Clinical characteristics of HNF1B-related disorders in a Japanese population.

BACKGROUND: Hepatocyte nuclear factor 1ß (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

Effectiveness and nephrotoxicity of a 2-year medium dose of cyclosporine in pediatric patients with steroid-dependent nephrotic syndrome: determination of the need for follow-up kidney biopsy.

BACKGROUND: High dose of cyclosporine (CyA) for ≥2 years in children with steroid-dependent nephrotic syndrome (SDNS) increases the risk for nephropathy. Considering this, risk can be lowered with lower doses of CyA; we evaluated the effects of a medium dose of CyA, with target serum level, C2, of 450 ng/ml, over a 2-year period of observation, to determine the need for follow-up kidney biopsy. METHODS: We retrospectively evaluated C2 levels in 38 patients (17 males, 5.2 ± 2.9 years old) with SDNS at treatment initiation, at 6, 12 and 18 months during treatment, and at the time of kidney biopsy, 2-year after treatment initiation. Fifteen patients were also treated with mizoribine or mycophenolate mofetil. A number of relapses-per-patient-per-year, relative to SDNS onset and initiation of CyA treatment, were evaluated. Serum levels of total protein, albumin and total cholesterol, blood urea nitrogen level, and the estimated glomerular filtration rate were measured at treatment initiation and at 1- and 2-year post-treatment initiation. RESULTS: Only one very mild case of CyA-associated nephrotoxicity was identified based on biopsy results at 2-year post-treatment initiation. C2 concentrations were maintained at 422.2 ± 133.5 ng/ml and the number of relapses decreased from 3.0 relapses-per-patient-per-year prior to CyA treatment to 0.47 relapses-per-patient-per-year after CyA treatment. No effects of the treatment on the estimated glomerular filtration rate were noted. CONCLUSION: A 2-year treatment with a medium dose of cyclosporine A with or without other immunosuppressive agents is relatively safe with regard to the development of cyclosporine A nephrotoxicity.

Warfarin-induced toxic epidermal necrolysis in combination therapy of Henoch-Schönlein purpura nephritis: a case report.

BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare life-threatening condition almost exclusively attributed to drugs. The main etiologic factors for TEN are sulphonamides, anticonvulsants, and antibiotics; however, there are no published reports of warfarin causing TEN. CASE PRESENTATION: We present the case of a 3-year-old patient who developed TEN while receiving treatment for Henoch-Schönlein purpura nephritis (HSPN). With multiple-drug therapy comprising prednisolone, mizoribine, dipyridamole, and warfarin, it is difficult to detect which drug is the causative agent. While in most cases, diagnosis of the causative drug is based on clinical history without a lymphocyte transformation test (LTT), we performed the test three times and identified the causative drug as warfarin at the late phase. We continued HSPN treatment without warfarin, and results showed good renal function without life-threatening complications. CONCLUSION: To our knowledge, this is the first report about TEN caused by warfarin. Repeated LTTs could be useful for identifying TEN-causative drugs even in the late phase.

Pitfalls of diagnosing urinary tract infection in infants and young children.

BACKGROUND: The aim of this study was to examine the sensitivity and specificity of pyuria-based diagnosis of urinary tract infection (UTI) in urine collected by transurethral catheterization, and the reliability of diagnosis of pyuria in urine collected in a perineal bag. The gold standard for UTI diagnosis is significant colony counts of a single organism in urine obtained in a sterile manner. METHODS: We enrolled 301 patients who underwent medical examination at the present hospital for possible UTI between January 2005 and December 2009. We collected 438 urine samples by transurethral catheterization. We investigated the accuracy of pyuria-based diagnosis of UTI using transurethral catheterization urine specimens, and the reliability of diagnosis of pyuria using bag-collected urine specimens. RESULTS: The false-negative rate of UTI diagnosis based on pyuria in transurethral catheterization urine sediments was 9.0%; there was no significant difference in the false-negative rate of UTI diagnosis between boys and girls. Approximately 28% of pyuria-positive bag-collected urine specimens were pyuria negative on transurethral catheterization; this rate was significantly higher in girls than in boys (56.7% vs. 8.9%, P < 0.0001). CONCLUSIONS: The absence of pyuria in transurethral catheterization urine sediments does not rule out UTI. Pyuria in bag-collected urine specimens frequently consists of urine leukocytes from external genitalia as well as from the urinary tract.

Stenosing ureteritis in Henoch-Schönlein purpura: report of two cases.

Stenosing ureteritis (SU), a rare complication of Henoch-Schönlein purpura (HSP), typically presents with severe symptoms. We report the cases of two HSP patients presenting with gross hematuria, blood clotting, and colicky flank pain, followed by purpura on the lower extremities. Early-stage ultrasonography indicated hydronephrosis, thickened renal pelvic mucous membrane, and ureteral dilatation (UD), suggesting HSP complicated with SU. After early SU treatment with prednisolone, kidney function, thickened renal pelvic mucous membrane, and UD progressively normalized and the pain gradually disappeared. Regular ultrasonography of HSP patients from the onset of gross hematuria can be useful to detect early SU and facilitate conservative therapy with prednisolone. Diagnosis of SU can be easily missed by assuming HSP nephritis, particularly owing to the non-specific symptoms. Common characteristics as well as treatment methods and prognosis of SU are given in the literature review.

The ratios of urinary ß2-microglobulin and NAG to creatinine vary with age in children.

BACKGROUND: Although urinary biochemical markers can be assessed by their ratio to urinary creatinine (U-Cr) concentration, reference values in adults may not be applicable to children because the amount of Cr excreted varies by body size. We therefore measured the relationship between age and the ratios of urinary ß-2-microglobulin (U-ß2MG), N-acetyl-ß-d-glucosaminidase (U-NAG), calcium (U-Ca) and protein (U-Pr) concentration to those of U-Cr in children. METHODS: Fifty-seven patients aged >1 year with benign familial hematuria (median age, 6.3 years) were divided into three age groups: 1-4, 5-9, and ≥10 years. Urinary biomarkers were assayed using actual values; ratios to actual U-Cr values; and our standardized metric, namely 100-fold the ratio of serum Cr to U-Cr concentration; and the relationship of each of these to age was determined. RESULTS: The ratios of U-ß2MG, U-NAG and U-Ca to Cr varied significantly by age, being higher in younger than in older children, but the actual and standardized values of each did not vary by age, nor did any measurement of U-Pr. CONCLUSIONS: The ratios of urinary markers of tubular function, including U-ß2MG, U-NAG and U-Ca, to Cr vary by age, being higher in younger children. In contrast, the ratios of urinary markers of glomerular filtration (such as U-Pr)to Cr do not vary by age, making them suitable for corrections relative to Cr.

Steroid- and immunosuppressant-based protocol of Henoch-Schönlein purpura nephritis without angiotensin inhibitors in the acute phase.

BACKGROUND: The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest initially using angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs) to treat Henoch-Schönlein purpura nephritis (HSPN). However, these guidelines might overlook the potential benefits of aggressive therapy. Therefore, we evaluated the efficacy of an HSPN protocol that primarily uses steroids and immunosuppressants, without ACE-Is or ARBs. METHODS: We determine treatment intensity based on International Study of Kidney Diseases in Children (ISKDC) grading. Fifty-one patients were treated with our protocol that primarily uses steroids and immunosuppressants. ACE-Is and ARBs were not used in the acute phase, including before renal biopsy. We evaluated the proteinuria disappearance rate, duration to proteinuria disappearance, and estimated glomerular filtration rate (eGFR) at the time of last observation and compared them to those in previous reports. RESULTS: Proteinuria disappeared in 49 patients (96%) within a median of 5 months. The median eGFR was 116.0 mL/min/1.73 m2 at the time of last observation. Six of 51 patients had acute kidney injury (eGFR<90 mL/min/1.73 m2) before treatment, but all recovered during the observation period (median 52 months). CONCLUSIONS: Our steroid- and immunosuppressant-based protocol without ACE-Is or ARBs in the acute phase of HSPN had almost equivalent efficacy to that in previous studies that used ACE-Is and/or ARBs with steroids and immunosuppressants.

Eculizumab for pediatric dense deposit disease: A case report and literature review.

Dense deposit disease (DDD), a subtype of complement component 3 (C3) glomerulopathy (C3G), results from alternative complement pathway hyperactivity leading to membrane attack complex formation. DDD treatment strategies are limited. We report a case of a 13-year-old girl diagnosed with DDD at 9 years of age, with nephritic and nephrotic syndrome and C3 nephritic factor-negative alternative complement pathway activation. Initial treatment with prednisolone, methylprednisolone pulses (MPs), and mizoribines was effective for 3 years, after which she relapsed. Despite MP treatment followed by prednisolone and mycophenolate mofetil (MMF), her kidney function and proteinuria deteriorated with a high soluble (s)C5b-9 level; she also developed dyspnea and pleural effusion (PE). Three days after the first eculizumab (ECZ) infusion, urine volume increased, respiratory condition improved, PE resolved, and proteinuria decreased in 1 month. Serum creatinine level decreased, and kidney function completely normalized within 7 weeks. The sC5b-9 level normalized, and although proteinuria decreased, nephrotic range proteinuria persisted during ECZ treatment with MMF for 53 weeks, even with increased treatment interval. Thus, complement activation pathway-targeted therapy may be useful for rapidly progressing DDD. Our data support the role of complement pathway abnormalities in C3G with DDD.

Histopathology of the trabecular meshwork and Schlemm's canal in primary angle-closure glaucoma.

PURPOSE: To investigate the detailed histopathology of trabecular meshwork changes associated with primary angle closure glaucoma (PACG). METHODS: Thirty trabecular blocks obtained from trabeculectomy (TLE) of 25 PACG patients were embedded in paraffin for immunohistochemical staining of thrombomodulin, CD68, D2-40, and epon for transmission electron microscopy. Eleven TLE blocks obtained from normal-tension glaucoma patients were used as a control. Histologic changes of outflow routes were analyzed by comparing the existence of iridotomy, gonioscopy-evaluated angle closure, intraocular pressure (IOP), episodes of acute attack, visual field defect classified by Aulhorn-Greve, anterior chamber depth, lens thickness, and axial length. RESULTS: Occlusion of the Schlemm's canal (SC) of <150 µm was observed in 11 eyes, which significantly correlated with gonioscopy-evaluated angle closure (T = 19.33 > χ² (f,α) = 9.488). Moderate correlation between SC occlusion and IOP before TLE was also observed (correlation coefficient: -0.540). Slightly negative or no correlations were found between SC occlusion and the other parameters. Thinned SC endothelium at the junction or degenerated SC endothelium and various degrees of SC occlusion and fusion of the trabecular beams where trabecular cells degenerated with damaged mitochondria were the general findings in the PACG eyes involved in this study. CONCLUSIONS: Persistent trabecular-iris contact or peripheral anterior synechia may block aqueous outflow resulting in a progressive process of SC endothelial damage and subsequent SC occlusion, as well as trabecular cell damage possibly due to impairment of mitochondrial function and subsequent fusion of the trabecular beams. These changes may be the reason for residual glaucoma after laser iridotomy or cataract surgery.