The pathophysiological basis of cocaine-related kidney injury involves renal hemodynamic changes; glomerular matrix synthesis and degradation; oxidative stress and renal atherogenesis induction, which may result in several renal manifestations, being associated with, acute glomerulonephritis, interstitial nephritis and rhabdomyolysis [6].
Cocaine stimulates the sympathetic nervous system through distinct mechanisms that include inhibiting catecholamine uptake at the sympathetic nerve terminals, as well as the release of epinephrine and norepinephrine by the adrenal medulla [6]. At the renal level, in addition to this potent vasoconstrictor effect, modifications in the structure and hemodynamics of this organ seem to occur. Fibrosis occurs due to excessive activation of the Renin-Angiotensin-Aldosterone System, as well as accelerated atherogenesis. These pathological alterations can occur in three clinical manifestations, which are acute kidney injury, chronic kidney disease and hypertension with different causes (Fig. 6) [7, 8].
A common fact to all cases was the occurrence of acute kidney injury. This entity is defined as a syndrome with rapid loss of renal function with accumulation of nitrogenous slags [9]. The diagnosis necessarily involves analysis of urea and creatinine levels, with oliguria being a little sensitive and specific symptom [10]. It should be emphasized that this injury shows high morbidity and mortality, if not promptly reversed [11].
It is well-known, as previously explained in the introduction, that the systemic spectrum, particularly the renal ones, course with several clinical manifestations [8]. Therefore, there should be a strong clinical suspicion in patients with a history of cocaine abuse, since many of the alterations caused by this substance are common to several other pathologies, hence being a diagnosis of exclusion [5].
The three cases reported here demonstrated several renal manifestations related to cocaine use. In the first case, we reported on a female patient with a positive pauci-immune ANCA-related RPGN (age group consistent with such pathology), who did not have the characteristic diffuse purpuric rash, which usually affects the extremities and ears, with a purpuric and consistent appearance [12, 13]. In spite of that, renal involvement hardly shows clinical manifestations [5]. The renal biopsy, immunofluorescence, and positive C-ANCA are compatible with the diagnosis of Pauci-Immune Rapidly Progressive Glomerulonephritis [14].
An important fact related to the association between cocaine and positive C-ANCA are the ANCA high titers. This fact supports the presence of cocaine-related vasculitis, instead of primary vasculitis [15]. Glomerulonephritis seems to be a synergistic effect of cocaine adulterated by substances such as levamisole [14]. Other effects also caused by levamisole are leukocytoclastic and thrombotic vasculitis [5, 16].
The pathophysiological mechanism of pauci-immune ANCA-related RPGN remains unknown. One of the proposed models suggests that the activation of neutrophils exposes ANCA antigens, which would promote the remaining activation of neutrophils, as well as adhesion and migration through the endothelium with consequent tissue injury [14]. Thus, T-cell activation is prevalent.
The second case reports on a patient with microangiopathy, thrombocytopenia and acute kidney injury secondary to cocaine use. These clinical and laboratory changes correspond to Thrombotic Microangiopathy (TMA), with the kidney being a frequent site of involvement [17, 18]. This syndrome has several etiologies, being related to both hereditary and acquired diseases. Severe hypertension crisis, drug-induced, infections (including Uremic Hemolytic Syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are some examples of etiology [17, 19].
The pathophysiology of TMA is also diverse, depending on the related etiology. In the case of TTP corresponds to a deficiency of ADAMST-13, in the case of HUS or atypical HUS corresponds to a deregulation in the complement system and in the case of drug-mediated may correspond to a set of mechanisms [19, 20]. TMA inducing by drugs is rare, and there are reports of different substances related to its occurrence. The pathophysiology is uncertain, being hypotheses ranging from immune changes to endothelial dysregulation of podocytes [21].
Cocaine inducing TMA or similar pictures has few reports in the literature. Patients users of this substance who present a recent history of microangiopathic hemolytic anemia should be in the differential diagnosis of TMA-induced drug. An important aspect in the approach of these patients is to have the dosage of ADAMTS-13 as it allows to exclude TTP frames. For logistic reasons, we do not have the test for the patient of the report 2 [22, 23].
The early diagnosis of TMA is essential, since early measures are required, often requiring early dialysis or immunosuppression [19].
The third case reports on a patient with sudden onset of myalgia, vomiting and nausea, suggesting rhabdomyolysis, which was later confirmed by laboratory tests. This pathology is the most common nephropathy related to cocaine use [21]. Generally, CPK levels > 5000 IU/L are expected in patients with rhabdomyolysis and renal failure. This patient only had CPK levels measured 5 days after admission; thus, it is possible to infer very high values at the clinical picture onset, considering that there is a daily reduction in serum CPK levels of 40 to 50% [24].
The epidemiology of cocaine-induced rhabdomyolysis includes young black male patients [22]. The typical clinical picture consists of delirium, hyperthermia and excitability, which are present in rhabdomyolysis, regardless of the etiology [24].
The incidence of rhabdomyolysis among cocaine users was 24% in a certain study. Despite the significant prevalence, the pathophysiology of this association remains uncertain. Among the hypotheses used to explain this association are vasoconstriction resulting in muscle ischemia and the direct toxic effects of cocaine (Fig. 7). An important fact is that other etiologies should be ruled out, such as trauma, alcohol consumption and infections, so that it can be inferred that rhabdomyolysis was caused by cocaine use [24].
The literature reports other etiologies of cocaine-induced kidney injury (Fig. 8) [6]. Acute interstitial nephritis is one of them, with very few published reports. The epidemiology of these patients consists in male gender individuals aged around 40 years at presentation [23]. The clinical manifestations suggested for these patients is the onset of oliguria with abdominal pain, with dialysis often being necessary. The treatment, despite the etiology, consists in the withdrawal of the inducing agent, with the use of corticosteroids remaining controversial [23].
Finally, renal infarction is another important etiology of cocaine-induced kidney injury. It is also an etiology with few published reports. There seems to be no higher incidence between genders. The exact pathophysiology is unknown; however, as shown in flow chart I, there is platelet aggregation, increased thromboxane production, as well as increased endothelin production, together with an atherogenic effect [8, 25].
The presence of valvular heart disease and atheroembolic events are common risk factors. The clinical manifestations observed in these patients comprise intense and persistent flank pain, associated with nausea and/or vomiting, which may occur regardless of the cocaine administration route [24]. There is no consensus regarding treatment, and basal conditions, such as associated coagulopathies, should be assessed [25].
Therefore, cocaine and its adulterants, especially levamisole, directly and indirectly contribute to renal function and structure alterations, mainly regarding microhemodynamics. Increase in oxidative stress, increased platelet activation, increased production and activation of prostaglandins, increased sympathetic activity and endothelial dysfunction are the main pathophysiological effects caused by cocaine use. Consequently, the spectrum is varied and can be gathered into three groups: hypertension, chronic kidney disease and acute kidney injury, which was the focus of the present study.
In conclusion basically, 05 etiologies of acute kidney injury should always be remembered: rhabdomyolysis, thrombotic microangiopathy, vasculitis, acute interstitial nephritis and renal infarction. Emphasis should be given to rhabdomyolysis due to its higher prevalence. Considering the increasing rates of cocaine use, especially with the use of adulterating substances, these pathologies will likely be increasingly prevalent.
At first, the treatment may not be different, but there are significant differences in the prognosis of these patients, as well as the time of intensive monitoring, among other measures. The scarcity of reported cases suggests underdiagnosis and / or underreporting of cocaine-induced kidney injury and high clinical suspicion is important in patients with risk factors.
The scarcity of reports contributes to the uncertainty regarding several aspects of cocaine-induced nephropathies.
