We experienced 9 cases with biopsy-proven idiopathic membranous nephropathy from January 1997 to June 2010. In our institute, steroid is chosen as the first line treatment for idiopathic membranous nephropathy accompanied with proteinuria more than 1g/day. The treatment and clinical courses were retrospectively reviewed.
 Of all, 3 cases presented proteinuria greater than 1g/day and only 1 of them satisfied the criteria of nephrotic syndrome. These 3 cases were treated with steroid for 2∼3 months and the proteinuria resolved within 2 months. Although the rest also achieved remission with dipyridamole, ACE inhibitor or ARB, the duration until remission was longer, ranging from 5 months to 7 years and 3 months.
 This study indicated a possibility that 2 months steroid therapy in these patients may shorten the period until remission.

View full abstract

 ‹Background› Live vaccines are descreibed as contraindications in the package inserts of immunosuppressive agents in Japan because of the risk of viral infection by vaccine strain. However, viral infections such as measles and chickenpox are associated with serious complications in immunocompromised children, and can sometimes be fatal. So, using live vaccines for patients receiving immunosuppressants is not prohibited in the immunization guideline in Japan and this issue has been controversial. We initiated immunization with attenuated live vaccines in children receiving immunosuppressants.
 ‹Patients and Methods› Patients receiving immunosuppressants (calcineurin inhibitors, purine synthesis inhibitors, or both of them) that showed negative or borderline antibody titers of IgG against the viruses that cause measles, rubella, chickenpox and mumps were included in the study. We immunized these individuals with attenuated live vaccines while underlying disease activities were stable, and after obtaining informed consent. Antibody titers against the viruses and adverse events were monitored.
 ‹Results› A total of 55 immunizations were performed in 40 patients (28 males and 12 females). The study subjects consisted of patients with nephrotic syndrome (31), renal transplant (7), and collagen disease (2). The median age at vaccination was 10 years (range 1-24-years old). Patients were receiving calcineurin inhibitors (cyclosporine or tacrolimus; n=24), purine synthesis inhibitors (mizoribine, mycophenolate mofetil or azathioprine; n=13) or both (n=18). Thirteen patients (24%) were also treated with a low dose of steroids. Measles-rubella (MR) vaccines were administered to 22 patients, varicella vaccines to 18 and a mumps vaccine to 15 individuals. The overall seroconversion rate was 65% (measles 90%, rubella 93%, varicella 44% and mumps 43%). Four patients (7%) showed mild adverse events (transient fever in 2, transient rash in 1, and relapse of nephritic syndrome in 1) but no serious adverse events were seen.
 ‹Conclusion› Immunization with attenuated live vaccines was effective and safe in children receiving immunosuppressants. More clinical data need to be collected to further evaluate their safety.

View full abstract

 Dynamic changes in calcium concentration trigger various physiological cellular responses, including secretion, cell growth, survival, and differentiation by versatile regulatory mechanisms. On the other hand, excessive calcium signaling often leads to inappropriate proliferation, migration, dedifferentiation, or apoptosis. There are lines of evidence that dysregulated calcium homeostasis in podocytes is involved in the podocyte damage and in the pathogenesis of proteinuria.
 Angiotensin II has been demonstrated to act directly on podocytes, and promote the dedifferentiation and apoptosis, leading to proteinuria and glomerulosclerosis. The canonical transient receptor potential TRPC 6, the cation channel expressed at podocyte slit diaphragm, is now known to play an important role in angiotensin II-dependent increase in Ca²⁺, because proteinuria and renal damage caused by angiotensin II is attenuated in TRPC 6-deficient mice. In human proteinuric kidney diseases, dysregulated TRPC 6 is directly linked to glomerulosclerosis. Mutations in TRPC 6 are responsible for familial forms of hereditary FSGS, and the expression of TRPC 6 is upregulated in some acquired kidney diseases.
 However, the mechanism how its channel activity is involved in the pathogenesis is unclear, because some mutations enhance the channel activity while others do not. Recently it has been reported that its activity is regulated by tyrosine phosphorylation, and slit diaphragm protein Nephrin binds to phosphorylated TRPC 6 and inhibits its surface localization, suggesting that podocyte-specific regulatory mechanism may exist.
 Downstream targets of TRPC 6 are also being recognized. Increased Ca²⁺ concentration triggered by TRPC 6 activates calcineurin, which dephosphorylates the nuclear factor of activated T cell (NFAT), or synaptpodin, leading to cytoskeletal rearrengement and morphological alteration of podocytes.
 This brief review presents an overview of the current knowledge concerning the roles of the calcium signaling in podocyte pathophysiology. Specific inhibition of these pathways might provide a potential therapeutic target for proteinuria.

View full abstract

 The treatment of patients with steroid-resistant-nephrotic syndrome (SRNS) is challenging. Although some case reports have suggested that rituximab could be effective in SRNS, little is known regarding appropriate therapy after the biological agent. The objective of this article is to analyze the results obtained in preliminary studies and to propose future perspectives for this drug in case of SRNS.

View full abstract

 Granzyme B (GrB) is a serine protease released by cytotoxic T cells and plays a role in cellular apoptosis in cooperation with perforin. Recently however, extracellular roles of GrB have been reported. In particular, GrB accumulates in extracellular tissue and contributes to the loss of structural integrity in a number of chronic inflammatory, autoimmune, and degenerative diseases. Furthermore, GrB in vitro has the ability to cleave extracellular matrix components such as laminin and vitronectin, which constitute the glomerular basement membrane (GBM). Although, whether or not extracellular GrB mediates the pathogenesis of pediatric idiopathic nephrotic syndrome (INS) has not been reported to date. Here we performed flowcytometric analysis on the expression of GrB in peripheral blood mononuclear cells in patients with INS and showed a significantly higher ratio of GrB-positive cells to CD3-positive T cells in steroid-resistant nephritic syndrome patients. As an additional pathogenesis of glomerulosclerosis in INS, we considered that GrB might play a role in the injury of the glomerular filtration wall by detaching endothelial cells or podocytes from the GBM.

View full abstract

 Lowe syndrome (oculocerebrorenal syndrome of Lowe, OCRL) is characterized by congenital cataracts and glaucoma, mental retardation, hypotonia with diminished to absent reflexes, and Fanconi syndrome of the proximal renal tubules. It is inherited in an X-linked recessive manner. The disorder arises from mutations in OCRL1. We have carried out analysis of OCRL1 gene in his family and made his family tree. The patient has low height, mental retardation and mild renal dysfunction at age 20. He currently works in a sheltered workshop and lives at home.
 In this report, we describe the clinical features and course of a 20-year-old male with Lowe syndrome.

View full abstract

 Lipoprotein glomerulopathy (LPG) is a rare hereditary disease characterized by intraglomerular lipoprotein thrombi and increased serum apolipoprotein E (APOE) concentrations. Several types of APOE mutations are known to associate with LPG. We have previously reported a 4-year-old girl with LPG who was a heterozygote of APOE-Sendai (Arg145Pro) mutation. This time, we present another 7-year-old girl with LPG carrying heterozygous APOE-Sendai (Arg145Pro) mutation. She was found to have proteinuria and hematuria by a routine school urinalysis at the age of 6 years. At the age of 7 years, the patient was referred to our hospital for evaluation of heavy proteinuria. There were no obvious abnormalities on physical examination at the first visit. Laboratory data showed she had no hypoproteinemia, hyperlipidemia and renal dysfunction. However, urinalysis showed positive for occult blood and protein test, and her urine protein/creatinine ratio was 3.8 g/g•cre. Then renal biopsy was performed due to the persistent urinary abnormality. Light microscopic examination showed marked dilatation of the capillary lumen in glomeruli by a pale-stained substance by periodic acid Schiff. Electron microscopy showed that thrombus-like substances in glomerular capillaries were composed of granules and vacuoles of various sizes, forming concentric lamellate. Gel electrophoresis analysis revealed the presence of a mid-band and VLDL fraction was elevated. Her serum APOE level was elevated to 12.2 mg/dl (reference range 2.8-4.6 mg/dl). Direct DNA sequencing revealed a heterozygote of APOE-Sendai mutation (Arg145Pro). These results led to diagnosis of LPG. Her mother and elder brother also had the same mutation, however, they had no signs of renal disease. We started to treat her with lipid-lowering agents, especially fibrates, triglycerides-lowering agent. At present, her urinary protein decreased and hematuria disappeared. Her APOE level decreased to 6.7 mg/dl.
 It is known that LPG patients initially show mild proteinuria and a half of the LPG patients progress to chronic renal failure. Recently, however, intensive therapy using lipid-lowering agents, including fibrates, were reported to improve patient's clinical condition with histological resolution. Early treatment with lipid-lowering agents is important to prevent the development of renal failure.
 Unlike other APOE variants, APOE-Sendai was detected in only north-east part of Japan, especially in Yamagata and Miyagi prefectures, suggesting a founder effect. There are many healthy carriers of APOE variants in the families with LPG, which suggests that additional factors also are involved in the onset of LPG. To elucidate the precise mechanism for LPG, we started the prevalence survey of APOE-Sendai among general population and hemodialysis patients in Yamagata prefecture. And we will determine the haplotype of APOE in the patients to see the founder effect of APOE-Sendai. Based on these data, we would like to elucidate the pathogenesis of LPG.

View full abstract

 Cystinuria is an autosomal recessive inherited disease that is characterized by the malabsorption of dibasic amino acid and cystine in the epithelial cells of the gastrointestinal tract and renal tubules. It is important to avoid the recurrence of urinary stones, which then progresses to renal failure. A 2-year-old boy presented with gross hematuria at around 10 months of age. He developed macroscopic hematuria and urinary retention again at 13 months, followed by spontaneous passage of the stone. Subsequently he was diagnosed with cystinuria by urinary stone and urine amino acid analysis. Medical management was mainly based on hyperhydration and urine alkalinization with oral sodium bicarbonate to maintain a urine pH>7.5. At the regular checkup 1 years after the initial diagnosis, urinalysis showed microhematuria although he showed normal renal function without any physical symptoms. Abdominal ultrasonography and CT scan demonstrated left ureterohydronephrosis with huge stones at left ureterovesical junction. Because extracorporeal shock wave lithotripsy is not indicated for cystine stones, his stones were removed surgically. Postoperatively, oral α-mercapto-propionylglycine was added to his regimen, continuing urine alkalinization and ensuring adequate urine output. Although it is not easy to ensure a sufficient urinary output in infants and to maintain a low protein diet in order to reduce methionine intake (a prescursor of cystine), the management of cystinuria should focus on avoiding urinary stone formation. Despite urine alkalinization, this patient developed recurrent urinary tract stones. Therefore, we considered that he was at high risk of stone formation and cystine solubilization therapy such as α-mercapto-propionylglycine administration was required. In patients with recurrent episodes of urinary stones, combined pharmacological therapy should be administered as early as possible.

View full abstract

 Amlodipine besilate, long-acting dihydropyridine type calcium channel blocker is widely used as an antihypertensive agent. In some reports, long-acting dihydropyridine type calcium channel blockers caused chylous ascites in peritoneal dialysis patients. In other report, manidipine hydrochloride, one of the long-acting dihydropyridine type calcium channel blocker caused massive chylous ascites in a patient with systemic lupus erythematosus (SLE), who was not receiving peritoneal dialysis. Here, we describe a case of Japanese boy with SLE who developed massive ascites after the initiation of treatment with amlodipine besilate. About 10 days after the initiation of treatment with amlodipine besilate, he developed abdominal fullness without any edema, and massive ascites were shown in an abdominal sonogram, but after the discontinuation of this agent, his ascites began to decrease immediately and disappeared within about 3 weeks. We speculated that the continuous peritoneal lymph-vascular dilation due to amlodipine besilate caused massive ascites in our case, through the similar mechanism that long-acting dihydropyridine type calcium channel blockers cause chylous ascites in previous reports. Additionally, the asymptomatic peritoneal lymph-vascular inflammation associated with SLE may increase the peritoneal lymph-vascular permeability and affect the development of ascites. So we concluded that amlodipine besilate caused ascites due to the peritoneal lymph-vascular dilation effects in the background of asymptomatic peritoneal inflammation with SLE in our case. Clinicians should be aware of the possibility of ascites due to the administration of long-acting dihydropyridine type calcium channel blockers, particularly in patients with SLE.

View full abstract

 Nephronophthisis (NPHP) is an autosomal recessive tubulointerstitial nephropathy and it is also one of the most frequent genetic disorders causing end stage renal disease in children.
 We experienced the case of an 8-year-old female who demonstrated NPHP due to a homozygous deletion of NPHP1. She had renal dysfunction, but no abnormalities as detected by a school urine test. Her development was normal. She had polyuria (2401ml/day), and a renal concentration defect (specific gravity 1.003), but no proteinuria or hematuria was observed. She had renal dysfunction (BUN 32.2mg/dl, Cr 1.36mg/dl, cystatinC 1.82mg/l, 24hr creatinine clearance 38.7ml/min/1.73m², β₂microgloblin 0.58 mg/ml).
 She was near-sighted, and during an ophthalmological examination, a color irregularity was seen in the ocular fundus, and subnormal electro-retinogram findings were also revealed. Small cysts were observed on kidney MRI. In a kidney biopsy, glomerulosclerosis and chronic tubulointerstitial nephritis were observed. We diagnosed the patient to have NPHP, and performed a polymerase chain reaction analysis of NPHP1, and a large deletion of NPHP1 was thus confirmed. A high density single nucleotide polymorphism (SNP) array was able to identify deletions in both alleles of the 2q13 region, including a part of MALL and all of NPHP1. Therefore, NPHP was considered to have been affected by the homozygous deletion of NPHP1. In addition, the patient had ocular manifestations, and was thus diagnosed to have Senior-Loken syndrome. Many patients with such a NPHP1 gene mutation also have a deletion of the MALL gene. The relationship between the MALL gene and the pathology of NPHP is still unclear. Recently, both NPHP1 and MALL genes are being studied in association with eye manifestation. The SNP array is thus considered to be a good method for performing a detailed analysis of NPHP1.

View full abstract

 We report a 19-year-old female case of short bowel syndrome (SBS) complicated with membranoproliferative glomerulonephritis. She underwent extensive resection of the small intestine and jejunoileostomy due to malrotation of the intestine in the neonatal period. Home parenteral nutrition has been conducted since infancy because of SBS with a 6 cm length of small intestine. At 19 years old, she was diagnosed with membranoproliferative glomerulonephritis by renal biopsy. Considering impaired absorption of steroids in this SBS patient, alternate-day prednisolone (PSL) therapy was first performed by intravenous administration for a fixed period, and then changed to the administration of oral medication. Urinary free cortisol was measured to evaluate PSL absorption status. High cortisol levels due to cross-reaction with PSL were observed on days of administration, and low cortisol levels due to suppressed adrenocortical function were observed on non-administration days. The fluctuation levels observed during the oral administration period were quite similar with the levels during the intravenous administration period. These findings indicate that oral PSL administration is available in this SBS patient with a less than 35 cm length of small intestine. Measurement of urinary free cortisol, a marker of endogenous steroid hormone secretion, also appears useful in the evaluation of adrenal function during steroid therapy.

View full abstract