"Eculizumab First" in the Management of Posttransplant Thrombotic Microangiopathy.

Introduction: Posttransplant thrombotic microangiopathy (PT-TMA) is an uncommon event that characterizes approximately 3% to 14% of kidney transplants (KTs), and that is associated with a higher risk of delayed graft function and graft loss. PT-TMA occurs more frequently within the first 3 months after transplant and can be a manifestation of de novo disease or the recurrence of previous atypical hemolytic uremic syndrome (aHUS). Abnormalities in complement regulation genes could explain the increased susceptibility of some patients to PT-TMA. Eculizumab is a humanized monoclonal antibody that inhibits the formation of the membrane attack complex C5b-9. The aim of this study is to evaluate the efficacy of eculizumab as treatment for PT-TMA. Methods: We retrospectively analyzed clinical records of 45 KT patients who received eculizumab immediately after the clinical diagnosis of PT-TMA. Results: Kidney biopsy was performed in 91.1% of patients, and complement genetic study was performed in 64.4%. Of the kidney biopsies, 85.4% showed signs of TMA; genetic analysis revealed 1 pathogenetic variant, 2 variants of uncertain significance, 1 likely benign variant, 8 risk polymorphisms, and 27 risk haplotypes. After 2 weeks from the treatment starting, hemoglobin and platelets significantly increased. A remarkable improvement in kidney function was also observed. After 6 months, 28.8% of patients had a complete renal recovery whereas 44.4% had a partial recovery. Conclusion: This is, to our knowledge, the largest series of KT patients with PT-TMA treated with eculizumab. These data suggest that eculizumab is associated with a normalization of hemolysis indices and an important and progressive improvement of graft function.

Rituximab as possible therapy in TNF inhibitor-induced IgA vasculitis with severe renal involvement.

BACKGROUND: We observe the increasing use of tumor necrosis factor (TNF) inhibitors in patients affected by chronic inflammatory diseases. These drugs provide good control of symptoms, contributing to significant improvement in the quality of life in individuals with high disease burden. On the other hand, along with their wider use and longer follow-up periods the number of reports regarding their adverse effects is also increasing. The reported complications include drug-induced vasculitis with possible kidney involvement. In the literature we can distinguish more frequently described ANCA-associated vasculitis and more rarely occurring immunoglobulin A vasculitis. Although uncommon, such complications may present with potentially life-threatening vital organ dysfunction; therefore, adequate monitoring and effective therapy are necessary. CASE PRESENTATION: We report two cases of TNF inhibitor-induced vasculitis with severe acute worsening of renal function and significant proteinuria. The first patient was receiving golimumab therapy for ankylosing spondylitis and the second patient was treated with adalimumab for psoriasis and psoriatic arthritis. In the second case dialysis treatment was necessary and the patient presented recurrence of vasculitis after rechallenge with adalimumab. Both patients underwent renal biopsy which showed findings compatible with drug-induced IgA vasculitis and both were treated successfully with corticosteroids and rituximab. CONCLUSIONS: To the best of our knowledge this is the first report of rituximab use in drug-induced IgA vasculitis with renal involvement. Combination of corticosteroids and rituximab can be an effective therapy in case of vasculitis with kidney failure and a preferable option for selected patients with drug-induced IgA vasculitis compared to cyclophosphamide. More studies are necessary to establish suitable short- and long-term treatment. Given the rarity of this disorder, case reports and case series can provide practical guidance until additional studies become available.

Caveolin-1 in situ expression in glomerular and peritubular capillaries as a marker of ultrastructural progression and severity of renal thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy is a severe and potentially life-threatening condition inducing severe endothelial injury in many organs, particularly native and transplanted kidneys. Current pathological studies by our group have identified the use of Caveolin-1 immunohistochemistry as a potential marker of endothelial damage and progression degree of thrombotic microangiopathy. The aim of the present work was to evaluate Caveolin-1 as a marker of severity in thrombotic microangiopathy kidney disease, according to the ultrastructural progression of the disease evaluated by transmission electron microscopy. MATERIALS AND METHODS: Twenty-nine patients (17 non-transplanted and 12 transplanted) were retrospectively selected, biopsied for suspected or histologically-confirmed thrombotic microangiopathy. Transmission electron microscopy was performed in all cases, and an ultrastructural score of thrombotic microangiopathy-related glomerular disease was assessed (from 0 to 3+). Immunohistochemistry for Caveolin-1 was automatically performed. RESULTS: The mean percentage of Caveolin-1-positive glomerular capillaries was 53.2 ± 40.6% and 28.0 ± 42.8% in the active thrombotic microangiopathy versus previous thrombotic microangiopathy cases (p = 0.085), considering both native and transplanted kidneys. The presence of progressive disease correlated with diffuse Caveolin-1 immunoreactivity (p = 0.031), and ultrastructural score correlated with glomerular Caveolin-1 positivity, progressively increasing from 22.5% of the Score 0 group to 95.5% of the Score 3 group (p = 0.036). DISCUSSION: Caveolin-1 proved to be a very useful marker of early endothelial damage in the course of thrombotic microangiopathy for both native and transplanted kidneys, therefore worth considering in routine practice. Diffuse glomerular Caveolin-1 immunoreactivity correlates with the severity of the thrombotic disease and it can appear very early, even before ultrastructurally evident endothelial damage.

Fabry Disease Nephropathy: Histological Changes With Nonclassical Mutations and Genetic Variants of Unknown Significance.

RATIONALE & OBJECTIVE: Fabry disease (FD) is an X-linked genetic disorder that causes lysosomal storage of glycosphingolipids, primarily globotriaosylceramide (Gb3) and its derivative globotriaosylsphingosine (lyso-Gb3), with multiorgan dysfunction including chronic kidney disease. Affected individuals may be carriers of gene variants that are of uncertain significance (GVUS). We describe kidney pathology at the early stages of FD-related kidney disease to gain insights into its association with GVUS and sex. STUDY DESIGN: Single-center, case series. SETTING & PARTICIPANTS: Thirty-five consecutively biopsied patients (aged 48.1±15.4 years, 22 females) from among 64 patients with genetically diagnosed FD. Biopsies were retrospectively screened using the International Study Group of Fabry Nephropathy Scoring System. OBSERVATIONS: Genetic mutation type, p.N215S and D313Y, sex, age, estimated glomerular filtration rate (eGFR), plasma lyso-Gb3 (pLyso-Gb3) levels, and histological parameters, including Gb3 deposits were recorded. Genetic analyses showed mostly missense mutations, p.N215S variant in 15, and the "benign polymorphism" D313Y in 4 of the biopsied patients. Morphological lesions were similar for men and women except for interstitial fibrosis and arteriolar hyalinosis being more common in men. Early in their clinical course, patients with normal/mild albuminuria had podocyte, tubular, and peritubular capillary vacuoles/inclusions, and evidence of chronicity, i.e., glomerulosclerosis, interstitial fibrosis, tubular atrophy. These findings appeared to be associated with pLyso-Gb3, eGFR, and age. LIMITATIONS: Retrospective design and inclusion of outpatients partially based on family pedigree. CONCLUSIONS: In early stages of kidney disease in the setting of FD, numerous histological abnormalities are present. These observations suggest that kidney biopsies early in FD may reveal activity of kidney involvement that may inform clinical management.

Synchronous hepatocellular carcinoma and renal cell carcinoma in young woman with sarcoidosis: A case report.

Hepatocellular carcinoma (HCC) and clear cell renal carcinoma are both frequent cancers, especially in patients with risk factors such as cirrhosis in the first case or genetic mutations such as Li-Fraumeni syndrome in the second case; however, their synchronous appearance is very rare especially in young patients with no apparent predisposing factors. We describe the case of a 33-year-old woman with acute pain onset in right hypochondrium. The ultrasound (US) imaging and the contrast-enhanced computed tomography (CECT) of the abdomen revealed 2 abdominal masses: one in the VI-VII segments of the liver and the other one in the right kidney. The chest CECT study, acquired for staging purpose, detected multiple micronodules with patchy peri-bronchial distribution at both lungs. At the histological examination, the tumor arising from the right kidney was finally diagnosed as clear cell renal carcinoma, whereas the tumor arising from the right lateral hepatic lobe as HCC. The histological examination of lung lesions revealed sarcoidosis granulomas. The patient is still being followed up for the occurrence of lung and lymph node metastases from HCC 14 months later.

Updated diagnosis and graft involvement for visceral leishmaniasis in kidney transplant recipients: a case report and literature review.

PURPOSE: Visceral leishmaniasis (VL) has become a rising concern to transplantation teams, being associated with graft dysfunction and reduced survival of renal transplant recipients. Here, we describe a case of VL occurring in a kidney transplant (KT) recipient in Italy, a country in which Leishmania infantum is endemic and we reviewed the literature on the clinical course and diagnosis of VL in KT recipients residing or travelling to southern Europe. RESULTS: The VL case was diagnosed 18 months after transplant and 28 days after the onset of symptoms by quantitative PCR (qPCR) on peripheral blood. A graft biopsy showed renal involvement, and PCR performed on graft tissue displayed the presence of Leishmania DNA. The retrospective confirmation of Leishmania-positive serology in a serum sample collected before transplantation, as well as the absence of anti-Leishmania IgG in the graft donor strongly suggest that reactivation of a latent parasitic infection caused VL in the current case. CONCLUSION: VL is often underdiagnosed in transplant recipients, despite the presence of latent Leishmania infection being reported in endemic countries. This case report, as well as the literature review on leishmaniasis in KT recipients, underline the importance of rapid VL diagnosis to promptly undergo treatment. Serology is scarcely sensitive in immunocompromised patients, thus molecular tests in peripheral blood should be implemented and standardized for both VL identification and follow-up.

DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a late-onset cilia-related disorder, characterized by progressive cystic enlargement of the kidneys. It is genetically heterogeneous with PKD1 and PKD2 pathogenic variants identified in approximately 78% and 15% of families, respectively. More recently, additional ADPKD genes, such as DNAJB11, have been identified and included in the diagnostic routine test for renal cystic diseases. However, despite recent progress in ADPKD molecular approach, approximately ~7% of ADPKD-affected families remain genetically unresolved. We collected a cohort of 4 families from our center, harboring heterozygous variants in the DNAJB11 gene along with clinical and imaging findings consistent with previously reported features in DNAJB11 mutated patients. Mutations were identified as likely pathogenetic (LP) in three families and as variants of uncertain significance (VUS) in the remaining one. One patient underwent to kidney biopsy and showed a prevalence of interstitial fibrosis that could be observed in ~60% of the sample. The presence in the four families from our cohort of ADPKD characteristics together with ADTKD features, such as hyperuricemia, diabetes, and chronic interstitial fibrosis, supports the definition of DNAJB11 phenotype as an overlap disease between these two entities, as originally suggested by the literature.

[Discovering uncommon nephropathies: a case of acute kidney damage from malaria].

Malaria is one of the most common infectious diseases in the world with a high prevalence in developing countries. Renal impairment occurs in 40% of Plasmodium falciparum infections; glomeruli, tubules or interstitium can be involved with different pathophysiological mechanisms. We describe a case of severe acute renal failure caused by P. falciparum malaria in a young woman from the Ivory Coast. Renal biopsy revealed severe and widespread acute tubular necrosis and the presence of blackish pigment granules in the glomerular and peritubular capillaries, negative for iron histochemical staining; in electron microscopy we found rounded-oval-shaped structures containing cytoplasmic organelles, electrondensic granules and cellular debris, likely of infectious origin, within monocyte-macrophages located in the tubular lumen. Specific Antigen for P. falciparum and malarial parasite in blood were positive, with very rare trophozoites and gametocytes compatible with Plasmodium falciparum. Steroid therapy and specific antiparasitic therapy were set up with progressive functional improvement until complete recovery. This case highlights the importance of paying maximum attention to low incidence pathologies in our country, considering the continuous migratory movements of these years that can cause an increase in these diseases; anamnestic data are essential for a timely diagnosis which can contribute to a rapid remission avoiding severe complications.

Amyloidosis: What does pathology offer? The evolving field of tissue biopsy.

Since the mid-nineteenth century pathology has followed the convoluted story of amyloidosis, recognized its morphology in tissues and made identification possible using specific staining. Since then, pathology studies have made a significant contribution and advanced knowledge of the disease, so providing valuable information on the pathophysiology of amyloid aggregation and opening the way to clinical studies and non-invasive diagnostic techniques. As amyloidosis is a heterogeneous disease with various organ and tissue deposition patterns, histology evaluation, far from offering a simple yes/no indication of amyloid presence, can provide a wide spectrum of qualitative and quantitative information related to and changing with the etiology of the disease, the comorbidities and the clinical characteristics of patients. With the exception of cardiac transthyretin related amyloidosis cases, which today can be diagnosed using non-biopsy algorithms when stringent clinical criteria are met, tissue biopsy is still an essential tool for a definitive diagnosis in doubtful cases and also to define etiology by typing amyloid fibrils. This review describes the histologic approach to amyloidosis today and the current role of tissue screening biopsy or targeted organ biopsy protocols in the light of present diagnostic algorithms and various clinical situations, with particular focus on endomyocardial and renal biopsies. Special attention is given to techniques for typing amyloid fibril proteins, necessary for the new therapies available today for cardiac transthyretin related amyloidosis and to avoid patients receiving inappropriate chemotherapy in presence of plasma cell dyscrasia unrelated to amyloidosis. As the disease is still burdened with high mortality, the role of tissue biopsy in early diagnosis to assure prompt treatment is also mentioned.

[Monoclonal gammopathies and kidney: a diagnostic challenge without any clues].

Diagnosis of monoclonal gammopathy of renal significance (MGRS) with histopathologic features of proliferative GN with monoclonal immunoglobulin deposits (PGNMID) is a challenge for clinicians because of the absence of laboratory findings suggestive of glomerular involvement in paraproteinemia. Renal biopsy remains the gold standard for diagnosis of PGNMID because it is a monoclonal gammopathy with kidney damage often "without a detectable serum/urine clone". Through this case report, we want to focus on the complexity both in the diagnostic process and in monitoring the renal-hematological response to therapy.

Renal Thrombotic Microangiopathy in Concurrent COVID-19 Vaccination and Infection.

We report on the development of nephrotic proteinuria and microhematuria, with histological features of renal thrombotic microangiopathy (TMA), following the first dose of BNT162b2 COVID-19 vaccine (Pfizer-BioNTech) and COVID-19 diagnosis. A 35-year-old previously healthy man was admitted at our hospital due to the onset of foamy urine. Previously, 40 days earlier, he had received the first injection of the vaccine, and 33 days earlier, the RT-PCR for SARS-CoV-2 tested positive. Laboratory tests showed nephrotic proteinuria (7.9 gr/day), microhematuria, serum creatinine 0.91 mg/dL. Kidney biopsy revealed ultrastructural evidence of severe endothelial cell injury suggestive of a starting phase of TMA. After high-dose steroid treatment administration, complete remission of proteinuria was achieved in a few weeks. The association of COVID-19 with renal TMA has been previously described only in patients with acute renal injury. Besides, the correlation with COVID-19 vaccine has not been reported so far. The close temporal proximity (7 days) between the two events opens the question whether the histological findings should be ascribed to COVID-19 itself or to vaccine injection.

Secondary bladder amyloidosis due to Crohn's disease: a case report and literature review.

The presence of amyloid deposits in bladder walls is a rare histological finding. It can be linked to primary (limited to bladder) or secondary (systemic, associated with chronic inflammatory disorders) amyloidosis. Secondary bladder involvement is very uncommon; it usually presents with gross hematuria, which is challenging to manage, due to frail bladder mucosa and/or necrosis. We present a case of 54-year old man with secondary bladder amyloidosis due to Crohn's disease, that caused gross hematuria and severe anemia, which was managed conservatively by endoscopic transurethral resection, diatermocoagulation, clot evacuation and urinary drainage by bilateral percutaneous nephrostomy, with spontaneous resolution. Secondary bladder amyloidosis is a rare condition that presents with severe hematuria, difficult to control with standard management. Owing to chronic nature of the disease, treatment should be aimed to a conservative approach whenever possible. In case of failure, invasive procedures should be considered as salvage therapies.

Renal dysfunction in psoriatic patients.

Psoriasis is a common chronic inflammatory disease of the skin that is increasingly being considered as a systemic inflammatory disorder due to its association with cardiovascular, metabolic, pulmonary, renal, liver, and neurologic diseases. Renal involvement is rare but well documented and psoriasis is recognized as an independent factor for CKD and ESKD. A careful monitoring of the urinalysis and of renal function is recommended in psoriatic patients, especially those with moderate-to-severe disease. In case of pathologic findings, the execution of a renal biopsy appears necessary to make an accurate diagnosis and to establish the most appropriate therapeutic strategies to prevent the progression of kidney damage. The mechanisms of kidney involvement are different and not yet fully clarified. We present here two case reports of renal dysfunction during psoriasis. In one case, we diagnosed IgA nephropathy with particularly severe clinical presentation; in the other, an advanced kidney injury due to nephrotoxicity after prolonged CNI treatment.

A case report of IgG4-related disease: an insidious path to the diagnosis through kidney, heart and brain.

BACKGROUND: IgG4-related disease, described around the years 2000 as a form of autoimmune pancreatitis, is now increasingly accepted as a systemic syndrome. The diagnosis is based on both comprehensive and organ-specific criteria. For the kidney, Mayo clinic classification and the guidelines of the Japanese Nephrology Society are used. Ultimately, together with parameters that characterize every organ or apparatus involved, the key element is the confirmation of growing levels of IgG4 in blood or in tissues. CASE PRESENTATION: We describe a male patient with chronic renal failure associated to hypertension without proteinuria. IgG4-related disease was diagnosed through renal biopsy. After an initial positive response to steroids, he presented tinnitus, and histological assessment showed cerebral and subsequently cardiac damage, both IgG4-related. This case appears unique for the type of histologically documented cardiac and neurological parenchymal involvement, and at the same time, exemplifies the subtle and pernicious course of the disease. Frequently, blurred and non-specific signs prevail. Here, kidney damage was associated with minimal urinary findings, slowly progressive renal dysfunction and other factors that can be equivocated in the differential diagnosis. Neurological involvement was represented by tinnitus alone, while cardiac alterations were completely asymptomatic. CONCLUSIONS: This report is representative of the neurological and cardiac changes described in the literature for IgG4-related disease, which may be correlated or not with the renal form and highlights the need, in some cases, of targeted therapeutic approaches. In addition to glucocorticoids, as in this case, rituximab may be necessary.

[Minimal change disease during lithium therapy: case report].

Lithium is a largely used and effective therapy in the treatment of bipolar disorder. Its toxic effects on kidneys are mostly diabetes insipidus, hyperchloremic metabolic acidosis and tubulointerstitial nephritis. Also, a correlation between lithium and minimal change disease has sometimes been described. We report here the case of a patient with severe bipolar disorder on lithium therapy who, without any pre-existing nephropathy, developed nephrotic syndrome and AKI with histopathologic findings pointing to minimal change disease. The patient was treated with symptomatic therapy; the discontinuation of lithium therapy resulted in the remission of AKI and of the nephrotic syndrome, thus suggesting a close relationship between lithium and minimal change disease.

[FSGS collapsing variant during anabolic steroid abuse: Case Report].

Anabolic Androgenic Steroids (AAS) is an hormone family whose use has considerably increased among body-builders during the last decades. The AAS abuse, especially associated with other drugs or nutritional supplements and protein loads, may cause a variety of pathologies to several organs with a mechanism related to dosage, timing and substance. The kidney is the main metabolizer of these drugs and it can be acutely or chronically damaged with ESKD. The literature reports some cases of Focal Segmental Glomerulosclerosis (FSGS) in body-builders who abused of AAS. However, the link is not well understood and limited to some case-studies. In this paper, we report the case of a young body-builder who developed a FSGS collapsing variant with ESKD after prolonged abuse of AAS and a strongly hyperproteic diet and other dietary supplements. The patient underwent a genetic test because of the rapid and irreversibile onset of ESKD. The test showed a gene mutation of ACTN4, predisposing and causal of some genetic forms of FSGS. It was a very complex case, caused by several factors. The mutant protein of ACTN4 gene makes most vulnerable the cytoskeleton of the podocytes to external disturbances. That would explain why in those patients where the mutation has occurred, only those patients subject to "unfavorable environmental conditions", like the abuse of AAS, can develop a disease.

Prediction of three-year outcome of renal transplantation from optimal donors versus expanded criteria donors.

BACKGROUND/AIMS: The shortage in organ supply has required the use of expanded criteria donors (ECD) for kidney transplantation. Current pre-transplant evaluations of ECD organs are based on histological, clinical or mixed criteria. This monocentric study investigates the predictivity of Karpinski's histological score on 3-year graft function in renal transplant. Ex-post classification using Nyberg's score was carried out to assess the reliability of a purely clinical score and its applicability for organ allocation. METHODS: We evaluated 407 deceased donors (251 optimal and 156 ECD) for renal transplants performed between 2001 and 2006. The differences in creatinine levels and MDRD-GFR at transplant and 1, 2 and 3 years post-transplant between optimal donors and ECD were recorded. Amongst ECD organs, the effect of different Karpinski score classes (0-1, 2, 3, 4, double transplants) on 3-year graft outcomes was analyzed. We then compared renal function over time across the Nyberg grades (A, B, C, and D). RESULTS: Karpinski scores 0-1 and 2 and double transplants were associated with improved graft function compared to scores 3 and 4. Nyberg's clinical score shows a good fit with medium-term outcome and Karpinski's score, but among the donors with a high Nyberg grade (C and D), it fails to differentiate between allocable or non-allocable organs (due to Karpinski's score ≥7). CONCLUSIONS: Our data demonstrate a correlation of histological damage at the time of transplant with 3-year graft function, but at present we are unable to provide any supposition on the possible outcome of the discarded kidneys.

Development of a Nephrotic Syndrome in a Patient with Gastrointestinal Stromal Tumor during a Long-Time Treatment with Sunitinib.

A patient with advanced gastrointestinal stromal tumor (GIST) receiving second-line treatment with sunitinib developed edema, increase of the serum creatinine, weight gain, nephrotic syndrome with proteinuria of 12 g/24 h, dyslipidemia, hypoalbuminemia and also presented with hypertension. A kidney biopsy showed an immunocomplex glomerulonephritis. Steroid treatment was started, but the clinical conditions and laboratory values did not improve. So in the hypothesis that the nephrotic syndrome was induced by sunitinib, sunitinib was temporarily discontinued with a subsequent reduction of proteinuria and improvement in blood pressure control. In the last years, the introduction of sunitinib has modified the natural history of advanced GIST. However, due to chronic and prolonged intake of this drug, there is increasingly frequent detection of late and unknown toxicities in clinical practice. In particular, the late renal toxicity from sunitinib may be the primary clinical problem with this drug in the case of prolonged treatment. Monitoring of kidney function and blood pressure should be performed for early detection of side effects such as hypertension and kidney dysfunction in advanced GIST patients receiving long-term treatment with sunitinib. A clinical collaboration between oncologists and nephrologists could be useful with the objective to optimize the management of sunitinib.