer drugs, etc.21,22 Another study found that in a rat model of rheumatoid arthritis induced by injection of Complete Freund’s adjuvant that ginger prevented damage to the kidneys.23 One especially encouraging animal study showed restoration of kidney function in rats that already had diabetes as shown in Figure 4.24 Summary Loss of kidney function and outright failure are an expensive and progressively more common problem. The causes are clear: toxins from the environment, from within, and by choice. Fortunately, several of our core nutritional and botanical medicines have been shown in animal and ever more human studies to not only help protect the kidneys from damage but to actually improve microcirculation and at least partially restore function. I would like to acknowledge and thank Australian master Pizzorno—The Path Ahead
herbalist Kerry Bone for many of the kidney function restoration ideas in this editorial.) In This Issue Associate editor, Jeffery Bland, PhD, leads this issue from his remarkable perspective of decades of deep study of nutrition research and biochemical individuality. I think his discussion is important to better understand the clinical implications of phenotypes existing in not only severe but also mild and moderate forms. Although the severely dysfunctional phenotypes are well recognized by conventional medicine, we clinicians must deal regularly with the much more common milder forms that are not nearly as well studied. Associate editor, David S. Riley, MD, leads a team of integrative medicine doctors—Robert Anderson, MD; Jennifer C. Blair, LAc, MaOM; Seroya Crouch, ND; William Meeker, DC, MPH; Scott Shannon, MD, ABIHM; Nancy Sudak, MD, ABIHM; Lucia Thornton, RN, MSN, AHN-BC; and Tieraona Low Dog, MD—who have worked together to compile the history of integrative medicine. I find quite fascinating how so many different areas of the country and diverse health professions seem to be arriving at similar perspectives on the causes of the health care crisis and best practices for restoring health. I also have come to wonder why orthomolecular medicine, which seems to be the first organization to apply rigorous science to this way of thinking about patients, did not evolve further. As usual, John Weeks keeps us apprised of the evolving political, economic, and structural environment in which we practice our patient-centered curative medicine. I have often thought that the key reason the many efforts for health care reform have been almost universally disappointing is that the core practitioners in the various settings did not have the right training. No, I am not saying diagnosis and treatment of disease are not important, but rather the disease treatment model that has dominated the past century fundamentally fails at core primary care. Very encouraging to see emerging demonstration models with our doctors at the core now showing what a real HEALTH CARE system looks like. We welcome with this issue a new associate editor, Tim Birdsall, ND. Most of IMCJ’s readers will be aware of his excellent research and leadership in integrative cancer care. As this is a challenge frequently facing most integrative medicine practitioners, I am very excited he is bringing us his welcome expertise. For his first commentary, he addresses the recently widely publicized reports downplaying the role of diet and lifestyle as causes of cancer. I am very pleased that we are able to publish abstracts from the Academy of Integrative Health & Medicine (AIHM) 2015 annual conference. Reviewing the summaries of these many dedicated researchers and clinicians, I am starting to see us build the necessary infrastructure of understanding and rigor necessary for this field to advance. Integrative Medicine • Vol. 15, No. 1 • February 2016
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My dear spouse Lara Pizzorno, MDiv, MA, LMT, provides us a 2-part series on the many underrecognized nutritional problems caused by bariatric surgery. As the population becomes ever-more obese, we will see more and more patients trying to deal with the aftermath of these procedures. As Lara and I reviewed the research, we were both quite surprised by how little awareness most clinicians have about how this procedure disrupts nutritional status and the dearth of studies on how to take care of these patients. I very much appreciate the rigorous case histories associate editor, David Riley, MD, has brought to IMCJ. Elliot T. Taxman, BA; Erin D. Conlon, BS; Alex Speers, BA; Kristin L. Dismuke, BS; Tonya S. Heyman, MD, FACOG; and Thomas L. Taxman, MD, FAAP, point out that one-half of cancer patients use integrative medicine, whether or not their oncologist is aware of their … dallying. Clearly, this is an area where astute and comprehensive integration and communication are critical for these patients—as well demonstrated by these expert clinicians. BTW, love the timeline, David. I don’t think we can adequately recognize and honor pioneer William Rea, MD, for his seminal work in environmental toxicity. He will be a keynote speaker on endocrine disrupting toxins at the upcoming Environmental Health Symposium, March 4 through 6, 2016, in San Diego, California. Managing editor, Craig Gustafson, interviewed him for this issue. This month, our clinician interview is with Karen Mercereau, RN. I was quite intrigued when I met her and learned of the network of nurses she and her team have created to provide greatly needed guidance for patients. I have always thought nurses with their extensive training are seriously underutilized. I think you will find this interview by Craig Gustafson quite encouraging. Associate editor, Bill Benda, MD, channels the famous philosopher, Pogo. In response, I assert, “Laughter is the best medicine,” the origin of which is apparently Proverbs 17:22: “A merry heart doeth good like a medicine: But a broken spirit drieth the bones.”
4. Kenjale AA, Ham KL, Stabler T, et al. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol. 2011;110(6):1582-1591. 5. Wang Z, Liu J, Sun W. Effects of asiaticoside on levels of podocyte cytoskeletal proteins and renal slit diaphragm proteins in adriamycininduced rat nephropathy. Life Sci. 2013;93(8):352-358. 6. Meng XM, Zhang Y, Huang XR, et al. Treatment of renal fibrosis by rebalancing TGF-β/Smad signaling with the combination of asiatic acid and naringenin. Oncotarget. 2015;6(35):36984-36997. 7. Pruijm M, Hofmann L, Charollais-Thoenig J, et al. Effect of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy volunteers. Clin Nephrol. 2013;80(3):211-217. 8. Al-Malki AL, Moselhy SS. The protective effect of epicatchin against oxidative stress and nephrotoxicity in rats induced by cyclosporine. Hum Exp Toxicol. 2011;30(2):145-151. 9. Nair AR, Masson GS, Ebenezer PJ, et al. Role of TLR4 in lipopolysaccharideinduced acute kidney injury: protection by blueberry. Free Radic Biol Med. June 2014;71:16-25. 10. Trujillo J, Chirino YI, Molina-Jijón E, et al. Renoprotective effect of the antioxidant curcumin: Recent findings. Redox Biol. September 2013;1:448-456. 11. Mansour SM, Bahgat AK, El-Khatib AS, Khayyal MT. Ginkgo biloba extract (EGb 761) normalizes hypertension in 2K, 1C hypertensive rats: role of antioxidant mechanisms, ACE inhibiting activity and improvement of endothelial dysfunction. Phytomedicine. 2011;18(8-9):641-647. 12. Cavuşoğlu K, Yapar K, Oruç E, Yalçın E. Protective effect of Ginkgo biloba L. leaf extract against glyphosate toxicity in Swiss albino mice. J Med Food. 2011;14(10):1263-1272. 13. Sener G, Sehirli O, Tozan A, et al. Ginkgo biloba extract protects against mercury(II)-induced oxidative tissue damage in rats. Food Chem Toxicol. 2007;45(4):543-550. 14. Yapar K, Cavuşoğlu K, Oruç E, Yalçin E. Protective role of Ginkgo biloba against hepatotoxicity and nephrotoxicity in uranium-treated mice. J Med Food. 2010;13(1):179-188. 15. Tozan A, Sehirli O, Omurtag GZ, et al. Ginkgo biloba extract reduces naphthalene-induced oxidative damage in mice. Phytother Res. 2007;21(1):72-77. 16. Coskun O, Armutcu F, Kanter M, Kuzey GM. Protection of endotoxininduced oxidative renal tissue damage of rats by vitamin E or/and EGb 761 treatment. J Appl Toxicol. 2005;25(1):8-12. 17. Kim MK, Chung SW, Kim DH, et al. Modulation of age-related NF-kappaB a c t i v at i on by d i e t ar y z i nge ron e v i a M A P K p at hw ay. E x p Gerontol. 2010;45(6):419-426. 18. Shalaby MA, Saifan HY. Some pharmacological effects of cinnamon and ginger herbs in obese diabetic rats. J Intercult Ethnopharmacol. 2014;3(4):144-149. 19. Onwuka FC, Erhabor O, Eteng MU, Umoh IB. Protective effects of ginger toward cadmium-induced testes and kidney lipid peroxidation and hematological impairment in albino rats. J Med Food. 2011;14(7-8):817-821. 20. Baiomy AA, Mansour AA. Genetic and histopathological responses to cadmium toxicity in rabbit’s kidney and liver: Protection by ginger (Zingiber officinale). Biol Trace Elem Res. September 2015. [Epub ahead of print.] 21. Shanmugam KR, Ramakrishna CH, Mallikarjuna K, Reddy KS. Protective effect of ginger against alcohol-induced renal damage and antioxidant enzymes in male albino rats. Indian J Exp Biol. 2010;48(2):143-149. 22. Baiomy AA, Attia HF, Soliman MM, Makrum O. Protective effect of ginger and zinc chloride mixture on the liver and kidney alterations induced by malathion toxicity. Int J Immunopathol Pharmacol. 2015;28(1):122-128. 23. Ramadan G, El-Menshawy O. Protective effects of ginger-turmeric rhizomes mixture on joint inflammation, atherogenesis, kidneydysfunction and other complications in a rat model of human rheumatoid arthritis. Int J Rheum Dis. 2013;16(2):219-229. 24. Kazeem MI, Akanji MA, Yakubu MT. Amelioration of pancreatic and renal derangements in streptozotocin-induced diabetic rats by polyphenol extracts of Ginger (Zingiber officinale) rhizome. Pathophysiology. 2015;22(4):203-209.
Joseph Pizzorno, ND, Editor in Chief [email protected] http://twitter.com/drpizzorno References
1. Chade AR. Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis. Am J Physiol Regul Integr Comp Physiol. 2011;300(4):R783-R790. 2. White CJ. Catheter-based therapy for atherosclerotic renal artery stenosis. Circulation. 2006;113:1464-1473. 3. Ferguson SK, Hirai DM, Copp SW, et al. Dose dependent effects of nitrate supplementation on cardiovascular control and microvascular oxygenation dynamics in healthy rats. Nitric Oxide. May 2014;39:51-58.
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Integrative Medicine • Vol. 15, No. 1 • February 2016
Pizzorno—The Path Ahead
