INTRODUCTION

Chronic kidney disease (CKD) is a common disease1, and it may be associated with a
variety of electrolyte disturbances2. One such disturbance, hyperkalemia, is of great concern
to providers treating patients with CKD because of its possible implications for patient safety
related to the potential for associated adverse cardiac outcomes 3–6. Patients with CKD may
be predisposed to hyperkalemia for a variety of reasons. Principal causes include their
impaired glomerular filtration rate (GFR) combined with a frequently high dietary potassium
intake relative to residual renal function, a commonly observed extracellular shift of
potassium caused by the metabolic acidosis of renal failure 2,3, and most importantly,
recommended treatment with renin-angiotensin aldosterone system (RAAS) blockers that
inhibit renal potassium excretion7–9.

Few studies have determined the frequency of hyperkalemia in a large CKD

population and the extent that this metabolic disturbance is associated with adverse
outcomes. Such information is needed to determine the significance of hyperkalemia as a
disease specific patient safety measure. In this study, we examined a national cohort of
patients cared for over a single year in the Veterans Health Administration (VHA) to
determine the incidence of hyperkalemia in CKD relative to non-CKD patients, and in the
presence or absence of treatment with a RAAS blocker. We determined the significance of
hyperkalemia by examining its association with subsequent short-term mortality in this
population.

Hyperkalemia, defined as an elevated serum potassium (K +) concentration of greater

than 5.0 or greater than 5.5 mEq/L (mmol/L), is an electrolyte abnormality with potentially
life-threatening consequences.10 The risk for development of hyperkalemia is increased in
patients with chronic kidney disease (CKD), diabetes, and heart failure (HF) and in
individuals receiving renin-angiotensin-aldosterone system inhibitors (RAASis).10-11-12

1
 Potassium Homeostasis and Hyperkalemia

Potassium homeostasis is largely maintained by the kidneys, although the gastrointestinal

tract and other systems are also involved to a lesser extent (Figure 1). 13-14 Hyperkalemia has
depolarizing effects on the heart,14 causing shortened action potentials and increasing the risk
of arrhythmias.15 Hyperkalemia causes neuromuscular symptoms,14-16 metabolic acidosis,
and suppression of ammoniagenesis.17

2
 Hyperkalemia Incidence-

Hyperkalemia is rare in the general population.35However, because it is a transient

condition, no prospective studies monitoring intraindividual serum K+ concentrations have
been conducted, and therefore, the exact incidence of hyperkalemia in the general population
is unclear. Different K+ thresholds also affect the reported incidence of hyperkalemia.
Among hospitalized patients, hyperkalemia incidence has been reported as 3.5% (>5.5
mEq/L) in Canada36 and 4.9% (>5.0 mEq/L) in Ireland.37 However, the likelihood of
detecting hyperkalemia depends on the frequency of K+ monitoring. Two studies
of inpatients and/or outpatients undergoing K+ testing over 3 years, one in Sweden and
another in the United States,38 observed higher rates of hyperkalemia (7% and 11% [>5.0
mEq/L] and 2% [>5.5 mEq/L],38 respectively). The worldwide incidence of hyperkalemia
could be underestimated because of the lack of routine K+ monitoring even in some high-risk
patient populations. Therefore, further epidemiological research in real-world populations is
needed to more accurately estimate hyperkalemia incidence, which may be higher than
observed in clinical trials because of the lack of consistent K+ monitoring and the lack of a
standardized hyperkalemia definition (eg, serum K+ >5.0, >5.5, or >6.0 mEq/L).

Risk Factors-

Certain patient populations have an increased risk of hyperkalemia-associated

morbidity and mortality, including patients with advanced stages of CKD, HF, resistant
hypertension, diabetes, myocardial infarction (MI), and/or combinations of these
conditions. Additional risk factors include RAASi usage, advanced age, and drugs such as
heparin, β-blockers, nonsteroidal anti-inflammatory drugs, calcineurin
inhibitors, trimethoprim, pentamidine, and K+-sparing diuretics. The risk of hyperkalemia
progressively increases as eGFR decreases. Because chronic loss of kidney function is
associated with an adaptive response in the remaining functional nephrons, allowing for an
increase in fractional K+ excretion and maintenance of serum K+ levels of less than 5.5
mEq/L, the risk of hyperkalemia is generally increased once the eGFR is less than 15
mL/min per 1.73 m2. Furthermore, patients receiving RAASi therapy who have an eGFR of
less than 60 mL/min per 1.73 m2 have an elevated hyperkalemia risk, which progressively
increases as eGFR decreases. In patients with CKD and/or chronic HF receiving RAASi, risk
factors for repeated hyperkalemia within 6 months of the first event include moderate to
severe initial hyperkalemia (≥5.6 mEq/L), low eGFR (<45 mL/min per 1.73 m2), diabetes,
and spironolactone use.
Hyperkalemia risk is slightly higher in men than in women after initiation of RAASi
therapyand differs among racial groups, in whom ethnicity, diet, and socioeconomic factors
may contribute. These factors currently do not impact hyperkalemia management; however,
the potentially additive effects of these differences may increase hyperkalemia risk.

3
 Classification of Hyperkalemia::

Although the precise K+ concentration thresholds for mild, moderate, and severe
hyperkalemia vary among current guidelines,18,19,20 a serum K+ level of 5.5 mEq/L or greater
is widely accepted as the threshold for hyperkalemia. Hyperkalemia-associated adverse
outcomes may extend beyond hyperkalemia thresholds (serum K+ >5.0 or >5.5 mEq/L) and
include high ―normal‖ K+ concentrations in patients with acute or chronic
HF,21,22 hypertension,23 or CKD.24 When deciding how to treat hyperkalemic episodes, it may
be useful to focus on hyperkalemia with clinical impact, as well as rapid fluctuations in
serum K+, rather than rigid and somewhat arbitrary serum K+ thresholds.

Potassium concentration thresholds for the classification of mild, moderate, and severe
hyperkalemia are useful; however, patient risk- and clinical impact-based classification may
also guide clinical intervention. Clinicians should consider using individualized serum
K+ concentration thresholds that take into account patient comorbidities and ―normal‖
K+ concentration ranges, as well as the rate or degree of change in serum K+ levels over time,
which enables proactive or preventive interventions and is a useful clinical variable for
hyperkalemia management.

Acute Hyperkalemia

Acute hyperkalemia is defined as a serum K+ concentration exceeding the upper limit

of normal that is not known to be chronic. Management of acute hyperkalemia depends on
the magnitude or severity of the increase in K+ concentration, especially when combined
with marked electrocardiographic (ECG) changes and severe muscle weakness.25 The most
commonly observed changes in ECG are peaked T waves and prolonged QRS
complexes. However, as noted in the observational REVEAL-ED (Real World Evidence
for Treatment of Hyperkalemia in the Emergency Department) study of emergency
department patients who presented with K+ concentrations of 5.5 mEq/L or greater,26 the
symptoms of hyperkalemia can be nonspecific, and although recommended for determining
the clinical relevance of elevated serum K+, ECG findings can be highly variable and not as
sensitive as a laboratory test in predicting hyperkalemia or its associated complications. A
deep learning model that may allow for noninvasive screening for hyperkalemia using ECG
is currently being developed27; however, this tool is not yet available for use in routine
clinical practice. Therefore, K+ measurements should be conducted on the basis of the
patient’s risk factors rather than clinical symptoms. The goal of managing acute
hyperkalemia is to prevent or minimize electrophysiologic effects on the heart to reduce the
immediate risk of arrhythmias.28 ,29 Treatment options for acute hyperkalemia include
intravenous calcium gluconate, insulin/glucose, inhaled β-agonists (eg,
salbutamol), intravenous sodium bicarbonate, and hemodialysis . Intravenous calcium
gluconate administration rapidly reduces the membrane excitatory effects of K+ on cardiac

4
tissue within 1 to 3 minutes, thereby minimizing the potential for cardiac arrhythmia, but
only minimally reduces serum K+ concentrations.,30 If no effect is observed within 5 to 10
minutes, another dose of calcium gluconate may be given.31 Intravenous insulin (plus
glucose) and inhaled β-agonists act within 30 minutes to promote redistribution of serum
K+ into the intracellular space but do not change total body K+ levels. Short-term treatment
with oral sodium bicarbonate may be used to promote K+ elimination through
increased urinary K+ excretion in patients with concurrent metabolic acidosis, countering the
release of K+ into the blood that is caused by metabolic acidosis by decreasing blood acidity
and promoting K+ excretion through increased distal sodium delivery.32 Dialysis increases
K+ elimination from the body and may be used as an adjunctive therapy in acute
hyperkalemia after instituting other approaches.

Several deficiencies associated with current management of acute hyperkalemia were

highlighted by the REVEAL-ED study, including a lack of standard, universally accepted
treatment protocols or algorithms for managing hyperkalemia in the emergency
department. The study documented the use of different treatments, alone or in combination,
depending on the institution and initial blood K+ concentration, including intravenous
calcium, inhaled β2-agonists, oral sodium polystyrene sulfonate (SPS), intravenous sodium
bicarbonate, dialysis, and intravenous diuretics. Insulin/glucose (alone or in combination
with other therapy) was the most commonly utilized option (64% of patients) within the first
4 hours, whereas the treatment option most likely to achieve normokalemia within 4 hours
was dialysis.

Chronic Hyperkalemia

Chronic hyperkalemia is defined as recurrent episodes of elevated serum

+
K concentrations that require ongoing maintenance therapy; however, based on the recent
KDIGO report,25 there is no consensus on the frequency, severity, or duration of these
episodes that describes chronicity. In general, chronic hyperkalemia is more likely to be
identified in individuals who have more frequent testing and is often
asymptomatic.25 Current recommendations regarding the management of chronic
hyperkalemia (long-term elevated serum K+) include the use of loop or thiazide diuretics,
modification of RAASi dose, and removal of other hyperkalemia-causing medications
.28,32,25 Diuretics promote urinary excretion of K+ in patients with CKD or DKD by
stimulating the flow and delivery of K+ to the renal collecting ducts.33 Fludrocortisone can
also increase K+ excretion but is associated with an increased risk of fluid retention,
hypertension, and vascular injury.28,15

5
 These long-term treatment options have limitations.28 Despite the beneficial effects
of diuretics on volume status and blood pressure in patients with CKD or HF, these agents
may increase the risk of gout, volume depletion, decreased distal nephron flow, worsening
kidney function, and reduced K+ excretion, and their effectiveness in managing hyperkalemia
relies on residual kidney function. Discontinuation or dose reduction of RAASi therapy may
lead to adverse cardiorenal outcomes, and current guidelines differ with regard to
recommendations on when to reinitiate RAASi .25,33, 34 Recently US Food and Drug
Administration–approved K+-binding agents may provide benefits for the management of
chronic hyperkalemia while avoiding these limitations. Educational initiatives on the safety
and efficacy of the newer K+ binders are needed for primary care physicians and internists to
increase their knowledge of hyperkalemia management, especially in regions where
specialist services may not be readily available. A team approach for chronic hyperkalemia
management is optimal, which may include specialists (eg, cardiologists, nephrologists),
primary care physicians, nurses, pharmacists, social workers, or dietitian

6
 Kraft MD, Btaiche IF, Sacks G.M.C. Rosano, J. Tamargo, K.P. Kjeldsen, et al.

Expert consensus document on the management of hyperkalaemia in patients with

cardiovascular disease treated with renin angiotensin aldosterone system inhibitors:
coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European
Society of Cardiology.

Z. Rafique, M.R. Weir, M. Onuigbo, et al.

Expert panel recommendations for the identification and management of hyperkalemia and
role of patiromer in patients with chronic kidney disease and heart failure

GS, Kudsk KA. Treatment of electrolyte disorders in adult 358 patients in the intensive care
unit.

Surawicz B, Chlebus H, Mazzoleni A. Hemodynamic and electrocardiographic effects of

hyperpotassemia. Differences in response to slow and rapid increases in concentration of
plasma K.

Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH.

Longitudinal follow-up and outcomes among a population with chronic kidney disease in
a large managed care organization.

7
FJ Gennari, AS Segal - Kidney international, 2002 - Elsevier

Hyperkalemia: An adaptive response in chronic renal insufficiency.

BackgroundHyperkalemia is a common feature of chronic renal insufficiency, usually
ascribed toimpaired K+ homeostasis. However, various experimental observations
suggest that theincrease in extracellular [K+] actually functions in a homeostatic
fashion, directly stimulating
renal K+ excretion through an effect that is independent of, and additive to,
aldosterone.Methods We have reviewed relevant studies in experimental animals
and in human subjects …
A Alfonzo, J Soar, R MacTier, J Fox, I Shillday… - UK Renal …, 2020 - ukkidney.org

Purpose This guideline provides an updated version of the original

Hyperkalaemiaguideline (2014). The main aims are to provide evidence-based
recommendations for the treatment of chronic hyperkalaemia in the community,
acute hyperkalaemia in the hospitalsetting and to reduce the risk of complications
associated with hyperkalaemia itself and itstreatment.

CG Musso

International Urology and Nephrology, 2004•Springer

Potassium is the main cation in the intracellular space and its content in healthy
adults is around 3700–mmol. Its retention is one of the dangers that accompanies
hronic renal failure, especially when glomerular filtration rate (GFR) falls toward 20%
of normal. There exist different mechanisms by which hyperkalemia is avoided in
patients with renal failure. These include spontaneous restriction of dietary
potassium intake to 40–60mmol/day and aldosterone induced increase in potassium
excretion in renal distal tubules and colonic epithelium. Although renal and intestinal
adaptation are important in maintaining overall potassium balance during CKD,
movement of potassium into the cells is extremely important in the body’s acute
defense against hyperkalemia, and occurs daily during postprandial potassium
overload, through shift of this cation into hepatic cells mediated by insulin and thus
avoiding postprandial hyperkalemia. The above described mechanisms contribute to
maintenance of normal serum potassium in patients with CKD.

8
The basic purpose project work and hospital training are expanding our knowledge about the
subject along with other ancillary matters like.

to prevent or treat life-threatening complications, replace the potassium deficit, and

to diagnose and correct the underlying cause.

A basic biochemical laboratory panel (including serum sodium, potassium, glucose,

chloride, bicarbonate, BUN and creatinine) is the core of screening in patients with
hypokalemia.

Non-potassium-sparing diuretics are commonly used in heart failure (HF). They activate
the neurohormonal system, and are potentially harmful. Yet, the long-term effects of
chronic diuretic use in HF are largely unknown. We retrospectively analysed the Digitalis
Investigation Group (DIG) data to determine the effects of diuretics on HF outc

The main aims are to provide evidence-based recommendations for the treatment of
chronic hyperkalaemia in the community, acute hyperkalaemia in the hospitalsetting and
to reduce the risk of complications associated with hyperkalaemia itself and itstreatment.

9
 PRINCIPLE:

Potassium reacts with sodium tetraphenol boron in a specially prepared buffer to form a
colloidal suspension. The amount of the turbidity produced is directly proportional to the
concentration of potassium in the sample .

SAMPLE COLLECTION AND PRESERVATION :

1. Serum free from hemolysis.

2. separate serum from the clot as soon as possible as.

3. potassium may leach from the RBCs which can elevate potassium level.

REAGENT PREPARATION AND STORAGE:

>>All reagents are ready to use.store reagents at room temperature(25-30 degree centrigrate)

CONTENTS :

Reagent 1 : Potassium Reagent

Reagent 2 : Potassium Standard 5 mEq/L

REAGENT STABILITY :

The reagents are stable until the expiration date mentioned on the Kit.

10
GENERAL SYSTEM PARAMETRES:

Reaction type : End point

Wavelength : 630 nm

Cuvette : 1 cm

Reaction Temperature : RT

Zero setting : Reagent blank

Reagent volume : 1.0 ml

Sample volume : 20 µl

Incubation time : 5 mins

Standard concentration : 5 mEq/L

ASSAY PROCEDURE :

Pipette into clean dry testtubes labeled as Blank (B), Standard(s)and Test(t).

ADDITION (B) (S) (T)

SEQUENCE
POTASSIUM 1.0 ml 1.0ml 1.0 ml
REAGENT
STANDARD - 20micro litre -
SAMPLE - - 20micro litre

Mix well and incubate at RT for 5 mins. Measure the absorbance of Standard (Abs.S) and
Test (Abs. T) against reagent blank at630 nm.

11
CALCULATION:

Concentration of potassium(mEq/L): Abs.T

----------× 5
Abs.s

NORMAL VALUES :

Serum/Plasma : 3.5 - 5.5 mEq/L.

It is recommended that each laboratory establish its own normal

range representing its patient population.

LINEARITY :

This procedure is linear upto 7 mEq/L. If values exceed

his limit dilute the sample with distilled water and multiply
results with proper dilution factor.

12
PRINCIPLE::

further reacts with a phenolic chromogen and hypochlorite to form a green coloured
complex. Intensity of the colour formed is directly proportional to the amount of urea present
in the sample.

REACTION:

Urea + H2O-UREASE2NH3+CO2

Ammonia + Phenoloic chromogen + Hypochlorite Green--GREEN COLOUR COMPLEX

CONTENTS:

Reagent 1 : Urea Enzyme Reagent

Reagent 2 : Urea Chromogen Reagent

Reagent 3 : Urea Standard 40 mg/dl

MATERIALS REQUIRED BUT NOT PROVIDED:-

- Clean & Dry Glassware.

- Laboratory Glass Pipettes or Micropipettes & Tips.

- Colorimeter or Bio-Chemistry Analyzer.

SAMPLES:

Serum, plasma, Urine. Dilute urine specimen 1 + 49 with distilled water

before the assay (results x 50 ). Urea is reported to be stable in serum for 5 days at 2-80c

13
GENERAL SYSTEM PARAMETERS:

Reaction type : End point

Wave length : 600 nm (600-630 nm)

Temperature : 37°C

Incubation : 5 + 5 minutes

Working reagent : 1.0 ml

Chromogen reagent : 1.0 ml

Sample volume : 10 µl

Standard concentration : 40 mg/dl

Zero setting : Reagent blank

Light path : 1.0 cm

PROCEDURE::Pipette into clean dry test tube labeled as blank(B),standard(s) and Test(T);

Addition sequence B S T
Workuing reagent 1ml 1ml 1ml
Standard - 10 micro L -
Sample - - 10micro L

Mix well and incubate for 5 minutes at 370c for 5 minutes……….

CHROMOGEN 1ml 1ml 1ml

REAGENT

Mixwell and incubate for 5 min at 370c .measure the absorbance of standard (Abs.S) and
test(Abs.T)against reagent blank at 600nm with in 60 minutes.

CALCULATION::
Abs.T/Abs.T*40
UREA (mg/dl)=

NORMAL RANGE—SERUM/PLASMA—10-50mg/dl
14
PRINCIPLE:

Picric acid in an alkaline medium reacts with creatinine to form an orange coloured complex
with the alkaline picrate. Intensity of the colour formed is directly proportional to the amount
of creatinine present in the sample.

Creatinine + Alkaline Picrate----- Orange Coloured Complex

CONTENTS:

Reagent 1 : Creatinine Buffer Reagent

Reagent 2 : Creatinine Picrate Reagent

Reagent 3 :Creatinine Standard 2 mg/dl

MATERIALS REQUIRED BUT NOT PROVIDED:-

- Clean & Dry Glassware.

- Laboratory Glass Pipettes or Micropipettes & Tips.

- Bio-Chemistry Analyzer.

STORAGE & STABILITY

All reagents are stable at 2 - 8°C. Till expiry mentioned on the label.
SAMPLE::
Unhaemolysed serum sample.

:: GENERAL SYSTEM PARAMETERS:

Reaction type : Fixed time (Increasing)

Wave Length : 505 nm (490 - 520 nm)

15
 Temperature : 37°C

Delay time : 30 Sec

Interval : 120 Sec.

Reagent volume : 1.0 ml

Sample volume : 50 µl

Standard concentration : 2.0 mg/dl

Zero setting : Deionised water

Light path : 1 cm

PROCEDURE
Pipette into a clean dry test tube labeled as Standard (S)and Test.

Addition sequence S T
WORKING REAGENT 1.0 ml 1.0ml
STANDARD 50 micro l -
SAMPLE - 5 micro L
Mix well and read the initial absorbance (A1 ) for the standard and Test after exactly 30
seconds. Read another absorbance (A2 ) of standard and test exactly120 seconds
later.Calculate the change in absorbance delta A for both the standard and test.

DETERMINE FOR STANDARD:: Delta AS=A2S-A1S

FOR TEST::Delta AT=A2T-A1T

CALCULATION: Creatinine conc. Mg/dl = DeltaAT/DeltaAS*2

NORMAL VALUE: Serum : Male 0.9 - 1.4 mg /dl , Female - 0.8 -1.2 mg/dl Each
laboratory should established its own normal range reprenting in patient population.

16
LINEARITY :

This procedure is linear upto 20 mg/dl.If value exceeds this limit

dilute the sample with normal saline (NaCl 0.9%) and repeat the

assay Multiply result by dilution factor.

LIMITATION & PRECAUTIONS :

1. Do not Freeze the Reagents.

2. During assay specified temperature has to be maintained.

3. The time interval should be adhered as the kit reagent are

Standardized accordingly

4. Do not pipette the reagent by mouth.

5. Use clean glassware free from dust or debris

QUALITY CONTROL :

For accuracy, it is advised to run known serum controls

with each assay.

17
SERIAL PATIENTS AGE/SEX UREA CREATININE POTASSIUM(mEq/L)
NO. ID. (mg/dl) (mg/dl)
1. OPD 1 33Y/M 15 0.91 4.23
2. OPD 2 39Y/M 19 0.92 4.19
3. OPD 3 31Y/M 21 0.52 4.34
4. OPD 4 29Y/M 17 0.62 3.99
5. OPD 5 38Y/M 48 0.95 4.96
6. CCU 1 78Y/M 342 10.6 7.50
7. CCU 2 58Y/F 378 7.3 7.23
8. CCU 3 62Y/M 118 4.2 5.23
9. CCU 4 78Y/F 159 10.34 6.72
10. CCU 5 82Y/M 149 5.89 6.96
11. CCU 6 69Y/F 75 2.12 6.50
12. CCU 7 58Y/F 80 2.23 6.65
13. CCU 8 65Y/M 45 0.13 3.91
14. CCU 9 68Y/F 78 3.16 5.99
15. CCU 10 83Y/M 106 4.56 7.01
16. CCU 11 48Y/F 152 3.59 6.16
17. CCU 12 61Y/M 88 2.18 5.91
18. CCU 13 59Y/F 79 2.31 5.01
19. CCU 14 91Y/M 442 16.1 7.69
20. CCU 15 55Y/F 92 4.26 5.29
21. CCU 16 63Y/M 56 1.69 4.89
22. CCU 17 58Y/F 68 2.58 5.46
23. CCU 18 64Y/M 229 6.57 7.23
24. CCU 19 59Y/F 104 5.29 6.54
25. CCU 20 46Y/M 89 6.25 5.14

18
26. MM 01 36Y/M 36 0.12 3.19
27. MM 02 55Y/M 74 1.12 5.11
28. MM 03 42Y/M 32 0.51 4.11
29. MM 04 61Y/M 86 3.19 6.89
30. MM 05 78Y/ M 96 4.25 7.96
31. MM 06 33Y/M 102 3.55 6.18
32. MM 07 49Y/M 21 0.25 3.56
33. MM 08 42Y/M 134 3.97 6.88
34. MM 09 55Y/M 98 1.14 5.11
35. MM 10 33Y/M 78 1.86 5.78
36. MM 11 46Y/M 32 1.01 4.99
37. MM 12 21Y/M 14 0.05 4.11
38. MM 13 23Y/M 35 0.85 4.96
39. MM 14 25Y/M 55 1.12 5.14
40. MM 15 40Y/M 36 0.54 4.19
41. FM 01 33Y/F 41 0.89 4.91
42. FM 02 37Y/F 32 0.45 4.12
43. FM 03 65Y/F 45 1.15 5.76
44. FM 04 72Y/F 55 2.56 6.76
45. FM 05 66Y/F 85 3.87 6.87
46. FM 06 45Y/F 102 4.25 5.97
47. FM 07 65Y/F 98 3.16 6.41
48. FM 08 60Y/F 155 9.32 8.14
49. FM 09 80Y/F 98 1.23 6.21
50. FM 10 58Y/F 102 2.14 6.41

19
Patient Condition Mean Value of Urea Mean Value of Mean Value of
Creatinine Potassium
Normal Patient 57.529 0.698 4.416
Hyperkalemia patient 126.529 4.778 6.535

140

120

100

80
Normal Patient
60 Affected Patient

40

20

0
Urea

4
Normal Patient
3 Affected Patient

0
Creatinine Potassium

20
DISCUSSION:Over the past decade, research has increasingly focused on studying
patient safety in the general population. Little attention, however, has been given to
disease specific measures of patient safety that are relevant to populations with chronic
illness like CKD. In this analysis, we focused on hyperkalemia as one measure of disease
specific patient safety relevant to health care provides managing patients with CKD.

Our results demonstrate that patients with CKD were significantly more likely than
patients without CKD to have a hyperkalemic event at all stages of renal disease. The
results, however, indicate that patients with CKD treated with a RAAS blocker are
slightly less likely to have both moderate and severe hyperkalemia than CKD patients
who are not on this treatment. The 1-day odds of death were greater after a
hyperkalemic event compared to a normokalemic event. However, hyperkalemic events
in patients without CKD were associated with higher odds of 1-day mortality than
hyperkalemic events in patients with CKD. There tended to be an inverse relationship
between the severity (stage) of CKD and odds of 1-day mortality following a
hyperkalemic event, and more severe hyperkalemia was associated with higher odds of
death.

Prior studies have documented modest hyperkalemia associated with the use of ACE-I
and/or ARB in patients with CKD in the setting of a clinical trial. In six separate clinical
trials of over 1500 individuals with renal insufficiency, elevations in serum potassium
levels between 0.3 and 0.6 mg/dl occurred in 3–5% of subjects randomized to an ACE
inhibitor. Other trials have shown similar increases among patients assigned to
treatment with ARBs. The observation in the present study that hyperkalemia is less
common among patients with CKD treated with a RAAS blocker has several potential
explanation. It is possible that the predisposition of CKD patients to developing
hyperkalemia may cause treating physicians to screen out prior to treatment of
patients who are prone to this metabolic disturbance. In those patients in whom they
elect to treat with a RAAS blocker, physicians may increase their surveillance for
hyperkalemia or spend more time determining means by which a patient can avoid this
consequence of therapy. However, our ability to elucidate the mechanism underlying
this finding is limited and beyond the scope of this study.

The observed lower 1-day mortality rate among patients with CKD versus those
patients without CKD and hyperkalemia has some plausible explanations. First, as
kidney function declines, there is likely to be an adaptive response which leads to
a new increased steady state serum potassium level. In patients with more severe
kidney disease, there is also an increased level of gut potassium excretion..

Potassium adaption is the response of the kidneys to a high dietary potassium

intake. In patients with chronic renal insufficiency, prior studies have described a
compensatory response to chronic hyperkalemia in which the body eventually
develops a new steady state potassium level which is often significantly higher
21
than normal. As GFR declines, serum potassium levels increase as potassium
filtration and secretion fall. When aldosterone or other kaliuretic factors fail to
maintain potassium homeostasis, extracellular [K+] may rise until it reaches a
level sufficient to produce a sustained increase in renal potassium excretion.
Increased extrarenal potassium excretion through the gut is another adaptive
mechanism which gradually develops in patients with chronic renal failure as
kidney function declines.

The lower mortality seen with hyperkalemia in CKD is consistent with evidence
suggesting that these patients may be less susceptible to cardiac toxicity from this
metabolic disturbance than patients without kidney disease. This may be
attributable to the fact that patients with CKD are more likely to develop chronic
hyperkalemia, which is reported to be better tolerated than an acute rise. It has
been noted that patients with CKD who develop chronic hyperkalemia can have
serum potassium levels in excess of 6.0 mg/dl without apparent
electrocardiographic or cardiovascular manifestations. Acute hyperkalemia can
cause a rapid reduction in resting membrane potential leading to increased
cardiac depolarization, muscle excitability and possible ECG changes. These
cardiac changes may be altered in the renal population where the presence of
other electrolyte disturbances could influence the cardiac membrane potential.

The findings reported in this study have important clinical implications. They
suggest that patients with CKD and those who are treated with RAAS blocker
have an increased risk of hyperkalemia, but that risk may be somewhat lowered
with proper patient selection for RAAS treatment. The increased risk of death
associated with hyperkalemia underscores the importance of clinical monitoring
and follow-up of patients with CKD or who are treated with RAAS blockers to
avoid the adverse outcomes that are associated with this metabolic disturbance.
Others have reported that a substantial portion of patients who have
hyperkalemia detected in a clinical setting do not have timely follow-up of this
abnormal lab value.Even though this study revealed an attenuation in the
morality risk associated with hyperkalemia and CKD consistent with the adaptive
mechanisms described, the higher frequency of this metabolic disturbance in this
disease population suggests that patients with CKD should be closely monitored
to minimize adverse outcomes.

Retrospective analyses such as this one have several inherent limitations which
should be considered when interpreting the findings. First, the incidence of
hyperkalemia is only detected at the time of a clinically ordered blood test and
does not account for the occurrence of this metabolic disturbance at unobserved
times. Therefore, our estimation of the incidence of hyperkalemia is subject to the
22
frequency of laboratory monitoring, which is non-random among the veterans in
this cohort. Nevertheless, the demonstrated odds of death associated with
hyperkalemia in both inpatient and outpatient labs, highlights the significance of
the detected events in this study. Using 1-day mortality as the outcome, we were
able to minimize the influence of confounding by severity of illness in the study.
The results of this study only included RAAS blockers, which are known to
increase serum potassium levels. However, it is quite possible that other agents
may have influenced the incidence of hyperkalemia. The emphasis in this study,
however, was on that class of agents which are a key element to disease
management in CKD. Finally, patients with Stage 5 CKD may have included
individuals with ESRD who are on dialysis and as a result may handle potassium
differently than those subjects who were dialysis independent. Given the small
number of patients with Stage 5 CKD in the cohort, the proportion on dialysis was
likely to be small.

The findings of this study support the consideration of hyperkalemia as a patient

safety measure in CKD. We have shown that this metabolic disturbance is more
common in CKD than in patients without this condition. Moreover, hyperkalemia
is linked to increased odds of mortality although the risk is lower in CKD versus
non-CKD populations. These findings suggest that the role of disease
management in the manifestation of this candidate safety measure is complex.
However, given the association of hyperkalemia with CKD and the elevated odds
of death associated with hyperkalemia, this metabolic disturbance should be
considered a disease-specific safety event. More work is needed to see to what
extent alterations in disease management will reduce the incidence of this patient
safety indicator.

23
Conclusions: Although clinical practice usually emphasizes greater attention
to elevated SK in the setting of CKD, our results suggest that patients who have
CKD Which are high urea ,creatinine and potassium level and they have moderate
to hyperkalemia.

Hyperkalemia (serum potassium [SK] ≥5.5 mmol/L) is common in patients with

ESRD. In the dialysis population, the prevalence of hyperkalemia has been
estimated to range from 5 to 10% . Hyperkalemia is thought to contribute to 2 to
5% of deaths among patients with ESRD and accounts for up to 24% of
emergency hemodialysis sessions in this population . Hyperkalemia has also been
associated with increased mortality (up to 17%) in the general hospitalized
population . Although nephron adaptation occurs in those with progressive renal
insufficiency by way of enhanced distal tubular secretion of ingested potassium,
mildly elevated potassium levels are not uncommon and dietary restriction of
potassium is frequently considered prudent for patients with advanced chronic
kidney disease (CKD) to avoid dangerous hyperkalemia.

Adverse effects of SK ≤3.5 mmol/L have been well documented in the

cardiovascular literature. Among patients with heart failure, hypokalemia is
associated with ventricular arrhythmias and death; however, little is known
about adverse effects of hypokalemia in the CKD population, which is known to
be at high risk for cardiovascular disease in general and sudden death in
particular.

We postulated that lower (<3.5 mmol/L) levels of SK would be associated with

higher risk for mortality in a CKD population. The aims of this study were to
examine the distribution and predictors of SK and association, if any, of SK with
mortality, the composite outcome of death ,and the composite of death or any
cardiovascular event in a CKD cohort.

The risk of hyperkalemia is increased with CKD, and its occurrence increases the
odds of mortality within one day of the event. These findings underscore the
importance of this metabolic disturbance as a threat to patient safety in CKD.

Although treatment of hyperkalemia was frequently suboptimal, no serious

arrhythmias and no deaths complicated management of 242 episodes of severe
hyperkalemia. A narrowly targeted effort to improve physician management of a
disorder with discrete treatment options did not improve therapy.

24
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