• ADPKD
• CKD progression
• endothelial dysfunction
• hypoxia
• oxidative stress

The mammalian (or mechanistic) target of rapamycin (mTOR) pathway has a key role in the regulation of a variety of biological processes pivotal for cellular life, aging, and death. Impaired activity of mTOR complexes (mTORC1/mTORC2), particularly mTORC1 overactivation, has been implicated in a plethora of age-related disorders, including human renal diseases. Since the discovery of rapamycin (or sirolimus), more than four decades ago, advances in our understanding of how mTOR participates in renal physiological and pathological mechanisms have grown exponentially, due to both preclinical studies in animal models with genetic modification of some mTOR components as well as due to evidence coming from the clinical experience. The main clinical indication of rapamycin is as immunosuppressive therapy for the prevention of allograft rejection, namely, in renal transplantation. However, considering the central participation of mTOR in the pathogenesis of other renal disorders, the use of rapamycin and its analogs meanwhile developed (rapalogues) everolimus and temsirolimus has been viewed as a promising pharmacological strategy. This article critically reviews the use of mTOR inhibitors in renal diseases. Firstly, we briefly overview the mTOR components and signaling as well as the pharmacological armamentarium targeting the mTOR pathway currently available or in the research and development stages. Thereafter, we revisit the mTOR pathway in renal physiology to conclude with the advances, drawbacks, and challenges regarding the use of mTOR inhibitors, in a translational perspective, in four classes of renal diseases: kidney transplantation, polycystic kidney diseases, renal carcinomas, and diabetic nephropathy.

Autosomal dominant polycystic kidney disease (ADPKD) causes progressive loss of renal function in adults as a consequence of the accumulation of cysts. ADPKD is the most common genetic cause of end-stage renal disease. Mutations in polycystin-1 occur in 87% of cases of ADPKD and mutations in polycystin-2 are found in 12% of ADPKD patients. The complexity of ADPKD has hampered efforts to identify the mechanisms underlying its pathogenesis. No current FDA (Federal Drug Administration)-approved therapies ameliorate ADPKD progression.

We used the de Almeida laboratory’s sensitive new transcriptogram method for whole-genome gene expression data analysis to analyze microarray data from cell lines developed from cell isolates of normal kidney and of both non-cystic nephrons and cysts from the kidney of a patient with ADPKD. We compared results obtained using standard Ingenuity Volcano plot analysis, Gene Set Enrichment Analysis (GSEA) and transcriptogram analysis. Transcriptogram analysis confirmed the findings of Ingenuity, GSEA, and published analysis of ADPKD kidney data and also identified multiple new expression changes in KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways related to cell growth, cell death, genetic information processing, nucleotide metabolism, signal transduction, immune response, response to stimulus, cellular processes, ion homeostasis and transport and cofactors, vitamins, amino acids, energy, carbohydrates, drugs, lipids, and glycans. Transcriptogram analysis also provides significance metrics which allow us to prioritize further study of these pathways.

Transcriptogram analysis identifies novel pathways altered in ADPKD, providing new avenues to identify both ADPKD’s mechanisms of pathogenesis and pharmaceutical targets to ameliorate the progression of the disease.

The online version of this article (doi:10.1186/s40246-016-0095-x) contains supplementary material, which is available to authorized users.

• Autosomal dominant polycystic kidney disease
• Bioinformatics
• Cystic kidney disease
• Kidney
• Pathway identification
• Transcriptogram

Autosomal dominant polycystic kidney disease (ADPKD), the most frequent cause of genetic renal disease affecting approximately 4 to 7 million individuals worldwide and accounting for 7%-15% of patients on renal replacement therapy, is a systemic disorder mainly involving the kidney but cysts can also occur in other organs such as the liver, pancreas, arachnoid membrane and seminal vesicles. Though computed tomography and magnetic resonance imaging (MRI) were similar in evaluating 81% of cystic lesions of the kidney, MRI may depict septa, wall thickening or enhancement leading to upgrade in cyst classification that can affect management. A screening strategy for intracranial aneurysms would provide 1.0 additional year of life without neurological disability to a 20-year-old patient with ADPKD and reduce the financial impact on society of the disease. Current treatment strategies include reducing: cyclic adenosine monophosphate levels, cell proliferation and fluid secretion. Several randomised clinical trials (RCT) including mammalian target of rapamycin inhibitors, somatostatin analogues and a vasopressin V2 receptor antagonist have been performed to study the effect of diverse drugs on growth of renal and hepatic cysts, and on deterioration of renal function. Prophylactic native nephrectomy is indicated in patients with a history of cyst infection or recurrent haemorrhage or to those in whom space must be made to implant the graft. The absence of large RCT on various aspects of the disease and its treatment leaves considerable uncertainty and ambiguity in many aspects of ADPKD patient care as it relates to end stage renal disease (ESRD). The outlook of patients with ADPKD is improving and is in fact much better than that for patients in ESRD due to other causes. This review highlights the need for well-structured RCTs as a first step towards trying newer interventions so as to develop updated clinical management guidelines.

• Autosomal dominant polycystic kidney disease
• Native nephrectomy
• Cyst decortication
• Kidney transplantation
• Hypertension
• Drug therapy
• End stage renal disease
• Extrarenal manifestatation
• Total kidney volume

• TORC inhibitors
• meta-analysis
• polycystic kidney disease
• somatostatin analogues
• vasopressin receptor antagonists

The average weight of a kidney is approximately 135 gm, measuring on average 10 × 6 × 4 cm. In hereditary conditions, autosomal dominant and autosomal recessive polycystic kidney disease, the shape, size, and the weight can be significantly abnormal, causing progressive renal failure, often necessitating dialysis or renal transplant for survival. We report a case of adult polycystic kidney disease in a 50-year-old female without a family history, who died of complications of the disease which included accelerated hypertension, and renal and cardiac failure.

• bosutinib
• everolimus
• lanreotide
• mammalian target of rapamycin
• octreotide
• polycystic kidney disease
• sirolimus
• somatostatin
• tolvaptan
• triptolide

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies.