RESUMO
BACKGROUND: Cystinuria is a rare genetic kidney stone disease, with no cure. Current treatments involve lowering urinary cystine levels and increasing cystine solubility. This systematic review evaluates the available literature regarding non-surgical interventions for cystinuria. METHODS: Key electronic databases were searched for studies that described the clinical management of cystinuria with high diuresis, alkalinizing agents and thiol-based drugs that were published between 2000 and 2022. Observational studies were included if they contained clinical investigation with at least one previous or current episode of cystine stones, urine cystine levels > 250 mg/L and patients being managed with urinary dilution, alkalinizing agents or other pharmacological agents. All included studies were assessed for study design, patient characteristics and outcomes. A qualitative and critical analysis was performed whereby study quality was assessed using Methodological Index for Non-Randomized Studies (MINORS). Two authors performed the quality assessment and excluded the studies with a low MINORS score. RESULTS: Fourteen studies met the review inclusion and quality criteria. Of the fourteen studies, two reported treatment using alkalinizing agents, six reported treatment using thiol-based drugs, and six reported combination treatment using alkalinizing agents and thiol-based drugs. These studies indicated that first-line therapies, including high fluid intake and urinary alkalinization, increased urine volume to > 3 L/day and urinary pH > 7.0, and were associated with reduced urinary cystine levels and cystine stone formation. Second-line therapy with cystine-binding thiol drugs, such as tiopronin and D-penicillamine, reduced urinary cystine levels, cystine crystal volume and increased cystine solubility, resulting in decreased cystine stone formation and stone recurrence rate. Further, combined intervention with alkalinizing agents and thiol-based drugs synergistically reduced stone recurrence. CONCLUSION: Cystinuria treatment may require a combined approach of high diuresis, alkalinization and pharmacological interventions with regular monitoring of urinary pH, cystine levels, cystine crystal volume and solubility. However, poor adherence to treatment is relatively frequent, hence the pressing urgency for improved therapies and treatments.
RESUMO
Renal failure is observed in the pathological progression of sepsis and septic shock. Renal mesangial cells (RMCs) have been implicated in renal failure as a result of producing mediators, such as monocyte chemoattractant protein-1 (MCP-1) in response to lipopolysaccharide (LPS). Mitogen-activated protein kinases (MAPKs) have been demonstrated to mediate the LPS-induced inflammatory response in RMCs. Although previous studies indicated a promising effect of apocynin in various inflammatory conditions, its antiseptic efficacy in mesangial cells remains to be clearly determined. In the present study, the anti-inflammatory effects of apocynin and its underlying mechanism were examined in LPS-challenged RMCs. Apocynin significantly inhibited nitric oxide (NO) production in LPS-challenged RMCs and the expression levels of inducible NO synthase and cyclooxygenase-2. In addition, the level of LPS-induced MCP-1 expression was significantly attenuated with apocynin. Furthermore, apocynin significantly suppressed the activation of MAPKs, such as extracellular signal-regulated kinases 1/2 and p38, but not c-Jun N-terminal kinases. Apocynin exhibited significantly increased expression of heme oxygenase-1 (HO-1) induction via nuclear factor (erythroid-derived 2)-like-2 (Nrf-2) phosphorylation. Inhibition of HO-1 with zinc protoporphyrin significantly abolished apocynin-induced suppression of MCP-1, indicating that HO-1 is significant in the suppression of MCP-1. Thus, apocynin exerts antiseptic activity via the suppression of pro-inflammatory signaling pathways and the activation of cytoprotective signaling pathways, such as HO-1/Nrf-2 in RMCs, indicating that apocynin may present as a promising candidate for in vivo evaluation of a therapeutic agent for inflammation-associated renal disorders.