The outbreak of the novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 in China is rapidly spreading worldwide. To date about more than four million cases were reported worldwide with 7% mortality from the disease as per the World Health Organization.
Extrapulmonary manifestations of COVID-19 are described in the literature including renal involvement, mainly in the form of acute kidney injury.
We report three cases of distal renal tubular acidosis (dRTA) in patients with COVID-19 infection picked up on the initial days of admission to the intensive care unit (ICU).
The characteristic chemistry findings of our patients were hypokalemia, and normal anion gap metabolic acidosis with inappropriately alkaline urine was found as an isolated defect or with mild renal impairment. The patients showed evidence neither of clear causes of RTA, nor taking any medication known to cause this metabolic acidosis.
RTA has not been reported before in association with COVID-19. We believe this is the first description of cases with RTA associated with COVID-19.
These cases emphasize the importance of RTA in the context of COVID-19 infection as the renal tubules are the main buffer in the body.
With COVID-19 infection and accompanying acidosis there will be no efficient buffering system owing to the loss of urine acidification, with resultant poor prognosis.
A 42-year-old male presented to the emergency room with a history of fever and progressive shortness of breath for two days. The patient had a history of contact with an unwell family member who displayed symptoms of COVID-19. There was no recorded history of any previous renal disease.
On examination, the patient’s temperature was 38°C and he was found to have a pulse rate of 110/min and systemic blood pressure (BP) of 126/65 mm Hg. He was tachypneic and severely hypoxic, with a respiratory rate of 46/min and pulse oximetry on nonrebreather mask oxygen of 67%. Chest examination showed bilateral crepitations. The remainder of his clinical examination was non-contributory. Supine chest X-ray showed bilateral peripheral infiltrates. Laboratory findings and arterial blood gas (ABG) report are shown in Table 1.
He was intubated and started on low-tidal volume lung protective strategy in the emergency room. Broad-spectrum antibiotics (tazocin and vancomycin) were started empirically. Later, his COVID-19 polymerase chain reaction (PCR) was found to be positive, and antiviral coverage including (hydroxychloroquine, azithromycin, and lopinavir/ritonavir) was started. He was admitted to the ICU and put on prone positioning to improve his oxygenation due to low PO2/FiO2 ratio of 60 mm Hg. On day 4, the patient had a severe hypoxemic respiratory failure for which veno-venous extracorporeal membrane oxygenator (VV-ECMO) was cannulated for 13 days. Therapeutic plasma exchange was started to treat the cytokine storm triggered by the novel coronavirus. On day 6, the patient had intravenous tocilizumab to ameliorate the cytokine storm besides regular plasma exchange, as per our ICU protocol.
During his ICU course, point of care ultrasound revealed distended inferior vena cava and right ventricle dilatation with mild dysfunction. Hemodynamics were maintained without vasopressor support and he had normal urine output with serum creatinine of 140–160 umol/L. Hyperchloremia was noticed before starting antiviral therapy and chemistry work up was diagnostic of dRTA. The patient was started on continuous renal replacement therapy (CRRT) with sorbent filter to treat his metabolic acidosis as it was resistant to high doses of intravenous bicarbonate and to help removal of fluids and inflammatory cytokines. Renal ultrasound and Doppler were normal. The metabolic acidosis improved only with CRRT (Figure 1).
A 47-year-old male known to have diabetes mellitus presented with fever, shortness of breath, and cough. There was no history of renal disease.
Upon admission, the patient appeared ill with severe respiratory distress. His measured temperature was 36.6°C, pulse rate was 93/min, systemic BP was 105/59 mm Hg, respiratory rate was 38/min and pulse oximetry was 88% on room air. Bilateral crepitations were present over both lungs. Physical examination was otherwise normal. Supine chest X-ray showed bilateral peripheral infiltrates. Laboratory findings and ABG report are shown in Table 1.
He was intubated due to high oxygen requirement necessitating admission to the ICU. Antiviral coverage for COVID-19 including hydroxychloroquine, azithromycin, and lopinavir/ritonavir was started, in addition to total plasma exchange as per our hospital protocol to treat the cytokine storm. Hyperchloremia secondary to dRTA was diagnosed which was noticed prior to antiviral regimen and managed by intravenous bicarbonate infusion. (Figure 1) However, after three days, the patient died of refractory shock and hypoxemia.
A 64-year-old male presented to the emergency department with right side gluteal pain and scrotal swelling for five-days. Vital signs examination revealed a temperature of 36.6°C, a pulse rate of 93/min, a BP of 131/66 mmHg, and oxygen saturation of 96% on room air. Scrotal, perianal and gluteal areas were inflamed with pustular discharge. Chest, cardiovascular and abdomen examinations were unremarkable. The patient had an emergency surgical debridement in the operation room, but weaning him from the mechanical ventilator proved to be difficult, so he was admitted to ICU. The patient had developed severe acute respiratory distress syndrome, acute coronary syndrome non-ST elevation myocardial infarction, and COVID-19 PCR confirmed positive.
Antiviral coverage for COVID-19 included hydroxychloroquine, azithromycin, and lopinavir/ritonavir, as per our local protocol, in addition to broad-spectrum antibiotics including imipenem, vancomycin, and clindamycin.
The inflammatory markers including C-reactive protein, D-dimer and creatine kinase were elevated. Hyperchloremia with normal anion gap was noticed prior to the start of antiviral medications as shown in Table 1. dRTA was entertained which was refractory to intravenous sodium bicarbonate therapy. CRRT with sorbent filter was initiated because of the acute kidney injury and refractory acidosis which led to significant improvement of the acidosis (Figure 1).
Informed consent was obtained from the patients and relatives for the publication of these case reports.
We have described three cases of distal RTA in patients with confirmed COVID-19 infection.
The metabolic acidosis was of normal anion gap with alkaline urine. No other causes of hyperchloremic acidosis such as diarrhea, intestinal or pancreatic fistula or surgical drains were present. None of the three patients showed evidence of generalized Fanconi syndrome. The presence of alkaline urine in the face of severe acidosis with normal anion gap was diagnostic of dRTA.
Neither osteomalacia, short stature, nephrolithiasis nor nephrocalcinosis as chronic features of RTA was present, which make an inherited form unlikely. Autoimmune disease screening was negative, and the patients were not taking any medications that can cause RTA. Antiviral therapy was started after the patients developed normal anion gap metabolic acidosis and the drugs lopinavir/ritonavir are not known to cause RTA, unlike Tenovir, which is reported to cause RTA and is not used.
The elevated urine pH, hypokalemia, and absence of generalized Fanconi syndrome alongside the acquired nature of the disease made it most likely that dRTA is associated with COVID-19.
RTA includes a heterogeneous group of disorders in which acidosis is due to tubular defect rather than impaired glomerular filtration rate. A simple classification of RTA into proximal and distal types is most useful as it relates to the site of the underlying renal tubular defect.
In proximal RTA, there is a failure to reab-sorb filtered bicarbonate along the proximal tubule, which can be demonstrated by giving an exogenous bicarbonate load and measuring a high fractional bicarbonate excretion (>15%). Initially, the pH can be inappropriately high (>5.5), but in severe forms there will be a sufficiently low plasma bicarbonate concentration and thus filtered bicarbonate so that the pH falls to <5.5.
Proximal RTA is seen most commonly as part of a generalized proximal tubular defect as in the renal Fanconi syndrome which may be familial or toxic in origin. Isolated proximal RTA is extremely rare and can occur in association with ocular abnormality due to mutations of the electrogenic sodium bicarbonate co-transporter or in association with osteopetrosis and cerebral calcification due to mutations of the enzyme carbonic anhydrase II.
dRTA is characterized by normal anion gap metabolic acidosis, hypokalemia, nephrocalcinosis, nephrolithiasis (related to the inability to acidify urine), hypercalciuria and low urine citrate, loss of calcium from bones.
dRTA is characterized by a decrease in net H+ secretion in the renal collecting tubule resulting in urine pH >5.5 in the presence of systemic acidosis is diagnostic.
An incomplete form of dRTA exists in which there is no systemic acidosis, but urine fails to acidify (pH >5.5) following exogenous acid load with ammonium chloride or during Furosemide-based urine acidification test. dRTA often presents as an isolated renal tubular defect in association with hypokalemia and sometimes muscle weakness and paralysis.
More chronic forms of dRTA can be associated with bone disease, nephrolithiasis, and calcium-phosphate nephrolithiasis. Inherited forms of RTA are rare and due to mutations in the electro-neutral anion exchanger and the electro-gradient (positive) pump (H+-ATPase). More commonly, dRTA is acquired and associated with auto-immune disease or dysproteinemias. A common association is with Sjogren’s syndrome although it has also been described in systemic lupus erythematosus, rheumatoid arthritis, Takamasa’s arthritis, chronic active hepatitis, primary biliary cirrhosis and other auto-immune diseases as well as idiopathic hypergammaglobulinemia. dRTA has been reported in HIV infection and as an adverse side effect of antiretroviral (HAART therapy).
COVID-19 infection is a multi-system disease that affects many organs. Kidneys are affected in 5%–42% of patients with COVID-19. Renal manifestations of COVID-19 include proteinuria and hematuria. However, according to the severity of illness, it can take a form of AKI due to hypovolemia, cardiorenal syndrome, the systemic inflammatory response by the cytokines release storm, tubular cytopathy, collapsing glomerulopathy or drugs related nephrotoxicity. AKI in hospitalized patients of COVID-19 can be associated with increased in-hospital mortality.
Our patients in this case series report had a different kind of kidney involvement. We believe this is a direct effect of the COVID-19 virus cytokine storm effect on the renal tubules giving distal RTA, as other causes of dRTA have been excluded.
As the kidneys are the main buffer of the body if affected and become unable to excrete acid in the face of any other form of acidosis, the prognosis will be worse. In particular, several cases have been reported to have acute right ventricular failure for which acidosis is detrimental to be corrected. Physicians should be alert to the development of tubular defects in COVID-19 patients to treat all forms of acidosis properly.
Our conclusion is that dRTA can be one of the manifestations of severe COVID-19 infection which is reported for the first time since the pandemic of the virus. Physicians should be alert to the development of tubular defect in COVID-19 patients to treat all forms of acidosis properly.
Conflict of interest:
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