A case of pseudo-Bartter/Gitelman syndrome caused by long-term laxative abuse, leading to end-stage kidney disease.

Pseudo-Bartter/Gitelman syndrome (PBS/PGS) is a disorder that presents with hypokalemia and metabolic alkalosis resembling Gitelman syndrome (GS) due to secondary factors, such as lifestyle and /or medicines. Notably, PBS/PGS is more likely to cause renal dysfunction than GS. We report the first case of PBS/PGS due to long-term laxative abuse leading to end-stage kidney disease (ESKD). The patient was a 49-year-old woman with a history of constipation since school, who had used excessive doses of laxatives on her own judgment for nine years at least from 22 years of age. Two years later, blood tests revealed hypokalemia (serum K 3.1 mEq/L), and nine years later, the patient's renal function began to deteriorate (Cr-eGFR 48.7 mL/min/1.73 m2). Since abuse of laxatives was suspected as the cause, it was changed to the proper dosage of laxatives. At 33 years, the patient developed acute kidney injury (AKI), due to a urinary tract infection, and required intensive treatment, including hemodialysis. Although the patient was eventually weaned off dialysis, the renal function did not recover to pre-AKI levels. In suspected GS, comprehensive genetic testing for renal disease-related genes was performed; however, no obvious pathogenic variants were identified. Thereafter, despite decreasing the laxative doses and potassium supplementation, her renal function continued to decline. At 49 years, the patient developed ESKD and was started on maintenance hemodialysis. PBS/PGS is a disease that can lead to ESKD. An early diagnosis of PBS/PGS is crucial to prevent renal function deterioration, and the underlying causes should be removed immediately.

Survey of the effects of a column for adsorption of ß2-microglobulin in patients with dialysis-related amyloidosis in Japan.

Dialysis-related amyloidosis is a serious complication of long-term hemodialysis. Its pathogenic mechanism involves accumulation of ß2-microglobulin in the blood, which then forms amyloid fibrils and is deposited in tissues, leading to inflammation and activation of osteoclasts. Lixelle, a direct hemoperfusion column for adsorption of ß2-microglobulin, has been available since 1996 to treat dialysis-related amyloidosis in Japan. However, previous studies showing the therapeutic efficacy of Lixelle were conducted in small numbers of patients with specific dialysis methods. Here, we report the results of a nationwide questionnaire survey on the therapeutic effects of Lixelle. Questionnaires to patients and their attending physicians on changes in symptoms of dialysis-related amyloidosis by Lixelle treatment were sent to 928 institutions that had used Lixelle, and fully completed questionnaires were returned from 345 patients at 138 institutions. The patients included 161 males and 184 females 62.9 ± 7.7 years age, who had undergone dialysis for 25.9 ± 6.2 years and Lixelle treatment for 3.5 ± 2.7 years. Based on self-evaluation by patients, worsening of symptoms was inhibited in 84.9-96.5% of patients. Of the patients, 91.3% felt that worsening of their overall symptoms had been inhibited, while attending physicians evaluated the treatment as effective or partially effective for 72.8% of patients. Our survey showed that Lixelle treatment improved symptoms or prevented the progression of dialysis-related amyloidosis in most patients.

Effectiveness of ß(2)-microglobulin adsorption column in treating dialysis-related amyloidosis: a multicenter study.

BACKGROUND/AIMS: The aim of this study was to determine whether treatment with ß(2)-microglobulin adsorption column (Lixelle) affects bone cysts and clinical symptoms in patients with dialysis-related amyloidosis (DRA). METHODS: Radiographic changes in the number and area of bone cysts of the wrist and the hip joint were compared between 39 hemodialysis (HD) patients treated with Lixelle (Lixelle group) and 28 HD patients treated with conventional therapy as retrospective control (HD group). Clinical symptoms of DRA were also evaluated. RESULTS: In the Lixelle group, the number of bone cysts and the cystic area in wrist joints were significantly decreased, although the changes in these parameters in hip joints were not significant. In the HD group, the corresponding parameters in the hip joints even significantly increased. Clinical symptoms notably improved after Lixelle treatment. CONCLUSION: Treatment with Lixelle reduces the radiolucency of bone cysts in the wrist joints, and improves clinical symptoms associated with DRA.

Clinical characteristics and cardiovascular outcomes of hemodialysis patients with atrial fibrillation: a prospective follow-up study.

BACKGROUND/AIMS: Among the cardiovascular complications in dialysis patients, atrial fibrillation (AF) is the most common arrhythmia. The purpose of this study was to clarify the characteristics and mortality of hemodialysis patients with AF, which are not completely elucidated. METHODS: The prevalence of AF in patients undergoing hemodialysis in our institutions was assessed. Patients with AF (AF group) and without AF (control group) were included in this study. Patients in the control group were matched for several important clinical risk factors. For further analysis, AF patients were divided into two groups on the basis of the type of AF (chronic AF (CAF) and paroxysmal AF (PAF) groups). These patients were evaluated for their clinical characteristics, laboratory data and echocardiographic parameters and prospectively followed up for 48 months. RESULTS: Among 328 study patients, 30 had AF (9.1%). Left atrial diameter (LAD) and the left ventricular mass index were significantly greater in the AF group than in the control group. Furthermore, cardiovascular and all-cause mortality and cumulative incidence of cardiovascular events were significantly higher in the AF group than in the control group, and tended to be higher in the CAF group. CONCLUSIONS: Our findings demonstrated that the prevalence of AF as 9.1% in hemodialysis patients, and that AF, especially CAF, were associated with high mortality.

Clinical efficacy and cost-effectiveness of lanthanum carbonate as second-line therapy in hemodialysis patients in Japan.

BACKGROUND AND OBJECTIVES: Lanthanum carbonate (LC) is a nonaluminum, noncalcium phosphate binder that is effective for hyperphosphatemia in dialysis patients. However, its efficacy and cost-effectiveness as second-line therapy have not been fully examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We first conducted a multicenter, open-label, 16-week clinical trial to examine the effect of additive LC in 116 hemodialysis patients who had uncontrolled hyperphosphatemia with conventional phosphorus-lowering therapy alone. Based on these clinical data, a state transition model was developed to evaluate the benefits and costs associated with LC as second-line therapy. Reduced risks for cardiovascular morbidity and mortality among patients treated with LC arise through more of the population achieving the target phosphorus levels. Uncertainty was explored through sensitivity analysis. RESULTS: After 16 weeks of additive LC treatment, mean serum phosphorus levels decreased from 7.30 ± 0.90 to 5.71 ± 1.32 mg/dl, without significant changes in serum calcium or intact parathyroid hormone levels. A subsequent cost-effectiveness analysis showed that compared with conventional treatment, additive LC incurred an average additional lifetime cost of $22,054 per person and conferred an additional 0.632 quality-adjusted life years (QALYs). This resulted in an incremental cost-effectiveness ratio of $34,896 per QALY gained. Applying a cost-effectiveness threshold of $50,000 per QALY, a probabilistic sensitivity analysis showed that additive LC had a 97.4% probability of being cost-effective compared with conventional treatment. CONCLUSIONS: Our results indicate that the use of LC as second-line therapy would be cost-effective among hemodialysis patients with uncontrolled hyperphosphatemia in Japan.

Uremic toxins and oral adsorbents.

Uremic toxins are associated with various disorders in patients with end-stage renal disease and it is difficult to remove some of these toxins by dialysis. Since some uremic toxins are generated by bacterial metabolites in the colon, oral adsorbents that interfere with the absorption of uremic toxins or their precursors are believed to prevent their accumulation in the body. AST-120 adsorbs various uremic retention solutes in the gastrointestinal system and has potential for providing clinical benefit. Sevelamer hydrochloride binds some harmful compounds in addition to phosphate and seems to have pleiotropic effects that include lowering serum LDL cholesterol levels and reduction of inflammation. The effect of sevelamer hydrochloride on indoxyl sulfate and p-cresol has been shown in an in vitro study; however, in vivo studies in mice or humans did not demonstrate this effect on protein-binding uremic toxins. Oral adsorbents are thus one of the important modalities in the treatment of uremic syndrome.

Association between indoxyl sulfate and skeletal resistance in hemodialysis patients.

Skeletal resistance to parathyroid hormone (PTH) in uremia is known, although the mechanism of resistance is not fully elucidated. To clarify the roles of indoxyl sulfate, which is a uremic toxin, in skeletal resistance, we examined the relationship between indoxyl sulfate and biochemical markers of bone turnover in hemodialysis patients. We obtained blood samples from 47 hemodialysis patients and measured serum indoxyl sulfate, intact PTH, oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), and various biochemical markers. The serum concentrations of alkaline phosphatase (ALP) and bone-specific alkaline phosphatase (BAP) were used as bone formation markers, and the concentration of tartrate-resistant acid phosphatase 5b (TRACP-5b) was used as a bone resorption marker. Serum indoxyl sulfate levels were much higher in hemodialysis patients than healthy subjects. Multiple regression analysis shows that indoxyl sulfate correlated negatively with ALP (beta = -1.897, P = 0.042) and BAP (beta = -0.310, P = 0.029), independent of intact PTH; however, indoxyl sulfate did not correlate with TRACP-5b or 8-OHdG. These findings suggest that indoxyl sulfate may relate skeletal resistance to PTH in uremia.

Risk factors for developing severe clinical course in HUS patients: a national survey in Japan.

BACKGROUND: Hemolytic uremic syndrome (HUS) is characterized by acute renal failure, thrombocytopenia and hemolytic anemia. Cases accompanied by prodromal gastrointestinal tract symptoms are referred to as typical HUS. Some severe HUS patients require dialysis or develop central nervous system (CNS) disorders after the onset of HUS. METHODS: Patients who developed typical HUS in 2001 and 2002 in Japan, 127 in all, were the study subjects. To identify the risk factors for the development of a severe clinical course, clinical and laboratory data were analyzed on logistic regression. RESULTS: Two of the 127 patients died (1.6%): one from acute cardiac failure and the other from a CNS disorder. Thirty-five patients required dialysis (28%) and 30 had CNS symptoms (24%). Multivariate analysis indicated that the risk factors for need for dialysis were serum sodium and alanine aminotransferase (ALT) levels of /=70 IU/L, respectively, at the onset of HUS and those for developing CNS disorders were dialysis and C-reactive protein (CRP) >/=5.0 mg/dL at the onset of HUS. CONCLUSIONS: Because patients with these risk factors, such as low serum sodium, high ALT or high CRP levels, may require dialysis or develop CNS disorders, they should be treated carefully in the early stage of HUS.

Prognosis and pathological characteristics of five children with non-Shiga toxin-mediated hemolytic uremic syndrome.

BACKGROUND: The three major signs of hemolytic uremic syndrome (HUS) are hemolytic anemia, thrombopenia and acute renal failure. HUS is classified into Shiga toxin-mediated HUS (Stx-HUS) and non-Shiga toxin-mediated HUS (nStx-HUS). The prognosis of nStx-HUS is reported to be less favorable than that of Stx-HUS. Although the association between the prognosis and pathological characteristics of HUS have been reported such that the prognosis was considered to be poor for thrombotic microangiopathy (TMA) with predominant arterial involvement (arterial TMA), good for TMA with predominant glomerular involvement (glomerular TMA) and dependent on the extent of necrosis in cases of renal cortical necrosis, it is not yet clear whether pathological findings are also related to the renal prognosis of nStx-HUS cases. Therefore the purpose of the present paper was to analyze renal biopsy findings and prognosis for five children with nStx-HUS. METHODS: Clinical records of five cases of nStx-HUS among 74 cases of diagnosed HUS were reviewed, and information and data were summarized. RESULTS: Histological examination of the kidney led to the diagnosis of arterial TMA in three cases, and glomerular TMA and severe renal cortical necrosis in one case each. Analysis of the relationship between renal histological findings and the prognosis found that three patients with arterial TMA and one patient with severe renal cortical necrosis later developed end-stage renal failure while one patient with glomerular TMA has continued to show normal renal function. CONCLUSIONS: These findings indicate that pathological findings are closely related to the prognosis in cases of nStx-HUS.

The effect of aldosterone blockade in patients with Alport syndrome.

Recent studies indicate that adding the mineralocorticoid receptor antagonist spironolactone (SP) to angiotensin converting enzyme inhibitors (ACEI) or ACEI and angiotensin receptor blocker (ARB), which is known as a triple blockade, enhances the more beneficial effects on urinary protein excretion of patients with chronic kidney diseases. In this study, we explored the effects of SP on urinary protein excretion in patients with Alport syndrome featuring persistent proteinuria in spite of the long-term use of ACEI (lisinopril) or both ACEI and ARB (candesartan). Five patients with Alport syndrome were enrolled and SP treatment (25 mg/day) was started. At the start of SP administration, all patients showed good renal function and none of them suffered from hypertension. We decided to assess the effect of SP by determining the morning urinary protein/creatinine ratio (U-P/C) and estimated glomerular filtration rate (EGFR). After SP treatment was started, U-P/C was significantly reduced at 3, 6, 12 and 18 months, while EGFR did not change. The drop in systolic and diastolic blood pressure was statistically significant and serum potassium level was slightly elevated. None of the patients showed signs of severe hyperkalemia (>5.0 mEq/l). These results suggest that aldosterone receptor blockade combined with ACEI and ARB therapy offers a valuable adjuvant treatment for the reduction of proteinuria in patients with Alport syndrome as in those with other chronic kidney diseases. SP can thus be expected to constitute a good renoprotective agent for Alport syndrome. These preliminary data indicate that large-scale trials of this therapy should be done.

High-dose mizoribine treatment for adolescents with systemic lupus erythematosus.

BACKGROUND: In treating pediatric patients with systemic lupus erythematosus (SLE), it is necessary to quickly attain remission to avoid sequelae in various organs and to maintain it over a long period. However, to maintain remission, the prolonged use of immunosuppressants which have various adverse effects, is often necessary in addition to steroids, and complications due to such immunosuppressants pose very important problems. A regimen of mizoribin (MZR) at 150 mg/day divided into two or three doses has been recommended, but while this regimen has been safe, its efficacy has not been satisfactory. However, MZR produces effects dose-dependently, and the dose recommended to date may have been insufficient for the treatment of children with SLE. METHODS: The authors administered oral MZR at 300 mg/day in two divided doses, which is twice the conventional dose for adults, to five adolescents with SLE. Three of these five were markedly steroid-dependent patients and two had previously been treated with steroids only. Thereafter, the authors evaluated the safety and efficacy of the regimen by following the patients for at least 7 months after the beginning of treatment. RESULTS: Patients 1 and 2 had been treated with prednisolone (PSL) and cyclosporine (CyA), but as the duration of CyA administration became long, it was replaced with 300 mg MZR. This transition could be accomplished smoothly. Patient 3 showed repeated recurrence during the treatment with PSL and CyA or CPM, but the symptoms could be controlled by the addition of 300 mg MZR. In patients 4 and 5, the control of symptoms with PSL alone was judged to be difficult, and concomitant administration of MZR at 300 mg was started. This resulted in a decrease in the dose of PSL. The Cmax (C2) of MZR was 1.33 microg/mL or higher in all five patients, and the efficacy of the treatment was satisfactory. Concerning side-effects, hyperuricemia was noted in two patients, but it was resolved in one of them by reducing the dose of MZR and in the other spontaneously while the treatment was continued. Temporary exacerbation of hair loss was observed in two patients, but it disappeared in both of them after a few months. CONCLUSION: MZR could be administered at a high dose effectively and safely. However, monitoring of the serum uric acid level was necessary. High-dose MZR therapy showed an efficacy and safety that would warrant its application to steroid-dependent pediatric patients with SLE.

Long-term follow-up of atypical membranoproliferative glomerulonephritis: are steroids indicated?

Atypical membranoproliferative glomerulonephritis (MPGN) has been reported to have a good prognosis when treated with corticosteroids. However, this recommendation is based on uncontrolled trials and is associated with many complications. The purpose of our study is to determine whether steroid therapy is indicated for atypical MPGN. The cases of seven patients with atypical MPGN are reported in this study. Urinary abnormalities of five of them were detected by urine screening at school, of two because of macrohematuria. Hypocomplementemia was noted in six patients. All but one patient were treated without corticosteroids, and five with angiotensin-converting enzyme inhibitors (ACEI) and/or the Chinese herbal medicine Sairei-to (TJ-114). One patient recovered spontaneously from proteinuria and was therefore not treated, and one who developed severe proteinuria during observation was treated with corticosteroids. After an average follow-up period of 10.0 years, five patients showed normal urinary findings, one had hematuria and one proteinuria. At the most recent follow-up, the renal function of all patients remained within the normal range, and serum C3 had returned to normal levels in five out of six. These findings suggest that the indication of steroid therapy for atypical MPGN should be re-examined, since most of the patients with atypical MPGN seem to have an excellent prognosis without treatment with corticosteroids.

Bio-intact parathyroid hormone and intact parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism receiving intravenous calcitriol therapy.

Intact parathyroid hormone (iPTH) assay has been the most widely used for the diagnosis of secondary hyperparathyroidism and evaluation of vitamin D therapy. However, 1-84 PTH assay might be a better diagnostic tool since iPTH detects not only 1-84 PTH but also large C-terminal fragments, which would antagonize PTH action. Therefore, we conducted a multicenter study to evaluate the clinical usefulness of a newly developed immunochemiluminometric assay for 1-84 PTH, Bio-Intact PTH (BiPTH). Thirty-five uremic patients with secondary hyperparathyroidism participated in the study. Intravenous calcitriol therapy was continued for 12 months. iPTH and bone-specific alkaline phosphatase (BAP) were monitored at each dialysis center to control the dose of calcitriol. Serum and plasma samples were collected from each center and both iPTH and BiPTH were measured using Allegro-Lite assay reagents from Nichols Institute Diagnostics (San Clemente, CA, USA). Intravenous calcitriol suppressed iPTH after 1 month as well as BiPTH. Bone-specific alkaline phosphatase decreased after 3 months. A high degree of correlation between Nichols iPTH and BiPTH (y = 0.3913 x + 19.517, r = 0.9561) was demonstrated with a BiPTH/iPTH ratio of approximately 0.44. Significant correlation between BAP and iPTH, or between BAP and BiPTH was not observed. Our limited data failed to demonstrate the superiority of BiPTH to iPTH. Therefore, further investigations would be necessary to examine the relationship between BiPTH and bone histomorphometry.

NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children.

Podocin is an integral membrane protein encoded by NPHS2, which is mapped to 1q25-31 and is exclusively expressed in glomerular podocytes. NPHS2 mutations are responsible for autosomal recessive familial steroid-resistant nephrotic syndrome (SRNS) with minor glomerular abnormalities or focal segmental glomerulosclerosis (FSGS), which is characterized by early childhood onset (age less than 6 years) and rapid progression to chronic renal insufficiency. This gene mutation is also responsible for an adolescent/adult onset form of autosomal recessive familial FSGS with heavy proteinuria. It has been demonstrated that sporadic SRNS and heavy proteinuria are also due to NPHS2 gene mutations. We isolated genomic DNA from 36 Japanese children with chronic renal insufficiency caused by SRNS or heavy proteinuria, and analyzed all eight exons and exon-intron boundaries of NPHS2 using the polymerase chain reaction and direct sequencing. The age at onset of disease was 3.9+/-0.5 years. There were 29 patients with SRNS and 7 with heavy proteinuria without nephrotic syndrome at the onset, but all patients developed chronic renal insufficiency 4.6+/-0.8 years after the onset. A new homozygous missense variant of NPHS2, G34E (G101A) in exon 1, was detected in 1 of 36 patients. However, this homozygous variant was also found in 1 of 44 normal controls, suggesting that the mutation is a polymorphism. Two silent variants (T954C and A1038G) in exon 8 of this gene were also identified in some of the patients and normal controls, indicating that the silent variants are also polymorphisms. There was no significant difference in the genotypic and allelic frequencies of T954C and A1038G polymorphisms between the patients and normal controls. In conclusion, NPHS2 gene mutations are not a major cause of chronic renal insufficiency caused by sporadic SRNS or heavy proteinuria in Japanese children.

Long-term outcome of focal segmental glomerulosclerosis after Japanese pediatric renal transplantation.

Focal segmental glomerulosclerosis (FSGS) is known to recur in some patients after renal transplantation. Over a prolonged period, we followed 13 pediatric patients with FSGS who had undergone transplantation from living-related donors, analyzing risk factors for recurrent disease. Native nephrectomies were performed bilaterally in all patients at least 1 month prior to transplantation. Immunosuppressive therapy consisted of cyclosporine (CyA), mizoribine, prednisone, and antilymphocytic globulin or deoxyspergualin. We examined age at onset, time in months between diagnosis and end-stage disease (dialysis or transplantation), the duration of dialysis, age at transplantation, time since nephrectomy, doses of immunosuppressive agents, and HLA mismatch. Five patients (42.8%) developed recurrent disease in the graft; all showed proteinuria within 24 h of transplantation. However, all allografts have functioned well for 34-156 months following transplantation despite the recurrences, although 1 of these patients now shows proteinuria. The remaining 8 patients have had no recurrence for 104.6+/-30.4 months (mean+/-SD). The serum level of creatinine in patients with recurrence and without recurrence was 1.1+/-0.42 mg/dl and 0.98+/-0.29 mg/dl, respectively. The interval from diagnosis to initiation of dialysis was significantly shorter in patients with recurrence than those without recurrence ( P<0.05), but no other variables differed between these two groups. No recurrence of FSGS was observed in the protocol biopsy at 100 days after transplantation. We believe that CyA and native nephrectomy may limit or reverse progression of recurrent FSGS in renal allografts of Japanese pediatric patients, although this is a limited study.