Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation

Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation.BackgroundSeveral families have been described in which an A to G transition mutation at position 3243 (A3243G) of the mitochondrial DNA (mtDNA) is associated with focal and segmental glomerulosclerosis (FSGS). However, the prevalence, clinical features, and pathophysiology of FSGS carrying mtDNA mutations are largely undefined.MethodsAmong 11 biopsy-proven primary FSGS patients of unknown etiology, we examined seven FSGS patients to determine whether any of the clinical and pathological features of FSGS were associated with an A3243G mtDNA mutation. In four subjects in whom the A3243G mtDNA mutation was discovered in blood leukocytes, as well as in urine sediments, we retrospectively reviewed the medical records and re-evaluated the renal biopsy specimen using light and electron microscopy. We further screened the patient's family members for the presence and degree of heteroplasmy for this mtDNA mutation and obtained medical histories that were consistent with mitochondrial cytopathy.ResultsThe four individuals identified with the A3243G mtDNA mutation were female. Proteinuria was diagnosed in these individuals during a routine annual health checkup in their teenage years. None of the patients showed any symptoms related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode, whereas diabetes mellitus in two of the patients and a hearing disturbance in one patient became manifest within a 3- to 13-year follow-up period. Strict maternal transmitted inheritance was confirmed by pedigree studies in all of these patients. Steroid therapy was ineffective in all four patients. In two of these patients, renal function declined slowly to end-stage renal failure. Histologic examination of biopsy specimens revealed that glomeruli were not hypertrophied, while electron microscopic examination identified severely damaged, multinucleated podocytes containing extremely dysmorphic abnormal mitochondria in all patients.ConclusionsFSGS may belong to the spectrum of renal involvement in A3243G mtDNA mutation in humans. Severely injured podocytic changes containing abnormal mitochondria may explain the pathogenesis of FSGS in association with the A3243G mtDNA mutation

Analysis of Factors Regarding Spa Therapy in Patients with Rheumatoid Arthritis

1998年4月より9月までの6ヶ月間に当院へ入院し温泉療法をうけた慢性関節リウマチ患者6例を対象に,温泉治療経験の有無,年齢,機能障害度(クラス),罹患年数の4項目が温泉療法効果に及ぼす影響につき検討した｡温泉治療経験の有無では治療経験を有する患者においてMHAQ(modified health assessment questionnaile),患者による疼痛評価,患者による全般活動性評価に有意な改善が見られ,年齢(75才以上,75才未満)では,75才未満においてMHAQに有意な改善傾向が見られた｡機能障害度(クラス3以上,クラス2以下),罹患年数(15年以上,15年未満)においては有意差は見られなかった｡温泉の永続効果を保つためには,年1～2回の入院を繰り返すことが効果的であることが示唆された｡In patients with rheumatoid arthritis (RA) who received spa therapy (ST) on admission, we examined factors for treatment response. This study included 6 RA patients and the following 4 parameters were investigated: presence or absence of previous ST, age, duration of RA, and grade of the functional disorder. Treatment response was evaluated according to the American College of Rheumatology core set measures. With respect to the presence or absence of previous ST, modified health assessment questionnaire (MHAQ), pain scale and patient global assessments in the group with previous ST were significantly improved compared to those in the group without previous ST. With respect to age, MHAQ in the group consisting of patients less than 75 years old was significantly improved compared to that in the group consisting of patients 75 years old or older. With respect to the grade of the functional disorder (class 2 or lower vs. class 3 or higher) and the duration of RA (less than 15 years vs. 15 years or more), there were no significant differences. These results suggest that repeated therapy is more effective in ST and treatment response may be relatively poor in elderly patients with RA aged over 75 years

Urinary thrombin: a novel marker of glomerular inflammation for the diagnosis of crescentic glomerulonephritis (prospective observational study).

Crescentic glomerulonephritis (CresGN), an uncommon rapidly progressive disease, is characterized by severe glomerular inflammation with fibrin deposition. The lack of specific CresGN biomarkers delays diagnosis and threatens life. Because fibrin deposits in CresGN glomeruli indicate thrombin generation, we hypothesized that thrombin is excreted in urine and is a specific CresGN biomarker.We measured urinary thrombin activity in 200 untreated patients (17 with CresGN, 183 with primary glomerulonephritis) and controls (8 patients with healed CresGN, 11 with nephrosclerosis, and 10 with tubulointerstitial nephritis, and 66 healthy volunteers). CresGN types included 15 pauci-immune and 2 immune complex. We assessed the diagnostic accuracy of thrombinuria in 169 patients with hematuria and proteinuria. Renal biopsy tissues were immunostained for tissue factor and fibrin. We analyzed the relationship of thrombinuria to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, glomerular fibrin deposition, antineutrophil cytoplasmic antibodies (ANCAs), and C-reactive protein (CRP). We studied changes in thrombin activities after glucocorticoid treatment in 12 patients with thrombinuria.The highest thrombinuria occurrence was in CresGN (70.6%), followed by membranoproliferative glomerulonephritis (41.7%), IgA nephropathy (9.2%), and acute glomerulonephritis (0%). More than 75% of patients with nonproliferative glomerulonephritis manifested no thrombinuria. No controls had thrombinuria. Thrombinuria showed high CresGN specificity (90.1%) and moderate sensitivity (70.6%) and was detected in 4 of 7 patients with ANCA-negative CresGN. In CresGN, thrombinuria was associated with fibrin deposition in glomerular extracapillary tissue, where monocytes/macrophages expressed tissue factor. Thrombinuria in CresGN was unrelated to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, and CRP. After glucocorticoid treatment, thrombinuria in patients with CresGN rapidly disappeared but proteinuria and hematuria persisted.Thrombinuria was specific for glomerular inflammation, was unaffected by systemic inflammation or coagulation, and demonstrated good diagnostic accuracy for CresGN including ANCA-negative cases. Thrombinuria measurement may provide risk-free diagnosis and screening for CresGN

Thrombinuria in glomerulonephritis and its diagnostic accuracy for crescentic glomerulonephritis (CresGN) and its relation to plasma thrombin-antithrombin complex (TAT), urinary TAT, and hemoglobinuria.

<p>(<b>A</b>) Occurrence of urinary thrombin detected (>0.2 U/L) in each group; fractions over the columns indicate the number of samples with thrombin activity per the total number of samples. (<b>B</b>) Thrombin excretion level for each type of glomerulonephritis, as shown by box plots that indicate the median-25th and 75th-median percentiles. Bars with asterisks (*) show only significant differences between two groups. MPGN, membranoproliferative glomerulonephritis; IgAN, IgA nephropathy; non-IgA mesPGN, non-IgA mesangial proliferative glomerulonephritis; AGN, acute glomerulonephritis; MCNS, minimal change glomerulopathy; MN, membranous nephropathy; FSGS, focal segmental glomerulosclerosis; and TIN, tubulointerstitial nephritis. gCr indicates gram of urinary creatinine. (<b>C</b>) The receiver operating characteristic (ROC) curve for diagnosis of CresGN in patients with hematuria and proteinuria. The asterisk indicates the diagnostic accuracy at the cutoff value of 0.6 U/gCr. CI indicates confidence interval. (<b>D</b>) Relation of thrombin excretion to plasma TAT. Circles indicate patients with ANCA-associated CresGN (16 measurements in 9 patients). gCr indicates gram of creatinine. (<b>E</b>) Relation of urinary thrombin to urinary TAT. (<b>F</b>) Relation of urinary thrombin to hemoglobinuria. In (<b>E</b>) and (<b>F</b>), each circle represents an individual patient with glomerulonephritis.</p

Characteristics of the patients.

<p>*The ages of patients with healed CresGN, CresGN, MN, or nephrosclerosis were significantly higher than those of the other groups (<i>P</i><0.01) except for the patients with TIN. The ages of patients with healed CresGN and CresGN were significantly higher than those of patients with with TIN at <i>P</i><0.05. The age of patients with IgAN was significantly lower than that of patients with non-IgA mesPGN, FSGS, or TIN and that of healthy volunteers at <i>P</i><0.01 and was significantly lower than that of patients with MPGN and MCNS at <i>P</i><0.05.</p><p>†Patients with MCNS and MN had significantly heavier proteinuria compared with patients with IgAN, non-IgA mesPGN, AGN, nephrosclerosis, or TIN at <i>P</i><0.01 and patients with MPGN or CresGN at <i>P</i><0.05. Patients with FSGS manifested heavier proteinuria than patients with IgAN at <i>P</i><0.01 and patients with non-IgA mesPGN, nephrosclerosis, or TIN at <i>P</i><0.05. gCr indicates gram of urinary creatinine.</p><p>‡For the estimated glomerular filtration rate (eGFR), patients with CresGN had a significantly lower eGFR than did patients with healed CresGN (<i>P</i><0.05) and the other patients (<i>P</i><0.01) except those with TIN. Patients with TIN had a significantly lower eGFR than did the other groups except patients with CresGN or healed CresGN. Patients with healed CresGN had a significanty lower eGFR than the other patients except those with CresGN, nephrosclerosis, or TIN. Healthy volunteers had significantly higher eGFR values than the other groups except patients with IgAN, non-IgA mesPGN, AGN, MCNS, or MN. Patients with FSGS and MPGN had significantly lower values than did healthy volunteers, and patients with FSGS had a significantly lower value than did patients with IgAN at <i>P</i><0.05.</p><p>§Negative proteinuria results were obtained via the test tape method.</p><p>Characteristics of the patients.</p

Characteristics of patients with crescentic glomerulonephritis.

<p>*Cases from Sendai Shakaihoken Hospital and Kumamoto Chuo Hospital are shown by s and k, respectively.</p><p>†eGFR indicates estimated glomerular filtration rate; gCr, gram of urinary creatinine.</p><p>‡Cases 2 and 7 were associated with rheumatoid arthritis and IgA nephropathy, respectively.</p><p>**Activities less than 0.6 U/gCr were regarded as zero.</p><p>Characteristics of patients with crescentic glomerulonephritis.</p

Glomerular tissue factor expression in biopsy tissues.

<p>(<b>A</b>) Representative tissue factor expression patterns of renal biopsy tissues as shown by immunostaining. All patients, except those with acute glomerulonephritis (AGN), had thrombinuria. (<b>a</b>) Crescentic glomerulonephritis (CresGN); (<b>b</b>) control staining of CresGN with normal mouse IgG; (<b>c</b>) membranoproliferative glomerulonephritis; (<b>d</b>) IgA nephropathy; (<b>e</b>) AGN; (<b>f</b>) minimal change glomerulopathy; (<b>g</b>) focal segmental glomerulosclerosis; and (<b>h</b>) membranous nephropathy. Mφ indicates monocytes/macrophages; Epithelial, epithelial cells; and Mesangium, mesangial areas. The broken line in (<b>a</b>) outlines a cellular crescent. (<b>B</b>) Double-staining pattern of CD68 (macrophages) and tissue factor in the CresGN glomerulus.</p

Thrombinuria and fibrin deposition in glomerular tissues in glomerulonephritis.

<p>*Thr and Fib indicate thrombinuria and fibrin deposition, respectively. Fibrin deposition was determined via immunofluorescence microscopy, and thrombin activities > and below the detection limit (0.2 U/L) were regarded as positive (+) and negative (-) thrombinuria, respectively.</p><p>CresGN indicates crescentic glomerulonephritis; IgAN, IgA nephropathy; Non-IgA mesPGN, non-IgA mesangial proliferative glomerulonephritis; MPGN, membranoproliferative glomerulonephritis; MCNS, minimal change glomerulopathy; FSGS, focal segmental glomerulosclerosis; and MN, membranous glomerulopathy.</p><p>Thrombinuria and fibrin deposition in glomerular tissues in glomerulonephritis.</p

Glucocorticoid effect on thrombinuria and proteinuria and thrombinuria vs. proteinuria or estimated glomerular filtration rate.

<p>(<b>A</b>) Thrombinuria (left panel) and proteinuria and hematuria (right panel) before (pre) and after (post) steroid pulse treatment in 6 patients with crescentic glomerulonephritis (CresGN) (#1 to #6) with thrombinuria. Three days of pulse therapy with intravenous methylprednisolone at 0.5–1 g/day was followed by oral prednisolone at 20–30 mg/day. gCr indicates gram of urinary creatinine. (<b>B</b>) Relation between urinary thrombin and urinary protein levels for various types of glomerulonephritis. Each circle represents an individual patient. (<b>C</b>) Relation between excretion level of thrombin and estimated glomerular filtration rate (eGFR) for various types of glomerulonephritis. Each circle represents an individual patient. IgAN, IgA nephropathy; MPGN, membranoproliferative glomerulonephritis; MCNS, minimal change glomerulopathy; FSGS, focal segmental glomerulosclerosis; and MN, membranous glomerulopathy. In (<b>B</b>) and (<b>C</b>), asterisks (*) and solid lines indicate statistically significant associations and correlation lines, respectively.</p