Pathophysiology of COVID-19-associated acute kidney injury
Although respiratory failure and hypoxaemia are the main manifestations of COVID-19, kidney involvement is also common. Available evidence supports a number of potential pathophysiological pathways through which acute kidney injury (AKI) can develop in the context of SARS-CoV-2 infection. Histopathological findings have highlighted both similarities and differences between AKI in patients with COVID-19 and in those with AKI in non-COVID-related sepsis. Acute tubular injury is common, although it is often mild, despite markedly reduced kidney function. Systemic haemodynamic instability very likely contributes to tubular injury. Despite descriptions of COVID-19 as a cytokine storm syndrome, levels of circulating cytokines are often lower in patients with COVID-19 than in patients with acute respiratory distress syndrome with causes other than COVID-19. Tissue inflammation and local immune cell infiltration have been repeatedly observed and might have a critical role in kidney injury, as might endothelial injury and microvascular thrombi. Findings of high viral load in patients who have died with AKI suggest a contribution of viral invasion in the kidneys, although the issue of renal tropism remains controversial. An impaired type I interferon response has also been reported in patients with severe COVID-19. In light of these observations, the potential pathophysiological mechanisms of COVID-19-associated AKI may provide insights into therapeutic strategies.
Over a quarter of patients hospitalized with coronavirus disease 2019 (COVID-19) have been reported to develop acute kidney injury (AKI).
Low molecular weight proteinuria, Fanconi syndrome and histological findings point towards tubular injury.
Analyses of kidney biopsy samples from patients with COVID-19 and AKI have inconsistently reported viral infection of kidney cells.
Collapsing glomerulopathy has been identified in patients with high-risk APOL1 genotypes, mostly in those without severe respiratory symptoms.
Regional inflammation, endothelial injury and renal microthrombi have been reported but their implication in the pathogenesis of COVID-associated AKI remains uncertain.
Anti-inflammatory drugs (for example, steroids and IL-6 receptor blockers) seem to limit the development of severe AKI in patients with COVID-19.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first described in December 2019 and is responsible for coronavirus disease 2019 (COVID-19) and the current global pandemic. The pulmonary manifestations of COVID-19 are most prominent, but acute kidney injury (AKI) is also now recognized as a common complication of the disease, and is often evident at hospital admission. Although initial reports from China suggested relatively low rates of kidney involvement 1 , 2 , 3 , 4 , subsequent reports from the USA and Europe indicate much higher rates of AKI, particularly in the intensive care setting, with up to 45% of patients in the intensive care unit (ICU) requiring kidney replacement therapy (KRT) 5 , 6 , 7 , 8 . Mortality among hospitalized patients with COVID-19-associated AKI (COVID-19 AKI) is higher than for those without kidney involvement 8 , 9 . As with all instances of AKI in the context of multi-organ failure requiring ICU admission, mortality among patients admitted to the ICU with COVID-19 AKI requiring KRT is especially high 10 . Anecdotal reports of a lack of renal recovery in those who survive relative to that reported for other forms of AKI is of particular concern 7 , 9 , 10 . However, long-term patient outcomes are not yet fully understood as they are complicated by prolonged hospital admissions and lack of reported follow-up. Ascertaining the true epidemiology of COVID-19 AKI is difficult owing to differences in the underlying comorbidities of the populations examined, as well as possible variations in the practice and methods of AKI diagnosis and reporting. Age, history of hypertension and diabetes mellitus have been repeatedly associated with a higher risk of AKI in patients with COVID-19. Chronic kidney disease (CKD) is a well identified risk factor for AKI in hospitalized patients, and was indicated to be the most relevant risk factor for AKI requiring KRT in 3,099 critically ill patients with COVID-19 (ref. 9 ). Indeed, several epidemiological studies have clearly demonstrated that CKD represents a relevant and independent risk factor for worse outcomes in COVID-19. A 2021 case–control study that compared patients with COVID-19 with the Danish general population matched for age, gender and comorbidities identified an association between lower estimated glomerular filtration rate (eGFR) and rate of hospital-diagnosed COVID-19 and death 10 . An OpenSAFELY analysis of variables associated with COVID-19-associated death in ~17 million patients identified CKD as one of the most prevalent comorbidities associated with mortality (HR 2.52 for patients with eGFR 0.5, 1+ or higher on dipstick or > 30 mg/dl on urinalysis) and haematuria (defined as 1+ or higher on dipstick or urinalysis), in 80% of patients with COVID-19 AKI 19 . Furthermore, >50% of patients without AKI as defined by KDIGO serum creatinine criteria had haematuria and over 70% presented with proteinuria. The presence of urinalysis abnormalities in those not meeting the definition of AKI suggests the existence of kidney injury without notable acute changes in kidney function. Fanconi syndrome (characterized by proteinuria, renal phosphate leak, hyperuricosuria and normo-glycaemic glycosuria) has been reported to precede episodes of AKI 25 (Fig. 2 ). This presentation is in keeping with stage 1S of new recommendations for AKI staging, when evidence of kidney injury exists that is not detected by creatinine and urine output criteria 26 .
Fig. 2: Different stages of COVID-19-associated acute kidney injury.
Proteinuria and/or haematuria is indicative of kidney injury, even in the absence of a rise in serum creatinine (SCr) level or a drop in glomerular filtration rate (GFR). Further injury is associated with a drop in GFR and rise in SCr. Underlying chronic kidney disease or factors such as ageing limits the baseline functional reserve and can precipitate the development of acute kidney injury (AKI). Kidney replacement therapy (KRT) is required for severe cases of AKI. COVID-19, coronavirus disease 2019.
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The proteinuria detected in patients with COVID-19 AKI is of low molecular weight rather than albuminuria, suggesting a tubular origin rather than glomerular injury, and can be used to identify patients with early-stage AKI 27 . The contribution of underlying CKD is unknown, but the proportion of patients with COVID-19 and proteinuria far exceeds the prevalence of stage 1 and 2 CKD in the general population 28 . Future studies are required to determine the association of biomarkers of glomerular and tubular function with serum creatinine-based AKI in the context of COVID-19 AKI. In addition, these clinical data should be integrated with pathological findings from analyses of kidney biopsy samples 29 , 30 , 31 , 32 , 33 to gain greater insights into the pathophysiology of COVID-19 AKI. Evidence from a study of biopsy data from 47 patients in France demonstrated that kidney injury seen in cases with the most severe respiratory disease in the ICU is predominantly tubular (66.7%); by contrast, collapsing glomerulopathy and focal segmental glomerulosclerosis were not seen in critically ill patients but were observed in 70.6% of cases not in the ICU 34 . More than two coexisting comorbidities were seen in over 60% of cases and the occurrence of collapsing glomerulopathy correlated highly with the expression of high-risk APOL1 genotypes.
Pathophysiology of COVID-19 AKI
The pathophysiology of COVID-19 AKI is thought to involve local and systemic inflammatory and immune responses, endothelial injury and activation of coagulation pathways and the renin–angiotensin system 31 , 35 . Direct viral infection with renal tropism of the virus has also been proposed but remains controversial 36 . Non-specific factors that are common in critically ill patients, such as mechanical ventilation, hypoxia, hypotension, low cardiac output and nephrotoxic agents, might also contribute to kidney injury and/or functional decline in the most severely affected patients (Box 1 ).
Box 1 Factors that may contribute to COVID-19-associated acute kidney injury
Acute tubular injury
COVID-19, coronavirus disease 2019.
Insights from renal histology
Autopsy studies demonstrate that acute tubular injury is by far the most common finding in kidneys of patients with COVID-19 AKI (Supplementary Table 1 ). Of note, tubular autolysis is a confounding factor in post-mortem histological analyses of acute tubular injury 31 , 37 . Analyses of post-mortem kidney samples from patients with stage 2 or 3 AKI and COVID-19 have revealed acute tubular injury characterized by mostly mild focal acute tubular necrosis 29 , 33 , 35 , 38 , illustrating an apparent uncoupling between the extent of histological injury and decline of kidney function — a finding previously reported in patients with non-COVID sepsis 39 . In an autopsy series of 9 patients in the UK, evidence of acute tubular injury was noted in all patients; viral load quantified by the use of quantitative real-time PCR targeting the viral E gene was observed in the kidneys of 3 patients and detection of subgenomic viral RNA in only 1 (11%) kidney sample 38 , 40 .
Another analysis of kidney biopsy samples from 17 patients with SARS-CoV-2 infection and mostly mild COVID-19 symptoms identified AKI and proteinuria in 15 and 11 patients, respectively. Acute tubular injury (n = 14; 82%), collapsing glomerulopathy (n = 7; 41%) and endothelial injury or thrombotic microangiopathy (n = 6; 35%) were the most common histological findings 41 (Supplementary Table 1 ). Virus detection (using immunohistochemistry for SARS-CoV-2 nucleocapsid and RNA in situ hybridization) were negative in patient samples on which it was performed. Another series from France demonstrated tubular injury in the most severely ill cohort whereas glomerular pathology was restricted to the non-ICU patients 34 . Of note, most biopsies were performed several weeks after the onset of COVID-19 symptoms, and most have failed to show notable SARS-CoV-2 infection of the kidney. Despite initial concerns about the methodology and interpretation of some early studies that reported direct viral tropism of the kidney 36 , 42 , 43 , 44 , one study that identified and isolated SARS-CoV-2 from post-mortem kidney tissue demonstrated that the virus could replicate in non-human primate kidney tubular epithelial cells, showing its ability to infect kidney cells 45 . The researchers further identified that 23 of 32 patients with AKI (72%) showed viral RNA in kidney tissue, whereas viral RNA was identified in only 3 of 7 (43%) patients without AKI. Another autopsy study that performed microdissection of kidneys from 6 patients with COVID-19 identified SARS-CoV-2 in different kidney compartments, particularly in the glomerulus 43 . Viral RNA and protein were also detected in kidney by in situ hybridization with confocal microscopy. In addition, SARS-CoV-2 particles have been observed in urine samples 33 , 46 , 47 — a finding that either reflects the release of virus from infected, damaged tubule epithelial cells or the filtration of viral fragments, as the high molecular weight of SARS-CoV-2 (600 kDa) should prevent it from being filtered through the intact glomerular filtration barrier 48 . Thus, a substantial body of evidence now suggests that SARS-CoV-2 can infect kidney tissue; however, a direct role of the virus in the development of AKI remains to be confirmed.
Collapsing glomerulopathy has been reported in several patients with COVID-19 (Supplementary Table 1 ). This entity has been described as COVID-19-associated nephropathy (COVAN), and seems to occur mostly in patients with non-severe respiratory symptoms of COVID-19 and isolated AKI or in those presenting with glomerular proteinuria 30 , 32 , 34 . Of note, collapsing glomerulopathy has previously been described in the context of other viral infections, including HIV parvovirus B19, cytomegalovirus and Epstein–Barr virus infections. COVAN is associated with high-risk APOL1 genotypes, and has been observed mostly in Black patients. The true incidence of collapsing glomerulopathy and its contribution to kidney failure in the context of COVID-19 compared with the effects of other underlying conditions (for example, hypertension or CKD) is unknown. Although the exact pathophysiology of COVAN remains unknown, it may share common mechanisms with HIV-associated nephropathy, with podocyte injury through disruption of autophagy and mitochondrial homeostasis 31 .
Endothelial dysfunction and coagulation
Biomarkers of coagulation and fibrinolysis activation (for example, fibrinogen and D-dimer) have been repeatedly associated with an increased risk of death in patients with COVID-19. Autopsy studies have reported a ninefold higher incidence of observed microvascular and macrovascular thrombosis in lungs of patients with COVID-19 than that of patients with influenza pneumonia 49 . Systemic microvascular and macrovascular thrombosis in organs, including the kidneys, have also been repeatedly reported in the context of COVID-19 (refs 50 , 51 , 52 ). Many critical illnesses are associated with microvascular and endothelial injury but SARS-CoV-2 is believed to specifically affect the endothelium. Post-mortem studies have reported vascular endotheliitis in patients with COVID-19 (refs 49 , 53 ). Moreover, findings from at least one report indicate viral infection of kidney endothelial cells 53 ; however, that report used electronic microscopy to identify viral elements, which is insufficiently specific and thus firm evidence of direct viral infection of kidney endothelial cells is lacking. Nonetheless, increased levels of plasma biomarkers of endothelial injury (for example, soluble (s) E-selectin, sP-selectin, ANG2, sICAM1 and von Willebrand factor antigen) and platelet activation (soluble thrombomodulin) are associated with poor prognosis 54 , 55 , 56 . Microvascular inflammation can trigger endothelial activation, leading to vasodilation, increased vascular permeability and pro-thrombotic conditions 57 , 58 , 59 . Complement activation — evidenced by increased circulating levels of soluble complement components C5b–9 and C5a and by tissue deposition of C5b–9 and C4d in lung and kidney tissues 60 , 61 , 62 — may further promote inflammation and coagulation pathways in COVID-19. The release of damage-associated molecular patterns from cells undergoing necrosis might further contribute to endothelial injury in COVID-19 (ref. 63 ). SARS-CoV-2 has furthermore been shown to bind to platelets via ACE2, leading to platelet activation and immunothrombosis 64 , 65 , 66 . Thus, platelet activation may represent a potential player in the pathophysiology of COVID-19 AKI 67 , 68 . Circulating prothrombotic autoantibodies that target phospholipids and phospholipid-binding proteins have also been reported 69 . In a cohort of 172 hospitalized patients with COVID-19, higher titres of prothrombotic antibodies were associated with lower eGFR. In vitro studies confirmed the autoantibodies to be drivers of endothelial cell activation, potentially contributing to the thrombo-inflammatory effects observed in severe COVID-19 (ref. 70 ).
However, macrothrombi and microthrombi have been inconsistently observed in kidneys of patients who have died with COVID-19, or have involved only a small proportion of renal capillaries. A small autopsy study from New York, USA, observed thrombotic microangiopathy within glomeruli in only 1 of 7 cases 51 . Another series of kidney biopsy samples from 17 patients with mild COVID-19 symptoms identified evidence of acute glomerular endothelial cell injury in 6 patients, most of whom demonstrated laboratory features of thrombotic microangiopathy 41 . Of note, no evidence of peritubular vascular injury was observed in that study. Neutrophils and neutrophil extracellular traps — frequently aggregating with platelets — have been observed in many organs including the kidneys, despite the sporadic presence of virus on histology, suggesting a role of inflammation in the development of intravascular thrombi 71 . Cases of renal artery thrombosis have also been anecdotally reported 72 , 73 . Finally, patients with severe COVID-19 often present with complications associated with chronic endothelial dysfunction, such as hypertension or diabetes, which are themselves associated with decreased endothelial nitric oxide synthase activity and bioavailability of nitric oxide — a major vasodilator and antithrombotic factor 74 .
The immune and inflammatory response
Several alterations in both innate and adaptive immune responses have been reported following SARS-CoV-2 infection. Immunosenescence — a term used to define the innate and adaptive immunological alterations that occur with ageing — is characterized by inflammageing, a low-grade inflammatory state that may have a key role in determining organ dysfunction, as well as by ineffective T cell responses and antibody production. These features have been reported in COVID-19 and may in part explain the higher mortality among elderly individuals and those with comorbidities as a consequence of inefficient viral clearance, the enhanced release of cytokines and chemokines, endothelial damage and activation of the coagulation and complement cascades 75 .
The enhanced release of inflammatory mediators by immune and resident kidney cells is likely to be a key mechanism of tissue damage in patients with COVID-19. Inflammatory mediators, such as TNF and FAS, can bind to their specific receptors expressed by renal endothelial and tubule epithelial cells causing a direct injury 76 , 77 . Such interactions have been observed in experimental models of sepsis and are supported by measurements of plasma cytokine levels in patients with sepsis-associated AKI 78 , although their role in COVID-19 AKI is yet to be clearly demonstrated.
Other studies have demonstrated a key role for type I interferon responses in suppressing viral replication and regulating the immune response in the context of COVID-19. Available evidence suggests that SARS-CoV-2 infection can lead to suppression of interferon release; moreover, patients treated with interferon demonstrated improved viral clearance with a concomitant reduction in levels of IL-6 and C-reactive protein 79 . One study demonstrated that patients with inborn errors of type I interferon immunity and extremely low serum levels of IFNα (20,000 pg/ml) and non-COVID ARDS (approaching 10,000 pg/ml in cytokine release syndrome) 112 . These observations are supported by a meta-analysis, which revealed that IL-6 levels in severe COVID-19 were lower than in patients with sepsis, septic shock or hyperinflammatory ARDS 112 . Similarly, a study from the Netherlands that compared levels of pro-inflammatory cytokines (IL-6, IL-8 and TNF) in critically ill patients with COVID-19 with those in other critically ill individuals 113 demonstrated that concentrations of circulating cytokines were lower in patients with COVID-19 than in patients with bacterial sepsis and similar to those of other critically ill patients. However, patients with COVID-19-related ARDS had lower APACHE2 scores than patients with other conditions, suggesting a lower severity of critical illness. These findings suggest that COVID-19 might not be characterized by CSS and its role in the development of COVID-19 AKI is therefore questionable. As discussed later, this proposal has important implications for the use of extracorporeal blood purification techniques. Importantly, the exclusion of a pathogenic role for CSS does not exclude a role for regional inflammation in the pathogenicity of COVID-19, which is supported by evidence of high levels of acute phase reactant inflammatory biomarkers, such as C-reactive protein, in patients with COVID-19 (ref. 112 ).
ACE2 and the renin–angiotensin system
Although ACE2 is considered to be the classic receptor by which SARS-CoV-2 gains entry into cells, a study published in preprint form identified kidney injury molecule 1 (KIM1; also known as T cell immunoglobulin mucin domain 1) as an alternative receptor for SARS-CoV-2 in tubule epithelial cells 114 . Kidney cells also express transmembrane protease serine 2 (TMPRSS2) — an enzyme that proteolytically cleaves ACE2 and is essential for the viral entry 43 , 115 . TMPRSS2 colocalizes to different compartments of the kidney, although its expression is greatest in the distal tubules, whereas ACE2 is predominantly expressed in the proximal tubules 116 , 117 , 118 .
In addition to mediating SARS-CoV-2 entry into cells, ACE2 acts as an enzyme within the renin–angiotensin system, metabolizing angiotensin II by cleaving a terminal peptide to form angiotensin(1–7) (Ang1–7) 119 , 120 . Ang(1–7) generally opposes the actions of angiotensin II, which include activation of endothelium and platelets, vasoconstriction and the release of pro-inflammatory cytokines. Following binding of SARS-CoV-2 to human ACE2, ACE2 is thought to be downregulated 121 , leading to increased levels of angiotensin II and decreased Ang(1–7) 122 , 123 , 124 . This proposal is in line with the observed decrease in plasma levels of angiotensin II observed in a patient with COVID-19 after administration of recombinant human sACE2, which, like endogenous sACE2, can act as a dummy receptor to bind and sequester SARS-CoV-2 (ref. 125 ). Recombinant human sACE2 also led to a marked reduction in IL-6 and IL-8 (ref. 125 ). Lower plasma levels of Ang1 and Ang(1–7) were also reported in patients with COVID-19 than in healthy controls and non-ICU patients 111 .
Importantly, although in the kidney, formation of Ang(1–7) from angiotensin II is predominantly mediated by ACE2, formation of Ang(1–7) in the plasma and lungs are reportedly largely independent of ACE2 (ref. 126 ). Of note, circulating levels of sACE2 are very low 110 , which, in theory, makes the kidney more sensitive to ACE2 activity with respect to the angiotensin II and Ang(1–7) balance. Whether an imbalance between angiotensin II and Ang(1–7) has a direct role in endothelial activation and COVID-19 AKI remains speculative at present 59 .
Polymorphisms in ACE2 have been described but no information exists with regard to their relationship to COVID-19 AKI 127 . Although some of these polymorphisms might enhance SARS-COV-2 entry into the tubule epithelial cells, future study should explore whether these genetic differences are associated with specific injury patterns.
Together, the available data suggest that the relationship between ACE2 and angiotensin II contributes to kidney injury in COVID-19. This interaction may, however, depend on the severity of the disease and the extent to which it represents an adaptive response to shock, as low levels of angiotensin II may be associated with poor outcomes in critically ill patients 128 , 129 . One small, single-centre study of critically ill patients with COVID-19 demonstrated an association between AKI and an increase in plasma renin levels, indicative of low angiotensin II activity 130 . This association is also observed in other critical care settings, such as distributive shock or cardiac surgery as a consequence of a relative deficit of angiotensin II, which induces renin release via a positive-feedback loop 129 , 130 . The existence of a similar mechanism in COVID-19 is suggested by the presence of lower angiotensin II levels in patients with COVID-19 and ARDS than in patients with milder disease 131 .
The impact of withholding renin–angiotensin system blockers, such as angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, in patients with COVID-19 has been intensely debated but does not seem to affect outcomes 132 , 133 . Studies in mice demonstrate that administration of captopril or telmisartan leads to a decrease in ACE2 expression in isolated kidney membranes, with no effect on ACE2 activity in isolated lung membranes, suggesting differential effects on the kidney and lung 134 . Furthermore, in a randomized controlled trial of patients admitted to hospital with COVID-19, discontinuation of renin–angiotensin system inhibitors had no impact on disease severity or kidney function 135 .
In addition to virus-specific responses, the pathogenesis of AKI in the context of COVID-19 most likely also involves factors that are not specific to the virus but are part of a general response to critical illness or its treatment, including haemodynamic factors, drug toxicity and the impact of organ support systems.
Organ crosstalk and lung–kidney interactions
Crosstalk between lung and kidney has been identified in critical illnesses; these interactions are complex and comprise several putative mechanisms 136 that are also likely to exist in patients with severe COVID-19 (Fig. 1 ). For example, acute hypoxaemia might alter kidney function and increase renal vascular resistance 74 , 137 , which might contribute to renal hypoperfusion 138 and acute tubular injury 139 .
Moreover, following the development of AKI, increases in levels of inflammatory cytokines, such as IL-6, as a consequence of their reduced renal clearance and increased production has been reported, and may contribute to respiratory failure via kidney–lung crosstalk 128 .
In patients with severe disease, mechanical ventilation can contribute to the development of AKI through immune-mediated processes and haemodynamic effects 140 . Mechanical ventilation has been associated with an increased risk of AKI among patients with COVID-19. In a cohort of veteran patients with COVID-19 in the USA, AKI was associated with more frequent mechanical ventilation use (OR 6.46; 95% CI 5.52–7.57) 23 . Whether this association reflects the greater severity of the disease and systemic inflammation or is a direct effect of the impact of mechanical ventilation is uncertain, but it is likely a combination of both.
Crosstalk between the cardiovascular system and kidneys is also likely to contribute to COVID-19 AKI. Rare cases of acute myocarditis 141 , 142 and myocardial injury 143 have been described in patients with COVID-19, which potentially result in impairment of cardiac function and thereby potentially compromise kidney perfusion through a decrease in cardiac output or through renal vein congestion 144 , 145 . As in other forms of ARDS, use of high positive end-expiratory pressure and/or tidal volumes increases intrathoracic pressure, right atrial pressure and right ventricular afterload, and can decrease cardiac output 140 . Right-sided heart dysfunction and increased venous pressures can result in increased interstitial and tubular hydrostatic pressure within the encapsulated kidney, which decreases net GFR and oxygen delivery to the kidney 146 . The observed association between mechanical ventilation or use of vasopressors with the risk of AKI further suggests that haemodynamic factors contribute to COVID-19 AKI 5 , 147 , 148 .
As with all patients at risk of AKI, drug stewardship with regard to potential nephrotoxic drugs should be paramount. COVID-19 AKI is in this regard no different from AKI from other causes. In particular, administration of antibiotics such as vancomycin and aminoglycosides, especially in the context of critical illness, can have an important role in its aetiology 149 , 150 . Administration of nephrotoxins (for example, vancomycin, colistin and aminoglycosides) has also been associated with an increased risk of AKI in patients with COVID-19 (ref. 151 ).
Several uncertainties exist with regard to the safety of antivirals used to treat COVID-19 in patients with AKI. Remdesivir is a nucleotide analogue that inhibits viral RNA-dependent RNA polymerase and is predominantly excreted via the kidneys. Although evidence of its efficacy have been reported by some, but not all studies, remdesivir may exert nephrotoxic effects through the induction of mitochondrial injury in renal tubule epithelial cells. This renal toxicity is most likely to occur after prolonged exposure or at high doses. A randomized controlled trial of 1,062 patients reported a shorter recovery time from COVID-19 symptoms with use of remdesivir — a benefit mainly observed among patients treated early after the onset of symptoms and not in critically ill patients 152 . A decline in eGFR was observed in 14% of patients in the placebo group and 10% in the treated group; however, patients with an eGFR