Kidney Allograft Fibrosis: Diagnostic and Therapeutic Strategies.

Interstitial fibrosis with tubule atrophy (IF/TA) is the response to virtually any sustained kidney injury and correlates inversely with kidney function and allograft survival. IF/TA is driven by various pathways that include hypoxia, renin-angiotensin-aldosterone system, transforming growth factor-ß signaling, cellular rejection, inflammation, and others. In this review, we will focus on key pathways in the progress of renal fibrosis, diagnosis and therapy of allograft fibrosis. This review discusses the role and origin of myofibroblasts as matrix producing cells and therapeutic targets in renal fibrosis with a particular focus on renal allografts. We summarize current trends to use multiomic approaches to identify new biomarkers for IF/TA detection and to predict allograft survival. Furthermore, we review current imaging strategies that might help to identify and follow-up IF/TA complementary or as alternative to invasive biopsies. We further discuss current clinical trials and therapeutic strategies to treat kidney fibrosis.

Preclinical development of small-molecular-weight folate-based radioconjugates: a pharmacological perspective.

The folate receptor (FR) has attracted attention as a target structure because of its frequent expression in cancer cells (FR-α) and activated macrophages (FR-ß). The vitamin folic acid has served as a promising targeting ligand allowing selective delivery of attached radionuclides suitable for imaging of the diseased sites and for therapeutic application. A large number of folate radioconjugates with variable chemical structures have been developed over the last 25 years. Accumulation of radioactivity in healthy organs and tissues was always seen in the kidneys due to the expression of the FR in the proximal tubule cells. In some cases unspecific uptake of radiofolates was also seen in the liver and the intestinal tract. To address this situation and improve the target-to-off-target ratios of accumulated radioactivity several strategies were undertaken, including chemical modifications of the folate conjugates, selection of appropriate radionuclides and application of drug combinations. Depending on the radionuclide which was employed various chelators and linker entities were investigated and additional functionalities with albumin-binding properties were tested with the aim to increase the serum half-life of the radioconjugates. A number of diagnostic radionuclides ((99m)Tc, (111)In, (67)Ga, (155)Tb, (125)I) emitting γ-radiation were employed for single photon emission computed tomography (SPECT) and, ß(+)-emitting radionuclides ((68)Ga, 44Sc, (152)Tb, (18)F) were used for positron emission tomography (PET). Moreover, therapeutic radionuclides emitting ß(-)-particles ((177)Lu, (161)Tb, (47)Sc, (131)I) and α-particles ((149)Tb) were also used with folate conjugates. The present review focuses on the development of radiofolates and their in vivo properties and on strategies which were employed to modify their pharmacokinetic and pharmacodynamic properties.

Effects of renal artery reconstruction on kidney perfusion and tubular function measured by new radionuclide techniques.

Therapeutic effects of renal artery reconstruction on kidney perfusion and function were studied in 36 patients using new methods for analyzing radionuclide studies. Effective renal plasma flow, glomerular filtration fraction and parameters indicating perfusion and tubular transport improved significantly in patients with postoperative normalization of blood pressure. Patients with a patent renal artery on angiogram but without normalization of blood pressure showed an improvement of parameters such as effective renal plasma flow, glomerular filtration fraction and tubular transport time, whereas the perfusion index remained unchanged. In the group with re-stenosis or re-occlusion all parameters deteriorated after surgery. Discriminant analysis of preoperative data showed that success of surgery could be predicted with high degree of certainty (65% for improvement and 92% for no improvement). The results indicate, that radionuclide methods and arteriography are complementary in the evaluation of the hemodynamic consequences of a renal artery stenosis. They also help to assess the effects of reconstructive surgery and to predict operative success.

Phase I study of the cisplatin analogue 1,1-diamminomethylcyclohexane sulfatoplatinum (TNO-6) (NSC 311056).

The cisplatin derivative TNO-6 was evaluated for clinical toxicity in a phase I trial. TNO-6 was given daily for 5 days every 3 weeks as a 30-min IV infusion without hydration. In all, 39 patients with advanced cancer were treated at doses of 2.5-9.0 mg/m2. No dose-limiting nephrotoxicity occurred, but evidence of mild, reversible tubular damage was found. Dose-limiting toxicity was hematologic with both thrombopenia and leukocytopenia, which with high dose levels reached WHO grade 4. Hematologic toxicity was most pronounced for pretreated patients. No antitumor activity was seen. The recommended dose for phase II trials will be 9.0 mg/m2 for previously untreated and 8.0 mg/m2 for pretreated patients.