Yusuke Koike

Pathophysiology of urinary incontinence in murine models.

Urethral closure mechanisms under stress conditions consist of passive urethral closure involving connective tissues, fascia and/or ligaments in the pelvis and active urethral closure mediated by hypogastric, pelvic and pudendal nerves. Furthermore, we have previously reported that the active urethral closure mechanism might be divided into two categories: (i) the central nervous control passing onto Onufs nucleus under sneezing or coughing; and (ii) the bladder‐to‐urethral spinal reflex under Valsalva‐like stress conditions, such as laughing, exercise or lifting heavy objects. There are over 200 million people worldwide with urinary incontinence, a condition that is associated with a significant social impact and reduced quality of life. Therefore, basic research for urinary continence mechanisms in response to different stress conditions can play an essential role in developing treatments for stress urinary incontinence. It has been clinically shown that the etiology of stress urinary incontinence is divided into urethral hypermobility and intrinsic sphincter deficiency, which could respectively correspond to passive and active urethral closure dysfunction. In this review, we summarize the representative stress urinary incontinence animal models and the methods to measure leak point pressures under stress conditions, and then highlight stress‐induced urinary continence mechanisms mediated by active urethral closure mechanisms, as well as future pharmacological treatments of stress urinary incontinence. In addition, we introduce our previous reports including sex differences in urethral closure mechanisms under stress conditions and urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury in female rats.

Upfront transection and subsequent ligation of the dorsal vein complex during laparoscopic radical prostatectomy

Laparoscopic radical prostatectomy for localized prostate cancer offers several advantages, including creation of a pneumoperitoneum that results in less blood loss than is seen with the corresponding open procedure. Transection of the deep dorsal vein complex remains among the most challenging aspects, however. Safe and secure completion of this procedure is important to minimize blood loss and maximize the chance of cure. Liberal use of coagulation for hemostasis at the dorsal vein complex (DVC) risks thermal damage to the sphincteric muscle. DVC ligation before transection, though commonly performed, can cause loss of some sphincteric fibers and potentially result in delayed recovery of urinary continence. Furthermore, ligation may at times prove difficult, especially in obese patients with a short and broad DVC, a large prostate gland, and a narrow pelvis. The presence of prominent pubic tubercles may further increase the difficulty. We have found that bleeding from the DVC is easily controlled without suture ligation through a combination of a modest pneumoperitoneum with pinpoint coagulation of one or two small arteries that are consistently found in the superficial layer of the complex. Precise, even‐level transection is possible under direct vision with no more than modest blood loss. A stitch in a Z‐shaped fashion is then applied to the entire transected stump of the DVC. This procedure is simple and easily performed, even by those with limited experience. Here we provide an overview of our current technique.

Combination therapy with β3-adrenoceptor agonists and muscarinic acetylcholine receptor antagonists: Efficacy in rats with bladder overactivity

To investigate the efficacy of combination therapy of a selective β3‐adrenoceptor agonist (mirabegron) and muscarinic acetylcholine receptor antagonists (a selective muscarinic acetylcholine receptor2 antagonist: methoctramine hemihydrate or a selective muscarinic acetylcholine receptor3 antagonist; 4‐DAMP) compared with monotherapy of either agent in rats with oxotremorine methiodide (a non‐selective muscarinic acetylcholine receptor agonist)‐induced bladder overactivity.

Successful treatment of recurrent Henoch–Schönlein purpura nephritis in a renal allograft with tonsillectomy and steroid pulse therapy

We report a case of recurrent Henoch–Schönlein purpura nephritis (HSPN) treated successfully with a tonsillectomy and steroid pulse therapy in a kidney transplant patient. A 29‐year‐old woman was admitted to our hospital for an episode biopsy; she had a serum creatinine (S‐Cr) of 1.0 mg/dL and 1.34 g/day proteinuria 26 months after kidney transplantation. Histological examination revealed increased amounts of mesangial matrix and mesangial hypercellularity with IgA deposition. Of note, one glomerulus showed focal endocapillary proliferation and tuft necrosis. We diagnosed active recurrent HSPN. Considering both the histological findings and refractory clinical course of the native kidney, she was treated for 3 consecutive days with steroid pulse therapy and a tonsillectomy. The patients proteinuria decreased gradually to less than 150 mg/day 6 months later. A second biopsy 6 years after kidney transplantation showed an excellent response to treatment and revealed a marked reduction in both the mesangial matrix and mesangial hypercellularity, with trace IgA deposition. We conclude that a tonsillectomy and steroid pulse therapy appeared to be useful in this patient with active recurrent HSPN. This paper is the first to report a tonsillectomy and steroid pulse therapy as a therapeutic option for active recurrent HSPN. Further studies are needed to elucidate the efficacy and mechanisms of tonsillectomy with recurrent HSPN in kidney transplant patients.

Time-dependent changes in bladder function and plantar sensitivity in a rat model of fibromyalgia syndrome induced by hydrochloric acid injection into the gluteus

What’s known on the subject? and What does the study add?

Association Between GLCCI1 Promoter Polymorphism (Rs37972) and Post-Transplant Hypertension in Renal Transplant Recipients

Background/Aims: Post-transplant hypertension is highly prevalent in renal transplant recipients and is a risk factor for graft loss, cardiovascular disease and death. Glucocorticoid is used to prevent rejection, but simultaneously increases the risk of post-transplant hypertension. The glucocorticoid-induced transcript 1 (GLCCI1) promoter polymorphism (rs37972) has been reported to be associated with response to glucocorticoid therapy in asthma. We therefore examined the association between GLCCI1 promoter polymorphism and post-transplant hypertension in renal transplant recipients. Methods: We conducted a retrospective cohort study of renal transplantation at a single university hospital from October 2003 to January 2014. Fifty consecutive adult recipients were analyzed, with clinical data retrieved from a prospectively collected database. Genotyping was carried out using genomic DNA derived from recipient’s blood. GLCCI1 immunoreactivity in vascular endothelial cells was quantitatively analyzed by immunohistochemical staining of recipients’ native kidney biopsy-specimens. The primary outcome measure was post-transplant hypertension. Results: Post-transplant hypertension was observed in 14/17 (82%) of recipients with CC, 18/20 (90%) with CT, and 2/13 (15%) with TT genotype. CC/CT genotype was significantly associated with post-transplant hypertension, even after adjustment for covariates (odds ratio, 10.6; 95% confidence intervals, 1.32 to 85.8; P = 0.026). In addition, we observed that GLCCI1 immunoreactivity in arteriolar endothelial cells was higher in kidney specimens obtained from recipients with a CC/CT genotype than a TT genotype (P = 0.021). Conclusion: GLCCI1 promoter polymorphism rs37972 may be associated with post-transplant hypertension.

Rare case of nephrocalcinosis in the distal tubules caused by hereditary renal hypouricaemia 3 months after kidney transplantation

We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41‐year‐old man who underwent living‐related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S‐Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S‐UA) of 1.9 mg/dL with a fractional excretion of uric acid (FEUA) of 29% (normal, <10%) and UA clearance of 26.8 mL/min (normal, 7.3–14.7 mL/min) 3 days after kidney transplantation. The donor also had a relatively low S‐UA of 2.4 mg/dL and high FEUA of 10.3%. Subsequent DNA direct sequencing followed by restriction fragment length polymorphism revealed that both the recipients and donors urate transporter 1 (URAT1) gene had a heterozygous nonsense mutation in exon 5 (C889T). Further, the immunoreactivity of antibodies for the C terminus of URAT1 revealed a partial deletion. De Galantha and von Kossa staining revealed that the nephrocalcinosis was due to urate crystals and calcium stones. Therefore, we diagnosed hereditary renal hypouricaemia. We directed the patient to avoid hard exercise, drink plenty of water, and alkalize the urine. The 1‐year follow‐up allograft biopsy showed no evidence of nephrocalcinosis in the distal tubules. This is the first report of nephrocalcinosis in the distal tubules as a diagnostic clue to hereditary renal hypouricaemia. We also review the related literature.

Clinicopathological features and outcomes of kidney allografts in plasma cell-rich acute rejection: A case series: Cases of plasma cell-rich acute rejection

Plasma cell‐rich acute rejection (PCAR) is a rare type of acute rejection in renal transplantation. Despite aggressive immunotherapy, approximately 40–60% of patients develop graft loss within 1 year after an episode of PCAR. However, the reason for this outcome remains obscure. This study retrospectively identified six patients with PCAR diagnosed between 2009 and 2015 at a single university hospital. Clinicopathological data were collected. Five of the six patients were male, and mean age at the onset of PCAR was 49.0 ±14.5 years. None of the patients showed overall poor adherence to medication. Mean time to diagnosis was 302 ±234 days post‐transplantation. All patients had preceding or concurrent viral infection. Four patients developed PCAR alone and two patients developed PCAR with antibody‐mediated rejection. One of the six patients showed both severe tubulointerstitial and microvascular inflammation (total of Banff tubulitis ‘t’ + interstitial inflammation ‘i’ + glomerulitis ‘g’ + peritubular capillaritis ‘ptc’ scores >10). This patient had progressive worsening of graft function and re‐initiated dialysis at 74 months after a PCAR episode. In addition, three of the six patients had long‐term recurrence of PCAR. With the recurrence of PCAR, patients with both moderate tubulointerstitial and microvascular inflammation (total of Banff ‘t’ + ‘i’ + ‘g’ + ‘ptc’ scores >6) had progressive worsening of graft function. In summary, the present results suggest that concurrent moderate to severe tubulointerstitial and microvascular inflammation may lead to poor outcomes of graft function after a PCAR episode.

Antibody-mediated rejection due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient: ABMR after pregnancy and delivery

Herein, we report a case of antibody‐mediated rejection (ABMR) due to anti‐HLA‐DQ antibody after pregnancy and delivery in a female kidney transplant recipient. A 34‐year‐old female recipient was admitted at 2 years after delivery for an examination of an elevated serum creatinine (S‐Cr) level. The patient had received a living kidney transplantation from her mother at 22 years of age, and her kidney graft function was almost stable. The episode biopsy showed peritubular capillaritis and transplant capillaropathy with C4d immunoreactivity in the peritubular capillaries. Additional examination revealed expression of a donor‐specific antibody (DSA) against HLA‐DQ5, leading to the diagnosis of chronic active ABMR. Intravenous immunoglobulin, plasma exchange, and rituximab were administered, and her S‐Cr level was maintained stable. This case demonstrates a possible relationship between pregnancy/delivery and development of ABMR due to a de novo DSA in a female kidney transplant recipient.

Successful Treatment of Plasma Cell-Rich Acute Rejection Using Pulse Steroid Therapy Alone: A Case Report

Despite the recent development of immunosuppressive agents, plasma cell-rich acute rejection (PCAR) has remained refractory to treatment. Herein, we report an unusual case of PCAR that responded well to pulse steroid therapy alone. A 47-year-old man was admitted for a protocol biopsy three months after kidney transplantation, with a stable serum creatinine level of 1.6 mg/dL. Histological examination showed focal aggressive tubulointerstitial inflammatory cell infiltration of predominantly polyclonal mature plasma cells, leading to our diagnosis of PCAR. Three months following three consecutive days of high-dose methylprednisolone (mPSL) therapy, an allograft biopsy performed for therapy evaluation showed persistent PCAR. We readministered mPSL therapy and successfully resolved the PCAR. Although PCAR generally develops more than six months after transplantation, we diagnosed this case early, at three months after transplantation, with focally infiltrated PCAR. This case demonstrates the importance of early diagnosis and prompt treatment of PCAR to manage the development and severity of allograft rejection.