Renal salt wasting syndrome in a patient with COVID-19; a case report and review of the literature

Introduction: Cerebral salt wasting or renal salt wasting (RSW) syndrome, may be more common than syndrome of inappropriate antidiuretic hormone secretion (SIADH) and may even occur in the absence of cerebral disease. We report a case of RSW in a Bangladeshi patient positive for COVID-19 without clinical cerebral disease. Case Presentation: A 53 years-old Bangladeshi patient presented with history of chest pain and acute MI. On examination, the patient was conscious, alert, vitally stable, chest with fine bilateral basal crepitation and heart with additional S3 sound and abdomen was lax with no organomegaly. There was no lower limbs oedema. His serum creatinine; 68 umol/L, urea; 3.4 mmol/L, K; 4.7 mmol/L, sodium; 135 mmol/L, uric acid; 141 mmol/L and phosphate was 1.3 mmol./L. Echocardiography (ECG) revealed anterior lateral wall STEMI. PCI was done for LAD. ECG revealed ejection fraction (EF) 10-15 %. Nasopharyngeal swab for COVID-19 was positive. Serum sodium decreased from 135 to 108 with signs of hypovolemia. Work up for hyponatremia revealed serum osmolality of 237 mOsm/kg, urine NA; 109 mmol/L, urine osmolality; 295 mOsm/kg, urine uric acid; 685 umol/L, and urine phosphate; 6.5 mmol/L. Additionally serum T3, T4, TSH and serum basal cortisol were normal. The patient received normal saline infusion and fludrocortisone and serum sodium increased to 134 mmol/L. Our patient had all the important clinical and laboratory characteristics of RSW in the absence of cerebral disease which include hyponatremia associated with hypovolemia, high urinary sodium excretion, increased fraction excretion of phosphate and persistent hypouricemia with increased fractional excretion of urate after correction of hyponatremia and with normal renal, adrenal and thyroid functions. Furthermore, there was a prompt response to saline replacement and fludrocortisone and steady improvement in serum sodium with negativity and improvement of COVID-19. Our diagnosis was RSW in the absence of cerebral disease and to our knowledge; this is the first case of RSW in a patient with COVID-19 in the literature. Conclusion: RSW should be considered in patients with COVID-19 with hyponatremia and absence of cerebral disease. We suggest changing cerebral salt wasting to the more appropriate term RSW.


Introduction
Cerebral salt-wasting syndrome (CSW), or renal salt wasting (RSW) described by Peters et al in 1950 (1), and may be more common than syndrome of inappropriate antidiuretic hormone secretion (SIADH).CSW syndrome is defined by the development of extracellular volume depletion due to a renal sodium transport abnormality in patients with intracranial disease and normal adrenal and thyroid function (1,2).CSW may even occur in the absence of cerebral disease (3)(4)(5).As such, it may be more appropriately termed RSW syndrome.
COVID-19 -the disease caused by the coronavirus that's led to the global pandemic -is known to damage the lungs.But, as more people become infected, more understanding of the disease emerges.Researchers are finding that this coronavirus -officially called SARS-CoV-2-can also cause severe and lasting harm in other organs, including the heart and kidneys (6)(7)(8)(9)(10)(11)(12).We report a case of RSW syndrome in a Bangladeshi patient positive for COVID-19 and to our knowledge; this is the first case report of RSW in a patient with COVID-19 in the literature.

Case Presentation
A 53 years-old Bangladeshi patient presented to Al-Adan hospital casualty, Kuwait on 28/4/2020, with a history of chest pain and acute myocardial infarction.On examination, the patient was conscious, alert, body mass index was 30 kg/m 2 , blood pressure 113/57 mm Hg, pulse 84 b/m, temperature 37.3 o C, chest with fine bilateral basal crepitation and heart with additional S3 sound and abdomen was lax with no organomegaly.There was no lower limbs edema.His serum creatinine ;68 umol/L, urea; 3.4 mmol/L, K; 4.7 mmol/L, sodium; 130 mmol/L, uric acid; 141 mmol/L, ALT; 39 IU/L, AST; abnormality that is undergoing dramatic changes in terms of its diagnostic approach and clinical outcomes (13).
In CSW or RSW, abnormalities in the proximal tubule result in excessive sodium losses, which lead to decreased effective circulating volume.This activates baroreceptors, which increase antidiuretic hormone (ADH) secretion.This results in water conservation and a return to an equilibrated state.In contrast, SIADH primarily occurs due to an inappropriate euvolemic rise in ADH secretion (14).In our case the abnormalities most probably in proximal tubule due to increased urinary sodium excretion with increased FEurate, urea and phosphate.
Differentiation of this disorder from the SIADH, a common cause of hyponatremia, can be difficult because both can present with hyponatremia and concentrated urine with natriuresis.However, distinguishing between the two disorders is important because treatment options differ.Attention to the volume status of the patient is important in making the distinction.Failure to distinguish CSW syndrome from SIADH in a patient with hyponatremia who has brain injury could lead to inappropriate therapy with fluid restriction.RSW should be considered a discrete clinical entity and may be more common than perceived (4).It should also be considered in patients without cerebral disease (3,15).
The relationship among serum urate, FEurate, and hyponatremia in CSW syndrome is unclear.FEurate may remain elevated even after correction of hyponatremia in patients with CSW syndrome.This is distinct from SIADH, in which FEurate returns to the reference range once the hyponatremia is corrected (4,15).The physiologic basis for this in CSW syndrome may be related to the receptormediated processing of sodium and urate in the proximal tubule, which may be defective in this syndrome.The physiologic basis for hypouricemia in SIADH remains unclear.
The abnormalities in proximal tubular transport may be secondary to a plasma natriuretic factor that reduces proximal and, possibly, distal sodium transport in renal salt-wasting syndrome.It may also inhibit the tubular transport of urate, phosphate, and urea in addition to sodium (16).
The cause of kidney involvement in COVID-19 is likely to be multifactorial, with cardiovascular comorbidity and predisposing factors (such as sepsis, hypovolemia, and nephrotoxins) as important contributors (6).
The patient received normal saline infusion 200 mL/h and serum sodium increased to 131 mmol/L and then dropped again to 124 mmol/L and fludrocortisone 0.2 mg tab twice daily (only two doses were given) was initiated with normal saline 60 mL/h and serum sodium increased to 128-129 mmol/L and normal saline stopped when serum sodium became 132 on May 22, 2020 and with follow up serum sodium was 134 on May 30, 2020 (Table 1).Serum electrolytes, BUN, creatinine, urate, and phosphate were determined concomitantly with urine osmolality, sodium, potassium, creatinine, urate, and phosphate at regular intervals during the study.Plasma renine, aldosterone, ADH not were assessed.Our patient had all the important clinical and laboratory characteristic of RSW in the absence of cerebral disease including hyponatremia associated with hypovolemia, high urinary sodium excretion, increased fraction excretion of phosphate (FE phosphate) and persistent hypouricemia with increased fractional excretion of urate (FE urate) after correction of hyponatremia and with normal renal, adrenal and thyroid functions.Furthermore, there was a prompt response to saline replacement and fludrocortisone and steady improvement in serum sodium with improvement and negativity of COVID-19 (Table 1).Our diagnosis was RSW in the absence of cerebral disease and to our knowledge, this is the first case report of RSW in a patient with COVID-19 in the literature.

Hyponatremia is the most common electrolyte 3
Table 1.Time course of clinical and laboratory examination of our patient Variables Autopsy data (7), indicates that the endothelium is affected in the lung and in the kidney, where it is probably responsible for proteinuria.Furthermore, virus particles were reported to be present in renal endothelial cells, indicating viremia as a possible cause of endothelial damage in the kidney and a probable contributor to AKI (7).
Other contributors to AKI might include rhabdomyolysis, macrophage activation syndrome, and the development of microemboli and microthrombi in the context of hypercoagulability and endotheliitis (7,12).
Maesaka et al (13) identified the various causes of hyponatremia by determining FEurate to propose an algorithm to approach hyponatremic conditions.In this algorithm, conditions with low FEurate <4% include extrarenal salt losses with normal kidney function, Addison's disease, and edematous states such as heart failure, cirrhosis, and nephrosis.Normal FEurate of 4%-11% include psychogenic polydipsia and reset osmostat (RO), and increased FEurate >11% SIADH/hydrochlorothiazide and C/RSW.SIADH can be differentiated from C/RSW by correcting the hyponatremia by any possible means and observing normalization of FEurate in SIADH as compared to being persistently increased in C/RSW.This algorithm greatly simplifies the diagnosis of patients with Addison's disease and RO.
The report of C/RSW occurring in patients without cerebral disease has led to proposal to change CSW to RSW (13).Maesaka et al (13) utilized this algorithm and differences in physiologic response to isotonic saline infusions between SIADH and RSW to evaluate hyponatremic patients from the general medical wards of the hospital.Isotonic saline does not induce excretion of dilute urines or correct the hyponatremia in SIADH as compared to inducing excretion of dilute urines and correction of the hyponatremia in RSW.
In the absence of cerebral disease and by exclusion of other reported causes that may be cause RSW as chemotherapy with cisplatin, myeloproliferative disorders, and post-operative fracture (13,16) and as our patient is positive for COVID-19, hence we suggest that COVID-19 is the cause of RSW by affecting proximal kidney tubule transport through SARS-CoV-2 which can directly infect the renal tubular epithelium and podocytes through an angiotensin-converting enzyme 2 (ACE2)-dependent pathway (8.9) and other different mechanism involves SARS-CoV-2-related immune response dysregulation, as indicated by observed lymphopenia and cytokine release syndrome (cytokine storm) (10,11).

Conclusion
In conclusion, RSW should be considered in patients with COVID -19 with hyponatremia and absence of cerebral disease.We suggest changing CSW to the more appropriate term RSW.
and subsequent acute kidney injury (AKI).Similarly, left ventricular dysfunction might lead to low cardiac output, arterial under-filling, and kidney hypoperfusion.

Implication for health policy/practice/research/ medical education
Renal salt wasting syndrome should be considered in patients with COVID -19 with hyponatremia and absence of cerebral disease.