[Tubulointerstitial nephritis with uveitis (TINU) syndrome. A relatively rare rheumatological differential diagnosis with unexplained uveitis]. / Tubulointerstitielle-Nephritis-mit-Uveitis (TINU)-Syndrom. Eine eher seltene rheumatologische Differenzialdiagnose bei unklarer Uveitis.

The tubulo-interstitial nephritis and uveitis (TINU) syndrome, first described in 1975, is a rare disease most probably of autoimmune origin that is characterized by unilateral or bilateral uveitis and tubulointerstitial nephritis. Most patients are adolescents and it is sometimes associated with other autoimmune diseases, such as spondyloarthritis, rheumatoid arthritis and hyperthyroidosis. This article reports the case of a 43-year-old female patient who presented with refractory recurrent bilateral uveitis despite therapy with high doses of corticosteroids in combination with cyclosporin. When the patient was referred to this hospital for rheumatological examination after almost 1 year of therapy, mild renal insufficiency and proteinuria were found. The kidney biopsy revealed interstitial nephritis, partly crescent-shaped and partly chronic. A diagnosis of TINU syndrome was made and treatment with adalimumab in combination with methotrexate was started. The favorable clinical outcome indicated that tumor necrosis factor (TNF) alpha may play an important role in the pathogenesis of TINU syndrome.

[From mice to men - insights from the hantavirus epidemic in 2010]. / Von Mäusen auf Menschen - Erkenntnisse aus der Hantavirus-Epidemie 2010.

HISTORY AND ADMISSION FINDINGS: With 2017 notified cases the largest hantavirus epidemic in Germany has occurred in 2010. We report on two interesting cases illustrating the wide range of the individual clinical course and the diagnostic problems in hantavirus disease. The first patient was a seriously ill 44-year-old man who needed dialysis after an onset of flu-like symptoms with oliguria. An initially negative result of a hantavirus serology focused attention on rapidly progressive glomerulonephritis. The second patient, a 22-year-old man, presented with severe neurological symptoms with seizures. TREATMENT AND COURSE: Pathological examination of the renal-biopsy specimen in Case 1 reportedly showed the typical pattern of tubulointerstitial damage in the renal cortex and the outer medulla as in hantavirus infection. In a repeated analysis Puumala virus RNA as a marker of acute infection was found. After dialysis and administration of higher-dose systemic glucocorticoids the patient slowly recovered. In Case 2 the severe neurological symptoms caused a complete neurological diagnostic with lumbar puncture and MRI before the detection of specific antibodies and Puumala virus RNA showed that nephropathia epidemica was the disease. The patient recovered after 10 days. CONCLUSION: Because of the variability of symptoms and the extrarenal manifestations of the disease the nephropathia epidemica can occasionally cause problems of differential diagnosis. A rapid diagnosis is important because of the urgent differentiation of other renal diseases with bad prognosis.

[Membranous glomerulonephritis: better therapy with autoantibody monitoring?]. / Membranöse Glomerulonephritis: Differenziertere Therapien durch Autoantikörperbestimmung?

Membranous nephropathy is the most common cause of nephrotic syndrome in adults. Binding of circulating autoantibodies to the glomerular filtration barrier leads to the development of this autoimmune disease. The clinical symptoms range from small proteinuria to severe nephrotic syndrome with enormous oedema, not controllable hyperlipidaemia and increased disposition for infection. One third of patients reach complete or partial remission of proteinuria under symptomatic treatment, which includes ACE-inhibitors and AT-I-blockers, loop diuretics and statins. Untreated the disease leads to loss of renal function over 5-10 years in 20-30% of patients. A risk score based on proteinuria and renal function is used to guide the decision when to start with an immunosuppressive therapy. A better adapted diagnostic and therapy of membranous nephropathy may be possible through measurement of circulating autoantibodies directed against a podocytic phospholipase-A(2) receptor.

A new role for the neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) in podocyte process formation and podocyte injury in human glomerulopathies.

Glomerular epithelial cell (podocyte) injury is characterized by foot process retraction, slit diaphragm reorganization, and degradation of podocyte-specific proteins. However, the mechanisms underlying podocyte injury are largely unknown. The ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a key modulator of ubiquitin modification in neurons. Like neurons, UCH-L1 expression was associated with an undifferentiated status in cultured human podocytes, whereas differentiation and arborization decreased UCH-L1 and monoUb expression. Inhibition of UCH-L1 induced time and concentration-dependent process formation with alpha-actinin-4 distribution to the cell membrane and processes. An immunohistochemical approach was used to evaluate whether UCH-L1 expression was associated with podocyte injury in 15 different human glomerular diseases. Whereas normal kidneys expressed no UCH-L1 and little ubiquitin, a subset of human glomerulopathies associated with podocyte foot process effacement (membranous nephropathy, SLE class V, FSGS) de novo expressed UCH-L1 in podocyte cell bodies, nuclei, and processes. Interestingly, UCH-L1 expression correlated with podocyte ubiquitin content and internalization of the podocyte-specific proteins nephrin and alpha-actinin-4. In contrast, minimal change glomerulonephritis, a reversible disease, demonstrated minimal UCH-L1 and ubiquitin expression with intact alpha-actinin-4 but internalized nephrin. Glomerular kidney diseases typically not associated with foot process effacement (SLE class IV, ANCA+ necrotizing GN, amyloidosis, IgA nephritis) expressed intermediate to no UCH-L1 and ubiquitin. These studies show a role for UCH-L1 and ubiquitin modification in podocyte differentiation and injury.

[A 42 year old patient with bilateral loss of sight and hypertension. Gemcitabine-associated thrombotic microangiopathy (TMA)]. / 42-jähriger Patient mit bilateralem Visusverlust und hypertensiver Entgleisung. Gemcitabin-assoziierte thrombotische Microangiopathie (TMA).

We report a case of a 42 year old male patient with a history of adrenocortical carcinoma, who was admitted with bilateral loss of sight and hypertension. Laboratory tests and further clinical evaluation showed hemolytic anemia, thrombocytopenia and acute renal failure. This was consistent with thrombotic microangiopathy / hemolytic uremic syndrome (HUS) due to gemcitabine therapy. The patient was successfully treated with prednisolon and antihypertensive drugs. Visus was completely restored, plasmapheresis was not needed. Clinicians should be aware of HUS as a rare complication of gemcitabine therapy.

Rapid development of severe end-organ damage in C57BL/6 mice by combining DOCA salt and angiotensin II.

The C57BL/6 mouse strain serves as the genetic background of many transgenic and gene knockout models; however, this strain appears to be resistant to hypertension-induced renal injury. We developed a new model of hypertensive end-organ damage in C57BL/6 mice by combining deoxycorticosterone acetate (DOCA) and salt with angiotensin II infusion. The systolic blood pressure (SBP) was significantly elevated in DOCA salt-angiotensin II mice compared to control mice or mice treated individually with DOCA salt or angiotensin II. Hypertensive glomerular damage, increased expression of profibrotic and inflammatory genes, albuminuria, tubular casts, increased plasma cholesterol, cardiac hypertrophy, and fibrosis were found in mice treated with DOCA salt-angiotensin II. The SBP in the angiotensin II-infused group was further increased by increasing the infusion rate; only mild injury was observed in these mice, suggesting that blood pressure was not a causal factor. Removal of DOCA and the angiotensin pump lowered blood pressure to normal; however, albuminuria along with the glomerular and cardiac damage did not completely resolve. Our study describes a new model of hypertensive end-organ damage and repair in C57BL/6 mice.

Acute hantavirus infection or renal transplant rejection.

Hantaviruses belong to the so-called emerging pathogens that are transmitted to humans by infected rodents and their excreta. In Central Europe, hantavirus infections usually occur in a mild to moderate form of hemorrhagic fever with renal syndrome. In contrast to the mostly benign or even asymptomatic course of hantavirus infections in previously healthy individuals, the acute hantavirus infection in kidney transplant recipients represents an exceptional situation regarding diagnosis and therapy. We describe the case of a 44-year-old kidney transplant recipient with acute renal transplant failure associated with acute hantavirus infection.

Multi-organ affecting CMV-associated cryoglobulinemic vasculitis.

We report on a 67-year-old female patient who was admitted to our intensive care unit with acute renal failure and severe hypoxemia. Transiently, the patient had to be treated with kidney replacement therapies and artificial ventilation. The actual illness started with general weakness, recurrent bloody diarrhea and intermittent dermatitis of the lower legs. Skin symptoms were initially observed 2 years before the actual clinical findings. The bloody diarrhea was attributed to an inflammatory stenosis of the sigma. The life-threatening clinical aggravation was due to diffuse alveolar hemorrhage and alveolitis. In the search for the cause of the systemic disease, both a monoclonal y-globulinemia, causing a cryoglobulinemia type II and an acute cytomegalovirus infection were diagnosed. Additionally, the course of the disease was complicated by a secondary antibody deficiency as well as an endocarditis of the aortic valve caused by Enterococcus faecium. A cryoglobulinemic vasculitis type II was histologically found in biopsy specimen of the kidney. Thus, the present case reports on a coincidence of a monoclonal gammopathy causing a cryoglobulinemia type II with extensive organ involvement and a florid CMV infection. We hypothesize that the CMV infection has triggered the cryoglobulinemia and its particular severe organ involvement.

[Dysfunction of a kidney allograft with life-threatening results]. / Dysfunktion einer Transplantatniere mit bedrohlichem Befund.

Post-transplant lymphoproliferative disease (PTLD) is a serious complication after organ transplantation. We describe the case of a 45-year old patient who developed an EBV associated B-cell lymphoma in a cadaveric renal allograft. This case underscores the importance of considering PTLD as possible differential diagnosis for allograft dysfunction. Careful diagnostic evaluation should be undertaken in patients who present with risk factors for development of PTLD such as high doses of immunosuppression for rejection therapy, suspicious EBV serologies or negative EBV serologies before transplantation. PTLD can be of donor or recipient origin. Independent of its origin PTLD needs an immediate therapy which depends on the histology of the lymphoma and on the clinical conditions of the patient. Therapeutic options are reduction of the immunosuppression, chemotherapy or radiation, administration of lymphocyte-specific antibodies or removal of the kidney allograft.

Crescentic glomerulonephritis associated with myeloperoxidase-antineutrophil-cytoplasmic antibodies: first report on the efficacy of primary anti-TNF-alpha treatment.

We report on successful induction of remission in a patient with necrotizing crescentic glomerulonephritis associated with myeloperoxidase-antineutrophil-cytoplasm antibodies by primary use of the anti-tumor necrosis factor (TNF)-alpha chimeric monoclonal antibody infliximab in combination with corticosteroids only. The standard treatment containing cyclophosphamide has reduced the former high mortality from systemic vasculitides. However, the toxicity of this alkylating agent limits its long-term use. As TNF-alpha has been shown to play a central pathogenic role in vasculitis as well as in crescentic glomerulonephritis, anti-TNF-alpha treatment in combination with cyclophosphamide has been found to be effective in therapy-resistant vasculitis. Previous reports on TNF-alpha-blocking therapies without additional cyclophosphamide did not include patients with active and severe crescentic glomerulonephritis. As our patient refused cyclophosphamide, he was given four infusions of infliximab (4 mg/kg on weeks 0, 2, 6 and 10) and methylprednisolone pulses (1 g on days 1-3), followed by daily oral prednisolone (starting with 2 mg/kg and tapering down to 5 mg daily within 3 months). After 12 weeks, control biopsy demonstrated lack of active glomerular inflammation while initially reduced renal function (creatinine 271 versus 172 mol/l, clearance 26 versus 62 ml/min) and proteinuria (2.4 versus 1.0 g/d) improved. Under remission maintenance therapy with azathioprine and prednisolone, the patient showed no relapses during a 1-year follow-up. Finally we demonstrate that there might be patients with crescentic glomerulonephritis who do not require therapy with alkylating substances and that less toxic agents such as the TNF-alpha-blocking monoclonal antibody infliximab could play a role in future primary treatment of crescentic glomerulonephritis.

[Minimal Change Glomerulonephritis]. / Minimal Change Glomerulonephritis.

We report two cases of minimal change glomerulonephritis (synonyms: idiopathic nephrotic syndrom, minimal change disease). A 47-year old female patient was admitted to our unit with a relapsing nephrotic syndrome since childhood. Another patient, a 22-year old female, presented with moderately swollen legs that developed over several months and a complaint of frequent upper respiratory tract infections during the last year. In both cases we suspected a minimal change glomerulonephritis which can only be proven by renal biopsy. Therapeutic options comprise steroids, cyclosporin, tacrolimus or even cyclophosphamide, depending on the clinical presentation of the disease in the individual case.

Infection with polyomavirus type BK after renal transplantation.

Tubulointerstitial nephritis caused by polyomavirus of the subtype BK (BK virus nephropathy, BKN) is an important cause of deterioration of renal allograft function after kidney transplantation. In 3 cases of BKN diagnosed at our center, the suspected diagnosis made on the basis of urine cytology and serum PCR was confirmed by electron microscopy and immunohistology of the renal graft biopsy. In 1 patient, stable renal function without further virus detection was seen after reduction of the immunosuppression. In 2 further patients there was loss of graft function. BKN is an important differential diagnosis of unclear deterioration of renal graft function. The risk is particularly high with use of tacrolimus and mycophenolate mofetil (MMF). Urine cytology and serum PCR are suitable screening tests, histology provides conclusive evidence. The only therapeutic option available at present is reduction of immunosuppressive therapy.

Renal involvement in sarcoidosis--a report of 6 cases.

This report concerns 6 patients with renal involvement in sarcoidosis. Two of the patients had no clinical symptoms at all. In 3 patients, no extrarenal organ manifestation was found. All 6 patients had elevated levels of serum creatinine, 2 were hypercalcemic. Five patients manifested with mild proteinuria, but in none of the cases was a nephritic sediment with erythrocytes found. Kidney biopsies in 5 patients showed epitheloid cell granulomatous interstitial nephritis, and 1 patient presented with nephrocalcinosis. All patients were treated with corticosteroids. The serum creatinine levels decreased significantly in 4 patients (> 50% decrease), and slightly in 2 patients, elevated serum calcium levels were normalized. Thus, even in the absence of other organ manifestations, sarcoidosis can be the cause of renal insufficiency, and it responds well to corticosteroid treatment. These patients demonstrate the importance of kidney biopsy in the unexplained deterioration of renal function.

Monocyte chemoattractant protein-1 and osteopontin differentially regulate monocytes recruitment in experimental glomerulonephritis.

BACKGROUND: This study evaluated the mechanisms of monocyte/macrophage (M/M) infiltration in a rat model of anti-glomerular basement membrane glomerulonephritis (GN). We focused on chemokines and osteopontin, which are known regulators of M/M recruitment. METHODS: Using immunohistology, in situ hybridization, and Northern blotting, the expression levels of chemokines and osteopontin were evaluated in isolated glomeruli and tubules 4, 10, and 20 days after the induction of GN. In vivo blocking experiments were performed by application of neutralizing antibodies against osteopontin and monocyte chemoattractant protein-1 (MCP-1). RESULTS: In nephritic animals, high glomerular MCP-1 and RANTES (regulated upon activation normal T cell expressed and secreted) expression levels were observed on days 4 and 10. The tubular expression of MCP-1, however, was only slightly enhanced. In contrast, tubular osteopontin production was maximally stimulated (day 10) and paralleled with peaks of albuminuria and tubulointerstitial M/M infiltration. Application of an anti-osteopontin antibody ameliorated tubulointerstitial and glomerular M/M recruitment, whereas treatment with an anti-MCP-1 antibody selectively reduced glomerular M/M recruitment. However, tubulointerstitial M/M infiltration remained unchanged. CONCLUSION: These studies show that chemokines and osteopontin are differentially expressed in glomeruli and tubules in this model of GN. Chemokines play a primary role in the glomeruli, whereas osteopontin has a predominant role in tubulointerstitial M/M recruitment. The roles of chemokines and osteopontin may thus be dependent on the renal compartment and on the disease model.

Mycophenolate mofetil in pediatric renal transplantation without induction therapy: results after 12 months of treatment. German Pediatric Renal Transplantation Study Group.

BACKGROUND: Acute rejection episodes (ARE) of kidney transplants are considered as risk factor in the development of chronic rejection. In adult renal transplantation (RTx), ARE have been significantly reduced by mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) and steroids (Pred). Reports of pediatric RTx on a maintenance immunosuppression with MMF are restricted to patients (P) after antibody induction therapy. METHODS: The efficacy and safety of MMF combined with CyA and Pred in pediatric RTx without induction therapy were evaluated in an open-labeled multicenter study. RESULTS: From 10/1996 to 6/1999, 65 pediatric P (MMF group) were followed for at least 6 months, 58 of 65 for 12 months. These P were compared with 54 retrospectively analyzed pediatric P who were transplanted between 1990 and 1996 and had received CyA, Pred, and azathioprine for immunosuppression (historic AZA group). Within the first 6 months after RTx, 18 of 65 (MMF group) and 32 of 54 (historic AZA group) P showed clinical signs of acute rejection (P<0.01). Thereafter only one further P in the MMF group developed a first ARE. Graft loss due to rejection occurred in one MMF- and seven AZA-treated P (P<0.05). The creatinine-clearance 3 and 6 months after RTx was higher in the MMF group. Major adverse events (MMF group) included infections of the urinary and the upper respiratory tract, diarrhea, and leukopenia. Cytomegalovirus-infection occurred in 13 P and 2 P developed cytomegalovirus disease. One P developed PTLD 10 months after RTx and recovered after the reduction of immunosuppression. CONCLUSIONS: The combination of MMF, CyA, and Pred reduced ARE in pediatric RTx without incurring major side effects.