Basic Science for the Clinician

Zinc Deficiency: A Potential Hidden Driver of the

Detrimental Cycle of Chronic Kidney Disease and
Hypertension
Adaku C. Ume,1 Tara-Yesomi Wenegieme,1 Danielle N. Adams,1 Sherry E. Adesina,2 and Clintoria R. Williams1

Abstract
Globally, over 103 million individuals are afflicted by CKD, a silent killer claiming the lives of 1.2 million people
annually. CKD is characterized by five progressive stages, in which dialysis and kidney transplant are life-saving
routes for patients with end stage kidney failure. While kidney damage impairs kidney function and derails BP
regulation, uncontrolled hypertension accelerates the development and progression of CKD. Zinc (Zn) deficiency
has emerged as a potential hidden driver within this detrimental cycle of CKD and hypertension. This review article
will (1) highlight mechanisms of Zn procurement and trafficking, (2) provide evidence that urinary Zn wasting can
fuel Zn deficiency in CKD, (3) discuss how Zn deficiency can accelerate the progression of hypertension and kidney
damage in CKD, and (4) consider Zn supplementation as an exit strategy with the potential to rectify the course of
hypertension and CKD progression.
KIDNEY360 4: 398–404, 2023. doi: https://doi.org/10.34067/KID.0007812021

Introduction BP10 in hopes of improving both cardiovascular and

Globally, an estimated 103 million individuals (1 in 10) kidney health.
are burdened with CKD,1 a life-threatening condition CKD is commonly accompanied by a deficiency in
that has catapulted to the 11th leading cause of global the essential dietary micronutrient, zinc (Zn). Several
deaths.2 CKD is commonly diagnosed by an estimated factors contribute to reduced serum Zn levels in patients
GFR of ,60 ml/minute per 1.73 m2 or albuminuria with CKD11-18 including (1) dietary protein restriction,
lasting for $3 months. While CKD progressively (2) decreased caloric intake, (3) intestinal malabsorption,
worsens in five stages, the National Institute of (4) hyperuricemia, (5) impaired kidney reabsorption
Diabetes and Digestive and Kidney Diseases reports and subsequent urinary wasting, (6) elevated fecal ex-
that approximately 90% of people in stages 1–3 are cretion, and (7) hemodialysis. It is worth noting that
unaware of their condition,3 earning CKD the grave patients with CKD are often in the elderly population19
moniker of being a silent killer.4 In addition to a host of and are on multiple medication regimens that alter taste
comorbidities, the looming risk of CKD-related deaths sensation,20 thus contributing to Zn deficiency through
and adverse cardiovascular events increases greatly decreased caloric intake. In addition to the mechanisms
with each stage.4 By stage 5, patients with kidney noted above, Zn redistribution can also contribute to Zn
failure require renal replacement therapy (dialysis or deficiency in CKD. Specifically, a study noted recruit-
kidney transplant) for life support. Of note, 85% of US ment of Zn from both bone and plasma into the bone
patients on the transplant waiting list require a kid- marrow to stimulate the production of new blood cells
ney,5 further highlighting an urgent need for effective in animal models of CKD.21
therapeutic strategies to halt the progression of CKD to As the impact of Zn in CKD onset and progression
end stage kidney failure. is now being more investigated, Zn supplementation
A major risk factor of the development of CKD is may be recognized as an effective therapeutic strat-
uncontrolled hypertension.6,7 Chronically elevated BP egy. However, progress in integrating Zn supple-
damages the kidneys; meanwhile, kidney damage im- mentation into clinical practice will remain difficult
pairs kidney function and derails BP control. This self- until the interplay between Zn homeostasis, kidney
perpetuating cycle of kidney damage and hyperten- function, and BP regulation is better defined. This
sion accelerates CKD progression. Despite the clinical review article will (1) highlight mechanisms of Zn
use of potent antihypertensive drugs, uncontrolled BP procurement and trafficking, (2) provide evidence
persists in up to 90% of patients with CKD6-9. As an that urinary Zn wasting can fuel Zn deficiency in
alternative strategy to address this critical demand, the CKD, (3) discuss how Zn deficiency can accelerate
National Institutes of Health Joint National Committee the progression of hypertension and kidney damage
recommended a concurrent dietary approach to lower in CKD, and (4) consider Zn supplementation as an

1
Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine, College of Science and Mathematics, Wright
State University, Dayton, Ohio
2
Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia

Correspondence: Dr. Clintoria R. Williams, Department of Neuroscience, Cell Biology and Physiology, Wright State University, 3640
Colonel Glenn Highway, Dayton, OH 45435. Email: [email protected]

398 Copyright © 2022 by the American Society of Nephrology www.kidney360.org Vol 4 March, 2023
KIDNEY360 4: 398–404, March, 2023 A Potential Hidden Driver of the Detrimental Cycle, Ume et al. 399

exit strategy with the potential to rectify the course of Cellular uptake of Zn constitutes an efficient homeostatic
hypertension and CKD progression. control mechanism that prevents excess serum Zn levels.12,16,23
Cellular Zn homeostasis is mediated by three main families of
Zn transport proteins (Figure 2). The Zrt-, Irt-like protein family
Mechanisms of Zn Procurement and Trafficking facilitates entry of Zn into the cytosol while Zn-binding metal-
The human body contains 2–3 g of Zn, with the largest lothioneins bind intracellular Zn. Intracellular Zn serves as a
fractions found in the skeletal muscle (approximately 50%) cofactor for the catalytic activity and structural integrity of over
and bone (approximately 30%)13,16,22 (Figure 1). Lower Zn 300 proteins, including those involved in macromolecule syn-
fractions are also present in the following tissues: kidney, thesis and cell division39-41. Finally, Zn transporters facilitate
prostate, liver, gastrointestinal (GI) tract, skin, lung, brain, exit of unbound, cytosolic Zn into organelles.
heart, and pancreas16,23,24 (Figure 1). Three major routes en-
able Zn entry into the human body12,25,26: (1) inhalation
through the lungs, (2) penetrance through the skin, and (3) in-
Evidence That Urinary Zinc Wasting Can Fuel Zinc
gestion through the GI tract. Notably, these organ systems
Deficiency in CKD
are also responsible for Zn loss. Approximately 0.8–2.7 mg The World Health Organization has deemed Zn
Zn/day are excreted in the feces23 while 500–600 mg Zn/day deficiency a global health crisis, affecting 31% of the
are excreted in sweat.27 The kidneys also regulate Zn excretion population.42,43 While Zn deficiency is well-documented in
as urinary losses amount to 500–800 mg/day.28 patients with CKD,14,17,44-48 it is worth acknowledging that
While the amount required to replenish lost Zn is primarily the following factors are associated with Zn deficiency: veg-
obtained by adequate dietary intake and proper intestinal etarian diets, older age, diabetes, diuretics, inflammatory
absorption, kidney reabsorption is also critical for Zn diseases, and digestive disorders. Thus, parsing out whether
procurement14,29,30 (Figure 2). Zn trafficking to target organs Zn deficiency is a cause or consequence of CKD is quite
subsequently occurs through the serum, where it primarily complicated given the aforementioned confounding factors
circulates bound to plasma proteins such as albumin, mac- in patients with CKD. Multiple mechanisms can contribute to
roglobulins, and transferrin31 (Figure 2). Serum Zn levels in Zn deficiency in patients with CKD, including low dietary
healthy individuals vary from 12 to 16 mM, which corre- intake and increased Zn excretion.18,49,50 A cross-sectional
sponds to , 0.1% of total body Zn.32 However, caution is study examining 145 patients at different stages of CKD
advised when interpreting serum Zn levels because many (stages 1–4) found that serum Zn levels decreased with
factors affect plasma Zn concentration32-38—including sex, CKD progression, whereas serum levels of copper, iron,
age, time of the day, meal consumption, medications (thia- and selenium did not.48 In a case-control study of patients
zides, oral contraceptive use), pregnancy, and inflammation. on maintenance hemodialysis, average serum Zn levels were
significantly lower (69.2 mg/dl617.29) than those in healthy
controls (82.9 mg/dl614.75).44 Although dialysis may con-
tribute to Zn deficiency,51 it should be noted that abnormal-
ities in Zn metabolism develop before end stage kidney
failure and the initiation of dialysis.47
The progressive decline in serum Zn levels observed in
patients with CKD is partially fueled by a newly uncovered
phenomenon—urinary Zn wasting (Figure 3). In a cohort
study, patients with CKD (regardless of stage) exhibited
lower plasma Zn levels (606 mg/L6106.3 versus 664.1 mg/
L6101.2), accompanied by higher urinary Zn excretion
(612.4 mg/day6425.9 versus 479.2 mg/day6293) than pa-
tients without CKD.14 A decline in GFR correlated with
enhanced urinary Zn wasting. A sharp increase in urinary
Zn was observed at stage 3, when most patients receive a
CKD diagnosis. Although hypertension contributes to CKD,
hypertensive patients without CKD also had higher urinary
Zn excretion than normotensive controls. This indicates that
hypertension, in the absence of CKD, can independently
promote urinary Zn excretion. Interestingly, these patients
were at greater risk of experiencing CKD development
within 3 years.14 Taken together, these critical findings in-
dicate that Zn deficiency, accelerated by urinary Zn wasting,
is both an early warning sign for the decline in kidney
Figure 1. Zinc distribution in organs (clockwise). Brain (11 mgZn/
function and a hidden driver of CKD progression.
gram, 0.6%), lungs (17 mg Zn/gram, 0.5%), heart (27 mg Zn/gram,
0.3%), spleen (15 mg Zn/gram, 0.1%), kidneys (55 mg Zn/gram, 0.6%),
skeletal muscles (51 mg Zn/gram, 50%), hair/skin/nails (279 mg
Zn/gram, 4.7%), bone (100 mg Zn/gram, 37%), blood vessels (6.81 mg Does Zinc Deficiency Accelerate the Detrimental
Zn/gram, 1.5%), pancreas (33.3 mg Zn/gram, 0.2%), liver (58 mg Zn/gram, Cycle of Hypertension and Kidney Damage in CKD?
3.4%), stomach (13.4 mg Zn/gram, 0.5%), and eyes (1.3 mg Zn/gram, The kidneys are essential in the maintenance of salt-water
,0.01%). balance and, subsequently, BP control. Because this critical
400 KIDNEY360

Figure 2. Normal zinc handling. MTs, metallothioneins; ZIPs, Zrt-, Irt-like proteins; ZnTs, Zn transporters.

homeostatic function is impaired in the setting of CKD, up stage 5.53 This stark reality creates a detrimental cycle in
to 90% of patients experience comorbid hypertension.6-9 which kidney damage causes hypertension, thus further
Notably, resistant hypertension is a common clinical prob- worsening damage to the kidneys. Hypertension in patients
lem, and CKD poses one of the greatest risks of developing with CKD has many etiologies including a hyperactive
treatment-resistant hypertension.52 The prevalence of renin-angiotensin-aldosterone system, reduced GFR, altered
hypertension increases with advanced CKD stages, with vascular reactivity, overactivity of the sympathetic nervous
nearly 100% of patients experiencing hypertension in system, and increased Na1 retention.6 As CKD progresses,
BP becomes increasingly Na 1 -sensitive due to the
fluid retention caused by salt intake. We present that the
disruption of renal Na1 excretory function that causes
Na1 retention is fueled by Zn deficiency 54 (Figure 3).
This overlooked culprit may consequently promote the
self-perpetuating cycle of hypertension and kidney damage
(Figure 3) that accelerates CKD progression to end stage
kidney failure.
Zn is an essential micronutrient present in the diet and
readily available as a supplement. The recommended di-
etary allowance of Zn is approximately 11 mg/day for men
and approximately 8 mg/day for women,55 with an in-
creased Zn demand (approximately 10–15 mg) during phys-
iological states of growth such as pregnancy or puberty.31,55
Zn supports numerous aspects of cellular metabolism, and
the coronavirus disease 2019 pandemic has highlighted the
utility of Zn in immune function.56,57 While Zn’s role in both
vascular58,59 and cardiac functions31,60 is well established, its
impact on kidney function is less known.31 Our laboratory
recently established a regulatory role for Zn in renal Na1
reabsorption by the distal nephron.54 Although most of
Na1 is reabsorbed in the proximal tubule, renal Na1 han-
dling is fine-tuned in the distal nephron. Specifically, this
nephron segment precisely integrates local changes in uri-
nary Na1 with hormonal signals to modulate Na1 excre-
tion, thus maintaining salt-water balance. This sequence of
Figure 3. Zinc deficiency can accelerate the detrimental cycle of physiological events culminates in BP control.
hypertension and kidney damage in CKD. Zn deficiency is partially
In CKD, however, distal nephron function is impaired,61
fueled by a newly uncovered phenomenon—urinary Zn wasting. Zn
resulting in three of five patients with salt-water retention,
deficiency alone causes kidney damage and is also sufficient to in-
duce hypertension. This overlooked culprit drives renal Na1 retention thereby fueling the initiation and persistence of hyperten-
and can consequently promote the self-perpetuating cycle of hy- sion.62 Our preclinical findings provide evidence that Zn
pertension and kidney damage that accelerates CKD progression to deficiency alone causes kidney damage63 and is sufficient to
end stage kidney failure. induce hypertension as a direct consequence of impaired
KIDNEY360 4: 398–404, March, 2023 A Potential Hidden Driver of the Detrimental Cycle, Ume et al. 401

the extent of this influence because study limitations

include small patient sample sizes and a lack of dietary
Zn intake reporting.
Zn supplementation is a potential therapeutic strategy
for many conditions because of its anti-inflammatory,
antifibrotic, and antioxidative properties in the body69-71.
Our findings reveal that Zn also exhibits anti-hypertensive
and reno-protective properties because of its critical role in
renal Na1 excretory function and BP regulation.54,63 There
is also evidence that Zn plays a protective role in other
organ systems relevant to BP, such as the vasculature and
heart. Specifically, the protective effects of Zn include pro-
moting cardiomyocyte redox balance and vascular integ-
rity.31 Interestingly, Zn supplementation in vitro led to the
complete restoration of the endothelial cell barrier,58,59,72
an effect not achieved with either calcium or magnesium
supplementation.
Collectively, our findings and others support future stud-
Figure 4. Zinc supplementation: A possible offramp from the road to ies exploring Zn supplementation to disrupt the detrimental
end stage kidney failure. cycle of hypertension and kidney damage burdening pa-
tients with CKD. Although clinical trial evidence in support
renal Na1 excretory function.54 Specifically, mice fed a Zn- of Zn supplementation in patients with CKD is limited,
deficient diet exhibited hypertension with a concurrent re- multiple preclinical studies have shown Zn to possess ben-
duction in urinary Na1 excretion.54 Consistent with higher eficial renal and cardiovascular effects. In rodent models
Na1 reabsorption activity in the distal nephron, thiazide of CKD, Zn supplementation slowed the progression of
treatment promoted natriuresis and importantly restored diabetic nephropathy,73,74 with the antifibrotic effects of
BP control.54 Mice fed a Zn-deficient diet also exhibited Zn reducing renal morphologic changes. These positive
multiple markers of kidney damage including oxidative outcomes attenuated diabetes-induced proteinuria, a
stress, renal fibrosis, and albuminuria.63,64 These same path- well-known feature of CKD. Furthermore, the antioxidative
ological events likely occur in the context of CKD. However, effects of Zn also protected against diabetes-induced aortic
future studies are necessary to (1) identify renal Zn-sensitive damage and endothelial dysfunction.75 In the same manner
pathways that drive hypertension and accelerate CKD pro- that Zn is cardio- and renoprotective in preclinical studies,
gression and (2) explore strategies using Zn supplementa- Zn supplementation likely exerts similar effects in patients
tion to provide an offramp from this detrimental cycle of with CKD. However, insights from clinical investigation are
hypertension and kidney damage. greatly needed.
In patients with CKD and low serum Zn levels, Zn sup-
plementation may be an effective therapeutic strategy to
Can Zinc Supplementation Provide an Exit Strategy to prevent disease progression. While urinary Zn wasting oc-
Rectify the Course of Chronic Kidney Disease and curs in CKD, oral Zn supplementation is sufficient to increase
Hypertension? serum Zn levels, even in patients on hemodialysis.76 Notably,
Current treatment strategies for hypertension in the CKD in patients with CKD and low serum Zn, drugs containing Zn
population attempt to restore salt balance to lower BP. were more renoprotective, leading to a reduction in the risk of
Particularly, (1) low-salt diets are often recommended to disease progression or death by 62%.11 The authors credit
enhance the effects of ACE inhibitors and angiotensin re- these outcomes to the anti-inflammatory and antioxidative
ceptor blockers9,65; (2) thiazide diuretics inhibit the distal benefits of Zn. Although these findings seem encouraging,
nephron Na1 reabsorption pathway to reduce Na1 reten- there is a paucity of evidence directly demonstrating the
tion mediated by the kidneys9; and (3) mineralocorticoid beneficial effects of Zn supplementation in the CKD popu-
receptor antagonists block aldosterone-stimulated reab- lation. However, the therapeutic index of Zn supplementa-
sorption of Na1 by the distal nephron.9,66 Although these tion should also be investigated because acute symptoms
treatment strategies exist as monotherapies to exploit renal after uptake of high doses of Zn include abdominal pain,
Na1 excretory function, even their use as combination nausea, and vomiting. Additional effects include lethargy,
therapies (three or more antihypertensive drugs) often fail anemia, and neurologic disturbances such as dizziness.12
to control BP in patients with CKD.52,62 Notably, these However, acute Zn intoxication is considered a rare event.12
antihypertensives also alter Zn homeostasis.67,68 A system- Long-term, high-dose Zn supplementation interferes with the
atic review of eight clinical studies, which included patients uptake of copper. Hence, many of the toxic effects of Zn
on antihypertensive therapy, reported reduced serum uptake are in fact attributed to copper deficiency.12 Until
Zn levels with daily doses of captopril (50–150 mg), large-scale clinical trials are conducted, the fate of Zn
hydrochlorothiazide (12.5 mg), and losartan (50 mg). supplementation remains unknown in the vulnerable CKD
Moreover, urinary Zn wasting was reported with the population. As such, future studies would provide data
use of captopril (50–75 mg), enalapril (20 mg), hydrochlo- directly examining Zn supplementation as a therapeutic
rothiazide (12.5–25 mg), furosemide (40 mg), and losartan intervention—serving as an offramp from the road to end
(50 mg). Further investigation is necessary to determine stage kidney failure (Figure 4).
402 KIDNEY360

Disclosures 11. Tokuyama A, Kanda E, Itano S, et al. Effect of zinc deficiency

The authors have nothing to disclose. on chronic kidney disease progression and effect modification
by hypoalbuminemia. PLoS One. 2021;16(5):e0251554.
Funding doi:10.1371/journal.pone.0251554
12. Paun S, Tudosie M, Petris R, Macovei R. The effects of zinc on
This work was supported by the National Institute of human body, including on renal failure and renal transplantation.
Diabetes and Digestive and Kidney Diseases Grants: R21 DK119879 J Med Life. 2012;5(Spec Issue):137–140.
(to C.R.W.), R21 DK119879-S (to A.C.U.), and R01 DK-133698 (to 13. Nakatani S, Mori K, Shoji T, Emoto M. Association of zinc de-
C.R.W.); by the William Townsend Porter Predoctoral Fellowship ficiency with development of CVD events in patients with CKD.
from the American Physiological Society (to A.C.U.); by the Nutrients. 2021;13(5):1680. doi:10.3390/nu13051680
14. Damianaki K, Lourenco JM, Braconnier P, et al. Renal handling of
American Heart Association Grant 16SDG27080009 (to C. R.W.); zinc in chronic kidney disease patients and the role of circulating
and by the American Society of Nephrology KidneyCure Transition zinc levels in renal function decline. Nephrol Dial Transplant.
to Independence Grant (to C.R.W.). 2020;35(7):1163–1170. doi:10.1093/ndt/gfz065
15. de Carvalho GB, Brandão-Lima PN, Maia CSC, Barbosa KBF,
Acknowledgments Pires LV. Zinc’s role in the glycemic control of patients with type
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The Kidney PathoPhysiology Research Group would like to doi:10.1007/s10534-017-9996-y
thank S. Daniel of In Scripto, LLC, for editorial assistance and 16. Kambe T, Tsuji T, Hashimoto A, Itsumura N. The physiological,
critical review of the article. We also acknowledge Kidney Krew biochemical, and molecular roles of zinc transporters in zinc
Members—Cindellynn Rudy and Kelia McMichael—for critically homeostasis and metabolism. Physiol Rev. 2015;95(3):749–784.
doi:10.1152/physrev.00035.2014
reviewing the article. Lastly, we thank Markel Haralson for con- 17. Mahajan SK. Zinc in kidney disease. J Am Coll Nutr. 1989;8(4):
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Author Contributions chronic kidney disease. J Am Soc Nephrol. 2007;18(10):
Conceptualization: Adaku C. Ume, Clintoria R. Williams. 2758–2765. doi:10.1681/ASN.2007040422
Funding acquisition: Adaku C. Ume, Clintoria R. Williams. 20. Pisano M, Hilas O. Zinc and taste disturbances in older adults: a
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15376516.2012.735277 Received: July 6, 2022 Accepted: December 18, 2022