Tubular dysfunction in renal transplant patients using sirolimus or tacrolimus

Banhara, Pedro B; Gonçalves, Renato Torres; Rocha, Pedro; Delgado, Alvimar G.; Leite, Maurilo; Gomes, Carlos Perez

doi:10.5414/cn108541

Cited by 14 publications

(10 citation statements)

References 15 publications

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“…Rapa is regularly used as an immunosuppressant in solid organ transplantation rejection, and its use has also been recently exploited for certain autoimmune diseases and cancers. 33 – 35 However, Rapa's systemic use has been limited by its side effects, including stomatitis, 36 nephrotoxicity, 37 , 38 and pulmonary toxicity. 39 In our previous study, nephrotoxicity was observed even with short-term use (three doses over 1 week).…”

mentioning

confidence: 99%

Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

Shah

Edman

Janga

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeTo evaluate the efficacy of topical rapamycin in treating autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome.MethodsWe developed rapamycin in a poly(ethylene glycol)-distearoyl phosphatidylethanolamine (PEG-DSPE) micelle formulation to maintain solubility. Rapamycin or PEG-DSPE eye drops (vehicle) were administered in a well-established Sjögren's syndrome disease model, the male nonobese diabetic (NOD) mice, twice daily for 12 weeks starting at 8 weeks of age. Mouse tear fluid was collected and tear Cathepsin S, a putative tear biomarker for Sjögren's syndrome, was measured. Lacrimal glands were retrieved for histological evaluation, and quantitative real-time PCR of genes associated with Sjögren's syndrome pathogenesis. Tear secretion was measured using phenol red threads, and corneal fluorescein staining was used to assess corneal integrity.ResultsLymphocytic infiltration of lacrimal glands from rapamycin-treated mice was significantly (P = 0.0001) reduced by 3.8-fold relative to vehicle-treated mice after 12 weeks of treatment. Rapamycin, but not vehicle, treatment increased tear secretion and decreased corneal fluorescein staining after 12 weeks. In rapamycin-treated mice, Cathepsin S activity was significantly reduced by 3.75-fold in tears (P < 0.0001) and 1.68-fold in lacrimal gland lysates (P = 0.003) relative to vehicle-treated mice. Rapamycin significantly altered the expression of several genes linked to Sjögren's syndrome pathogenesis, including major histocompatibility complex II, TNF-α, IFN-γ, and IL-12a, as well as Akt3, an effector of autophagy.ConclusionsOur findings suggest that topical rapamycin reduces autoimmune-mediated lacrimal gland inflammation while improving ocular surface integrity and tear secretion, and thus has potential for treating Sjögren's syndrome–associated dry eye.

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confidence: 99%

Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

Shah

Edman

Janga

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…A high prevalence of distal RTA has been documented in the transplant recipients receiving the mTOR inhibitor sirolimus, suggesting that this immunosuppressant may also cause distal tubular dysfunction. However, it is known if sirolimus can cause proteinuria and hypokalemia, the mechanism of development and prevalence of RTA in these patients remain unclear (3,34).…”

Section: •Other Causesmentioning

confidence: 99%

“…The amount of alkali administered should compensate for the urinary loss of bicarbonate plus the amount of acid generated by the protein catabolism. Besides, it has been strongly proposed that alkalitherapy represents a welltolerated, safe and cost-effective treatment which can slow the progression towards graft failure, therefore prolonging long-term graft survival (34). In clinical practice, metabolic acidosis is usually corrected when serum bicarbonate level is <22 mmol/L (3).…”

Section: Rta Treatmentmentioning

confidence: 99%

Hyperchloremic metabolic acidosis in the kidney transplant patient

Avila-Poletti

Azevedo

Iommi

et al. 2019

Postgraduate Medicine

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Hyperchloremic metabolic acidosis of renal origin results from a defect in renal tubular acidification mechanism, and this tubular dysfunction can consist of an altered tubular proton secretion or bicarbonate reabsorption capability. Studies have documented that all forms of renal tubular acidosis (RTA), type I to IV, are documented in kidney transplant patients. Among RTA pathophysiologic mechanisms have been described such as renal mass reduction, hyperkalemia, hyperparathyroidism, graft rejection, immunologic diseases, and some drugs such as renin-angiotensin-aldosterone blockers, and calcineurin inhibitors. RTA can lead to serious complications as is the case of muscle protein catabolism, muscle protein synthesis inhibition, renal osteodystrophy, renal damage progression, and anemia promotion. RTA should be treated by suppressing its etiologic factor (if it is possible), avoiding hyperkalemia, and/or supplying bicarbonate or a precursor (citrate). In conclusion: Hyperchloremic metabolic acidosis of renal origin is a relatively frequent complication in kidney transplantation patients, which can be harmful, and should be adequately treated in order to avoid its renal and systemic adverse effects.

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“…Despite its high clinical efficiency, tacrolimus has been well known for its adverse reactions. In particular, patients receiving tacrolimus chronically are at high risk to develop cholestasis and renal damage (Yadav et al, 2013;Banhara et al, 2015). Nephrotoxicity was reported in approximately 52% of kidney transplantation patients, 40% of liver transplantation patients receiving tacrolimus and in 59% of heart transplantation patients in US randomized trial (Boudjema et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…In concordance, the results obtained from the present study showed that microscopical examination of the kidney of adult albino rats treated with tacrolimus showed vacuolation of glomeruli and distal tubule. Banhara et al (2015) reported that distal tubular dysfunction is prevalent among kidney transplant patients using tacrolimus. Moreover, Boudjema et al (2011) suggested that tacrolimus induced nephrotoxicity is dose-dependent in transplant patients.…”

mentioning

confidence: 99%

Spirulina protects against tacrolimus-induced hepatic and renal toxicity in rats: A biochemical and histological study

Elzawahry¹,

Abass²,

El-Haleem³

et al. 2016

J. Toxicol. Environ. Health Sci.

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Tacrolimus is a powerful immunosuppressive agent with hepatotoxic and nephrotoxic effects. It has a protective role against many toxicants. This study was conducted to evaluate the possible protective role of spirulina against tacrolimus induced hepatotoxicity and nephrotoxicity. Forty adult male albino rats divided into 4 groups. Group I, control group, Group II, spirulina group (received spirulina 500 mg/Kg body weight (bw)/day orally), Group III, tacrolimus group (received tacrolimus 12 mg/kg bw/day orally); and Group VI, prophylactic group (orally administered spirulina for 3 days before and 28 days concurrently with tacrolimus in the same previous doses). Tacrolimus induced adverse effects on both liver and kidney functions and structure that was manifested by elevated hepatic transaminases, total and direct bilirubin, albumin, blood urea nitrogen, serum creatinine and creatinine clearance. There was a significant decrease in serum total antioxidant capacity (TAC) and hepatic and renal total thiol molecules (TTM), with a significant increase in serum malondialdehyde in tacrolimus group. Histopathologically, tacrolimus induced swelling and granulation of hepatocytes, congestion of blood sinusoids and degeneration of bile ductiles, glomerular hypertrophy and segmentation, swelling, degeneration and hyalinosis of renal tubules. Spirulina pre-and co-treatment significantly improved these deleterious effects. This was accompanied by partial restoration of the expression of PCNA near to the normal level observed in control rats. Moreover, spirulina treatment did not alter the trough blood tacrolimus levels or tacrolimus-induced immunosuppression. Further studies are warranted to evaluate whether transplant patients on tacrolimus treatment may benefit from the protective effects of spirulina.

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Tubular dysfunction in renal transplant patients using sirolimus or tacrolimus

Cited by 14 publications

References 15 publications

Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

Hyperchloremic metabolic acidosis in the kidney transplant patient

Spirulina protects against tacrolimus-induced hepatic and renal toxicity in rats: A biochemical and histological study

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