Successful Preemptive Kidney Transplantation With Rituximab Induction in a Patient With Focal Segmental Glomerulosclerosis and Massive Nephrotic Syndrome: A Case Report.

Primary focal segmental glomerulosclerosis (FSGS) recurs in 30% of patients receiving their first kidney transplant and often leads to graft loss. In the past, patients with FSGS and overt nephrotic syndrome rarely underwent transplantation. Rituximab (RTX), an anti-CD20-specific monoclonal antibody, was previously reported to be a valuable option in treating relapsing FSGS after kidney transplantation. We report here the first successful kidney transplantation in a young patient with primary FSGS and massive nephrotic syndrome treated with RTX induction. The patient was a 24-year-old woman who had developed nephrotic syndrome at the age of 4 years. FSGS was confirmed by results of a kidney biopsy, with subsequent treatment with cyclosporine and steroids, without remission. She was referred for a preemptive, deceased donor kidney transplant despite proteinuria levels reaching ∼10 g/d. She received induction therapy with 2 doses of RTX (375 mg/m2) at days 0 and 7, followed by tacrolimus 5 mg twice daily, mycophenolate mofetil 500 mg twice daily, and steroids after transplantation. Immediate kidney graft function was observed, with no proteinuria since day 13 posttransplant. The pretransplant soluble urokinase-type plasminogen activator receptor serum concentration was 4550 pg/mL; it decreased to 2191 pg/mL at day 13 and was 2073 pg/mL at 6 months' posttransplant. Thirty months after transplantation, the patient's serum creatinine level is 0.8 mg/dL, and no proteinuria has been observed. Successful kidney transplantation in a patient with pretransplant overt nephrotic syndrome secondary to FSGS, using rituximab as an induction therapy, is possible. Further recommendations for transplantation in such patients, however, should be based on results from larger clinical trials.

Glycated and carbamylated albumin are more "nephrotoxic" than unmodified albumin in the amphibian kidney.

There is increasing evidence that proteins in tubular fluid are "nephrotoxic." In vivo it is difficult to study protein loading of tubular epithelial cells in isolation, i.e., without concomitant glomerular damage or changes of renal hemodynamics, etc. Recently, a unique amphibian model has been described which takes advantage of the special anatomy of the amphibian kidney in which a subset of nephrons drains the peritoneal cavity (open nephrons) so that intraperitoneal injection of protein selectively causes protein storage in and peritubular fibrosis around open but not around closed tubules. There is an ongoing debate as to what degree albumin per se is nephrotoxic and whether modification of albumin alters its nephrotoxicity. We tested the hypothesis that carbamylation and glycation render albumin more nephrotoxic compared with native albumin and alternative albumin modifications, e.g., lipid oxidation and lipid depletion. Preparations of native and modified albumin were injected into the axolotl peritoneum. The kidneys were retrieved after 10 days and studied by light microscopy as well as by immunohistochemistry [transforming growth factor (TGF)-ß, PDGF, NF-κB, collagen I and IV, RAGE], nonradioactive in situ hybridization, and Western blotting. Two investigators unaware of the animal groups evaluated and scored renal histology. Compared with unmodified albumin, glycated and carbamylated albumin caused more pronounced protein storage. After no more than 10 days, selective peritubular fibrosis was seen around nephrons draining the peritoneal cavity (open nephrons), but not around closed nephrons. Additionally, more intense expression of RAGE, NF-κB, as well as PDGF, TGF-ß, EGF, ET-1, and others was noted by histochemistry and confirmed by RT-PCR for fibronectin and TGF-ß as well as nonradioactive in situ hybridization for TGF-ß and fibronectin. The data indicate that carbamylation and glycation increase the capacity of albumin to cause tubular cell damage and peritubular fibrosis.

Prenatal causes of kidney disease.

It has recently been increasingly recognised that disturbed intra-uterine development may impact on renal and cardiovascular risk in adult life, e.g. albuminuria and chronic kidney disease, hypertension, type 2 diabetes or cardiovascular events. According to Barker's hypothesis, when resources in utero are restricted, their allocation to the development of the kidney and pancreatic islets is restricted to guarantee appropriate development of the brain and heart. The underlying epigenetic mechanisms involve modification of gene expression by altered DNA methylation and histone acetylation as well as by allocation of stem cells. The result of this trade-off between the brain and kidney during organogenesis is a diminished number of nephrons ('nephron underdosing') which predisposes to albuminuria and risk of chronic kidney disease, as well as hypertension. In parallel, changed appetite centres, insulin resistance and beta-cell development predispose to obesity, metabolic syndrome and type 2 diabetes and the resulting renal sequelae. Numerous factors may trigger intra-uterine restriction of fetal growth, such as uterine underperfusion, maternal malnutrition, hyperglycaemia and hyperinsulinaemia of the mother, smoking or medications.

Growth hormone treatment prevents osteoporosis in uremic rats.

INTRODUCTION: Growth hormone (GH) is responsible for longitudinal bone growth. GH-receptor in the growth plate was found to be decreased in chronic renal insufficiency. A therapeutic use of GH in chronic renal insufficiency is not established. The current study aims to clarify the effects of GH treatment on bone metabolism in a uremic rat model. METHODS: Sprague Dawley rats were subjected to subtotal surgical renal ablation (SNX) or sham operation. SNX rats were randomized into 4 groups: treated with different doses of GH (1.5, 4.0, or 10.0 mg/kg) or vehicle after 10 weeks of uremia and treated for 6 weeks. Bone and renal morphology was evaluated: bone density, thickness of spongiosa, osteoblast surface, osteoid volume, osteoclast quantity, and resorptive volume. RESULTS: GH treatment resulted in a decrease of resorption area and lower number of osteoclasts. Osteoid volume, number of osteoblasts, percentage of active osteoblasts, thickness of the growth plate and mean cortical width increased. GH receptor (GHR) protein expression increased in GH treated rats. IGF-1 expression was decreased in osteoblasts and chondroblasts of SNX-V rats and increased following GH treatment. The TGF-beta expression was down regulated in SNX+V group in osteocytes and chondroblasts as compared to sham operated animals. The down regulation was prevented in treated animals irrespective of the dose given. CONCLUSIONS: Treatment with GH in uremic animals increased bone density to the levels of non-uremic controls. Thus GH seems to have a potential of preventing renal osteodystrophy.