Atypical histological abnormalities in an adult patient with nephronophthisis harboring NPHP1 deletion: a case report.

BACKGROUND: Nephronophthisis (NPHP) is a chronic tubular interstitial disorder that exhibits an autosomal recessive genetic form and causes progressive renal failure in children. Patients with NPHP rarely show urinary abnormalities, edema, or hypertension. Thus, NPHP is often detected only when renal failure becomes advanced. NPHP can be divided into three types based on the age of end-stage renal failure, i.e., infant type (approximately 5 years old), juvenile type (approximately 13-14 years old), and adolescent type (approximately 19 years old). Here, we report a case of NPHP diagnosed by genetic analysis at 26 years of age with atypical histological abnormalities. CASE PRESENTATION: A 26-year-old woman showed no growth disorders or urinary abnormalities in annual school physical examinations. However, at a check-up at 26 years old, she exhibited renal dysfunction (eGFR 26 mL/min/1.73 m2). Urine tests indicated low specific gravity of urine, but not proteinuria or microscopic hematuria. Urinary ß2-microglobulin was high (805 µg/L), and renal biopsy was performed for definitive diagnosis. Histological findings showed no significant findings in glomeruli. However, moderate fibrosis was observed in the interstitial area, and moderate atrophy was observed in the tubules. There were no significant findings in immunofluorescence analysis, and no electron dense deposits were detected by electron microscopy. Although cyst-like expansion of the tubules was unclear, tubular atrophy was dominantly found in the distal tubule by cytokeratin 7 staining. Genetic analysis of the NPHP1 gene showed complete deletion of this gene, leading to a definitive diagnosis of NPHP. CONCLUSIONS: NPHP is not merely a pediatric disease and is relatively high incidence in patients with adult onset end-stage of renal disease. In this case, typical histological abnormalities, such as cyst-like expansion of the tubular lesion, were not observed, and diagnosis was achieved by genetic analysis of the NPHP1 gene, which is responsible for the onset of NPHP. In patients with renal failure with tubular interstitial disease dominantly in the distal tubules, it is necessary to discriminate NPHP, even in adult cases.

Icatibant promotes patients' behavior modification associated with emergency room visits during an acute attack of hereditary angioedema.

Hereditary angioedema due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) induces an acute attack of angioedema. In 2018, icatibant available for self-possession and subcutaneous self-administration was licensed for on-demand treatment in addition to intravenous C1-INH administration in Japan. We retrospectively evaluated the percentage of attacks in critical parts at emergency room (ER) visits and the time until visiting ER for C1-INH administration before and after the initial prescription of icatibant. The percentage of attacks in critical parts at ER visits before the prescription was 69.2%, but that was 80.0% when patients visited ER for additional C1-INH administration after the self-administration of icatibant. The time from the onset of an acute attack to visiting ER for the additional treatment after the self-administration of icatibant significantly increased from 6.2 h to 19.2 h (p < 0.001). Icatibant, therefore, promoted the patients' behavior modification associated with ER visits for C1-INH administration during an acute attack of HAE-C1-INH.

A case of hereditary angioedema due to C1-inhibitor deficiency with recurrent abdominal pain diagnosed 40 years after the occurrence of the initial symptom.

Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare disease, which induces an acute attack of angioedema mediated by bradykinin. HAE-C1-INH can cause serious abdominal pain when severe edema develops in the gastrointestinal tract. However, because it takes a long time, 13.8 years on average in Japan, from the occurrence of the initial symptom to the diagnosis due to low awareness of the disease, undiagnosed HAE-C1-INH patients sometimes undergo unnecessary surgical procedures for severe abdominal pain. We herein present a 56-year-old patient with HAE-C1-INH, who underwent numerous abdominal operations. He frequently needed hospitalization with the administration of opioid due to severe abdominal pain. However, after he was accurately diagnosed with HAE-C1-INH at 55 years of age, he could start self-administration for an acute attack with icatibant, a selective bradykinin B2 receptor antagonist. Consequently, he did not need hospitalizing for ten months after the beginning of the treatment. A series of an accurate diagnosis and appropriate treatment for HAE-C1-INH improved his quality of life. Thus, HAE-C1-INH should be considered, when we meet patients with unidentified recurrent abdominal pain. This case highlights significance of an early diagnosis and appropriate treatment for HAE-C1-INH.

Cut-off value of C1-inhibitor function for the diagnosis of hereditary angioedema due to C1-inhibitor deficiency.

Hereditary angioedema caused by C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare autosomal dominant disease. Primary care physicians sometimes face difficulties in diagnosing HAE-C1-INH owing to fluctuations in C1-INH function levels influenced by blood sampling conditions. International major guidelines do not stipulate a cut-off value of C1-INH function for the diagnosis. We aimed to explore the distribution of C1-INH function levels in patients with HAE-C1-INH and elucidate the influence of blood sampling conditions using healthy volunteers' samples to confirm the cut-off value of C1-INH function. In 48 patients with HAE-C1-INH who visited the Juntendo University Hospital in Japan between 2013 and 2019, C1-INH function levels were evaluated for 160 samples during symptom-free periods and 147 samples during an acute attack. Fluctuations of C1-INH function level were also evaluated for 8 healthy volunteers, wherein the samples were divided into 3 groups according to different sampling conditions. C1- INH function levels in all patients with HAE-C1-INH were found to be < 50%. The average C1- INH function level in healthy volunteers measured soon after blood collection in an appropriate sampling condition was 77% (61-92%) with some having lower C1-INH function levels than the reference value. C1-INH function levels fluctuated unstably in inappropriate sampling conditions. In conclusion, we can confirm that a < 50% C1-INH function level can be used as the diagnostic cut-off value for HAE-C1-INH. Moreover, it is necessary to repeat measurements of C1-INH function level in appropriate blood sampling conditions to accurately diagnose HAE-C1-INH.

Suffocation due to Acute Airway Edema in a Patient with Hereditary Angioedema Highlighted the Need for Urgent Improvements in Treatment Availability in Japan.

A 42-year-old Japanese man with hereditary angioedema suffered accidental trauma to his jaw in Shizuoka Prefecture, Japan, which gradually caused facial edema. Since plasma-derived human C1 inhibitor (pdh C1-INH) was unavailable, he had to be transferred to Juntendo University Hospital in Tokyo. Due to his severe edema, he suffered asphyxiation leading to cardiopulmonary arrest upon arrival. The patient was resuscitated and promptly treated with pdh C1-INH. In Japan, the self-administration of pdh C1-INH is not allowed, and every prefecture does not always possess stocks of pdh C1-INH. This case emphasizes the need for urgent improvements in treatment availability in Japan.

A case of primary immunoglobulin light chain amyloidosis with a delayed appearance of Bence Jones protein in urine.

We report here a case of a 58-year-old man who had nephrotic syndrome and immunoglobulin light chain (AL) amyloidosis. This patient underwent a renal biopsy to confirm the diagnosis. Treatment with permanganate before Congo red staining showed systemic secondary amyloidosis (AA) fibrils, which were sensitive to permanganate oxidation. Although this patient was initially diagnosed as having AA amyloidosis, he did not have any chronic inflammatory disease and/or malignancy. The level of amyloid A protein (7.9 microg/mL) in sera was within the normal range (0-8.0 microg/mL). Therefore, we performed an immunostaining of the precursor protein (amino terminus of constant region: kappa and lambda light chains, and AA protein) using duodenal biopsy specimens for a precise diagnosis. Immunostaining was positive for the amino terminus of constant region of the lambda light chain, and negative for the amino terminus of constant region of the kappa light chain and AA protein. No plasma cell proliferation in the bone marrow was observed. We finally diagnosed this patient as having primary AL amyloidosis. It appears that a pathological diagnosis must be performed by immunostaining the precursor proteins with the permanganate digestion technique in tissue of patients with amyloidosis. There were no abnormalities in serum and urine immunoelectrophoresis at the time of renal biopsy in this patient. During the follow-up period, after discharge, Bence Jones protein appeared in the urine, but not in the serum. It is necessary to observe patients with primary AL amyloidosis carefully to determine if they their condition will progress to multiple myeloma.

Beta-trace protein, a new marker of GFR, may predict the early prognostic stages of patients with type 2 diabetic nephropathy.

The relationship between serum levels of beta-trace protein (BTP) or serum creatinine (s-Cr) and the prognostic stages of type 2 diabetic nephropathy was determined. Serum samples from 174 patients with type 2 diabetes were obtained from Juntendo University Hospital, Tokyo, and Juntendo Urayasu Hospital, Chiba, Japan. They were classified into four groups according to the Report of the Ministry of Health and Welfare of Japan (1991, p 251-256) as follows: Stage I (normoalbuminuric stage), Stage II (microalbuminuric stage), Stage IIIA (macroalbuminuric stage without renal dysfunction), Stage IIIB (macroalbuminuric stage with renal dysfunction), and Stage IV (renal failure stage). Among these patients, 68 were Stage I, 29 Stage II, 32 Stage IIIA, 17 Stage IIIB, and 28 Stage IV. Levels of serum BTP were measured using the nephelometric assay on a BNA II analyzer (Dade Behring Diagnostics, Marburg, Germany). The mean levels of serum BTP in Stage IIIA were significantly higher than those in Stage I or II (P < 0.00001, P < 0.002, respectively). However, the mean levels of s-Cr in Stage IIIA were not significantly higher than that in Stage I or II. In conclusion, serum BTP was a good marker for the identification of early renal impairment in type 2 diabetes.