10/19/2017 Chronic Kidney Disease Treatment & Management: Approach Considerations, Delaying or Halting Progression of Chronic Kidney Disease,

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Chronic Kidney Disease Treatment & Management

Updated: May 01, 2017
Author: Pradeep Arora, MD; Chief Editor: Vecihi Batuman, MD, FASN more...

TREATMENT

Approach Considerations
Early diagnosis and treatment of the underlying cause and/or the institution of secondary preventive measures are
imperative in patients with chronic kidney disease (CKD). These steps may delay, or possibly halt, progression of the
disease. Early referral to a nephrologist is of extreme importance.

The medical care of patients with CKD should focus on the following:

Delaying or halting the progression of CKD

Diagnosing and treating the pathologic manifestations of CKD
Timely planning for long-term renal replacement therapy

In February 2014, the Canadian Society of Nephrology released new guidelines that recommend delaying dialysis in
CKD patients without symptoms until their estimated glomerular filtration rate (eGFR) drops to 6 mL/min/1.73 m2 or
until the first onset of a clinical indication (which includes symptoms of uremia, fluid overload, and refractory
hyperkalemia or acidemia). [51, 52] Close monitoring should begin when eGFR reaches 15 mL/min/1.73 m2.
Additional factors that may affect dialysis initiation include patient education and modality selection, the severity of
existing uremic symptoms, and the rate of renal function decline. [51, 52]

Patients with CKD acutely presenting with indications for dialytic therapy should be transferred to a hospital center
where acute dialysis can be performed.

The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) has issued several clinical
practice guidelines for managing all stages of CKD and related complications in adults.

Delaying or Halting Progression of Chronic Kidney Disease

Measures indicated to delay or halt the progression of chronic kidney disease (CKD) are as follows:

Treatment of the underlying condition if possible

Aggressive blood pressure control to target values per current guidelines
Treatment of hyperlipidemia to target levels per current guidelines
Aggressive glycemic control per the American Diabetes Association (ADA) recommendations (target
hemoglobin A1c [HbA1C] < 7%)
Avoidance of nephrotoxins, including intravenous (IV) radiocontrast media, nonsteroidal anti-inflammatory
agents (NSAIDs), and aminoglycosides
Use of renin-angiotensin system (RAS) blockers among patients with diabetic kidney disease (DKD) and
proteinuria
Use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) in patients
with proteinuria

A prospective cohort study indicated that in patients with advanced CKD and stable hypertension, antihypertensive
treatment with ACEIs or ARBs reduces the likelihood of long-term dialysis and lowers the mortality risk as well. [53,
54, 55]

The study involved 28,497 predialysis patients with advanced CKD, hypertension, and anemia. Based on a median
follow-up period of 7 months, the investigators found that in those patients who were treated with ACEIs or ARBs,

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the need for long-term dialysis was 6% lower than in patients who were not treated with these drugs, with the
composite outcome of long-term dialysis or death also being 6% lower.

The rate of hyperkalemia-associated hospitalization was higher in the ACEI/ARB patients, but no significant increase
was found in hyperkalemia-related predialysis mortality.

In a retrospective simulation study to determine the effectiveness of angiotensin-converting enzyme inhibitors

(ACEIs) and angiotensin II receptor blockers (ARBs) in preventing ESRD in older patients with CKD, researchers
found that these treatments had only marginal benefit. Among over 370,000 patients aged 70 years and above with
CKD, the number needed to treat (NNT) to prevent 1 case of ESRD was more than 100 for most patients (even with
an exposure time of >10 y). In younger patients, the researchers found that the NNT ranged from 9-25. The
investigators suggested that differences in baseline risk and life expectancy between older and younger patients
may cause older patients to derive reduced benefits from interventions to prevent ESRD. [56, 57]

Blood pressure control

Aggressive blood pressure control can help to delay the decline in renal function in patients with CKD. The Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) and the
National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) suggest a target blood pressure
of less than 130/80 mm Hg.

Systolic blood pressure (SBP) control is considered more important than diastolic blood pressure control. However,
SBP is also considered difficult to control in elderly patients with CKD.

In a diverse, community-based study by Peralta et al, high SBP appeared to account for most of the risk of
progression to end-stage renal disease (ESRD). [58] The risk began at an SBP of 140 mm Hg, as opposed to the
current recommended goal of less than 130 mm Hg. The highest risk was found among patients with an SBP of at
least 150 mm Hg. These researchers concluded that to improve blood pressure control in CKD, treatment
approaches that lower SBP may be required. [58]

Use ACEIs or ARBs as tolerated, with close monitoring for renal deterioration and for hyperkalemia. With every dose
change, serum creatinine levels need to be monitored. If serum creatinine levels increase more than 30% from
baseline after adding RAS blockers, RAS blockers should be stopped. Avoid these agents in advanced patients with
renal failure, bilateral renal artery stenosis, or renal artery stenosis in a solitary kidney.

The time of day at which patients take antihypertensive medications can affect circadian patterns of blood pressure,
and this may translate into an effect on clinical outcome. Hermida et al reported, after a median follow-up of 5.4
years, that hypertensive patients with CKD who took at least 1 of their antihypertensive medications at bedtime had
an adjusted risk for total cardiovascular events that was approximately one third that of patients who took all of their
medications upon awakening. [59]

Management of protein

Data support the use of ACEIs or ARBs in diabetic kidney disease with or without proteinuria. However, in
nondiabetic kidney disease, these agents are effective in retarding the progression of disease among patients with
proteinuria of more than 500 mg/day.

In the Modification of Diet in Renal Disease (MDRD) Study, dietary protein restriction (0.58 g/kg/day, versus a usual-
protein diet of 1.3 g/kg/day) did not significantly affect the mean change in glomerular filtration rate (GFR) over 3
years. Secondary analyses, however, suggested that a low-protein diet may slow the GFR decline in patients with
the most rapidly declining GFR and reduce proteinuria. [60] A meta-analysis by Kasiske et al suggested that dietary
protein restriction retards the rate of renal function decline, but the magnitude of the effect is relatively weak. [61]

National Kidney Foundation (NKF) guidelines advise that if a patient is started on protein restriction, the physician
needs to closely monitor the patient's nutritional status. [46] Predialysis low serum albumin is associated with a poor
outcome among dialysis patients. Protein restriction is not recommended in pediatric patients with CKD.

Vitamin D supplementation

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Paricalcitol (Zemplar), a synthetic vitamin D analogue, is approved by the US Food and Drug Administration (FDA)
for the prevention and treatment of secondary hyperparathyroidism associated with CKD stage 5. However, a meta-
analysis has found that paricalcitol also can safely reduce protein excretion in patients with CKD stages 2-5.
Whether paricalcitol can slow the development of ESRD or reduce mortality is not yet known. [62]

In a prospective, controlled study, daily vitamin D supplementation decreased albuminuria in patients with stage 3-4
chronic kidney disease (CKD) who had low vitamin D levels and high parathyroid hormone (PTH) levels. The study
population was composed of 50 CKD patients with hyperparathyroidism who were given 666 IU of oral
cholecalciferol daily and 51 CKD patients without hyperparathyroidism who acted as controls. [63, 64]

At 6 months, cholecalciferol supplementation led to a mean increase in vitamin D (25(OH)D) levels of 53%. Urinary
albumin-to-creatinine ratio decreased, from 284 to 167 mg/g, without alterations in other factors that could affect
proteinuria. Control patients showed no change.

Changes in 25(OH)D levels were significantly and inversely associated with those in the urinary albumin-to-
creatinine ratio , supporting a possible antiproteinuric effect of vitamin D receptor activation. Treated patients also
had a mean drop of 13.8% in PTH, with a mild rise in phosphate and calcium-phosphate product. There was no
change in controls. [63, 64]

Nephrotoxins
A study by Plantinga et al found that a great number of individuals with CKD may be unaware of their disease and
thus may be at risk for further kidney injury through use of NSAIDs. [65] Persons who knew that they had CKD were
less likely to use NSAIDs, suggesting that primary care physicians should be involved in communication regarding
the risks of NSAIDs. [65]

Encourage smoking cessation, as smokers tend to reach ESRD earlier than nonsmokers. A large-population
Norwegian study found that smoking cessation decreased the risk for future onset of kidney failureespecially in
men, who tended to be heavier smokers than women in this cross-section. [66]

Subclinical hypothyroidism

In a study of 113 patients with CKD stages 2-4 and subclinical hypothyroidism, thyroid hormone replacement therapy
(THRT) with L-thyroxine delayed the rate of decline in kidney function to end-stage renal disease (ESRD). [67, 68] On
average, before patients were treated with THRT, their estimated GFR declined by 4.31 0.51 mL/min per 1.73 m2
each year; following treatment, the estimated GFR decline slowed to 1.08 0.36 mL/min per 1.73 m2 each year. [67,
68]

Based on the slope of the decline in estimated GFR prior to THRT, linear regression analysis predicted that 53 of the
113 patients (46.9%) would reach stage 5 CKDwhere they would require dialysis or a kidney transplantwithin 10
years. However, using the altered slope of the decline of estimated GFR after patients received therapy, it was
estimated that only 10 patients (8.8%) would reach this outcome in 10 years. Thus, THRT delayed reaching stage 5
CKD in 43 of the predicted 53 patients (81%). [67, 68]

Treating Pathologic Manifestations of Chronic Kidney Disease

Treat these pathologic manifestations of chronic kidney disease (CKD) as follows:

Anemia: When the hemoglobin level is below 10 g/dL, treat with an erythropoiesis-stimulating agent (ESA)
such as epoetin alfa or darbepoetin alfa (previously, peginesatide was also considered an option for anemia in
CKD, but this agent was withdrawn from the market in February 2013 due to serious hypersensitivity reactions
[69] ); caution should be exercised in patients with malignancy
Hyperphosphatemia: Treat with dietary phosphate binders and dietary phosphate restriction
Hypocalcemia: Treat with calcium supplements with or without calcitriol
Hyperparathyroidism: Treat with calcitriol, vitamin D analogues, or calcimimetics
Volume overload: Treat with loop diuretics or ultrafiltration
Metabolic acidosis: Treat with oral alkali supplementation

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Uremic manifestations: Treat with long-term renal replacement therapy (hemodialysis, peritoneal dialysis, or
renal transplantation)
Cardiovascular complications: Treat as appropriate
Growth failure in children: Treat with growth hormone

Anemia treatment
With erythropoietin treatment, the goal is a hemoglobin level of 10-12 g/dL, as normalization of hemoglobin in
patients with CKD stages 4-5 has been associated with an increased risk of adverse outcomes. Before starting
erythropoietin, patients should have their iron stores checked. The aim is to keep iron saturation at 30-50% and
ferritin at 200-500 ng/mL.

A study by Shurraw et al showed that in people with nonhemodialysis-dependent CKD, a hemoglobin A1c (HbA1c)
level higher than 9% is associated with worse clinical outcomes. Lower levels of HbA1c also seemed to be
associated with excess mortality. Appropriate and timely control of the HbA1c level in people with diabetes mellitus
and CKD may be more important than previously realized, but findings also suggest that intensive glycemic control
may lead to increased mortality. [70]

Management of mineral and bone disorder

Treatment of abnormal mineral homeostasis in patients with CKD includes the following [71] :

Lowering high serum phosphorus levels

Maintaining serum calcium levels
Lowering serum parathyroid hormone levels
Providing osteoporosis prophylaxis

The Kidney Disease: Improving Global Outcomes (KDIGO) Implementation Task Force published guidelines on the
management of CKDmineral and bone disorder in 2009. [71] An update of the guidelines is currently in progress.
The guidelines, which were issued after the quality and the depth of evidence, when available, were weighed,
propose a common-sense approach to the evaluation and treatment of mineral and bone disorder in different stages
of CKD. London et al summarized the best evidence and the KDIGO recommendations on this topic. [72]

Management of hyperphosphatemia

Definitive evidence on the benefit of lowering phosphate levels in CKD is lacking, and guideline recommendations
vary. KDIGO guidelines recommend maintaining serum phosphate levels within the normal range in stages 3-5 CKD
and lowering levels toward normal in stage 5D. [71] United Kingdom National Institute for Health and Clinical
Excellence (NICE) guidelines provide recommendations only for stages 4, 5, and 5d. [73]

Restricting dietary phosphate is one strategy for correcting hyperphosphatemia. However, because of its complexity
and challenges, diet control by iself is insufficient and unreliable for keeping phosphate concentrations within the
recommended range. Consequently, the use of phosphate binders (eg, calcium acetate, sevelamer carbonate,
lanthanum carbonate) has been proposed as a means of reducing elevated phosphorus levels in patients with CKD.
[74] Unfortunately, calculation of the cost-effectiveness of the various agents is complicated. [75]

KDIGO guidelines suggest that the choice of phosphate-binding agent for the treatment of hyperphosphatemia take
into account CKD stage, presence of other components of CKD mineral and bone disorder, concomitant therapies,
and side-effect profile. [71] For adult patients, NICE guidelines recommend calcium acetate as the first-line phosphate
binder to control serum phosphate, in addition to dietary management. [73] For full discussion of management, see
Hyperphosphatemia.

Block et al reported that in patients with CKD who have normal or near-normal serum phosphorus levels, these
agents significantly reduce serum and urinary phosphorus and discourage secondary hyperparathyroidism
progression. The investigators also reported, however, that phosphate binders encourage vascular calcification. [76]

These results are in contrast to those reported in previous experimental findings in animals with CKD and in human
clinical trials, in which the use of phosphate binders did not reduce elevated phosphorus levels or decrease the
progression to secondary hyperparathyroidism. Moreover, the effect of calcification is different among patients taking
calcium-containing phosphate binders relative to those taking noncalcium-containing phosphate binders.
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Furthermore, no randomized, controlled trials have shown improved mortality in dialysis patients who were treated
with phosphate binders, activated vitamin D, or cinacalcet to manage moderate to severe hyperparathyroidism.

Management of metabolic acidosis

The evidence for the benefits and risks of correcting metabolic acidosis is very limited, with no randomized,
controlled trials in patients who are not yet in ESRD, none in children, and only 3 small trials in dialysis patients.
These trials suggest that there may be some beneficial effects on protein and bone metabolism, but the studies were
underpowered and so did not provide robust evidence. Experts recommend alkali therapy to maintain the serum
bicarbonate concentration above 22 mEq/L.

De Brito-Ashurst et al found that patients with CKD who receive bicarbonate supplementation show a slower decline
in renal function. [77] In this study, 134 adult patients with CKD (ie, creatinine clearance [CrCl], 15-30 mL/min/1.73
m2; serum bicarbonate, 16-20 mmol/L) were randomly assigned to receive oral sodium bicarbonate supplementation
or standard care for 2 years. A slower decline in CrCl was observed in the bicarbonate group (1.88 mL/min/1.73 m2)
than in the control group (5.93 mL/min/1.73 m2). [77]

Patients in the bicarbonate group were also less likely to experience rapid disease progression (9%) than were
members of the control group (45%), and fewer patients who received bicarbonate supplementation developed
ESRD than did controls (6.5% vs 33%, respectively). [77] In addition, nutritional parameters improved with
bicarbonate supplementation.

Management of cardiovascular risks

Guidelines issued in December 2013 by the Kidney Disease: Improving Global Outcomes (KDIGO) workgroup
recommend wider statin use among patients with CKD. Specific recommendations include the following [78, 79] :

Adults aged 50 years or above with an estimated glomerular filtration rate (GFR) of less than 60 mL/min/1.73
m 2 who are not being treated with long-term dialysis or kidney transplantation should be treated with a statin
or a statin plus ezetimibe
Treatment with statins or statin/ezetimibe should not be initiated in adults with dialysis-dependent CKD
Patients already being treated with a statin at the time of dialysis should continue
Adult kidney transplant patients should be treated with a statin because of an increased risk for coronary
events
Adults aged 18-49 years with an estimated GFR of less than 60 mL/min/1.73 m 2 who are not being treated
with dialysis or kidney transplantation should be treated with statins if they have coronary disease, diabetes,
prior ischemic stroke, or an estimated 10-year incidence of coronary death or nonfatal myocardial infarction
exceeding 10%
Low-density lipoprotein cholesterol is an insufficient test for cardiovascular risk in individuals with CKD, and
adults with newly diagnosed CKD should undergo lipid profile testing
Adults aged 50 years or older with CKD and an estimated GFR of 60 mL/min/1.73 m2 or higher should be
treated with a statin

Renal Replacement Therapy

Indications for renal replacement therapy in patients with chronic kidney disease (CKD) include the following:

Severe metabolic acidosis

Hyperkalemia
Pericarditis
Encephalopathy
Intractable volume overload
Failure to thrive and malnutrition
Peripheral neuropathy
Intractable gastrointestinal symptoms
In asymptomatic adult patients, a glomerular filtration rate (GFR) of 5-9 mL/min/1.73 m, [6] irrespective of the
cause of the CKD or the presence of absence of other comorbidities

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Timely planning for long-term renal replacement therapy

Consider the following:

Early patient education regarding natural disease progression, different dialytic modalities, renal
transplantation, and option to refuse or discontinue chronic dialysis
Timely placement of permanent vascular access (arrange for surgical creation of primary arteriovenous fistula,
if possible, and preferably at least 6 mo in advance of the anticipated date of dialysis for patients in whom
transplantation is not imminent)
Timely elective peritoneal dialysis catheter insertion
Timely referral for renal transplantation

Diet
Protein restriction

Protein restriction early in chronic kidney disease (CKD) as a means to delay a decline in the glomerular filtration
rate (GFR) is controversial; however, as the patient approaches CKD stage 5, this strategy is recommended in
adults (but not in children) to delay the onset of uremic symptoms.

Piccoli and colleagues observe that the choice of low-protein diets is extremely wide, and that moderate protein
restriction may be feasible in the context of several traditional diets, such as the Mediterranean diet, which also
address other therapeutic goals in CKD. However, these authors note that diet is deeply rooted in personal
preferences and social habits, so the best compliance is probably obtained by personalization and comprehensive
counseling. [80]

Patients with CKD who already are predisposed to becoming malnourished are at higher risk for malnutrition with
overly aggressive protein restriction. Malnutrition is a well-established predictor of increased morbidity and mortality
in the population with end-stage renal disease (ESRD) and must be avoided if possible.

Salt restriction

Reduction in salt intake may slow the progression of diabetic CKD, at least in part by lowering blood pressure. A
meta-analysis found that dietary salt reduction significantly reduced blood pressure in type 1 and type 2 diabetes,
with results comparable to those of single-drug therapy. [81] This finding is consistent with other evidence relating salt
intake to blood pressure and albuminuria in hypertensive and normotensive patients. The dietary sodium
recommendation for the general population in public health guidelines is less than 5-6 g daily.

Children and adults with tubulointerstitial diseases may experience salt wasting, and salt restriction would not usually
be required in that situation.

A randomized, controlled trial by Slagman et al found that moderate dietary sodium reduction (approximately 2500
mg/day of Na+ or 6 g/day of NaCl) added to angiotensin-converting enzyme (ACE) inhibition compared with dual
blockade (ACE inhibitor [ACEI] and angiotensin receptor blocker [ARB]) was more effective in reducing proteinuria
and blood pressure in nondiabetic patients with modest CKD. Furthermore, a low-sodium diet added to dual
blockade therapy yielded additional reductions in blood pressure and proteinuria . [82]

Vegter et al found that among patients with CKD but without diabetes, a high dietary salt intake (>14 g/day)
interfered with the antiproteinuric effect of ACEI therapy and increased the risk for ESRD. [83] The risk was
independent of blood pressure control.

Other dietary restrictions

The following dietary restrictions may also be indicated:

Phosphate restriction starting early in CKD

Potassium restriction
Sodium and water restriction as needed to avoid volume overload

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Fruits and vegetables

A study by Goraya et al showed that increasing the amount of alkali-inducing fruits and vegetables in the diet may
help to reduce kidney injury. [84] In this report, 30 days of a diet that included fruits and vegetables, in amounts
calculated to reduce dietary acid by half, resulted in decreased urinary albumin, N-acetyl -D-glucosaminidase, and
transforming growth factor in patients with moderately reduced estimated GFR as a result of hypertensive
nephropathy. [84]

Nutritional guidelines

The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) issued a clinical practice
guideline for Nutrition in Chronic Renal Failure, as well as a 2008 revision of recommendations for Nutrition in
Children with CKD. For adult patients on maintenance dialysis, the KDOQI guidelines recommend routine
assessment of the following nutritional parameters:

Predialysis or stabilized serum albumin: Monthly

Percentage of usual postdialysis (hemodialysis) or postdrain (peritoneal dialysis) body weight: Monthly
Percentage of standard (National Health and Examination Survey II [NHANES II]) body weight: Every 4 months
Subjective global assessment: Every 6 months
Dietary interview and/or diet diary: Every 6 months
Protein Equivalent of Total Nitrogen Appearance normalized to body weight (nPNA): Monthly with
hemodialysis; every 3-4 months with peritoneal dialysis

Consultations and Long-Term Monitoring

Consultations for the management of patients with chronic kidney disease (CKD) may include the following:

Early nephrology referral (decreases morbidity and mortality)

Renal dietitian
Surgery for permanent vascular access or for peritoneal catheter placement
Referral to renal transplant center

Patients with CKD should be referred to a nephrologist early in the course of their disease and have continued
nephrologic follow-up until initiation of chronic renal replacement therapy, during dialysis, and after kidney
transplantation. Moreover, a multidisciplinary approach to care, including involvement of the nephrologist, primary
care physician, renal dietitian, nurse, and social worker, should be initiated early in the course of CKD, with close
patient follow-up.

Patients should be monitored for obstructive sleep apnea (OSA), which occurs with increased frequency in patients
receiving dialysis. Sakaguchi et al also found a high incidence (65%) of OSA in Japanese patients with nondialysis
CKD, with the OSA being moderate or severe in about one third of the patients who had it. [85] The study also found
that a decreased glomerular filtration rate (GFR) was associated with an increased risk of OSA. [85]

Medication

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Contributor Information and Disclosures

Author

Pradeep Arora, MD Assistant Professor of Medicine, University of Buffalo State University of New York School of
Medicine and Biomedical Sciences; Attending Nephrologist, Veterans Affairs Western New York Healthcare System

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane
University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians,
American Society of Hypertension, American Society of Nephrology, International Society of Nephrology, Southern
Society for Clinical Investigation

Disclosure: Nothing to disclose.

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Acknowledgements

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and Pharmacology, Section of
Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research,
American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation

Disclosure: Nothing to disclose.

Laura Lyngby Mulloy, DO, FACP Professor of Medicine, Chief, Section of Nephrology, Hypertension, and
Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in Immunology, Medical College of Georgia

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mauro Verrelli, MD, FRCP(C), FACP Assistant Professor, Department of Medicine, Section of Nephrology,
University of Manitoba, Canada

Disclosure: Nothing to disclose.

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