Isogeneic MSC application in a rat model of acute renal allograft rejection modulates immune response but does not prolong allograft survival.

Application of mesenchymal stromal cells (MSCs) has been proposed for solid organ transplantation based on their potent immuno-modulatory effects in vitro and in vivo. We investigated the potential of MSCs to improve acceptance of kidney transplants in an MHC-incompatible rat model including isogeneic kidney transplantation (RTx) as control. MSCs were administered i.v. or i.a. at time of transplantation. No immunosuppression was applied. Renal function was monitored by serum-creatinine, histopathology, immunochemistry for graft infiltrating cells and expressions of inflammatory genes. We demonstrated the short-term beneficial effects of MSC injection. In the long term, however, MSC-related life-threatening/shortening events (thrombotic microangiopathy, infarctions, infections) were evident despite decreased T- and B-cell infiltration, lower interstitial inflammation and downregulated inflammatory genes particularly after i.a. MSC injection. We conclude that i.a. MSC administration provides efficient immunomodulation after allogeneic RTx, although timing and co-treatment strategies need further fine-tuning to develop the full potential of powerful cell therapy in solid organ transplantation.

Secondary nephrogenic diabetes insipidus as a complication of inherited renal diseases.

BACKGROUND/AIMS: Nephrogenic diabetes insipidus (NDI) is a serious condition with large water losses in the urine and the risk of hypernatremic dehydration. Unrecognized, repeated episodes of hypernatremic dehydration can lead to permanent brain damage. Primary NDI is due to mutations in either AVPR2 or AQP2. NDI can also occur as a secondary complication, most commonly from obstructive uropathy or chronic lithium therapy. We observed NDI in patients with inherited tubulopathies and aimed to define the clinical and molecular phenotype. METHODS: We reviewed the medical notes of 4 patients with clinical NDI and an underlying molecularly confirmed diagnosis of nephropathic cystinosis, Bartter syndrome, nephronophthisis and apparent mineralocorticoid excess, respectively. RESULTS: The patients all failed to concentrate their urine after administration of 1-desamino[8-D-arginine] vasopressin. None had an identifiable mutation in AVPR2 or AQP2, consistent with secondary NDI. Patients experienced repeated episodes of hypernatremic dehydration, and in 2 cases, NDI was initially thought to be the primary diagnosis, delaying recognition of the underlying problem. CONCLUSION: The recognition of this potential complication is important as it has direct implications for clinical management. The occurrence of NDI in association with these conditions provides clues for the etiology of aquaporin deficiency.

Nodular B-cell aggregates associated with treatment refractory renal transplant rejection resolved by rituximab.

Acute rejection episodes leading to treatment refractory early graft loss are increasingly rare events in living related renal transplantation today. Pathophysiologic pathways often remain unsolved. We report on tubulointerstitial and vascular rejection developing within 2 weeks after transplantation in a 12-year-old boy treated with cyclosporine, mycophenolate, steroids and double blinded basiliximab. Despite steroid pulses, switch to tacrolimus and ATG serum creatinine peaked at 347 micromol/L with imminent graft loss and ongoing C4d negative cellular vascular rejection. Permanent gain of function was only achieved after a single dose of rituximab. Retrospectively CD20+ nodular B-cell aggregates could be demonstrated in all three biopsies obtained prior to rituximab and resolved concomitantly with functional improvement. Our case for the first time demonstrates resolution of nodular CD20+ infiltrates and decline of OX40, NF-kappaB and CTL transcription shortly after rituximab indicating a B-cell facilitated C4d negative pathway. Single dose rituximab may effectively reverse even long-lasting refractory rejection.

Cyclosporin A monitoring by 2-h levels: preliminary target levels in stable pediatric kidney transplant recipients.

Clinical trials in adults have shown that management of transplanted patients with cyclosporin A (CsA) 2-h levels (C2) lead to superior outcome compared with monitoring of 12-h trough levels (C0). In both adults and children, C2 levels enabled a better estimation of the area under the curve concentration than C0 levels. Therefore, it can be suspected that C2 monitoring might also lead to a better outcome in children. Until now C2 target levels for children have not been defined. We measured C2 levels in 101 stable pediatric kidney recipients with a minimum time of 1 yr after transplantation. C2 levels were compared with changes in glomerular filtration rate (GFR) 6 months later. Median C2 levels in children after renal transplantation were 714 ng/mL (95% confidence interval 654-774). Patients with C2 levels below 750 ng/mL had a significantly higher percentage of decline in GFR than patients with C2 levels above 750 ng/mL (p < 0.05). In children with C2 levels below 500 ng/mL three acute rejections occurred in comparison with no rejection in the remaining patients (p < 0.05). We conclude that the lower C2 target level should be above 750 ng/mL in stable pediatric transplant recipients. An upper target level above 1000 ng/mL should be avoided. The question, whether C2 monitoring in pediatric kidney recipients is superior to C0 monitoring, is yet to be answered.