Repeat renal biopsy in a girl with tubulointerstitial nephritis and uveitis syndrome

A Japanese girl aged 8 years who presented with a 2-month history of uveitis subsequently developed tubulointerstitial nephritis. A percutaneous renal biopsy revealed massive interstitial mononuclear cell infiltrates consisting of CD4-positive T cells. Despite administration of topical corticosteroids, the ocular symptoms persisted. Systemic corticosteroid therapy dramatically reduced the ocular symptoms and urinary β₂-microglobulin (β 2MG) concentration. However, reducing the prednisolone dosage induced recurrence of uveitis associated with increased levels of urinary β 2MG. The CD4-positive T cell infiltration persisted in the second renal biopsy performed 6 months after the first renal biopsy. These observations suggest that the interstitial cell infiltration persists for a relatively long time in a proportion of patients with tubulointerstitial nephritis and uveitis syndrome (TINU). Although the renal outcome of TINU has been reported to be favorable, prolonged interstitial cell infiltration may affect long-term renal outcome. Selected patients with TINU should be followed with close observation. Received: 7 February 2001 / Revised: 8 June 2001 / Accepted: 27 June 2001     

Tubulointerstitial nephritis and uveitis syndrome with transient hyperthyroidism in an elderly patient

A 69-year-old Japanese woman without any specific medical or family history was admitted to our hospital for renal insufficiency with proteinuria. On laboratory examinations, deteriorated renal function (blood urea nitrogen level was 34.9 mg/dL and creatinine level was 1.78 mg/dL) and elevated urinary levels of N-acetyl-β-d-glucosaminidase (23.4 U/L) and β2-microgloblin (20200 μg/L) were observed. We performed a renal biopsy. The biopsied specimen showed severe diffuse infiltration of mononuclear cells into the interstitium, with normal glomeruli, and these findings were compatible with acute tubulointerstitial nephritis (ATIN). At that time, ATIN seemed to be idiopathic. We performed gallium scintigraphy, and the results revealed uptake by the bilateral kidneys, thyroid gland, and right parotid gland. Serum thyroid stimulating hormone (TSH) was undetectable, free triiodothyronine was normal (3.11 pg/mL), and free thyroxine was elevated to 2.4 ng/dL. The titers of antithyroglobulin and antithyroid microsomal and TSH-receptor antibodies were not elevated. Two months later, burning pain and conjunctival congestion developed in both eyes. She had uveitis, as diagnosed by slit-lamp examination. Topical corticosteroid was used for the uveitis with success. We could not detect any cause of the uveitis, so a diagnosis of tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) with associated hyperthyroidism was made. Treatment was started with 15 mg/day of prednisolone. Now her renal function is slowly recovering. There are few reports of TINU syndrome with transient hyperthyroidism. This case suggests the possibility of thyroid dysfunction in patients with TINU syndrome. A laboratory evaluation of thyroid function should be considered in the diagnostic evaluation of TINU syndrome.     

Serial renal biopsies in three girls with tubulointerstitial nephritis and uveitis syndrome

Tubulointerstitial nephritis and uveitis (TINU) syndrome is considered to have a good prognosis even without any immunosuppressive therapy, although there is no histological evidence to support this. The objective of this study was to evaluate, retrospectively, serial renal biopsy findings in three girls with TINU syndrome who were treated with prednisolone. At presentation, all patients had significantly elevated urinary β₂-microglobulin levels (7583–19,313 μg/l) and high serum creatinine levels (0.93–1.3 mg/dl). The elevated β₂-MG and creatinine levels persisted for 1 month, and renal biopsies were performed to establish a definitive diagnosis. The initial biopsy specimens of all patients revealed marked interstitial enlargement consisting of infiltration of lymphocytes; there was also notable tubulitis and infiltration of eosinophils. All patients received prednisolone therapy following the diagnosis. A second renal biopsy was performed 9 months after the first biopsy for two of three patients, and 2 years later for the third patient. The biopsy specimens taken at 9 months still showed histological changes of acute inflammation; in contrast, that taken at 2 years showed a lower degree of acute inflammation, but scar formation was observed in some regions. Based on these results, we conclude that selected TINU syndrome patients require some immunosuppressive therapy.     

Clinical outcome and occurrence of uveitis in children with idiopathic tubulointerstitial nephritis

Acute idiopathic tubulointerstitial nephritis (TIN) is considered a condition with a good long-term prognosis. However, there is evidence that some patients develop permanent renal impairment. The aim of this study was to evaluate the clinical characteristics of TIN at the time of diagnosis in children and determine whether the findings upon presentation predict renal outcome. The clinical data and biopsy findings from 26 children with idiopathic TIN admitted to four Finnish university hospitals were analyzed retrospectively. Twenty-five patients (96%) manifested renal insufficiency. After the mean follow-up time of 2.75 years (SD 2.5; 0.9–13.5), 4 patients (15%) had permanent renal insufficiency and 8 patients (31%) had persistent low-molecular weight proteinuria. Uveitis was found in 12 patients (46%). Four of these patients (33%) developed chronic uveitis. Our analysis showed that none of the laboratory or biopsy findings upon presentation prognosticated renal outcome. No correlation between renal disease and uveitis could be found either. The occurrence of uveitis among TIN patients was higher than previously reported. Uveitis may develop late and without recurrence of renal dysfunction. Therefore, follow-up by a pediatrician and by an ophthalmologist is warranted in children with acute TIN for at least 12 months from diagnosis.     

Tubulointerstitial nephritis and uveitis in association with Epstein-Barr virus infection

 The case of a 13.5-year-old girl with acute tubulointerstitial nephritis and uveitis (TINU syndrome) is presented. The etiology of this rare syndrome, which in most cases involves female adolescents and usually regresses spontaneously, is still unknown. An infection-triggered pathological immune reaction has been considered to play a role in the pathogenesis of this disorder. Here we report for the first time the association of TINU syndrome and Epstein-Barr virus infection. Received: 4 May 1998 / Revised: 20 August 1998 / Accepted: 26 August 1998     

Tubulointerstitial nephritis and uveitis syndrome in a mother and her son

A mother and her son, both with tubulointerstitial nephritis and uveitis syndrome (TINU) are reported. The nephritis presented itself at 13 years in the mother and at 10 years in her son. Glomerular filtration (GFR) decreased in both, and renal biopsies confirmed the diagnosis. Nephritis preceded the onset of uveitis in both. Clinical course and renal function improved quickly on oral steroids in the boy. The mother’s hyperazotemia decreased spontaneously (without steroids), but not to normal range, and remained stable for 35 years of follow-up. Local steroids due to recurrences of uveitis were repeatedly needed in both. We believe this is the first report on familial occurrence of inherited TINU syndrome in two generations.     

Acute tubulointerstitial nephritis in 21 Japanese children

PATIENTS AND METHODS: We studied 21 Japanese children aged 1.2 to 14.9 years with biopsy-proven acute tubulointerstitial nephritis (ATIN; 5 drug-induced, 7 infection-related, 3 tubulointerstitial nephritis and uveitis syndrome (TINU), and 6 unclassified) for clinical presentation, laboratory findings, and outcome to clarify the clinical features of the entity. All developed acute renal failure with peak BUN values from 25 to 164 mg/dl (mean 83 mg/dl) and peak serum creatinine values from 1.5 to 15.1 mg/dl (mean 6.5 mg/dl). All the 7 infection-related ATIN were associated with Yersinia pseudotuberculosis infection. Four of the 21 patients underwent dialysis therapy for anuria and 1 patient in the unclassified ATIN showed progression to chronic renal failure. RESULTS: In 20 patients, renal insufficiency lasted for 6 to 73 days: 5 drug-induced; median and ranges 25 (12-33) days, 7 infection-related; 15 (6-22) days, 3 TINU; 65 (55-73) days, and 5 unclassified; 24 (6-34) days. Oral steroid therapy was introduced to the 3 TINU patients because of the prolonged renal dysfunction. Although it was effective in all, 2 of them showed a deterioration of clinical symptoms or renal function after reducing the dosage of steroid. CONCLUSION: Consequently, TINU patients required a longer period of time for the improvement of renal function compared to the other etiologies.     

A case of adult-onset tubulointerstitial nephritis and uveitis (“TINU syndrome”) associated with sacroileitis and epstein-barr virus infection with good spontaneous outcome

The authors report a case of tubulointerstitial nephritis and uveitis (TINU syndrome) in a 48-year-old woman. The patient's ocular symptoms (relapsing bilateral uveitis) began 4 months before the renal disease was diagnosed and were treated successfully with local steroid therapy. The main baseline laboratory findings were anemia, a rapid sedimentation rate, and a decreased renal function. Urinalysis results showed mild proteinuria and some hyaline and hyaline-granular casts. Immunoglobulin (Ig) G and IgM antibodies to Epstein-Barr virus (EBV) were present. The renal biopsy showed interstitial lymphocytes and infiltration by rare plasma cells, tubular atrophy without granulomas, and slight expansion of the mesangium; electronic microscopy showed rare electron-dense deposits in the mesangium; no vascular alterations were seen, and immunofluorescent staining was uniformly negative. X-ray of the pelvis showed bilateral sacroileitis, which has been previously described in only 1 case of TINU syndrome; human leukocyte antigen B27 was negative. After 6 months without any therapy, all laboratory findings were normal; after 30 months, renal function was still normal, uveitis had not relapsed, but sacroiliac involvement was still present; EBV-viral capsid antigen (VCA) IgM were still high (28 UA/mL), and the EBV IgG titers were increased (VCA>170, EBV-nuclear antigen 108 UA/mL). This case confirms that this rare entity, originally observed in children, may occur and have a favorable spontaneous renal outcome also in the adult; EBV may play a role, as previously suggested. This is, to the authors’ knowledge, the first reported case of TINU syndrome with the association of a well-documented bilateral sacroileitis.     

Tubulointerstitial nephritis and uveitis (TINU) syndrome caused by the Chinese herb “Goreisan”

A 58-year-old man was admitted to our hospital complaining of fever and arthralgia. His clinical course and marked ciliary hyperemia led us to suspect tubulointestinal nephritis and uveitis (TINU) syndrome, which was confirmed ophthalmologically and by renal biopsy. Results of a drug-induced lymphocyte-stimulating test were positive for the Chinese herb “Goreisan.” This is the first case in which the use of “Goreisan” was causally related to TINU syndrome.     

Acute tubulointerstitial nephritis with uveitis syndrome presenting as multiple tubular dysfunction including Fanconi's syndrome

We describe an 11-year-old male patient with acute tubulointerstitial nephritis with uveitis (TINU) syndrome. He presented with easy fatigability, pallor, nocturia and weight loss. laboratory examination disclosed anaemia, polyclonal hypergammaglobulinaemia, low molecular weight proteinuria, glycosuria, aminoaciduria, proximal and distal renal tubular acidosis, a urine concentration defect and decreased creatinine clearance. The multiple renal tubular dysfunction and slight glomerular dysfunction subsided spontaneously. Bilateral anterior uveitis was manifested 7 months after the onset of the disease. This is the first reported case of TINU syndrome with multiple proximal and distal tubular dysfunction including a complete type of Fanconi's syndrome.     

Delayed onset of uveitis in TINU syndrome

We report here the clinical features and outcomes of two patients who presented idiopathic tubulo-interstitial nephritis and uveitis syndrome (TINU syndrome) with ocular disease following the onset of nephropathy. The initial symptoms were renal impairment with asthenia, anorexia and weight loss. An increase in urinary beta2-microglobulin was noticed at the initial checkup in both patients. Renal biopsies showed interstitial cellular infiltration without granulomas or tubular atrophy. No glomerular and vascular alterations were seen and immunofluorescent staining was uniformly negative. Systemic steroid therapy was given and renal function returned to normal within three months. Anterior uveitis occurred in both patients eight months later and responded well to local steroid therapy. Renal involvement in TINU syndrome mostly has a favorable outcome. Despite the possibility of spontaneous regression, systemic steroids may be beneficial in reducing the development of interstitial fibrosis.     

Tubulointerstitial nephritis and uveitis in monozygotic twin boys

We describe monozygotic male twins who developed tubulointerstitial nephritis and uveitis (TINU) almost 2 years apart. They presented with non-specific symptoms and were noted to have glycosuria and renal impairment. Both children have uveitis. One had biopsy-proven interstitial nephritis and the other had biochemical evidence of transient tubular dysfunction. While the renal parameters improved, they are still under treatment for uveitis. The occurrence of TINU in identical twins at an interval of just under 2 years supports a strong genetic element in the aetiology of this syndrome. We believe this is the first report of male twins with TINU.     

Long-term enteral nutrition in infants and young children with chronic renal failure

An inadequate nutritional intake is common in infants and young children with chronic and end-stage renal failure (CRF/ESRF), causing poor weight gain and growth retardation. In a programme of enteral feeding (EF), growth, nutritional intake and outcome for oral feeding were evaluated in 35 children with CRF/ESRF, mean (range) age 1.6 (0–4.9) years at start of EF for 30 (12–60) months. Twenty-nine had a glomerular filtration rate of 12.1 (6–26) ml/min per 1.73 m² and 6 were on peritoneal dialysis. Mean (SD) weight standard deviation scores (SDSs) in the 0 to 2-year age group (n=26) were –3.3 (1.0) 6 months before EF, –3.1 (1.3) at the start, –1.7 (1.4) at 1 year, (P=0.0003) and –1.4 (1.8) at 2 years, (P=0.0008). Height SDSs were –2.9 (0.7), –2.9 (1.2), –2.2 (1.2) (P=0.008) and –2.1 (1.3) (P=0.004). Weight SDSs in the 2 to 5-year age group (n=9) were –2.3 (1.2), –2.0 (1.1), –1.1 (1.3) (P=0.002) and –0.9 (1.0) (P=0.04). Height SDSs were –2.8 (0.6), –2.3 (0.7), –2.0 (0.7) and –2.0 (0.8). There was no change in energy intake as a percentage of the estimated average requirement, nor was this exceeded. Percentage energy from the EF in the 0 to 2 year age group remained unchanged despite an absolute increase in energy intake with age. Twenty-one have had renal transplants, of whom 86% eat and drink normally. Long-term EF prevents or reverses weight loss and growth retardation in children with CRF/ESRF, with the achievement of significant catch-up growth if started before age 2 years. Received: 27 July 1998 / Revised: 19 November 1998 / Accepted: 20 November 1998     

The 1998 report of the Japanese National Registry data on pediatric end-stage renal disease patients

We carried out a nationwide survey on patients less than 20 years of age with pediatric chronic end-stage renal disease (ESRD) in Japan for the year 1998. There were 582 patients who had started on renal replacement therapy before 1998, and 105 patients who had been newly introduced to renal replacement therapy in that year. The prevalence rate of the ESRD patients already on treatment was 22 per million population (aged 0–19 years) in 1998. Older patients had a higher prevalence rate than younger ones. There were 345 patients on dialysis as of 1 January 1998, and 237 patients with transplants. The major diseases causing ESRD were renal hypoplasia/dysplasia and focal segmental glomerulosclerosis. Of the 237 patients (46.9%) who had received renal transplants before 1 January 1998, 262 patients (96%) received their transplants from living kidney donors. The incidence rate for the new ESRD patients was 4 per million population (aged 0–19 years) in 1998. Older patients had a slightly higher incidence rate than younger ones. Peritoneal dialysis was used more frequently than hemodialysis under 15 years (85%–95% and 39% respec-tively), especially in very young patients. The major diseases causing ESRD were the same as in the patients already on treatment. The transplant rate for the year 1998 was 10 per 100 dialysis patient-years (patients aged 0–19 years) with 9 living kidney donors. The death rate was 15.6 per 1,000 dialysis patient-years (patients aged 0–19 years); the major causes of death being cardiovascular diseases and infections. Received: 30 January 2001 / Revised: 3 January 2002 / Accepted: 4 January 2002     

Tubulointerstitial nephritis and uveitis syndrome associated with hyperthyroidism

We report a 17-year-old male patient with tubulointerstitial nephritis and uveitis (TINU) associated with hyperthyroidism. He presented with a 2-month history of fatigue, loss of appetite, low-grade fever, and a 12-kg weight loss when he was admitted to our hospital. He had iritis, which was complicated by fibrin in the anterior chamber, diagnosed by slit-lamp examination. On laboratory examinations, deteriorated renal function (blood urea nitrogen level was 25.9 mg/dl and creatinine level was 2.82 mg/dl) and elevated urinary levels of N-acetyl-β-D-glucosaminidase (33.1 U/l) and β2-microglobulin (78 600 μg/l) were observed. Serum thyroid-stimulating hormone (TSH) was undetectable, at less than 0.01 μIU/ml, and free triiodothyronine and free thyroxine were elevated, up to 5.23 pg/ml and 2.85 ng/dl, respectively. The titers of antithyroglobulin and antithyroid microsomal and TSH-receptor antibodies were not elevated. Abdominal and thyroidal ultrasonography showed evident bilateral enlargement of the kidneys and diffuse enlargement of the thyroid gland. Iodine-123 scintigraphy showed low uptake in the thyroid gland. The biopsied renal specimen showed mild edema and severe diffuse infiltration of mononuclear cells and few eosinophils in the interstitium, without any glomerular or vascular abnormalities. Based on the clinical features and pathological findings, a diagnosis of TINU syndrome with associated hyperthyroidism was made. Treatment was started with 30 mg/day of prednisolone. The iritis disappeared, and the patient's clinical status improved remarkably. This case suggests the possibility of thyroid dysfunction in some patients with TINU syndrome, and we believe thyroid function should be measured in all TINU patients. Moreover, histopathological diagnosis of the thyroid glands before treatment is necessary for TINU patients with thyroid dysfunction.     

Drug-induced TINU syndrome and genetic characterization

Tubulointerstitial nephritis and uveitis (TINU) syndrome is due to a disregulation of cell-mediated immunity and genetical predisposition due a particular molecular characterization. We report the case of a 50-year-old woman who was admitted for acute renal failure. She had recently taken flurbiprofen for 10 d for recurrent bronchitis. A renal biopsy revealed acute tubulointerstitial nephritis. Prednisone was started and prognosis was favorable. Three months later the patient developed transitory blurred vision. The diagnosis was bilateral uveitis and she received topic and systemic corticosteroid therapy, with resolution of ocular symptoms. Recurrent episodes of uveitis experienced during the next 12 months were treated with same therapy. Genomic haplotype in our patients was HLA A*0278/2631,-B*1517/3802,- Cw*0701/1202, -DRB1*0101/1359 (DRB3* 52), -DQA1*0102/0102, DQB1*0603/0603. TINU syndrome is characterized by tubulointerstitial nephritis that tends to be selflimiting, whereas uveitis tends to relapse. HLA-DQA1*01 and -DQB1*06 haplotypes are strongly associated with TINU syndrome. This is the first report of TINU syndrome induced by flubiprofen intake. Our case emphasizes the importance of the association between drug exposure and strong susceptibility to TINU syndrome giving the molecular characterization.     

Repeat renal biopsy in tubulointerstitial nephritis and uveitis syndrome: report of a case

A Japanese girl aged 12 years who presented with a month history of uveitis developed a significant elevation of urinary beta 2 microglobulin (beta 2MG) up to 13,933 micrograms/l. A percutaneous renal biopsy revealed a dense CD4-positive T-cell infiltration with focal tubulitis in the interstitium. The tubulointerstitial score (TI score) described by Foster et al. was 7 points. She was diagnosed as having tubulointerstitial nephritis and uveitis syndrome (TINU). Due to the severe interstitial infiltration, a 6-month course of prednisolone at the dose of 30 mg per alternate day was started. The levels of urinary beta 2MG dramatically decreased following treatment and the renal function remained normal. The second renal biopsy performed 6 months later revealed mild persistent CD4-positive T-cell infiltration associated with 19% periglomerular thickening, with the TI score of 4 points. These clinical observations suggest that the interstitial cell infiltration persists for a relatively long time in a proportion of patients with TINU. Since persistent interstitial infiltration has been known to be harmful to the kidney, we therefore speculate that prompt administration of corticosteroids might be beneficial to these patients. Although the renal outcome of TINU has been reported to be favorable to date, patients with severe interstitial infiltration should be followed under close observation. Study of similar patients is needed to clarify our understanding of effective therapy for TINU.     

Furosemide in indomethacin-treated infants – systematic review and meta-analysis

 This study was designed to assess: (1) whether furosemide modifies the incidence of failure to close a symptomatic patent ductus arteriosus (PDA) in response to indomethacin in premature infants, (2) whether furosemide decreases renal and hydromineral side effects of indomethacin, and (3) whether the effects of furosemide on renal function depend on initial extracellular volume [assessed by blood urea nitrogen (BUN)/creatinine ratio]. We did a systematic review and meta-analysis of all published controlled trials assessing either ductal closure or renal function after randomized allocation to treatment with indomethacin and furosemide versus indomethacin alone. All of the three studies meeting entry criteria were small and had methodological limitations. The number of patients was too small to rule out a 10% risk increase in failure of ductal closure. After the first dose of indomethacin, patients receiving furosemide had higher urine output, fractional excretion of sodium, and osmolar clearance than controls. Among patients with initial BUN/creatinine ratio <20, those on furosemide had a higher glomerular filtration rate (GFR) than controls. Among patients with initial BUN/creatinine of 20–30, those on furosemide had a lower GFR than controls. Thus, dehydration appears to be a contraindication for furosemide administration in premature infants treated with indomethacin for symptomatic PDA. The risk-benefit ratio of administering furosemide in well-hydrated patients treated with indomethacin for symptomatic PDA could only be assessed by a large randomized clinical trial. Received: 1 July 1998 / Revised: 22 September 1998 / Accepted: 23 September 1998     

Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome in a 52-Year-Old Female: A Case Report and Review of the Literature

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare entity first described in 1975, affecting mainly young women and adolescents. We present a case of a 52-year-old female patient (one of the oldest in the literature) who complained of fever, anorexia, nausea, and vomiting. After she was admitted to our hospital, laboratory tests revealed tubular proteinuria, elevated erythrocyte sedimentation rate (ESR), anemia, and renal insufficiency (serum creatinine 4.2 mg/dL) with metabolic acidosis. Ophthalmologic examination revealed anterior uveitis (iritis) and renal biopsy showed acute tubulointerstitial nephritis. The diagnosis of TINU syndrome was established and the patient was treated with oral corticosteroids. All symptoms and ophthalmologic abnormalities disappeared after 6 weeks of treatment. Renal function also recovered completely and remained stable at follow-up. TINU syndrome should be considered in the differential diagnosis of unexplained tubulointerstitial nephritis, especially in the presence of ocular findings. Corticosteroid therapy is still controversial, but it helps in the quick resolution of renal and mainly eye abnormalities.