Presentation and progression of MPO-ANCA interstitial lung disease.

The association between MPO-ANCA-associated vasculitis (AAV) and interstitial lung disease (ILD) has been well established. Pulmonary fibrosis may coexist with, follow, or even precede the diagnosis of AAV, and its presence adversely affects the prognosis. The optimal approach to investigating ANCA in patients with ILD remains a subject of ongoing debate. Here we aim to describe presentation and progression of MPO-ANCA ILD. We conducted a retrospective evaluation of a cohort of individuals diagnosed with MPO-ANCA ILD, with or without accompanying renal impairment, at the Immunology and Cell Therapy Unit, Careggi University Hospital, Florence, Italy, between June 2016 and June 2022. Clinical records, imaging studies, pathologic examinations, and laboratory test results were collected. Among the 14 patients identified with MPO-ANCA ILD, we observed a significant association between MPO-ANCA titers assessed at the time of ILD diagnosis and renal involvement. Renal impairment in these cases often manifested as subclinical or slowly progressive kidney damage. Interestingly, complement C3 deposits were consistently found in all renal biopsy specimens, thereby suggesting the potential for novel therapeutic targets in managing renal complications associated with MPO-ANCA ILD. The presentation of MPO-ANCA vasculitis as ILD can be the first and only clinical manifestation. MPO-ANCA levels at ILD diagnosis could warn on the progression to renal involvement in patients with MPO-ANCA ILD, hence caution is needed because renal disease can be subclinical or smoldering.

Clinical-Pathological Characteristics of Renal Injuries Identify Different Clusters in Patients With Antiphospholipid Antibodies.

Introduction: Significant heterogeneity still exists in the nomenclature of renal involvement in antiphospholipid syndrome (APS). Methods: We applied a hierarchical cluster analysis to determine subgroups of patients according to clinical, laboratory, and renal histology characteristics in a cohort of subjects with confirmed antiphospholipid antibodies (aPL) positivity and biopsy proven aPL-related renal injuries. Kidney outcomes were then assessed at 12 months. Results: A total of 123 aPL-positive patients were included in the study (101 [82%] female, 109 [88.6%] with systemic lupus erythematosus [SLE], 14 (11.4%) with primary APS [PAPS]). Three clusters were identified. Twenty-three patients (18.7%) were included in the first cluster (cluster 1), characterized by a higher prevalence of glomerular capillary and arteriolar thrombi and fragmented red blood cells in the subendothelial space. Cluster 2 included 33 patients (26.8%) and showed a higher prevalence of fibromyointimal proliferative lesions as seen in hyperplastic vasculopathy. Cluster 3 was the largest (67 patients, mainly with SLE) and was characterized by higher prevalence of subendothelial edema, of both glomerular capillaries and arterioles. Conclusion: Three different clusters of patients with aPL and renal injuries emerged from our study as follows: the first, with the worst renal prognosis, was associated with features of thrombotic microangiopathy (TMA), thrombosis, triple aPL positivity and higher adjusted Global APS Score (aGAPSS) values; the second, characterized by hyperplastic vasculopathy with an intermediate prognosis, was seen more frequently in patients with cerebrovascular manifestations; and the third, more benign in terms of outcomes and with no overt association with thrombotic features, was characterized by endothelial swelling in concomitant lupus nephritis (LN).

De novo collapsing glomerulopathy after kidney transplantation: Description of two cases.

BACKGROUND: Among different forms of de novo focal segmental glomerulosclerosis (FSGS), which can develop after kidney transplantation (KTx), collapsing glomerulopathy (CG) is the least frequent variant, but it is associated with the most severe form of nephrotic syndrome, histological findings of important vascular damage, and a 50% risk of graft loss. Here, we report two cases of de novo post-transplant CG. CLINICAL PRESENTATION: A 64-year-old White man developed proteinuria and worsening of renal function 5 years after KTx. Before the KTx, the patient was affected by an uncontrolled resistant hypertension, despite multiple antihypertensive therapies. Blood levels of calcineurin inhibitors (CNIs) were stable, with intermittent peaks. Kidney biopsy showed the presence of CG. After introduction of angiotensin receptor blockers (ARBs), urinary protein excretion progressively decreased in 6 months, but subsequent follow-up confirmed a progressive renal function decline. A 61-year-old White man developed CG 22 years after KTx. In his medical history, he was hospitalized twice to manage uncontrolled hypertensive crises. In the past, basal serum cyclosporin A levels were often detected above the therapeutic range. Low doses of intravenous methylprednisolone were administered due to the histological inflammatory signs shown on renal biopsy, followed by a rituximab infusion as a rescue therapy, but no clinical improvement was seen. DISCUSSION AND CONCLUSION: These two cases of de novo post-transplant CG were supposed to be mainly caused by the synergic effect of metabolic factors and CNI nephrotoxicity. Identifying the etiological factors potentially responsible for de novo CG development is essential for an early therapeutic intervention and the hope of better graft and overall survival.

A multidisciplinary case report of multiple myeloma with renal and cardiac involvement: a look beyond amyloidosis.

BACKGROUND: Multiple myeloma (MM) is a malignant neoplasm associated with kidney involvement in nearly half of the patients. Cast nephropathy, monoclonal immunoglobulin deposition disease (MIDD), and light chain (AL) amyloidosis are the most common monoclonal immunoglobulin-mediated causes of renal injury. Cardiac involvement is also present in MM, characterized by restrictive cardiomyopathy generated by light chain deposit or amyloid. Thromboembolic complications such as deep vein thrombosis or pulmonary embolism are also described. CASE PRESENTATION: We present an unusual multidisciplinary case of a woman with a newly diagnosed MM associated with severe proteinuria and high natriuretic peptide. A renal and fat pad biopsy with Congo red staining were performed but amyloid deposition was not discovered. While immunofluorescence on fresh frozen unfixed tissue was not contributory, the immunofluorescence on fixed tissue and electron microscopy revealed the correct diagnosis. During subsequent investigations, two intracardiac right-sided masses and massive pulmonary embolism were also detected. CONCLUSIONS: This case highlights that multiple organ involvement in patients with MM may result from a combination of paraprotein-dependent and -independent factors. Moreover, renal diseases induced by monoclonal gammopathies are a group of complex and heterogeneous disorders. Their subtle presentation and their potential multiorgan involvement require the expertise of a multidisciplinary team able to provide the most appropriate diagnostic and therapeutic assessment.

Robot-assisted kidney transplantation: Is it getting ready for prime time?

Kidney transplantation (KT) is the treatment of choice for patients with end-stage renal disease, providing a better survival rate and quality of life compared to dialysis. Despite the progress in the medical management of KT patients, from a purely surgical standpoint, KT has resisted innovations during the last 50 years. Recently, robot-assisted KT (RAKT) has been proposed as an alternative approach to open surgery, especially due to its potential benefits for fragile and immunocompromised recipients. It was not until 2014 that the role of RAKT has found value thanks to the pioneering Vattikuti Urology Institute-Medanta collaboration that conceptualized and developed a new surgical technique for RAKT following the Idea, Development, Exploration, Assessment, Long-term follow-up recommendations for introducing surgical innovations into real-life practice. During the last years, mirroring the Vattikuti-Medanta technique, several centers developed RAKT program worldwide, providing strong evidence about the safety and the feasibility of this procedure. However, the majority of RAKT are still performed in the living donor setting, as an "eligible" procedure, while only a few centers have realized KT through a robotic approach in the challenging scenario of cadaver donation. In addition, despite the spread of minimally-invasive (predominantly robotic) surgery worldwide, many KTs are still performed in an open fashion. Regardless of the type of incision employed by surgeons, open KT may lead to non-negligible risks of wound complications, especially among obese patients. Particularly, the assessment for KT should consider not only the added surgical technical challenges but also the higher risk of postoperative complications. In this context, robotic surgery could offer several benefits, including providing a better exposure of the surgical field and better instrument maneuverability, as well as the possibility to integrate other technological nuances, such as the use of intraoperative fluorescence vascular imaging with indocyanine green to assess the ureteral vascularization before the uretero-vesical anastomosis. Therefore, our review aims to report the more significant experiences regarding RAKT, focusing on the results and future perspectives.

A Report of 2 Cases of Kidney Involvement in ADA2 Deficiency: Different Disease Phenotypes and the Tissue Response to Type I Interferon.

Adenosine deaminase 2 (ADA2) deficiency is a rare autosomal recessive disease that is caused by loss-of-function mutations in the ADA2 gene. It is considered a monogenic form of polyarteritis nodosa and frequently is positive for a type I interferon (IFN) signature. Renal manifestations in ADA2 deficiency are poorly characterized. We herein report 2 cases of ADA2 deficiency with different kidney patterns due, respectively, to a predominantly macroscopic and microscopic vasculopathy, and review the literature on kidney disease in ADA2 deficiency. Patient 1 presented with a spontaneous perirenal hematoma; angiography demonstrated multiple microaneurysms but no further defects of the renal parenchyma; his kidney function remained normal. Patient 2 experienced slowly deteriorating kidney function and proteinuria. No major angiographic abnormalities were detected, while kidney biopsy revealed massive vasculopathy resembling chronic thrombotic microangiopathy (TMA) of the small and medium-sized vessels. Both patients had a positive peripheral type I IFN signature. In immunofluorescence staining of a kidney biopsy sample from patient 2, we observed marked expression of the type I IFN-induced protein MXA within endothelial cells, especially in vessels with TMA, and in infiltrating T cells. Our findings confirm that the kidney phenotype of ADA2 deficiency results from small and medium-sized vessel vasculopathy and suggest that type I IFN may be involved in the pathogenesis of kidney lesions.

Parapelvic cysts, a distinguishing feature of renal Fabry disease.

Background: Fabry's disease (FD) is a rare, multi-organ lysosomal disease, caused by the deficiency of the enzyme α-galactosidase A, and is difficult to diagnose. Although parapelvic cysts (PC) were previously associated with FD, their prevalence and significance are unclear. Methods: The present study aimed to: (i) evaluate, by renal ultrasound, the real prevalence of PC and of their determinants in a multicentre, nationwide cohort of FD patients (n = 173, Study 1) and (ii) ascertain whether a greater accuracy of PC detection improved their identification, in FD patients from a single centre (n = 67, Study 2). In both studies, for each FD patient, an age- and renal function-matched subject was selected for comparison (1:1). Results: In Study 1, PC were detected in 28.9% of FD subjects and in only 1.1% of control subjects (P < 0.001). The presence of other renal abnormalities did not differ between the groups, nor differences exist in the main demographic and laboratory parameters between the groups. In Study 2, the greater accuracy of ultrasound increased PC prevalence from 29.8% to 43.3% in the same subjects (P < 0.05). In both studies, no correlation was detected between PC and the main demographic, clinical and biochemical parameters, including use of enzyme replacement therapy (P < 0.1, minimum value). Finally, no difference existed between FD patients with and without PC. Conclusions: The present study suggests that the presence of PC in renal patients should alert physicians to consider the diagnosis of FD, primarily in subjects with an unclear family history of renal disease and in the presence of other stigmata of the disease.

Thrombotic microangiopathy induced by interferon beta in patients with multiple sclerosis: three cases treated with eculizumab.

BACKGROUND: Interferon-beta (IFN-beta) is one of the most widely prescribed medications for relapsing-remitting multiple sclerosis (RRMS). IFN-related thrombotic microangiopathy (TMA) is a rare but severe complication, with a fulminant clinical onset and a possibly life-threatening outcome that may occur years after a well-tolerated treatment with IFN. Most patients evolve rapidly to advanced chronic kidney disease and eventually to renal failure. METHODS: We performed a retrospective analysis of TMA cases diagnosed and managed in our Nephrology Department from 2010 to 2015, and performed a literature review of IFN-beta-induced TMA. RESULTS: Three cases of TMA among patients treated with IFN-beta were identified who did not show any renal improvement following conventional therapy: IFN withdrawal and plasma exchange (PE, range 8-18) sessions. All of them responded favourably to eculizumab, with progressive clinical and renal improvement, allowing dialysis discontinuation, without recurrence of TMA during a long-term follow-up (range 1-5 years). CONCLUSIONS: TMA is a recognized severe complication in RRMS patients treated with IFN-beta. Withdrawal of IFN and treatment with PE, steroids or rituximab did not improve the poor renal prognosis in our three patients and in all the previously described cases in the literature. In our experience, eculizumab had a strikingly favourable effect on renal recovery, suggesting a role of IFN-beta as a trigger in complement-mediated TMA. Neurologists and nephrologists should be vigilant to this complication to prevent possibly irreversible renal damage.

1,25 Dihydroxyvitamin D circulating levels, calcitriol administration, and incidence of acute rejection, CMV infection, and polyoma virus infection in renal transplant recipients.

Observation that 1,25-Dihydroxyvitamin-D3 has an immunomodulatory effect on innate and adaptive immunity raises the possible effect on clinical graft outcome. Aim of this study was to evaluate the correlation of biopsy-proven acute rejection, CMV infection, BKV infection, with 1,25-Dihydroxyvitamin-D3 deficiency and the benefit of calcitriol supplementation before and during the transplantation. Risk factors and kidney graft function were also evaluated. All RTRs received induction therapy with basiliximab, cyclosporine, mycophenolic acid, and steroids. During the first year, the incidence of BPAR (4% vs 11%, P=.04), CMV infection (3% vs 9%, P=.04), and BKV infection (6% vs 19%, P=.04) was significantly lower in users compared to controls. By multivariate Cox regression analysis, 1,25-Dihydroxyvitamin-D3 deficiency and no calcitriol exposure were independent risk factors for BPAR (HR=4.30, P<.005 and HR=3.25, P<.05), for CMV infection (HR=2.33, P<.05 and HR=2.31, P=.001), and for BKV infection (HR=2.41, P<.05 and HR=2.45, P=.001). After one year, users had a better renal function: eGFR was 62.5±6.7 mL/min vs 51.4±7.6 mL/min (P<.05). Only one user developed polyomavirus-associated nephropathy vs 15 controls. Two users lost their graft vs 11 controls. 1,25(OH)2-D3 deficiency circulating levels increased the risk of BPAR, CMV infection, BKV infection after kidney transplantation. Administration of calcitriol is a way to obtain adequate 1,25(OH)2-D3 circulating levels.

Posttransplant outcome of atypical haemolytic uraemic syndrome in a patient with thrombomodulin mutation: a case without recurrence.

Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and renal impairment. Mutations in genes encoding inhibitors of the alternative pathway of the complement system are involved in ∼50% of the cases. Thrombomodulin (THBD) gene mutations occur in ∼3-5% of the cases. The risk of aHUS recurrence after kidney transplantation depends on the complement abnormality involved. In all three cases of THBD mutation reported to date, aHUS recurred after kidney transplantation (KT) with early graft loss. No data exist about therapeutic approaches before kidney transplantation to reduce the risk of recurrence in patients carrying this mutation. Favourable data on the use of eculizumab have been reported, in terms of plasmatherapy withdrawal and renal function recovery in aHUS recurrence after KT. To our knowledge, this case report presents the first case of successful kidney transplantation in a patient with aHUS due to THBD mutation who was treated with a single plasma-exchange immediately before surgery without recurrence of the disease 12 months after transplantation.

Impact of the pre-transplant histological score on 3-year graft outcomes of kidneys from marginal donors: a single-centre study.

BACKGROUND: The reliability of kidney biopsy as the sole means for assessing kidneys from extended-criteria donors (ECDs) to be allocated to single or dual transplantation is still a matter of debate. METHODS: We compared retrospectively 3 years graft survival and renal function in 44 recipients of a single kidney graft from a marginal donor with good renal function and a Karpinski histological score of ≤ 3 and 56 recipients of a single transplant with a Karpinski score of 4 or 5. The donors' and recipients' characteristics were compared by means of Wilcoxon's rank-sum test and Fisher's exact test, and survival was analysed using the log-rank test and Cox regression survival analysis. RESULTS: The donors with the worse histological scores were slightly younger (68.0 ± 4.74 versus 71.3 ± 4.6 years, P < 0.01) and had a higher glomerular filtration rate (85.8 ± 28.2 versus 76.3 ± 26.53 mL/min, P = 0.013), but there was no difference in serum creatinine levels (0.83 ± 0.24 versus 0.85 ± 0.30 mg/dL, P = 0.381). Three years after transplantation, there was no difference between the two groups in terms of recipient serum creatinine levels (1.94 ± 0.69 versus 1.74 ± 0.49 mg/dL, P = 0.134), estimated glomerular filtration rate (eGFR, 45.6 ± 21.1 versus 51.7 ± 22.0 mL/min, P = 0.331) or the rates of graft loss (27.3 versus 35.7%, P = 0.47), delayed graft function or acute rejection. CONCLUSIONS: In our experience, provided the donor has a normal renal function, a difference in the pre-transplant histological score of kidneys from marginal cadaveric donors do not have a significant influence on the outcome 3 years after transplantation. Our findings might represent a basis for designing a randomized controlled trial of using a higher histological score threshold for the DKT allocation of grafts from ECDs with a normal renal function.

Everolimus leads to a lower risk of BKV viremia than mycophenolic acid in de novo renal transplantation patients: a single-center experience.

BACKGROUND: There are limited published data concerning the effects of different immunosuppressive regimens on the development of polyomavirus (BKV) viremia. We examined the risk of developing BKV viremia in kidney transplant recipients receiving everolimus (EVR) or mycophenolic acid (MPA) as maintenance therapy. METHODS: We observationally analyzed 296 patients who underwent renal transplantation at our center between 2005 and 2010: 58 were treated with EVR and low-dose cyclosporine (LD-CyA) (group 1) and 238 with MPA and standard-dose CyA (group 2). All of the patients received induction therapy with basiliximab and maintenance steroids. BKV viremia (a whole-blood viral load of >850 copies/mL) was measured by means of real-time polymerase chain reaction at least once a month during a 12-month follow-up period. RESULTS: BKV viremia was detected in 57 patients (19%), five (9%) in group 1 and 52 (22%) in group 2. Kaplan-Meier analyses showed that freedom from BKV viremia was significantly more frequent in group 1. The mean time of onset of BKV viremia was about four months after transplantation in both groups. The median viral load was greater in group 2 (12.5 ± 6.1 vs. 2.5 ± 1.8 × 10(4) copies/mL; p = 0.01). After the onset of BKV viremia, graft function significantly declined in group 2: 11 patients developed polyomavirus-associated nephropathy (PVAN) and four presumptive PVAN; nine experienced an acute rejection after the discontinuation of MPA, and 11 (21%) lost their graft. There was no graft loss in group 1. CONCLUSION: These findings suggest that in comparison with MPA and Cya, an EVR and LD-CyA regimen lowers the risk of BKV viremia after kidney transplantation and favorably alters outcomes.

[Severe recurrent intrahepatic cholestasis in systemic AL amyloidosis without obvious liver involvement: unexplained hepatic toxicity or a case of misdiagnosed liver amyloidosis?]. / Colestasi intraepatica in corso di amiloidosi sistemica AL senza evidenza istologica di un coinvolgimento epatico: un caso di epatopatia tossica o una mancata diagnosi di amiloidosi epatica?

We report the case of a 50-year-old woman who was admitted to the hospital for acute abdominal pain with nephrotic proteinuria, rapidly progressive renal failure, and moderate anemia. Laboratory tests showed mild Bence Jones (λ) proteinuria with negative serum immunofixation and a mild increase in λ free light chains. A bone marrow biopsy and a fat tissue aspirate showed multiple myeloma and amyloidosis. Because of the end-stage renal disease, the patient began regular dialysis treatment and was started on bortezomib 1.3 mg/m2 plus dexamethasone 40 mg on days 1, 4, 8 and 11 of 21-day cycles. Ten days later she complained of a new episode of abdominal pain with jaundice. A CT scan and an MRI scan ruled out all secondary causes of cholangitis including cancer. Acute intrahepatic cholestasis due to amyloid deposition was then hypothesized. After 4 well tolerated cycles of bortezomib and dexamethasone, blood tests showed a complete hematological response with full reversal of cholestasis. After three months, a new episode of abdominal pain occurred and this time the patient was operated on and found to have an intestinal volvulus. Because of the jaundice, a transjugular liver biopsy was performed showing no evidence of amyloid deposits. Two months later the patient died of septic shock. Although no autopsy was performed and the ultimate cause of the cholestasis could not be ascertained, amyloidosis remains the major culprit in this unfortunate case.