Kunio Kawanishi

Neutral Solution Low in Glucose Degradation Products Is Associated with Less Peritoneal Fibrosis and Vascular Sclerosis in Patients Receiving Peritoneal Dialysis

♦ Background: The effects of novel biocompatible peritoneal dialysis (PD) solutions on human peritoneal membrane pathology have yet to be determined. Quantitative evaluation of human peritoneal biopsy specimens may reveal the effects of the new solutions on peritoneal membrane pathology. ♦ Methods: Peritoneal specimens from 24 PD patients being treated with either acidic solution containing high-glucose degradation products [GDPs (n = 12)] or neutral solution with low GDPs (n = 12) were investigated at the end of PD. As controls, pre-PD peritoneal specimens, obtained from 13 patients at PD catheter insertion, were also investigated. The extent of peritoneal fibrosis, vascular sclerosis, and advanced glycation end-product (AGE) accumulation were evaluated by quantitative or semi-quantitative methods. The average densities of CD31-positive vessels and podoplanin-positive lymphatic vessels were also determined. ♦ Results: Peritoneal membrane fibrosis, vascular sclerosis, and AGE accumulation were significantly suppressed in the neutral group compared with the acidic group. The neutral group also showed lower peritoneal equilibration test scores and preserved ultrafiltration volume. The density of blood capillaries, but not of lymphatic capillaries, was significantly increased in the neutral group compared with the acidic and pre-PD groups. ♦ Conclusions: Neutral solutions with low GDPs are associated with less peritoneal membrane fibrosis and vascular sclerosis through suppression of AGE accumulation. However, contrary to expectation, blood capillary density was increased in the neutral group. The altered contents of the new PD solutions modified peritoneal membrane morphology and function in patients undergoing PD.

Successful therapeutic use of a single-dose of rituximab on relapse in adults with minimal change nephrotic syndrome.

Minimal change nephrotic syndrome (MCNS) usually is considered to have a good renal prognosis, but the frequency of relapses is a therapeutic challenge to physicians. The treatment of patients with multiple relapses remains a matter of controversy, because few controlled studies are available. We report the case of a 25-year-old man who experienced relapses of MCNS. Single-dose rituximab therapy (total dose 500 mg) was given during the fourth relapse. Complete remission occurred 10 days later, when no CD19/20-positive B cells were detected in the blood. This the first report of efficacy of single-dose rituximab therapy to treat multi-relapsing MCNS in an adult patient.

Peritoneal cell sheets composed of mesothelial cells and fibroblasts prevent intra-abdominal adhesion formation in a rat model.

Postoperative intra‐abdominal adhesions remain an unsolved problem despite significant progress in the surgical procedures themselves. They often lead to small‐bowel obstruction, chronic abdominal and pelvic pain, as well as female infertility. The loss of mesothelial cells and several components of the inflammatory system following injury to the peritoneum results in fibrin formation and angiogenesis. The remaining fibrin matrix and angiogenesis lead to replacement by fibroblasts and fibrous band formation. The aim of this study was to develop a new therapeutic method of preventing intra‐abdominal adhesions. We fabricated transplantable peritoneal cell sheets from the rat peritoneum by cell sheet engineering using a temperature‐responsive culture system. The peritoneal cell sheets developed were composed of an upper monolayer of mesothelial cells and underlying multilayered fibroblasts, similar to the peritoneum in vivo. Transplantation of peritoneal cell sheets prevented tissue adhesion, fibrin deposition and angiogenesis, and, moreover, lymphangiogenesis and macrophage infiltration in a rat caecum cauterization adhesion model. Copyright

Morphological characteristics in peritoneum in patients with neutral peritoneal dialysis solution

Peritoneal dialysis solution (PDS) plays a role in functional and morphological damage to the peritoneum. This study aimed to clarify the effect of neutral PDS in preventing morphological changes by assessing peritoneal damage and comparing morphological alterations between PD patients treated with neutral PDS and acidic PDS. Sixty-one patients participated from seven hospitals. All patients were treated with neutral PDS excluding icodextrin, during their entire PD treatment, and experienced no episode of peritonitis. The thickness of submesothelial compact (SMC) zone and the presence of vasculopathy in the anterior parietal abdominal peritoneum were assessed. The impact of icodextrin, hybrid therapy, and peritoneal rest and lavage in morphological alterations were determined. There was no significant difference in the average SMC thickness between neutral and acidic PDS. The vessel patency in patients using neutral PDS was significantly higher compared to that in acidic PDS at any time during PD. There were no significant suppressive effects from interventions or use of icodextrin with respect to peritoneal morphological injury. A monolayer of mesothelial cell was observed in approximately half the patients, especially in their receiving lavage patients. Neutral PDS, accompanied by other preventive approaches against peritoneal injury, might suppress the development of peritoneal morphological alterations.

Two cases of kidney transplantation‐associated thrombotic microangiopathy successfully treated with eculizumab

Transplantation‐associated thrombotic microangiopathy (TA‐TMA) is relatively rare and requires immediate intervention to avoid irreversible organ damage or death; however, consensus regarding the treatment approach is lacking. Atypical haemolytic uraemic syndrome (aHUS) is a rare disease caused by dysregulation of the alternative complement pathway resulting in TMA. aHUS is histologically similar to TA‐TMA; approximately 60% of TA‐TMA patients have complement dysregulation. Eculizumab, a humanized anti‐C5 monoclonal antibody, inhibits terminal membrane‐attack complex formation and TMA progression. Eculizumab has been successfully used to treat aHUS post‐transplant. We present two cases of kidney TA‐TMA due to unknown causes, suspected antibody‐mediated rejection, or calcineurin inhibitor (CNI)‐related toxicity that developed on day 1 or 2 post‐kidney transplantation. Low platelet count and haemoglobin level with red cell fragments were detected. Despite steroid pulse, plasma exchange (PE), and intravenous immunoglobulin therapy, TA‐TMA did not improve; therefore, eculizumab was administered despite no genetic testing. Laboratory data, including renal function, improved immediately. TA‐TMA treatment primarily involves PE initiation or CNI discontinuation; eculizumab can be used to safely treat TA‐TMA and then be ceased in the short term. Therefore, eculizumab administration might be beneficial for kidney TA‐TMA as early as the diagnosis of refractory to PE.

Three cases of late-onset oligomeganephronia

Oligomeganephronia is classified as a subgroup of renal hypoplasia, characterized by histopathologic abnormalities which progress to end-stage renal disease (ESRD) by school age. We describe three adult cases of oligomeganephronia who have not yet developed ESRD. We performed a renal biopsy in all of them. The pathological features, consisting of a reduced number of enlarged glomeruli, were diagnostic of oligomeganephronia. It was assumed that the condition had not progressed to ESRD in the patients because the degree of loss of glomeruli may have been milder than that in typical cases of oligomeganephronia.

Glomerulopathy with Homozygous Apolipoprotein E2: A Report of Three Cases and Review of the Literature

Most cases of type III hyperlipoproteinemia are accounted for by apolipoprotein E2 (apoE2) homozygotes, a genetic mutation of apoE (Arg158Cys). Glomerulopathy with homozygous apoE2 is rare and characterized by marked foam cell infiltration in the glomerular capillaries and mesangium. Here, we report 3 cases of apoE2 homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 cases were middle-aged or elderly males complicated with diabetes for at least a decade. The kidney biopsies showed massive foam cell infiltration in the glomerular capillaries and expanded mesangium accompanied by histological findings of diabetic glomerulosclerosis. The lipid profiles showed type III hyperlipoproteinemia and phenotypic/genetic analyses revealed homozygosity of apoE2. Two of the cases showed nephrotic proteinuria and progressed to renal failure in 3 and 8 years after the diagnosis of kidney disease.

Diverse properties of the mesothelial cells in health and disease

Abstract Mesothelial cells (MCs) form the superficial anatomic layer of serosal membranes, including pleura, pericardium, peritoneum, and the tunica of the reproductive organs. MCs produce a protective, non-adhesive barrier against physical and biochemical damages. MCs express a wide range of phenotypic markers, including vimentin and cytokeratins. MCs play key roles in fluid transport and inflammation, as reflected by the modulation of biochemical markers such as transporters, adhesion molecules, cytokines, growth factors, reactive oxygen species and their scavengers. MCs synthesize extracellular matrix related molecules, and the surface of MC microvilli secretes a highly hydrophilic protective barrier, “glycocalyx”, consisting mainly of glycosaminoglycans. MCs maintain a balance between procoagulant and fibrinolytic activation by producing a whole range of regulators, can synthetize fibrin and therefore form adhesions. Synthesis and recognition of hyaluronan and sialic acids might be a new insight to explain immunoactive and immunoregulatory properties of MCs. Epithelial to mesenchymal transition of MCs may involve serosal repair and remodeling. MCs might also play a role in the development and remodeling of visceral adipose tissue. Taken together, MCs play important roles in health and disease in serosal cavities of the body. The mesothelium is not just a membrane and should be considered as an organ.

A Preliminary Study Into the Significance of Intrarenal Reflux in BK Virus Nephropathy After Kidney Transplantation.

Background The BK virus typically colonizes the lower urinary tract and is the causative agent in BK virus nephropathy (BKVN), which can progress to allograft dysfunction and graft loss. Urinary reflux in kidney allografts is induced by vesicoureteral reflux or disturbances in intrarenal reflux (IRR), believed to be associated with BKVN. This study was designed to elucidate the relationship between BKVN and IRR. Methods We examined 30 renal transplant recipients histologically diagnosed with BKVN using anti-Simian virus 40 immunohistochemistry and 60 clinically matched control recipients. The BKVN patients were divided into stable (n = 12) and progressive (n = 18) groups according to allograft kidney function 1 year after diagnosis. Histological rejection scores according to the pathological classification of rejection in renal allografts (Banff classification), histological BKVN stages, and histological polyomavirus load levels (pvl) proposed by the Banff working group were evaluated. The IRR was quantified by histological reflux scores defined with retention and reflux of immunostained Tamm-Horsfall protein in renal tubules and glomeruli. Results Higher reflux scores were observed in the BKVN group compared with that in the control group. No differences in clinical parameters were observed between the BKVN and control groups. Reflux scores and pvl were significantly higher in the progressive group than in the stable BKVN group with no significant difference in BK stage observed between groups. Reflux scores were found to be significantly correlated with pvl. Conclusions Our preliminary study suggested that IRR might be a predisposing and prognostic factor in BKVN.

A case of recurrent focal segmental glomerulosclerosis after kidney transplantation associated with variant conversion in the Columbia classification

Focal segmental glomerulosclerosis commonly recurs following kidney transplantation. A 33‐year‐old man underwent living donor kidney transplantation. Proteinuria appeared two months after transplantation, and an episode biopsy on postoperative day 66 revealed recurrent focal segmental glomerulosclerosis lesions of the cellular variant by Columbia classification. We reviewed the native kidney biopsy and confirmed collapsing variant focal segmental glomerulosclerosis. Plasma exchange therapy was performed, and his proteinuria temporarily resolved. A second allograft biopsy performed on postoperative day 200 showed no evidence of focal segmental glomerurosclerosis. He experienced incomplete remission with a proteinuria of 0.5 g/day during the subsequent three years until his urinary protein level rose to 1.3 g/day. A third biopsy performed on postoperative day 1248 showed focal segmental glomerulosclerosis cellular variant lesions. Plasma exchange was resumed in combination with additional rituximab, but his proteinuria persisted. Intermittent plasma exchange was performed 42 times in total. However, his proteinuria continued, and his renal function gradually worsened. A fourth biopsy performed on postoperative day 2540 showed focal segmental glomerulosclerosis collapsing variant lesions with severe interstitial fibrosis and tubular atrophy. He ultimately required hemodialysis seven years after transplantation. Intensive therapy with long‐term intermittent plasma exchange and rituximab suppressed proteinuria and preserved graft function for seven years, at which time graft failure occurred. We here present the clinical course and histological findings from consecutive allograft biopsies.