Acute eosinophilic interstitial nephritis and uveitis (TINU syndrome) associated with granulomatous hepatitis.

A 23-year-old male presented with renal failure, cholestatic liver enzyme elevation and uveitis. Percutaneous renal biopsy revealed marked eosinophilic infiltration of the renal interstitium, which made the diagnosis of TINU syndrome (Tubulo-Interstitial Nephritis and Uveitis). Percutaneous liver biopsy showed granulomatous hepatitis, which was not described as a part of TINU syndrome. The diagnostic dilemma and the literature are discussed.     

Tubulointerstitial nephritis and uveitis syndrome (TINU) with Fanconi's syndrome

We report a 57-year-old woman with concurrent tubulointerstitial nephritis and uveitis syndrome (TINU) and Fanconi's syndrome. She presented with sudden onset of bilateral ocular pain, blurred vision, acute renal failure, glucosuria and proteinuria. Slit lamp examination revealed acute bilateral anterior uveitis. Tubulointerstitial nephritis was confirmed by kidney biopsy. Laboratory examination revealed normoglycemic glucosuria, proteinuria, normal anion-gap metabolic acidosis, phosphaturia, urinary uric acid wasting and kaliuresis leading to hypokalemia. Her vision and renal function improved gradually after systemic steroid therapy. There have been rare reports of TINU syndrome which had features of Fanconi's syndrome. The prevalence of TINU syndrome may be underestimated, and its association with Fanconi's syndrome requires further investigation.     

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.     

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.     

Acute tubulo-interstitial nephritis and uveitis syndrome (TINU syndrome)

Acute renal failure due to tubulo-interstitial nephritis developed in a 15-year-old girl. The disease was accompanied by uveitis and an inflammatory syndrome, consisting of a markedly increased erythrocyte sedimentation rate and high serum gamma globulin levels. The nephropathy as well as the inflammatory syndrome subsided spontaneously. A topical antiphlogistic treatment healed the ocular disease, which has not relapsed so far. The association of acute tubulo-interstitial nephritis and acute uveitis observed in several patients has led to the identification of a specific syndrome with a very particular symptomatology and course, the so-called TINU syndrome, the interest of which resides in the predictability of the complete reversibility of the nephropathy either spontaneously or after steroid treatment, contrasting with the marked tendency towards relapse of the uveitis. The demonstration of circulating immune complexes in the serum during the acute phase of the illness, as in our patient, further points to the involvement of immune processes in the syndrome, but the origin and pathogenesis remain as yet unknown.     

Clinical characteristics of IgA nephropathy associated with low complement 4 levels

Abstract

Objective: C4 deficiency is the most commonly inherited immune disorder in human. The present study investigated the characteristics of the IgAN patients with low serum C4 levels. Methods: We performed a prospective observational study. Clinical as well as histopathologic parameters were assessed. A Kaplan–Meier survival analysis was performed concerning the primary outcome defined as the serum creatinine increased 1.5-fold from baseline. The prognostic significances of clinical and histopathologic parameters were determined using Cox proportional hazards models. Results: Five-hundred twelve biopsy proven IgAN cases were available for analysis with a median follow-up of 38.4 months. Ninety-nine cases (19.34%) presented with low C4 levels (LowC4 group) and the other 413 cases did not (NlowC4 group). At the time of renal biopsy, renal injury was lighter in the LowC4 group compared with the NlowC4 group. Renal C4 deposition was significantly decreased while IgM deposition was increased in the LowC4 group. A correlation analysis shows that lower C4 levels were associated with better renal presentations at biopsy. However, the risk of developing the primary outcome was significantly greater in those with low C4 levels. Specifically, during the follow-up period, the risk of developing primary outcome was nearly ten folds higher in those with low C4, compared to those without low C4. Conclusion: There is a high prevalence of low C4 levels in IgAN patients. These patients with low C4 levels exhibited better renal presentations at the time of renal biopsy, whereas might be associated with a poor prognosis.     

Hereditary partial deficiency of the third component of complement associated with minimal change nephrotic syndrome

We describe a 10 year old patient admitted to the Children's Hospital of Buffalo with hypocomplementemia associated with steroid responsive minimal change nephrotic syndrome. The sibling also had a low serum C₃ concentration and all family members studied hadC ₃ slow phenotypes. Factor I levels were at the lower limit of normal in the patient and his brother. Functional assays for CH50, total hemolyticC ₃ and serum concentration of C₂, C₄–C₉ and factors B and H were all within normal limits. This case confirms that a depressed serum complement level can occur in minimal change nephrotic syndrome and indicates that this depression could represent a preexisting inherited rather than an acquired deficiency. The findings are consistent with the pressence of a null or hypomorphicC ₃ slow allele in hypocomplementemic family members. Additional studies are needed to resolve the association between the inherited partialC ₃ deficiency and minimal change nephrotic syndrome.     

The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome

Mutations in the gene encoding complement factor H (CFH) that alter the C3b/polyanions-binding site in the C-terminal region impair the capacity of factor H to protect host cells. These mutations are also strongly associated with atypical hemolytic uremic syndrome (aHUS). Although most of the aHUS-associated CFH mutations seem "unique" to an individual patient or family, the R1210C mutation has been reported in several unrelated aHUS patients from distinct geographic origins. Five aHUS pedigrees and 7 individual aHUS patients were analyzed to identify potential correlations between the R1210C mutation and clinical phenotype and to characterize the origins of this mutation. The clinical phenotype of aHUS patients carrying the R1210C mutation was heterogeneous. Interestingly, 12 of the 13 affected patients carried at least one additional known genetic risk factor for aHUS. These data are in accord with the 30% penetrance of aHUS in R1210C mutation carriers, as it seems that the presence of other genetic or environmental risk factors significantly contribute to the manifestation and severity of aHUS in these subjects. Genotype analysis of CFH and CFHR3 polymorphisms in the 12 unrelated carriers suggested that the R1210C mutation has a single origin. In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations.     

A case report of Tubulo-Interstitial Nephritis with Uveitis (TINU syndrome) and follow-up for one year

International Urology and Nephrology -     

Faecal incontinence associated with reduced pelvic sensation

Eight patients with faecal incontinence associated with high threshold of rectal sensation are described. All had a normal anal sphincter on clinical and physiological assessment including anal manometry, pudendal nerve latency estimation and single fibre electromyography. In each case however rectal sensation was abnormal. The threshold of rectal sensation was 143 +/- 33 ml (range 110-200 ml) compared with control values of 39 +/- 14 ml (range 25-65 ml) (P less than 0.005) in 12 normal age-matched individuals. The degree of rectal distension required to initiate the recto-anal reflex was no different in the incontinent patients (19 ml, range 15-25 ml, compared with 22 ml, range 15-30 ml, in the controls). There was also no difference in the maximal tolerated volume of rectal distension between the groups (291 +/- 87 ml and 279 +/- 91 ml respectively). These observations may have defined a small group of patients with incontinence in whom an abnormality of rectal sensation rather than sphincter incompetence could be a part of the pathophysiological disorder.     

Persistent anemia associated with reduced serum vitamin B12 levels in patients undergoing regular hemodialysis therapy.

Four patients on regular hemodialysis therapy with a persistent anemia and reduced serum vitamin B12 levels are discribed. In each case a significant improvement occurred with B12 therapy and it is suggested that the vitamin B12 content of a 70 g protein/day diet may not be adequate to maintain stores of the vitamin.     

Nephrotic syndrome associated with hemophagocytic syndrome

Hemophagocytic syndrome (HPS) is defined by bone marrow and organ infiltration by activated, nonmalignant macrophages, which phagocytose blood cells. The clinical spectrum of HPS is broad, but renal involvement has rarely been investigated. We report a previously unknown renal manifestation of HPS: nephrotic syndrome. This multicentric retrospective study included patients fulfilling the following criteria: (i) no history of nephropathy; (ii) HPS diagnosis with histologic evidence of hemophagocytosis; (iii) occurrence of nephrotic syndrome during HPS; and (iv) available renal histology. Using the same criteria, we also searched the literature for additional cases. We identified nine patients retrospectively and found two additional cases in the literature (five males and six females, whose mean age was 34 +/- 27 years). Black African patients predominated (63.6%). HPS was due to lymphoma (six cases), infectious disease (three cases), and autoimmune disease (one case), and was primary in one patient. Acute renal failure was associated with nephrotic syndrome in 10/11 cases. Renal histology showed acute tubular necrosis associated with collapsing glomerulopathy in five patients (all Africans with negative human immunodeficiency virus serology), minimal change glomerulopathy in four, and thrombotic-microangiopathy with abnormal podocytes in two. Death occurred in seven cases. Nephrotic syndrome should be included among the renal complications of HPS with acute renal failure. We postulate that abnormal T-cell activation and/or high pro-inflammatory cytokine levels during HPS might cause podocyte injuries, especially among African patients with a susceptible genetic background.     

An in vitro model of pig liver xenotransplantation--pig complement is associated with reduced lysis of wild-type and genetically modified pig cells

Hara H, Campanile N, Tai H‐C, Long C, Ekser B, Yeh P, Welchons D, Ezzelarab M, Ayares D, Cooper DKC. An in vitro model of pig liver xenotransplantation—pig complement is associated with reduced lysis of wild‐type and genetically modified pig cells. Xenotransplantation 2010; 17: 370–378. © 2010 John Wiley & Sons A/S. Abstract: Background: After pig liver transplantation in humans, the graft will produce pig complement (C). We investigated in vitro the lysis of wild‐type (WT), α1,3‐galactosyltransferase gene‐knockout (GTKO), and CD46 transgenic (CD46) pig peripheral blood mononuclear cells (PBMC) caused by human anti‐pig antibodies (Abs) + pig C. Methods: Human serum IgM/IgG binding to WT and GTKO PBMC was determined by flow cytometry, and lysis of pig PBMC by a C‐dependent cytotoxicity assay using (i) human serum (human Abs + C), (ii) GTKO pig serum (anti‐Gal Abs + pig C), (iii) heat‐inactivated human serum (human Abs) + rabbit C, or (iv) human Abs + pig C (serum). Results: Binding of human IgM and IgG to GTKO PBMC was less than to WT PBMC (P < 0.05). In the presence of human Abs, lysis of WT and GTKO PBMC by rabbit C was 87 and 13%, respectively (WT vs. GTKO, P < 0.01), but was only 37 and 0.4% in the presence of pig C (WT vs. GTKO, P < 0.05). Human/rabbit C‐induced lysis was greater than pig C‐induced lysis for both WT and GTKO PBMC. CD46 pig PBMC reduced rabbit/human C‐ and pig C‐mediated lysis (P < 0.05). Conclusions: Pig livers, particularly from GTKO and CD46 pigs, are likely to have an immunologic advantage over other organs after transplantation into humans. In the absence of pig antibodies directed to human tissues, pig complement is unlikely to cause problems after liver xenotransplantation, especially if GTKO/CD46 pigs are used as the source of the livers.