Immunosuppressive therapy reduction and early post-infection graft function in kidney transplant recipients with COVID-19


Background: Kidney transplant (KT) recipients with COVID-19 are at high risk of poor outcomes due to the high burden of comorbidities and immunosuppression. The effects of immunosuppressive therapy (IST) reduction are unclear in patients with COVID-19.
Methods: A retrospective study on 45 KT recipients followed at the University Hospital of Modena (Italy) who tested positive for COVID-19 by RT-PCR analysis.
Results: The median age was 56.1 years (interquartile range,[IQR] 47.3-61.1), with a predominance of males (64.4%). Kidney transplantation vintage was 10.1 (2.7-16) years, and 55.6 % of patients were on triple IST before COVID-19. Early immunosuppression minimization occurred in 27 (60%) patients (reduced-dose IST group) and included antimetabolite (88.8%) and calcineurin inhibitor withdrawal (22.2%). After SARS-CoV-2 infection, 88.9% of patients became symptomatic and 42.2% required hospitalization. One patient experienced irreversible graft failure. There were no differences in serum creatinine level and proteinuria in non-hospitalized patients before and post-COVID-19, whereas hospitalized patients experienced better kidney function after hospital discharge (P=0.019). Overall mortality was 17.8%. without differences between full- and reduced-dose IST. Risk factors for death were age (odds ratio [OR]: 1.19; 95%CI: 1.01-1.39), and duration of kidney transplant (OR: 1.17; 95%CI: 1.01-1.35). One KT recipient developed IgA glomerulonephritis and two ones experienced symptomatic COVID-19 after primary infection and SARS-CoV-2 mRNA vaccine, respectively.
Conclusions: Despite the reduction of immunosuppression, COVID-19 affected the survival of KT recipients. Age of patients and time elapsed from kidney transplantation were independent predictors of death . Early kidney function was favorable in most survivors after COVID-19.

Keywords: COVID-19, kidney transplant, immunosuppressive therapy, graft function, proteinuria, mortality, transplant, SARS-COV-2, reinfection


Since SARS CoV-2 infection was first identified in December 2019, the pandemic spread quickly around the world, with a disruptive impact on social and economic life. This virus yielded several new challenges to our healthcare systems that had to cope with an increased rate of morbidity and mortality among the most vulnerable populations [1]. Kidney transplant (KT) recipients are a subset of the population at high risk of severe COVID-19 due to the high burden of comorbidities and the cumulative side effects of immunosuppressive therapy (IST) [2]. Data collected so far show that transplant recipients are extremely susceptible to the SARS-CoV-2 infection, much more than the general population [3, 4]. The causes are multiple, but principally revolve around the use of long-term IST. 

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AKI in hospitalized patients with COVID-19: a single-center experience

Dear Editor,

since December 2019, the COVID-19 pandemic is straining hospitals and nephrology services worldwide. Although this disease manifests mostly with pneumonia, acute kidney injury (AKI) is recognized as a common complication in patients with severe manifestations of COVID-19. The pathogenesis of COVID-19 is still unclear but recent evidence supports a multifactorial etiology [1]. Generally, kidney involvement following SARS-CoV-2 infection is proportionate to the gravity of the infection and is commonly diagnosed in hospitalized patients with lung involvement [2]. As in another clinical scenarios, kidney injury is independently associated with morbidity and mortality in patients with SARS-CoV-2 infection [3,4].

The distribution of AKI in patients with COVID-19 is extremely variable across countries [5]. The first reports from China described a low prevalence of AKI in hospitalized patients [6] but subsequent evidence, coming from the USA and Europe, suggested a higher kidney involvement, especially in the intensive care setting [7] and among vulnerable patients [8]. Few studies have estimated the rate of AKI in hospitalized patients admitted to non-intensive care units in Italy. It ranges between 13.7-22.6% [911] and is similar to the prevalence detected in other European countries (4.5-22%) [1214]. In order to broaden the knowledge of this phenomenon, we report the data on the prevalence and clinical characteristics of AKI in COVID-19 patients.

We evaluated a cohort of 792 COVID-19 patients hospitalized at the University Hospital of Modena, Italy, between February 25 and December 14, 2020 for severe symptoms of COVID-19. The diagnosis of COVID-19 was performed through reverse transcriptase-polymerase chain reaction (RT-PCR). We excluded patients aged <18 years (n=2), patients on dialysis (n=5), and patients without serum creatinine on admission (n=19). The diagnosis of AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria [15], without considering the urine output criteria. Baseline serum creatinine (sCr) coincided with sCr at admission. All the enrolled patients were discharged or died at the end of the follow-up.

According to the Istituto Superiore di Sanità (ISS), the coronavirus pandemic in Italy can be subdivided in three waves during 2020: first wave (February-May), transitional period (June-August) and second wave (September- December) [16]. As a result, the study population was subdivided into three groups: wave-1 (n=389), transitional period (n=57) and wave-2 (n=346).

Data are expressed as mean ± standard deviation or a percentage (%). Statistical differences were tested using Student’s t-test or Chi-square as appropriate. Cox regression analysis evaluated the influence of AKI on the hazard of death. The study was approved by the regional ethical committee of Emilia Romagna (n. 0013376/20).

In a cohort of 792 hospitalized patients, 122  cases (15.4%) of AKI were diagnosed. Patients with AKI were older (77.4 vs 64.3 years; P=<0.001) and had a higher baseline sCr (1.37 vs 0.96 mg/dl; P=0.004) than non-AKI patients (Table I). As expected, patients with AKI showed increased levels of inflammatory markers (CRP; P=0.001), tissue damage (LDH; P=0.01) and hypoxia (PO2/Fi02;P=<0.001). We detected a higher burden of morbidity and comorbidity compared to non-AKI patients, as indicated by a higher SOFA (P=<0.001) and Charlson score (P=<0.001), respectively. In particular, AKI patients had a high rate of non-invasive ventilation (NIV; P=0.001), high flow nasal oxygen (HFNO; P=<0.001), mechanical ventilation (P=0.001) and, consequently, ICU admission (P=0.01). Given the burden of multiorgan dysfunction, AKI patients experienced a prolonged hospital stay (22.4 vs 13.2 days; P=0.008).

AKI stage 1 was the most frequent event (n=82; 67.2%) followed by AKI stage 2 (n=15; 12.2%) and AKI stage 3 (n=25; 20.4%). In this latter group, renal replacement therapy was necessary for 11 patients (44%).

The overall mortality rate was 19.1% and it increased up to 61.5% in patients with an acute worsening of kidney function (Figure 1). AKI was an independent risk factor for death after adjustment for age, sex, PO2/FiO2, baseline creatinine, BMI, LDH, CRP, diabetes and cardiovascular disease (HR, 3.39; CI95% 1.032-11.1; P=0.04). Of the survivors with AKI, 40.4% did not recover kidney function at discharge.

Variable All patients (n=792) No AKI (n=670) AKI patients (n=122) p-value
Age 66.3±16.1 64.3±16.18 77.4±10.92 0.012
Males (%) 511 (64.5) 425 (63.4) 86 (70.5) 0.15
White blood cells (cell/mm3) 8587±7170 7657.1±5696.6 9737.7±7380.5 0.053
Hemoglobin (gr/dl) 12.7±1.8 12.6±1.8 13.1±1.6 0.084
Platelets (103/mm3) 253.7±116.3 261.8±111.2 207.8±133.5 0.85
CRP (mg/dl) 8.9±8.2 8.3±7.89 12.3±9.6 0.001
LDH (U/L) 648.9±991.9 592±283.4 950±238.9 0.01
Baseline sCr (mg/dl) 1±0.71 0.96±0.25 1.37±0.08 0.004
sCr peak (mg/dl) 1.2±1.1 1.01±0.65 2.72±1.76 <0.001
sCr at discharge (mg/dl) 1±0.89 0.84±0.44 2.23±1.57 <0.001
MAP 90.3±13.2 88.8±12.2 95.5±14.2 0.12
PO2/FO2 250.6±105.2 261.11±101.3 184.87±106 <0.001
SOFA score 2±2 1.7±1.6 3.5±2.7 <0.001
Charston score 3.4±2.9 3 ±2.8 5.1±3.1 <0.001
Comorbidities§ (%)
COPD (%) 32 (14.5) 22 (12.1) 10 (26.3) 0.04
Diabetes (%) 75 (31.9) 61 (31.1) 14 (35.9) 0.576
Hypertension (%) 182 (65.9) 150 (64.7) 32 (72.6) 0.386
CVD (%) 50 (22.5) 30 (16.5) 20 (50) <0.001
CKD (%) 35 (15.8) 24 (13.1) 11 (28.9) 0.025
BMI>30 (%) 113 (32.2) 99 (33.6) 14 (25) 0.275
ACE inibitors (%) 102 (12.9) 90 (13.4) 12 (9.8) 0.307
FANS (%) 21 (2.7) 17 (2.5) 4 (3.3) 0.550
Nephrotoxic antibiotic (%) 20 (2.5) 15 (2.2) 5 (4.1) 0.216
Use of chonic diuretic therapy (pre-AKI) (%) 259 (32.7) 182 (27.2) 77 (63.1) 0.001
Antiviral (%) 253 (31.9) 215 (32.1) 38 (31.1) 0.91
IV hydratation with cystalloids pre-AKI (%) 233 (29.4) 189 (28.2) 44 (36.1) 0.085
Steroid (%) 287 (38.5) 232 (36.7) 55 (48.7) 0.021
Immunotherapy  (%) 326 (43.4) 275 (43.4) 326 (43.7) 0.758
O2 therapy (%) 537 (67.8) 454 (67.8) 83 (68) 1
HFNO (%) 101 (18.5) 71 (15.4) 30 (35.7) <0.001
NIV (%) 172 (31.3) 128 (27.8) 44 (49.4) 0.001
Mechanical ventilation (%) 91 (12.2) 59 (9.3) 32 (28.3) 0.001
ICU admission (%) 153 (20.5) 111 (7.5) 42 (37.2) 0.001
BMI 28.5±5.3 28.5±5.1 28.1±6.2 0.109
Time elapsed from admission to AKI (day) 11.8±9.34 NA 11.8±9.34 0.063
Hospitalization (day) 14.7±13.7 13.28±11.3 22.45±21.38 0.008
Death (%) 151 (19.1) 76 (11.3) 75 (61.5) <0.001
Legend: CRP, C-reactive protein; LDH, lactate dehydrogenase; MAP, mean arterial pressure; sCr, serum creatinine; SOFA, Sequential Organ Failure Assessment; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; CKD, chronic kidney disease; BMI, body mass index; HFNO, high-flow nasal oxygen; NIV, noninvasive ventilation; AKI, acute kidney injury; ICU, intensive care unit.
Table I: Demographics and clinical manifestation of COVID-19 patients
Figure 1: Kaplan Mayer curves showing survival of AKI and non-AKI patients with COVID-19
Figure 1: Kaplan Mayer curves showing survival of AKI and non-AKI patients with COVID-19

From an epidemiological point of view, the prevalence of AKI remained similar during the first (15.9%) and the second wave (14.7%) (P=0.89) (see Figure 2). The rate of ICU admission (P=0.42) was similar in these two groups but during the second wave AKI patients were more frequently treated with steroids (P=0.007), HFNO (P=0.001) and required less mechanical ventilation (P=0.019) compared to patients admitted during the first wave. Nevertheless, the mortality of AKI patients did not change between the first (59.7%) and the second (70.6%) wave of COVID-19 (P=0.243).

Figure 2: AKI prevalence during the first wave, the trasitional period and the second wave
Figure 2: AKI prevalence during the first wave, the trasitional period and the second wave

The findings of this study provide new information on the epidemiology of AKI in COVID-19. We found that the overall rate of AKI in unvaccinated hospitalized patients with COVID-19 accounted for 15.4% and that the prevalence of AKI remained relatively steady (about 15%) during the three phases of the COVID-19 pandemic that hit Italy and Europe during 2020. These data are in line with the results of a recent metanalysis, reporting a comparable pooled incidence (15.4%) among 25,566 patients, enrolled in 39 studies [17]. However, the distribution of AKI is not homogeneous among the published studies, where prevalence ranged from 0.5%-60%. Multiple factors may have affected this epidemiological variability including the surge capacity of the healthcare system, how the care was delivered (publicly or privately) and the method of patients selection (e.g. criteria for hospital admission).

In our study, subjects with AKI showed different demographic and clinical characteristics compared to non-AKI patients. Kidney injury was indeed experienced by elder patients affected by a more severe disease than non-AKI patients. COVID-19 patients with kidney involvement had a higher rate of morbidity (lung involvement, ICU admission, length of stay) and a 3.4-fold increase in mortality than non-AKI patients. No clear differences were detected in terms of AKI prevalence between the first and second wave, despite some therapeutic improvements (steroids, remdesivir, immunomodulant) were made in the management of these patients.

Since AKI is an independent risk factor  in COVID-19, many efforts should be made to identify and correct predisposing factors for kidney injury. From a practical point of view, the prevention measures that we put in place were not different from those we follow for AKI from other causes in critically ill patients [15,16]. These were based mainly on surveillance of kidney function, maintenance of normovolemia and avoidance of nephrotoxic agents.

In conclusion, our study confirms that AKI is a common event (15.4%) in COVID-19 and its prevalence was stable through 2020. AKI was more common in older patients who experienced a severe COVID-19. The outcome of patients with AKI was poor, as more than half died at the end of the follow-up and 40% of survivors had not recovered kidney function at hospital discharge. The heterogeneity of COVID-19-associated AKI in terms of incidence and etiology presents many challenges to its prevention and management. Further studies are required to investigate the effects of new virulent SARS-CoV-2 variants on the development of AKI, the impact of vaccination in the prevention of kidney involvement and the long term consequences of AKI.



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Treating anaemia in patients with chronic kidney disease: what evidence for using ESAs, after a 30-year journey?


Erythropoiesis Stimulating Agents (ESAs) are well-tolerated and effective drugs for the treatment of anaemia in patients with chronic kidney disease.

In the past, scientific research and clinical practice around ESAs have mainly focused on the haemoglobin target to reach, and to moving towards the normality range; more cautious approach has been taken more recently. However, little attention has been paid to possible differences among ESA molecules. Although they present a common mechanism of action on the erythropoietin receptor, their peculiar pharmacodynamic characteristics could give different signals of activation of the receptor, with possible clinical differences.

Some studies and metanalyses did not show significant differences among ESAs. More recently, an observational study of the Japanese Registry of dialysis showed a 20% higher risk of mortality from any cause in the patients treated with long-acting ESAs in comparison to those treated with short-acting ESAs; the difference increased in those treated with higher doses. These results were not confirmed by a recent, post-registration, randomised, clinical trial, which did not show any significant difference in the risk of death from any cause or cardiovascular events between short-acting ESAs and darbepoetin alfa or methoxy polyethylene glycol-epoetin beta. Finally, data from an Italian observational study, which was carried out in non-dialysis CKD patients, showed an association between the use of high doses of ESA and an increased risk of terminal CKD, limited only to the use of short-acting ESAs.

In conclusion, one randomised clinical trial supports a similar safety profile for long- versus short-acting ESAs. Observational studies should always be considered with some caution: they are hypothesis generating, but they may suffer from bias by indication.

Keywords: anaemia, erythropoiesis stimulating agents, ESAs, mortality, chronic kidney disease, long acting, short acting

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Dalla pubblicazione dello storico lavoro di Eschbach più di 30 anni fa [1], il trattamento dell’anemia con i farmaci stimolanti l’eritropoiesi (Erythropoiesis Stimulating Agents, ESAs) ha rivoluzionato la qualità della vita dei pazienti con malattia renale cronica (Chronic Kidney Disease, CKD). In quegli anni i pazienti erano gravemente anemici e spesso sopravvivevano con livelli di emoglobina anche inferiori a 5 g/dL, ricorrendo a periodiche trasfusioni, con alto rischio di trasmissione di un’epatite allora sconosciuta, definita “non A-non B” (oggi chiamata C) e con conseguente accumulo di grandi quantità di ferro. Nei casi più gravi i nefrologi erano costretti ad intervenire con un trattamento chelante a base di desferriossamina, a sua volta gravato da serie complicanze come la mucoviscidosi. Improvvisamente, grazie all’utilizzo dell’eritropoietina, i pazienti ricominciarono a vivere. Tale era l’entusiasmo dei nefrologi nel poter finalmente correggere efficacemente la grave anemia dei loro pazienti cronici, che si fecero trascinare fino a una correzione troppo rapida dei valori di emoglobina, portando a complicanze come un aumento dei valori pressori sino a severe crisi ipertensive e, a volte, convulsioni. 

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