Hyponatremia in Chronic Kidney Disease

Introduction

Prevalence of Hyponatremia has been documented from 6% to 44% in general population but not seen specifically in chronic kidney disease (CKD) [1, 2]. Although if we see specifically in dialysis population then hyponatremia is not uncommon [3, 4]. Lot of literature has been written on subject of Hyponatremia still it seems lot more is needed because of its clinical importance. The wide variety of its presentation, association, and outcome keep pressing clinician to write more on this subject. The most vulnerable population identified to develop hyponatremia so far is elderly population because of increased comorbidity burden in this age group and impaired excretion of salt [5]. After this, the second vulnerable population group is CKD and Congestive heart failure (CCF) patients, as there is tendency of retaining excessive water and there is also frequent use of diuretics in these patients [6, 7]. The osmotic balance maintained mainly by sodium concentration with the help of aquaporin channels, comes under risk when glomerular filtration rate (GFR) declines with progression of CKD [8, 9].

In order to manage hyponatremia patients properly, knowledge of patient’s age, comorbidity, volume status at that time, duration of hyponatremia whether acute or chronic, and drugs which patient has been taking, are required. Based on this, Clinician decides aggressiveness of management plane. Aggressive plane includes use of hypertonic saline (3%saline), opted for acute hyponatremia (<48 hour of duration), or symptoms suggestive of central nervous system (CNS) i.e. confusion, fits, coma etc. Conservative approach mainly includes plain water restriction, salt addition in water and diet, and use of isotonic saline. This is in addition of the treatment of primary disease which is usually associated in clinical setting.

Here caution must be exercised before deciding 3% saline to correct sodium rapidly as this may be proved as counterproductive if sodium corrected rapidly more than what was desired. This rapid overcorrection is manifested clinically as locked-in due to sudden change in serum osmolality in brain [10]. Danger of sodium overcorrection would also be there where patients have volume overload in background of CCF and CKD with hyponatremia and dialysis comes as a rescuer. In this circumstance, dialysis duration with low sodium conductivity is employed [11]. In both of these aggressiveness (using 3% saline and dialysis), risk of overcorrection and thus central pontine myelinosis would always be there if not handled judiciously [12]. Therefor the risk carrying therapy should only be restricted to a very selected group of patients whose neurological symptoms are not otherwise explained.

Methodology

This observational study was conducted at the Indus Hospital and Health Network, Karachi campus from July 2017 to April 2020 after the approval of ethical committee (IRB). All those (age >16 years) of either gender who were admitted under care of various specialties with Hyponatremia (serum sodium<135 meq/L) and renal impairment were enrolled in this study after getting consent. These patients were subjected to detailed history and general physical examination; their demographic were noted and relevant investigations were done. Serum sodium on day of admission, enrollment and on discharged were noted and its severity was categorized as mild (From 130 to 134), moderate (From 125 to 129) and severe (<125 meq/L). Volume status of patient was decided on basis of presence or absence of edema, jugular venous pressure, bibasilar inspiratory crepitation and gallop sound on auscultation at the time of enrollment. Based on these finding, these patients were categorized as hypovolemic, normovolemic, and hypervolemic. Laboratory parameters i.e. serum sodium, urea, creatinine, spot urine sodium, chloride, potassium, urine and serum osmolalities, random blood sugar and echocardiography finding (left ventricular function) were noted in questionnaire. Chronic kidney diseases (CKD) patients were further categorized into five CKD stages with the help of Modified of diet and Renal disease (MDRD) equation. Any surgical procedure/Operation if done was also noted. Diagnosis/Impression of patient and use of hypertonic saline (3%saline) were also noted. Final outcome of patients i.e. those who improved sodium and symptoms, discharge/expired along with total hospital stay was noted in pre-formed questionnaire.

Results

There were a total of 262 patients enrolled in our study; out of which analysis was performed on 171 patients who are established cases of CKD. The female to male ratio was 93/78 (1.19/1). The mean age was 55.8 ± 15.16 years, with a minimum of 16 and a maximum of 86 years. The mean serum sodium and osmolality were as 125.19 ± 5.82 and 298.62 ± 38.13. The most prevalent comorbid was HTN 128 (74.9%), followed by DM 108(63.1%) and IHD 53 (31%). Mild hypernatremia was noted in 56 (32.7%), Moderate 71 (41.5), and Severe 44 (25.7%) patients. From tonicity point, Hypertonic were 81 (47.4%), Hypotonic 51 (29.8%), Normotonic 39 (22.9%). Normovolemic were 44 (25.7%), hypovolemic 80 (46.8%) and hypervolemic 47 (27.5). Total symptomatic hypernatremia out of 171 patients were 23 (13.5%). Left Ventricular dysfunction (LV dysfunction) was seen in 44 (25.7%). Spot urine sodium >20 meq/L was seen in the majority of patients 150 (87.7%).While Urine to serum electrolyte ratio <50% was in 101 (59.1%) patients.

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Analysis was done with a chi-square test to see the relation of CKD stages with the severity of hyponatremia, which was not statistically significant (p-value 0.621),

Discussion

This study was conducted over 171 CKD patients with variable degree of hyponatremia admitted under medical and surgical specialties. The most prevalent comorbid was HTN, followed by DM and IHD. The most common volume status of the patients was hypovolemia. The majority of patients were having moderate degree of hyponatremia. Symptomatic hyponatremia was seen in 23 (13.5%) patients. The overall mortality remained at 9.4%. From a tonicity point in our studied patients, we observed hypertonic hyponatremia was the most often seen phenomenon. This hypertonicity must be contributed by blood sugar and urea as our studied population is CKD and diabetes is significantly present in them. In absence of these osmoles (urea, glucose), another possibility remains the presence of excessive lipids, proteins, methanol, or ethanol in blood. The possibility of the presence of these osmoles becomes more when measured osmolality comes more than calculated osmolality (osmolar gap>10) [13].

The kidney is the major organ in regulating electrolytes and volume in the body which come under stress when its function lowers due to any reason. This results in the accumulation of excessive water in the body and often gives rise to hypervolemia which is sometimes present as hyponatremia [14, 15, 16] but this is not always the case as on several occasions, the volume of the body remains either unchanged or even reduced sometimes along with hypernatremia. In such cases, salt is excreted more through the kidneys and this can be measured objectively with the laboratory test of a spot urine sample. Spot urine value >20 meq/L is suggestive of the salt-losing behavior of kidneys in presence of hyponatremia and patient is not on diuretics [17]. The salt-losing behavior of kidney is not only found in presence of renal failure or patient is on diuretics but also syndrome of inappropriate ADH secretion may cause it. We found in our population the mean value of spot urine sodium >20 meq/L, which is suggestive of significant number of patients lose sodium from kidney. It is also important to mention the predominant volume status of our patients is hypovolemia. (See Table.2) Under normal circumstance (without renal failure), kidney behavior is assumed to conserve sodium and this can be manifestoed as spot urine sodium <20 meq/L. Although this finding cannot be said impossible or false when we deal with CKD patients, but predominant hypovolemic status does not favor it. This query was helped when we studied simultaneously the ratio of sum of the urinary sodium plus potassium divided by serum sodium. The majority of the patients were having ratio less than 50%, which suggest salt conservation behavior of kidneys [18]. The conclusion can be drawn with these findings that although sodium is being lost in majority of patients but aggregated salt (sodium + potassium) is not being lost in majority of the patients.

Hypertension has long been discussed as a cause and consequence of CKD [19]. Therefore its presence significantly in our studied population is not surprising altogether. Other than this, significant presence of diabetes mellitus and Ischemic heart disease (IHD) as comorbidities in our studied population, also contribute for developing hypertension. Several factors related with CKD play their role in the pathogenesis of hypertension i.e overactive sympathetic nervous system, sodium retention, and activated RAAS etc [20]. This increases the risk of cardiovascular mortality. Hypertension has also been established an independent risk factor for CV mortality [21].

The association of congestive heart failure (CHF) with hypernatremia is well established in the literature [22, 23]. Over the years, this has been realized that the mortality in CKD patients increases many fold once ischemic heart disease is present which results in CCF [24]. This occurs primarily secondary to an increased level of vasopressin (AVP) and increased sympathetic activity. This leads to accumulation of water, making it a dilutional form of hyponatremia. This marks the severity of heart failure and plays role in morbidity and mortality [25, 26]. In our studied population, Low LV function has been observed in one-fourth of all populations where hypervolemia was the predominant volume status. This comorbid contributed statistically significant in mortality while studying our studied population.

There is different mortality rate has been seen in hypernatremia but this question remained debatable that this mortality is secondary to hypernatremia or its associated primary disease [27, 28, 29]. Whatever the reason for death among these patients but once CKD is associated, mortality increases. In our studied population, mortality remained around (9%) which is not bad enough especially if we count CKD with comorbidities. Factors found contributing to mortality were symptomatic hypernatremia and low LV function. Further studies need to be done to find actual mortality in context of CKD and factors leading to it.

Conclusion

Hyponatremia is an undoubtedly most frequently observed medical condition in hospitalized patients and often multifactorial in origin. Presence of CKD makes patients even prone for this derangement. Outcome is not often bad when management is preferably done more conservatively on part of hyponatremia and aggressiveness can be reserved for the treatment of primary disease. Severity of hyponatremia do not make prognosis worse while Symptomatic hypernatremia and low LV function do.

Acknowledgement

We gratefully acknowledge Nida Ghori for preliminary analysis of data in this manuscript and Dr. Jhanzeb Khan for incorporation of data in SPSS.

Conflict of Interest

There is no conflict of interest in this study.