Successful renal transplantation in a family with a novel mutation in COL4A3 gene and autosomal recessive Alport syndrome

Alport syndrome (AS) is an inherited disorder of basement membranes caused by mutations affecting specific proteins of the type IV collagen family, presenting with nephropathy and extrarenal manifestations such as sensorineural deafness and ocular anomalies. Ten percentage to 15% of the patients with AS have autosomal recessive (ARAS) due to mutation in either COL4A3 or COL4A4 gene. We report a novel mutation in the COL4A3 gene in an Indian family with ARAS. The above‐mentioned genetic anomaly was a missense variation in exon 26 of the COL4A3 gene (chr2:228137797G>A; c.1891G>A) that resulted in the amino acid substitution of Arginine for Glycine at codon 631 (p.Gly631Arg) that was present in the heterozygous state in the asymptomatic parents and homozygous state in the male offspring who presented with early‐onset end‐stage renal disease, lenticonus and hearing loss. The patient (male offspring) underwent successful renal transplantation with his mother as a donor.     

Long-Term Outcomes of Pancreas After Kidney Transplantation in Small Centers: Is It Justified?

Background

Currently, the long-term advantages of having a pancreas transplantation (PT) are debated, particularly in patients receiving pancreas after kidney (PAK) allografts. The United Network for Organ Sharing (UNOS) requires that a transplant center perform a minimum number of PT per year to remain an active PT center. The long-term outcomes and challenges of PAK in small pancreas transplant centers are not well studied.

Methods

In this retrospective analysis, we report short- and long-term outcomes in a small center performing 2–9 PT annually.

Results

Forty-eight PT (25 simultaneous pancreas and kidney transplantation [SPK], 23 PAK) were performed in our center. Donor and recipient demographics were similar in both groups. All suitable local donors were used for SPK. All organs for PAK transplantation were imported from other UNOS regions. Mean follow-up was 61 ± 46 and 74 ± 46 months for SPK and PAK, respectively. Patient and graft survival rates were similar in SPK and PAK groups and better than the reported national average. Four patients (11%) died (1 due to trauma, 1 brain lymphoma, 1 ruptured aneurysm; and 1 unknown cause). Two patients (4%; 1 SPK, 1 PAK) lost their grafts because of thrombosis on postoperative days 3 and 5 in 2002. No graft thrombosis occurred since 2002. Seven patients (15%) required reoperation (4 for bleeding, 2 anastomotic leaks, 1 small bowel perforation). Two patients (4%) developed post-transplantation lymphoproliferative disease. Five patients (11%) experienced cytomegalovirus antigenemia which responded well to antiviral therapy.

Conclusions

Compared with outcomes for diabetic patients on dialysis, current SPK and PAK short- and long-term results are favorable even in a small PT center. Therefore, unless there is a contraindication, PT should be offered to all type 1 diabetic patients with end-stage renal disease at the time of kidney transplantation or afterward.     

Phosphoproteomic Analysis Reveals Regulatory Mechanisms at the Kidney Filtration Barrier

Diseases of the kidney filtration barrier are a leading cause of ESRD. Most disorders affect the podocytes, polarized cells with a limited capacity for self-renewal that require tightly controlled signaling to maintain their integrity, viability, and function. Here, we provide an atlas of in vivo phosphorylated, glomerulus-expressed proteins, including podocyte-specific gene products, identified in an unbiased tandem mass spectrometry–based approach. We discovered 2449 phosphorylated proteins corresponding to 4079 identified high-confidence phosphorylated residues and performed a systematic bioinformatics analysis of this dataset. We discovered 146 phosphorylation sites on proteins abundantly expressed in podocytes. The prohibitin homology domain of the slit diaphragm protein podocin contained one such site, threonine 234 (T234), located within a phosphorylation motif that is mutated in human genetic forms of proteinuria. The T234 site resides at the interface of podocin dimers. Free energy calculation through molecular dynamic simulations revealed a role for T234 in regulating podocin dimerization. We show that phosphorylation critically regulates formation of high molecular weight complexes and that this may represent a general principle for the assembly of proteins containing prohibitin homology domains.The kidney filter consists of three layers: fenestrated endothelial cells, the glomerular basement membrane, and podocytes.¹ Damage to any of these compartments becomes clinically evident as proteinuria and the development of kidney disease.² Of particular importance for the regulation of podocyte biology through signaling is the slit diaphragm, a specialized intercellular junction that bridges the 40-nm gap in between foot processes of neighboring podocytes. It also serves as a signaling platform regulating podocyte function. Mutations in genes encoding for components of the slit diaphragm, such as nephrin,³ podocin,⁴ CD2AP,⁵ and TRPC6,^6,7 are important causes of genetic forms of proteinuria. Alteration of these proteins results in defective signaling causing podocyte dysfunction, progressive glomerulosclerosis, and kidney failure. The slit diaphragm protein complex is a lipid-multiprotein supercomplex.⁸ Of central importance to the integrity and function of the protein complex is the prohibitin homology (PHB) domain protein podocin,⁹ which forms multimeric complexes and is required to control signal transduction through associated transmembrane proteins.^10,11Signaling processes governing podocyte function, integrity, and survival largely depend on signaling processes involving phosphorylation.^12,13 Comprehensive analyses of the signaling events in podocytes in vivo have been hampered by the fact that interference with these signaling cascades by genetic deletion often results in massively disrupted and dysfunctional podocytes. One of the primary aims of this study was to use phosphoproteomics to analyze thousands of phosphorylation sites in native murine glomeruli within single samples. Within this study, we show that this approach allows the introduction of new concepts into signaling processes at the kidney filtration barrier.     

Beating heart versus conventional reoperative coronary artery bypass surgery

BACKGROUND: The incidence of reoperative coronary artery bypass grafting is increasing with an increase in the number of patients undergoing coronary artery bypass surgery. The clinical outcome of redo coronary artery bypass grafting without cardiopulmonary bypass and conventional coronary artery bypass grafting using cardiopulmonary bypass are different. METHODS AND RESULTS: We compared clinical parameters in patients who underwent off-pump (n=156) versus on-pump (n=194) redo coronary artery bypass grafting performed between January 1995 and December 2001 in our institute, to determine if off-pump surgery has improved the surgical outcome of redo coronary artery bypass grafting and emerged as an ideal technique. Patients who underwent on-pump redo surgery required more postoperative blood transfusion (86.53% on-pump v. 12.82% off-pump. p=0.001), prolonged ventilatory support (>24 hours) (16.49% on-pump v. 7.7% off-pump, p=0.021) and higher inotropic support (23.71% on-pump v. 10.89% off-pump, p=0.003). On-pump redo coronary artery bypass grafting was also associated with a prolonged stay in the intensive care unit (40+/-6.2 hours on-pump v. 20+/-4.1 hours off-pump, p=0.001) and longer hospital stay (9+/-4.2 days on-pump v. 5+/-3.4 days off-pump, p=0.001). In-hospital mortality was higher in on-pump patients than in off-pump ones (7.7% v. 3.2%); however, this was not statistically significant (p=0.114). CONCLUSIONS: Off-pump redo coronary artery bypass grafting is a safe method of myocardial revascularization with lower operative morbidity and mortality, less requirement of blood products and early hospital discharge, compared with conventional on-pump redo coronary artery bypass grafting.     

Helicobacter pylori infection occurs via close contact with infected individuals in early childhood

BACKGROUND: The manner in which Helicobacter pylori is transmitted is of fundamental importance when considering strategies for its control, yet, to date, the exact mode of transmission remains uncertain. METHODS: The seroprevalence of H. pylori in a relatively isolated rural town in Japan (A-town) was examined to analyse the H. pylori infection route. The immunoglobulin G antibodies against H. pylori in 1684 subjects who had received public health examinations in A-town were determined with an enzyme-linked immunosorbent assay. The seroprevalence was compared in five areas according to the water source. The possibility and frequency of intrafamilial infection was analysed by comparing the seroprevalence among family members residing in the same home. RESULTS: The seroprevalence of H. pylori did not differ significantly between the five areas examined. Seropositivity was significantly more common in the children whose mothers were seropositive (45.0%, 27/60) than in the children whose mothers were seronegative (10.0%, 2/20; odds ratio (OR) = 7.36, P = 0.0036, 95% confidence interval (CI) = 1.57-34.59). Seropositivity was significantly more common in the children whose older siblings were seropositive (55.0%, 22/40) than in the children whose older siblings were seronegative (23.5%, 20/85; OR = 3.97, P = 0.00051, 95% CI = 1.79-8.84). There was no significant relationship in seroprevalence between children and fathers, grandchildren and grandfathers, grandchildren and grandmothers, or within couples. Seropositivity was significantly more common in the adolescents who had attended a nursery school (44.4%, 20/45) than in the adolescents who had not attended a nursery school (25.6%, 109/426) (OR = 2.33, P = 0.0070, 95% CI = 1.24-4.36). CONCLUSIONS: The acquisition of H. pylori infection occurs by close contact with infected individuals in early childhood, especially via contact with infected mothers and other infected children.