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Back to Journal »International Journal of Nephrology and Renovascular disease» Volume 14

Author Mira FS, Costa Carvalho J, Almeida PA, Pimenta AC, Alen Coutinho I, Figueiredo C, Rodrigues L, Sousa V, Ferreira E, Pinto H, Escada L, Galvão A, Alves R

Published on December 3, 2021, Volume 2021: 14 pages, pages 421-426

DOI https://doi.org/10.2147/IJNRD.S345898

Single anonymous peer review

Editor approved for publication: Prof. Pravin Singhal

Filipe S Mira,1,2,* Jóni Costa Carvalho,3,* Patricia Amaral de Almeida,4 Ana Carolina Pimenta,1 Iolanda Alen Coutinho,3 Carolina Figueiredo,1 Luís Rodrigues,1,2 Vítor Sousa,2,5 Emanuel Ferreira ,1,2 Helena Pinto,1,2 Luís Escada,1,2 Ana Galvão,1,2 Rui Alves1,2 1Department of Nephrology, University Hospital of Coimbra, Coimbra, Portugal; 2Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 3 Department of Allergy and Clinical Immunology, Coimbra University Hospital, Coimbra, Portugal; 4 Internal Medicine, Figueira da Foz Hospital, Figueira da Foz, Portugal; 5 Coimbra, Portugal Department of Pathological Anatomy, University Hospital of Bracoimbra* These authors have contributed equally to this work. The development of a vaccine to prevent the COVID-19 outbreak has achieved very positive results, but there have also been some unexpected side effects. The BNT162b2 SARS-CoV 2 vaccine has rare side effects. Case introduction: We introduced a 45-year-old female patient who developed acute kidney injury one week after the second vaccination of BNT162b2 SARS-CoV 2 and required emergency hemodialysis. She also developed macular rash on her lower limbs and palms. A kidney biopsy was performed 10 days after vaccination, and the diagnosis was acute interstitial nephritis and cellular acute tubular necrosis. The patient received 3 pulses of corticosteroids and then took prednisolone daily. We witnessed clinical improvement after 4 days of initial corticosteroid treatment, with gradual recovery of renal function and discontinuation of hemodialysis. After 2 weeks, the patient's renal function recovered. Immune phenotype analysis was performed, and hypersensitivity to vaccines and polyethylene glycol excipients was diagnosed. Conclusion: The patient may have an acute reaction to the vaccine. In this case, the symptoms seem to be significantly related to their vaccination. Although this situation has good results, clinicians and patients must be aware of these side effects. Keywords: acute kidney injury, acute interstitial nephritis, proteinuria, COVID-19 vaccine

Since the start of the 2019 Coronavirus (COVID-19) pandemic, people have longed for a risk-free and effective vaccine that can prevent a new wave of diseases. In the past few months, with the explosive development of several vaccines, this has become possible, although their side effects are still a problem, and some are still unknown. Most vaccines produced in history are harmless and cause only minor side effects, but in rare cases, they can cause glomerular disease and acute kidney injury (AKI). 1 Currently, 4 vaccines have been approved to prevent COVID-19: BNT162b2, mRNA-1273 (both mRNA vaccines), JNJ-78436735 and ChAdOx1 nCoV-19 vaccines (both viral vector vaccines). Many side effects common to all SARS-CoV 2 vaccines have been described, but most of them seem to be of short duration and have minimal clinical effects, such as fever, muscle pain, chills, and pain at the injection site. A small number of cases have reported renal side effects related to AKI, proteinuria, and the need for hospitalization after vaccination with BNT162b2 vaccine and ChAdOx1 nCoV-19 vaccine. 2-6 Although hemodialysis is necessary in some cases, most patients return to baseline serum creatinine values ​​3 months after the initial vaccination. There are also two cases of new vasculitis after mRNA-1273 (Moderna) vaccine, which improved after immunosuppression and plasma exchange. 7 A recent case series reported a greater association between mRNA vaccines (BNT162b2 and Moderna) and kidney disease, manifested mainly in minimal change disease and IgA nephropathy. 8,9 AIN seems to be present in only a few cases. We introduced a patient with AIN who required hemodialysis. After being injected with the BNT162b2 COVID-19 vaccine, we described immunological research and the examination to determine the stimulating excipients.

A 45-year-old white female presented to the emergency room for 1 week due to persistent discomfort related to anorexia, nausea, vomiting, and decreased urine output the day before admission. These symptoms started 24 hours after the second dose of BNT162b2 COVID-19 vaccine. The patient denied taking any new drugs in the past few months. She denied fever and any cardiopulmonary symptoms.

Due to a multinodular goiter, she received chronic medications after total thyroidectomy, including levothyroxine. No history of hypertension or kidney disease (previous laboratory results showed that serum creatinine was 0.85 mg/dL 4 months ago).

She does not smoke and does not drink often. No history of taking any homeopathic medicine/herbal tea.

On physical examination, the patient's body temperature is not high, blood pressure is 126/78mmHg, and the peripheral blood oxygen saturation of indoor air is 98%. The patient appears to be normal blood volume and does not have orthostatic hypotension. She said that her breathing was stinky, like a "festering wound", and there were pimples on her lower limbs, mainly on the knees, thighs and palms, without itching.

The initial blood test (Table 1) showed normal cell orthochromic anemia with normal platelets. Serum creatinine levels are severely elevated (18.4 mg/dL, normal range: 0.5-0.9 mg/dL) accompanied by hyperkalemia and increased erythrocyte sedimentation rate (58 mm/1h). Chest X-ray examination was normal, and renal ultrasound showed enlarged kidneys (both 14-15 cm) with no obvious structural abnormalities. Her arterial blood gas analysis revealed metabolic acidosis (pH 7.157 and HCO3 7.6 mmol/L), normal lactic acid, and an anion gap of 16. Table 1 Preliminary laboratory results

Considering these results, the patient was transferred to the central hospital to start hemodialysis. A central venous catheter was placed, and there were no complications during the treatment. Enter the nephrology department for a comprehensive immune evaluation (Table 2), including antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), protein electrophoresis, and C3 and C4 serum levels, all of which are normal. Urinalysis Shows that there are red blood cells and white blood cells and proteinuria in the urine. The proteinuria collected in the 24-hour urine was 531 mg/24 hours. Table 2 Complete immunity assessment and specific tests

Table 2 Complete immunity assessment and specific tests

The patient maintained a low urine output for the first three days, so a kidney biopsy was performed (10 days after the onset of symptoms).

The glomerulus is slightly congested, but the basement membrane is not obvious, there is no mesangium or too much cells in the capillaries. The tubular interstitial compartment showed mild AIN, edema, and acute tubular necrosis (ATN). The interstitial infiltration is mainly monocytes, but focal areas of eosinophils are also observed. Interstitial fibrosis and tubular atrophy (IFTA) is estimated to involve 20% of the renal cortex (Figure 1A, C, and D). IgM, IgG, IgA, C3, Kappa and Lambda light chain immunofluorescence are all negative. Electron microscopy showed that the insignificant focal podocyte foot processes disappeared, and there were no significant findings in other aspects (Figure 1B). Figure 1 Renal biopsy results. (A) The glomerular compartment is not significant: the capillary wall is normal, there is no mesangium or too many cells in the capillary, and the renal cortex is inflamed ((A) Periodic acid-Schiff staining, original magnification, 200 times; (B) Electron microscopy showed that the focal foot process of podocytes disappeared without changes in the glomerular basement membrane; (C) The renal cortex showed mild interstitial edema and inflammation and acute tubular injury. (H&E staining, original magnification Magnification, 100 times); (D) Normal capillary wall, no mesangium or too many cells in the capillaries (Silver Jones stain, original magnification, 200 times).

Figure 1 Renal biopsy results. (A) The glomerular compartment is not significant: the capillary wall is normal, there is no mesangium or too many cells in the capillary, and the renal cortex is inflamed ((A) Periodic acid-Schiff staining, original magnification, 200 times; (B) Electron microscopy showed that the focal foot process of podocytes disappeared without changes in the glomerular basement membrane; (C) The renal cortex showed mild interstitial edema and inflammation and acute tubular injury. (H&E staining, original magnification Magnification, 100 times); (D) Normal capillary wall, no mesangium or too many cells in capillaries (Jones Menamide silver staining, original magnification, 200 times).

Methylprednisolone starts with 500 mg pulses 3 times a day, followed by 50 mg prednisolone (1mg/kg). Five days after treatment, her urine output gradually increased. The central venous catheter was removed at this time. The rash subsided the next day after cortical treatment.

A blood test at the time of discharge (15 days after admission) showed a decrease in serum creatinine by 4.4 mg/dL, a normal ion pattern, and a hemoglobin of 10.7 g/dL. The ratio of protein to creatinine in the urine sample was 193 mg/g.

The patient returned to the clinic 4 days later and the clinical condition was good. Laboratory examination showed no anemia, and serum creatinine was 1.9 mg/dL. Two weeks later, her kidney function had returned to normal (1.02 mg/dL), and her proteinuria was 33 mg/g. Repeated kidney ultrasound examination showed no structural abnormalities in a normal-sized kidney.

She continued to undergo nephrology follow-up every three months and gradually stopped corticosteroids.

Two months after being discharged from the hospital, the patient was evaluated in the Allergy and Clinical Immunology Department. The drug-induced hypersensitivity reaction (HSR) was considered, and the epidermal test, basophil activation test (BAT) and lymphocyte transformation test (LTT) were carried out. The epidermal test includes BNT162b2 SARS-CoV-2 vaccine solution diluted 10% and 30% with saline, polyethylene glycol (PEG) 1500 solution (100 mg/mL) polysorbate 20 and 80.10 with a concentration of 5% petrolatum. The readings were taken at 48 hours, 72 hours, and 96 hours, and all the allergens tested were negative. BAT and LTT were performed with vaccine solution and PEG 1500 (100 mg/mL). The method and concentration (4 times five-fold dilution) are based on existing literature. 11-13 If the irritation index of two different concentrations is higher than 2, the result is considered positive. The BAT result was negative, while LTT was positive for the vaccine solution and PEG 1500.

AKI associated with vaccination has previously been associated with influenza vaccine. 1 Regarding the COVID-19 vaccine, there have been cases of AKI associated with proteinuria, especially the BNT162b2 COVID-19 vaccine. 3-5 In some of these cases, hemodialysis was performed due to oliguria AKI and fluid overload, but each case reported recovery of renal function at least 3 months after the initial vaccination. In our case, the patient showed initial proteinuria and AKI, mainly ATN and AIN. The association between vaccines and AKI can be based on time relationships and LTT results, because symptoms appear approximately 24 hours after vaccination, and AKI appears one week later. The patient's disease was completely relieved a few days after starting corticosteroids, which is consistent with previous case reports of corticosteroids. 4,5

BAT quantifies the degranulation of basophils in vitro after drug-specific stimulation. Basophils are related to other mechanisms of IgE and immediate HSR. 11 In clinical practice, the categories of hypersensitivity reactions may overlap, especially when mixed mechanisms are involved, so even if the clinical history indicates a delayed response, BAT should be performed. 11 A negative result indicates the unlikely implication of the IgE-mediated mechanism.

LTT determines in vitro whether a patient has a drug-specific T cell response to a specific substance. Significant activation and proliferation of T cells after direct drug binding indicates that the result is positive, so it may be allergic to the drug. 12,13 LTT is a useful diagnostic procedure that can be used to diagnose hypersensitivity reactions caused by various types of drugs, including AIN. 14-17 In our case, in theory, any compound in the vaccine could cause HSR. Excipients are usually the cause and are not the active ingredient. 18 PEG 2000 is pointed out as the main allergenic component of BNT162b2 SARS-CoV-2 vaccine. Therefore, LTT is PEG 1500 made with vaccine solution and excipients (PEG has an approximate molecular weight because PEG 2000 cannot be used in our center’s testing ). 18 The positive results of LTT for PEG and vaccine solution support the participation of T cells, especially for PEG-specific T cells. Therefore, it is pointed out that according to Gell and Coombs classification, it belongs to type IV hypersensitivity. 18,19 Koenig et al. classified AEFI (adverse events after immunization) based on immune response. Our case may be included in "classical adaptive immune-mediated diseases" (mainly involving B cells and T cells and primary Lymphoid organs) or "innate immune-mediated diseases" (cells that affect the innate immune system) category. 28

For the participation of T cells, various potential immune pathogenic mechanisms have been proposed.

The hypothesis of delayed HSR related to antigenic mechanisms (such as direct binding or conjugation of vaccine components and host proteins to antigen-specific lymphocytes) is consistent with the time of symptom onset and the test results seen in our case. The drug-induced AIN-like reaction seems to be the most likely cause of the patient’s symptoms.

We can speculate that T cell-mediated damage is part of the abnormal innate and subsequent adaptive immune response. 20-23 mRNA expressing SARS-CoV-2 spike protein and PEG as immunogenic substances can trigger HS-like reactions by itself. 21,24 The exaggerated reactogenicity may cause a series of immune events, and eventually lead to abnormal activation of the immune system, leading to the activation of the pro-inflammatory cascade and immune pathways. These pathways may play a role in the development of AKI as a systemic reaction. 20,21,24

On the other hand, we may consider, despite the remoteness, the recurrence of immune diseases after mRNA vaccines, as described in several reports, including minor changes in the disease and membranous nephropathy. 25-27 However, our patient has no history of kidney disease.

This serious AKI that leads to the need for hemodialysis can be demonstrated not only by the degree of AIN, but also by the presence of ATN in a kidney biopsy. In addition, tubular proteinuria exists in both ATN and AIN, which can justify the existence of proteinuria. In our patients, 20% of IFTA was also found, which may be a confounding factor and may be related to previously unrecognized kidney disease. Since a complete immune assessment is normal, and the patient's kidney size and function have been restored, no further diagnostic tests are required.

This case raises awareness of the previously reported potential serious side effects of the BNT162b2 COVID-19 vaccine. The difference is that renal failure requires hemodialysis. 4 Renal function was completely relieved after corticosteroid treatment, and there was no recurrence after the gradual withdrawal of the drug.

In addition, as far as we know, this is the only study that correlates this systemic symptom with an increase in T cells in the immune phenotype, not only with the vaccine itself but also with PEG.

This case reveals some questions: If a patient wants to receive a third dose of vaccine, should we advise her to apply for a different vaccine? Is she at risk of having a similar reaction to the same vaccine or other vaccines that may cause similar side effects (such as the flu vaccine)?

Since there is little information on this topic, and considering the possibility of reproducibility of HSR after re-vaccinations, as in any drug-induced AIN, it is recommended to avoid the use of the culprit drugs. Therefore, it is recommended to choose COVID-19 vaccines with different mechanisms and excipients.

With more reports of similar cases, the symptoms described in our clinical cases seem to be related to the BNT162b2 COVID-19 vaccination and may represent major side effects that clinicians and patients must be aware of.

AIN, acute interstitial nephritis; AKI, acute kidney injury; ATN, acute tubular necrosis; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; BAT, basophil activation test; HSR, Hypersensitivity; IFTA, interstitial fibrosis and renal tubular atrophy; LTT, lymphocyte transformation test; PEG, polyethylene glycol.

The approval of the ethics committee was abandoned.

Written consent for the release of this information was obtained from the study participants.

There is no funding to report.

Filipe S Mira and Jóni Costa Carvalho are the co-first authors of this study. The authors declare that they have no competing interests.

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