Significance of kidney biopsy in autosomal dominant tubulointerstitial kidney disease-UMOD: is kidney biopsy truly nonspecific?

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. METHODS: Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. RESULTS: Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6-53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. CONCLUSIONS: Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.

Effects of the magnitude of pressure on the severity of injury and capillary closure in rat experimental pressure ulcers.

Experimental pressure ulcers were successfully produced in the rat abdominal wall at 100 mmHg in our previous study. We hypothesized that injury is less severe when pressures are lower than 100 mmHg and explored a critical pressure in the production of pressure ulcers. At 70 and 60 mmHg, repeated compressions for 4 h daily for 5 consecutive days resulted in partial skin necrosis and eschar formation in the majority of rats, whereas skin injuries were absent or very mild in most of the rats at 50 mmHg. The extent of ischemia was also examined by visualization of capillary blood flow using intravascular infusion of Lycopersicon esculentum lectin. Rat abdominal walls were compressed in the range from 0 (control) to 100 mmHg. The percentages of open capillaries were 62.8 ± 10.1% at 0 mmHg and 34.7 ± 18.5% at 10 mmHg. The ratio of open capillaries was further decreased with increasing pressure, but not pressure dependently. In conclusion, the severity of injury at 50 mmHg was drastically milder than that at 60 mmHg or higher, whereas the extent of ischemia (capillary closure) was not significantly different. The pressure is vitally important; however, other factor(s) besides ischemia is likely to promote the development of pressure ulcers.

Telmisartan treatment decreases visceral fat accumulation and improves serum levels of adiponectin and vascular inflammation markers in Japanese hypertensive patients.

Hypertension contributes to the occurrence and progression of cardiovascular diseases. The angiotensin II type 1 receptor blocker telmisartan is reported to activate the peroxisome proliferator-activated receptor gamma and improve insulin sensitivity. We investigated the effects of telmisartan treatment on visceral fat, serum adiponectin and vascular inflammation markers in Japanese hypertensive patients. This was an open-label, non-controlled study. Twenty-eight essential hypertensive patients (22 men and 6 women; age 60.6+/-1.9 years; body mass index [BMI] 25.5+/-0.6 kg/m(2)) participated. Fat area was assessed with computerized tomography. All the subjects were started on telmisartan 40 mg/day, which was increased to 80 mg/day to achieve the blood pressure target of less than 130/80 mmHg. We assessed the visceral and subcutaneous fat areas, serum adiponectin levels, and vascular inflammation markers at baseline and 24 weeks of telmisartan treatment. There were significant reductions in visceral fat area (from 103.1+/-7.9 to 93.3+/-8.4 cm(2), p<0.01) and pulse wave velocity (from 1,706+/-52 to 1,587+/-51 cm/s, p<0.01) at 24 weeks. In contrast, significant increases in serum high-density lipoprotein cholesterol (from 5.06+/-0.15 to 5.32+/-0.13 mmol/L, p<0.05) and adiponectin levels (from 8.27+/-0.76 to 9.13+/-0.81 microg/mL, p<0.05) were observed. Also, there were reductions in the interleukin-6 level (from 2.26+/-0.27 to 1.60+/-0.14 pg/mL, p<0.01). We also conducted these investigations in male subjects alone and similar findings were obtained for all of these parameters. In conclusion, telmisartan treatment was associated with an improvement of vascular inflammation, reductions in visceral fat and increases in serum adiponectin.

Hints to the diagnosis of uromodulin kidney disease.

BACKGROUND: Uromodulin kidney disease (UKD) is an inherited kidney disease caused by a uromodulin (UMOD) gene mutation. The UMOD gene encodes the Tamm-Horsfall protein (THP), which is the most abundant protein in healthy human urine. Because of its rarity, the incidence of UKD has not been fully elucidated. The purpose of the present study is to clarify the frequency of UKD among patients who underwent renal biopsy. METHODS: Immunostaining for THP was performed for patients <50 years of age with renal insufficiency and hyperuricemia without overt urinalysis abnormality from renal biopsy databases. Serum and urinary THP concentrations were evaluated in available individuals. RESULTS: Fifteen patients were selected for immunostaining from a total of 3787 patients. In three independent patients, abnormal THP accumulation in renal tubular cells was observed. A novel missense A247P UMOD mutation was detected in two of the three patients, including one having a typical family history of familial juvenile hyperuricemic nephropathy. Serum and urinary THP concentrations of all available patients with UMOD A247P mutation were significantly lower than those of controls. CONCLUSIONS: In the present study, UKD was detected in <1 in 1000 subjects who underwent renal biopsies. However, in subjects meeting all of the above criteria, abnormal THP accumulation was detected in 20% (3/15), suggesting that renal biopsy with immunostaining for THP is a good tool for diagnosing UKD. Also, low serum THP concentration detected in the present subjects might be a good diagnostic marker or important in understanding the pathogenesis of UKD.

Does the use of insulin in a patient with liver dysfunction increase water retention in the body, i.e. cause insulin oedema?

A 68-year-old female with mild diabetes mellitus was admitted because of acute liver dysfunction due to autoimmune hepatitis. While 40 mg/day of prednisolone improved hepatic dysfunction dramatically, her diabetic milieu deteriorated seriously. The induced hyperglycaemia could not be controlled sufficiently, despite a high dose of insulin (> 110 units/day), suggesting the existence of insulin insensitivity and hyperinsulinaemia. Soon after introduction of insulin therapy, she developed severe anasarca, including marked peripheral oedema, ascites and pleural effusion. Anasarca eventually subsided within 4 weeks with the use of a diuretic agent. We conjectured that the side effects of insulin, such as anti-natriuresis and increased vascular permeability, might be pronounced in the presence of the hepatic dysfunction that accompanies insulin insensitivity, hyperinsulinaemia and hypoalbuminaemia.

Acute urinary retention as an unusual manifestation of aseptic meningitis.

A formerly healthy 32-year-old woman was hospitalized for a closer examination of undiagnosed fever with mild headache. Despite lack of distinct findings on physical and laboratory examinations at admission, she suddenly developed anuresis due to acontractile neurogenic bladder. On the basis of her symptoms and the faint nuchal rigidity revealed later, as well as the results of cerebrospinal fluid analyses, a diagnosis of aseptic meningitis was eventually reached. While aseptic meningitis subsided within 3 weeks, about 10 weeks, including a 26-day period of anuria, was necessary for complete restoration of normal voiding function, necessitating intermittent self-catheterization. Acute urinary retention should be considered an uncommon but critical manifestation of aseptic meningitis.

Lispro is superior to regular insulin in transient intensive insulin therapy in type 2 diabetes.

OBJECTIVE: The optimal approach to relatively recent onset type 2 diabetes patients is still unknown. We speculated that the use of short-acting insulin analogs might be of particular benefit in this context. PATIENTS AND METHODS: To explore this possibility, we compared the effect on beta- and alpha-cell function of transient intensive insulin therapy using lispro versus human regular insulin in a total of 21 type 2 diabetic patients who were randomly assigned to 14-days intensive insulin therapy consisting of bedtime NPH insulin plus three injections of mealtime lispro (n=11) or regular insulin (n=10). The dosages of both types of insulin were adjusted to attain preprandial glucose levels of <6.1 mmol/l within 1 week with similar rates of glucose decline. An oral glucose tolerance test (OGTT) was performed at day 0 (baseline), 7, and 14; plasma glucose, serum insulin, and plasma glucagon responses over 0-120 minutes were measured, and calculated as the area under the curve (AUC). RESULTS: Lispro led to a significant reduction in glucose-AUC and also an increase in insulin-AUC versus regular insulin on day 7. Glucagon secretion following OGTT was well suppressed with lispro on day 14 compared to regular insulin. CONCLUSION: Two-week intensive insulin therapy with lispro appeared to be more effective than that with regular insulin in type 2 diabetes in attaining both more rapid beta-cell rest and greater suppression of glucagon. These changes may provide significant long-term benefits.

Simultaneous, clonally identical T cell expansion in tonsil and synovium in a patient with rheumatoid arthritis and chronic tonsillitis.

In some patients with rheumatoid arthritis (RA), the disease improves following tonsillectomy. We describe a 28-year-old woman with treatment-resistant RA and chronic tonsillitis. Initially, her arthritis had been well controlled with methotrexate and corticosteroids, but the RA activity became difficult to control in spite of addition of bucillamine to the treatment regimen and repeated arthrocentesis with infusion of corticosteroid into her swollen joints. Closer examination revealed that the period of exacerbation of her chronic tonsillitis paralleled that of the systemic arthritis, and administration of antibiotics brought transient relief of the systemic symptoms. Her arthritis was ameliorated after successful tonsillectomy and synovectomy, with marked reduction of the serum rheumatoid factor concentration. Analysis of infiltrating T cell clones in tonsil and synovium using T cell receptor V(beta) repertoire and third complementarity-determining region size distribution analysis followed by nucleotide sequencing revealed common clonal T cell expansion in both tissues. This finding suggests the possible involvement of chronic focal infection in refractory RA.