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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. [52, 53, 54]
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, 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. [55, 56]
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 Foundation’s 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). [57] 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. [57]
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. [58]

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. [59] 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. [60]
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. [45] 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
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. [61]
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. [62, 63]
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. [62, 63]
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. [64] 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. [64]
However, despite the availability of guidelines and recommendations that include
lists of medications that are relatively contraindicated and those that require renal
dose adjustment, noncompliance with dosing guidelines and use of relatively
contraindicated medications are common in patients with CKD. A cross-sectional
study that included 373 adult patients with stage III/IV CKD found that 46.6% of them
were prescribed at least one relatively contraindicated drug (acarbose,
chlorpropamide, glyburide, nitrofurantoin or any NSAID) during the 2-year study
period; 34.0% were prescribed NSAIDs. [88]
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 failure—especially in men, who tended
to be heavier smokers than women in this cross-section. [65]
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). [66, 67] 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. [66, 67]
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 CKD—
where they would require dialysis or a kidney transplant—within 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%). [66, 67]

reating 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 [68] );
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
 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 non–hemodialysis-
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. [69]
Management of mineral and bone disorder
Treatment of abnormal mineral homeostasis in patients with CKD includes
the following [70] :
 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 updated its guidelines on the management of CKD–mineral and
bone disorder in 2017. [70] The guidelines, which were issued after
weighing the quality and the depth of evidence, when available, propose a
common-sense approach to the evaluation and treatment of mineral and
bone disorder in different stages of CKD.
The National Kidney Foundation convened a work group to provide a US
perspective on the KDOQI CKD-MBD guidelines. While agreeing with most
of the KDIGO recommendations, the work group had some concerns about
the suggestions related to hypocalcemia and hypercalcemia, phosphate-
binder choice, and treatment of abnormal parathyroid hormone
concentrations. [71]
Management of hyperphosphatemia
Definitive evidence on the benefit of lowering phosphate levels in CKD is
lacking, and guideline recommendations vary. KDIGO guidelines suggest
lowering elevated phosphate levels toward the normal range in stages 3a-
5d CKD. [70] United Kingdom National Institute for Health and Clinical
Excellence (NICE) guidelines provide recommendations only for stages 4,
5, and 5d. [72]
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. [73]Unfortunately, calculation of the
cost-effectiveness of the various agents is complicated. [74]
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. [70] For adult patients, NICE guidelines recommend calcium acetate as
the first-line phosphate binder to control serum phosphate, in addition to dietary
management. [72] 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. [75]
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 non–calcium-
containing phosphate binders.
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. [76] 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). [76]
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). [76] 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 [77, 78] :
 Adults aged 50 years or above with an estimated glomerular filtration rate
(GFR) of less than 60 mL/min/1.73 m2 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
m2who 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 m², [2] irrespective of the cause of the CKD or the
presence of absence of other comorbidities
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. [79]
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. [80] 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 . [81]
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. [82] 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

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. [83] 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 β-D-glucosaminidase, and transforming growth
factor β in patients with moderately reduced estimated GFR as a result of
hypertensive nephropathy. [83]
Nutritional guidelines
The National Kidney Foundation’s 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