Kidney and pancreas transplant candidacy.

PURPOSE OF REVIEW: Kidney and/or pancreas transplantation candidacy criteria have evolved significantly over time reflecting improved pre and post-transplant management. With improvement in medical care, potential candidates for transplant not only are older but also have complex medical issues. This review focuses on the latest trends regarding candidacy for kidney and/or pancreas transplantation along with advances in pretransplant cardiac testing. RECENT FINDINGS: More candidates are now eligible for kidney and/or pancreas transplantation owing to less stringent candidacy criteria especially in regards to age, obesity, frailty and history of prior malignancy. Pretransplant cardiovascular assessment has also come a long way with a focus on less invasive strategies to assess for coronary artery disease. SUMMARY: Criteria for kidney and/or pancreas transplantation are expanding. Patients who in the past might have been declined because of numerous factors are now finding that transplant centers are more open minded to their candidacy, which could lead to better access to organ transplant wait list.

Deficit of p66ShcA restores redox-sensitive stress response program in cisplatin-induced acute kidney injury.

Overwhelming oxidative stress and compromised tubular cell antioxidant response have been incriminated for cisplatin (Cis)-induced acute kidney injury (AKI). We hypothesized that Cis-induced AKI was the outcome of the deactivated redox-sensitive stress response program (RSSRP). Wild type (WT) and heterozygous p66ShcA(p66(+/-)) mice in groups of six were administered either normal saline (WT) or Cis (12.5 mg/kg, intraperitoneal, Cis/WT). Renal biomarkers were collected and kidneys were harvested for renal histology. Cis/WT showed elevated blood urea nitrogen levels and enhanced tubular cell apoptosis, necrosis, and dilated tubules filled with casts when compared to Cis/p66(+/-). Cis/p66(+/-) developed only a clinically occult AKI (normal blood urea levels and only microscopic alterations). Immunoblots from the lysates of renal tissues of Cis/WT displayed enhanced expression of phospho-p66ShcA, and phospho-Foxo3A but attenuated expression of MnSOD and catalase; conversely, p66 deficit prevented these alterations in Cis milieu. In in vitro studies, Cis treated mouse proximal tubular cells (MPTCs) displayed enhanced phosphorylation of p66ShcA and no increase in tubular cell expression of MnSOD. In addition, renal tissues of Cis/WT and Cis-treated MPTCs displayed enhanced phosphorylation of p53 and Bax expression. However, MPTC partially silenced for p66ShcA displayed partial inhibition of Cis-induced tubular cell apoptosis as well as necrosis. These findings indicate that Cis-induced AKI is the outcome of the deactivated RSSRP (attenuated anti-oxidant response) and activation of pro-apoptotic (p53-induced Bax expression) pathway.

Sirolimus modulates HIVAN phenotype through inhibition of epithelial mesenchymal transition.

HIV-associated nephropathy (HIVAN) is characterized by proliferative phenotype in the form of collapsing glomerulopathy and microcystic dilatation of tubules. Recently, epithelial mesenchymal transition (EMT) of renal cells has been demonstrated to contribute to the pathogenesis of proliferative HIVAN phenotype. We hypothesized that sirolimus would modulate HIVAN phenotype by attenuating renal cell EMT. In the present study, we evaluated the effect of sirolimus on the development of renal cell EMT as well as on display of HIVAN phenotype in a mouse model of HIVAN (Tg26). Tg26 mice receiving normal saline (TgNS) showed enhanced proliferation of both glomerular and tubular cells when compared to control mice-receiving normal saline (CNS); on the other hand, Tg26 mice receiving sirolimus (TgS) showed attenuated renal cell proliferation when compared with TgNS. TgNS also showed increased number of α-SMA-, vimentin-, and FSP1-positive cells (glomerular as well as tubular) when compared with CNS; however, TgS showed reduced number of SMA, vimentin, and FSP1+ve renal cells when compared to TgNS. Interestingly, sirolimus preserved renal epithelial cell expression of E-cadherin in TgS. Since sirolimus attenuated renal cell ZEB expression (a repressor of E-cadherin transcription), it appears that sirolimus may be attenuating renal cell EMT by preserving epithelial cell E-cadherin expression.

HIV-associated nephropathy: role of AT2R.

AT(1)R has been reported to play an important role in the progression of HIV-associated nephropathy (HIVAN); however, the effect of AT(2)R has not been studied. Age and sex matched control (FVB/N) and Tg26 mice aged 4, 8, and 16weeks were studied for renal tissue expression of AT(1)R and AT(2)R (Protocol A). Renal tissue mRNA expression of AT(2)R was lower in Tg26 mice when compared with control mice. In Protocol B, Tg26 mice were treated with either saline, telmisartan (TEL, AT(1) blocker), PD123319 (PD, AT(2)R blocker), or TEL+PD for two weeks. TEL-receiving Tg26 (TRTg) displayed less advanced glomerular and tubular lesions when compared with saline-receiving Tg26 (SRTg). TRTgs displayed enhanced renal tissue AT(2)R expression when compared to SRTgs. Diminution of renal tissue AT(2)R expression was associated with advanced renal lesions in SRTgs; whereas, upregulation of AT(2)R expression in TRTgs was associated with attenuated renal lesions. PD-receiving Tg26 mice (PDRTg) did not show any alteration in the course of HIVAN; whereas, PD+TEL-receiving Tg26 (PD-TRTg) showed worsening of renal lesions when compared to TRTgs. Interestingly, plasma as well as renal tissues of Tg26 mice displayed several fold higher concentration of Ang III, a ligand of AT(2)R.