Prescription Drug Overdose, Depression, and Other Mental Disorders in the Context of Kidney Disease.

Clinical Background: Mental disorders, especially depression, are associated with several comorbidities in the kidneys. Depression is the psychiatric disorder that mostly affects individuals with chronic kidney disease (CKD) and end-stage kidney disease. Epidemiology: The mainly prescribed drugs involved in overdose cases are opioids, benzodiazepines, and antidepressants. Antidepressants are the main psychiatric drugs that lead to kidney injury, mainly the second-generation ones. However, the prevalence of depression in dialysis patients varies from 22.8 to 39.3%. Therefore, psychiatric patients have 1.5-3 times more hospitalization compared to patients having only CKD. Challenges: Randomized clinical studies should be encouraged. Studies have shown an association between depression and progression of kidney disease. The mechanisms are not completely clear, but changes on neurotransmitter release and endocrine functions appear to be related to it. Additionally, the use of antidepressant and other psychoactive drugs can induce kidney injury. Hyponatremia induced by second-generation antidepressant drugs is an important feature and can be a risk factor for elderly or patients with comorbidities such as cerebral edema, brain damage or coma. Besides this class, drugs used for anxiety and bipolar disorders or sympathomimetic drugs of abuse can trigger acute kidney injury, possibly due to endothelial dysfunction and thromboembolic and ischemic events. Prevention and Treatment: The early detection of renal impairment and the prescription of nephroprotective strategies has been a clinical challenge. Some studies aim to describe the biochemical mechanisms involved and develop clinical management strategies for these patients. This chapter brings attention to this topic, discussing the major mechanisms and clinical features of kidney injury associated with mental illness, and the most relevant clinical strategies.

Novel renal biomarkers show that creatine supplementation is safe: a double-blind, placebo-controlled randomized clinical trial.

The aim of this study was to evaluate the impact of creatine supplementation (CS) on renal function in young, healthy, and active subjects. We used a randomized, double-blind, placebo-controlled clinical trial as the study design. Thirty-six healthy male university students were recruited and divided into three groups: group placebo, group G3 (3 g/day of CS), and group G5 (5 g/day of CS). To assess renal function, new kidney biomarkers, kidney injury molecule-1 (KIM-1) and monocyte chemoattractant protein-1 (MCP-1), were quantified. Serum albumin, serum creatinine, serum urea, estimated glomerular filtration rate (eGFR), proteinuria, and albuminuria were also measured. All groups were evaluated at two times: prior CS or placebo (pre) and after 35 days on CS or placebo (post). After 35 days of intervention, all characteristics were maintained without significant difference (P > 0.05) between the groups, including serum creatinine, eGFR, and more sensitive kidney biomarker concentrations (KIM-1 and MCP-1). The paired analysis showed that the supplemented groups (G3 and 5G) had increased serum creatinine and decreased eGFR levels (P < 0.05). However, the values were still within the normal reference range. In conclusion, the results of renal function evaluation did not show any difference between the evaluated groups. Increased serum creatinine and decreased eGFR levels in CS groups can be explained by increased creatine stores and metabolism, since creatinine is a by-product of creatine metabolism. These findings indicate that the use of CS at doses of 3 g and 5 g/day for a short period (35 days) is safe and did not impair the kidneys or renal function in young healthy subjects.

Interleukin-18 promoter -137 G/C polymorphism (rs187238) is associated with biochemical markers of renal function and cardiovascular disease in type 2 diabetes patients.

BACKGROUND: Interleukin-18 (IL-18), a proinflammatory and proatherogenic cytokine, has been associated with type 2 diabetes, metabolic syndrome, stroke and coronary artery disease. Some studies have indicated that the IL-18 promoter -137 G/C polymorphism seems to be associated with changes in the IL-18 expression and may contribute to the development of cardiovascular disease (CVD). The aim of this study was to evaluate the association between -137 G/C polymorphism and the levels of IL-18, biochemical markers for cardiovascular disorders, anthropometric profile and cardiovascular disease in Brazilian patients with type 2 diabetes (T2DM). DESIGN & METHODS: Study subjects comprised 125 T2DM patients undergoing follow-up at a reference endocrinology service in northeastern Brazil. The -137G/C polymorphism in the IL-18 gene and serum IL-18 levels were determined by using allele-specific polymerase chain reaction (PCR) and enzyme-linked immune assay (ELISA), respectively. The anthropometric parameters were assessed using a Body Composition Monitor with Scale, and the laboratory data were measured using an automatic analyzer as well as spectrophotometric analysis. RESULTS: The genotype distribution of IL-18 -137 G/C genetic polymorphism was significantly different among T2DM patients with and without CVD. The results show an association between the CC genotype of -137G/C polymorphism and CVD in T2DM patients (p < 0.001). Serum levels of IL-18 were significantly higher in CC carriers (843.1 pg/mL) compared with GG or GC carriers (303.6 pg/mL and 292.0 pg/mL, respectively). In addition, the present study showed that carriers of the CC genotype also had significantly higher concentrations of creatinine and albuminuria than carriers of the GG or GC genotypes (p < 0.05 in both). CONCLUSION: These results suggest that Brazilian T2DM patients with the CC genotype seem to show a predisposition to CVD, as well as an elevation in markers of renal function.

Purification and biological effects of L-amino acid oxidase isolated from Bothrops insularis venom.

Bothrops insularis is a snake from Ilha da Queimada Grande, an island located about 20 miles away from the Southeastern coast of Brazil. Compared with other Brazilian species of Bothrops, the toxinology of B. insularis is still poorly understood, and so far, no fraction from this venom with amino acid oxidase activity had been isolated or its biological activity tested. We investigated the biochemical and biological effects of one l-amino acid oxidase enzyme isolated from B. insularis snake venom (BiLAO), which was purified using HPLC and sequence grade. We also evaluated the renal effects induced by BiLAO. Chromatographic profile of B. insularis whole venom disclosed seven main fractions (I, II, III, IV, V, VI and VII) and the main LAO enzymatic activity was detected in fraction II. The group treated with BiLAO showed a decrease in perfusion pressure (C(120)=110.28+/-3.69; BiLAO(120)=82.2+/-5.6 mmHg*); renal vascular resistance (C(120)=5.48+/-0.53; BiLAO(120)=4.12+/-0.42 mmHg/mL/g/min*), urinary flow (C(120)=0.160+/-0.020; BiLAO(120)=0.064+/-0.012 mL/g/min*), glomerular filtration rate (C(120)=0.697+/-0.084; BiLAO(120)=0.176+/-0.017 mL/g/min*), sodium (C(120)=79.76+/-0.56; BiLAO(120)=65.39+/-6.19%*), potassium (C(120)=69.94+/-6.86; BiLAO(120)=60.26+/-2.24%*) and chloride tubular reabsortion (C(120)=78.53+/-2.33; BiLAO(120)=64.58+/-6.68%*). Acute tubular necrosis foci were observed in the group treated with the LAO fraction of the B. insularis snake venom. Some findings have the same morphological aspect of apoptosis, more evident cortically; otherwise, reversible degenerative phenomena represented by hydropic ballooning with extensive cytoplasmic vacuolization and discontinuity of the cell brush borders in the proximal tubular epithelium were observed; furthermore, necrotic detachment of these cells into the tubular lumina, and increased amount of protein deposits in the distal and proximal tubules were observed. In conclusion, the slowness of blood flow and of glomerular filtration resulted in more time for filtration and tubular reabsorption, with elevation of the total percentage of sodium and chlorine reabsorption. The maintenance of the decrease in glomerular filtration rate would determine the subsequent decreases, which were noticed in these parameters. The necrosis observed was the result of damage cell induced by l-amino acid oxidase isolated from B. insularis venom.

Purification and biological effects of C-type lectin isolated from Bothrops insularis venom.

Bothrops insularis is a snake from Queimada Grande Island, which is an island located about 20 miles away from the southeastern coast of Brazil. Compared to other Brazilian species of Bothrops, the toxinology of B. insularis is still poorly understood. Its C-type lectin is involved in several biological processes including anticoagulant and platelet-modulating activities. We purified the C-type lectin (BiLec) from Bothrops insularis venom and investigated its effect in the isolated kidney. BiLec was purified after two chromatographic steps; firstly, the whole venom was submitted to an HPLC molecular exclusion chromatography followed by a second purification through affinity chromatography. B. insularis lectin (BiLec) was studied as to its effect on the renal function of isolated perfused rat kidneys with the use of six Wistar rats. The concentration of 10mug/mL increased perfusion pressure (PP; control(60)=108.27+/-4.9; BiLec(60)=112.9+/-5.4 mmHg; *p<0.05) and renal vascular resistance (RVR; control(60)=5.38+/-0.51; BiLec(60)=6.01+/-0.57 mmHg; *p<0.05). The urinary flow reduced significantly at 90 and 120 min of perfusion (UF; control(120)=0.160+/-0.020; BiLec(120)=0.082+/-0.008 mL g(-1) min(-1); *p<0.05). Glomerular filtration rate (GFR; control(120)=0.697+/-0.084; BiLec(120)=0.394+/-0.063 mL g(-1) min(-1); *p<0.05) diminished only at 120 min. BiLec did not change the percentage of sodium (TNa(+)), potassium (TK(+)) and chloride tubular transport (TCl(-)). The histological alterations probably reflected direct injury on glomerular and tubular renal cells, as demonstrated by the rise in permeability of glomerular endothelial cells, revealed by the presence of a proteinaceous material in the Bowman space. We postulate that the C-type lectin B. insularis promoted its effects probably through interactions with endothelial cells or through the release of other mediators by tubular, mesangial and endothelial cells.

Renal effects and vascular reactivity induced by Tityus serrulatus venom.

Tityus serrulatus, popularly known as yellow scorpion, is one of the most studied scorpion species in South America and its venom has supplied some highly active molecules. The effects of T. serrulatus venom upon the renal physiology in human showed increased renal parameters, urea and creatinine. However, in perfused rat kidney the effects were not tested until now. Isolated kidneys from Wistar rats, weighing 240-280 g, were perfused with Krebs-Henseleit solution containing 6% (g weight) of previously dialysed bovine serum albumin. The effects of T. serrulatus venom were studied on the perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), sodium tubular transport (%TNa+), potassium tubular transport (%TK+) and chloride tubular transport (%TCl-). Tityus serrulatus venom (TsV; 10 microg/mL) was added to the system 30 min after the beginning of each experiment (n=6). This 30 min period was used as an internal control. The mesenteric bed was perfused with Krebs solution kept warm at 37 degrees C by a constant flow (4 mL/min), while the variable perfusion pressure was measured by means of a pressure transducer. The direct vascular effects of TsV (10 microg/mL/min; n=6), infused at a constant rate (0.1 mL/min), were examined and compared to the infusion of the vehicle alone at the same rate. TsV increased PP (PP30'=127.8+/-0.69 vs PP60'=154.2+/-14 mmHg*, *p<0.05) and RVR (RVR30'=6.29+/-0.25 vs RVR60'=8.03+/-0.82 mmHg/mLg(-1)min(-1)*, *p<0.05), decreased GFR (GFR30'=0.58+/-0.02 vs GFR60'=0.46+/-0.01mLg(-1)min(-1)*, *p<0.05) and UF (UF30'=0.135+/-0.001 vs UF60'=0.114+/-0.003mLg(-1)min(-1)*, *p<0.05). Tubular transport was not affected during the whole experimental period (120 min). On the other hand, the infusion of TsV (10 microg/mL/min) increased the basal perfusion pressure of isolated arteriolar mesenteric bed (basal pressure: 74.17+/-3.42 vs TsV 151.8+/-17.82 mmHg*, *p<0.05). TsV affects renal haemodynamics probably by a direct vasoconstrictor action leading to decreased renal flow.

The renal effects of alginates isolated from brown seaweed Sargassum vulgare.

Alginates isolated from Sargassum vulgare, present a strong antitumor activity, associated with kidney reversible damage, as analysed by histopathology of treated animals. In the present study, the renal alteration mechanisms of S. vulgare alginates were investigated using the isolated perfused rat kidney and the isolated perfused rat mesenteric blood vessel methods. The results showed that the effects of Sargassum vulgare low viscosity (SVLV) alginate were more potent than those of Sargassum vulgare high viscosity (SVHV) alginate in the isolated rat kidney. The SVLV alginate caused considerable changes in renal physiology, as shown by an increase in parameters such as perfusion pressure, renal vascular resistance, glomerular filtration rate, urinary flow and sodium, potassium and chloride excretion and by reduction of chloride tubular transport. The effects of SVHV were weaker than those of SVLV. The effects of SVLV on kidney could be related to direct vascular action as demonstrated with SVLV alginate on mesenteric blood vessels. In conclusion, the Sargassum vulgare alginate altered the renal function parameters evaluated. S. vulgare low viscosity alginate renal effects were more potent than S. vulgare high viscosity alginate. It is suggested that physicochemical differences between SVHV and SVLV could explain the differences found in the results.