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.

Diet and Physical Activity in Adult Dominant Polycystic Kidney Disease: A Review of the Literature.

Autosomal polycystic kidney disease is the most common inherited kidney disease determining 5% of all end-stage kidney disease. The only therapy approved for this condition is Tolvaptan, which, with its aquaretic effect, has a strong effect on patients' daily life. Recently, the literature has been enriched with new works that analyze possible non-pharmacological therapeutic strategies to slow cysts' enlargement and chronic kidney disease progression. Among them, dietary schemes reducing carbohydrate intake and inducing ketoses have been demonstrated to have efficacy in several pre-clinical and clinical studies. A ketogenic diet, calorie restriction, intermittent fasting, and time-restricted feeding can reduce aerobic glycolysis and inhibit the mTOR pathway, producing a reduction in cyst cell proliferation, a reduction in kidney volume, and helping to preserve kidney function. ADPKD's burden of disease has an impact on patients' quality of life, and the possibility to play sports or carry out physical exercise can help people in everyday life. The multisystemic character of the disease, especially cardiovascular involvement, needs to be carefully evaluated to establish the quality and quantity of physical activity that patients can safely carry out.

[IgA nephropathy and granulomatosis with polyangiitis-overlap: a rare coexistence of two glomerular nephropathies with remission after steroids and rituximab].

Granulomatosis with polyangiitis (GPA) is an ANCA-positive systemic vasculitis that mainly involves lungs and kidneys. This condition rarely overlaps with other glomerulonephritides. A 42-year-old man with constitutional symptoms and haemophtoe was admitted to the Infectious Diseases department, where he was subjected to fibrobronchoscopy with BAL (broncho-alveolar lavage) and lung transbronchial biopsy that showed histological signs of vasculitis. The association with severe acute kidney injury with urine sediment alterations (microscopic haematuria and proteinuria) led the consultant nephrologist to a diagnosis of GPA. Thus the patient was transferred to the Nephrology department. During the hospitalization, the worsening of the clinical course and the development of alveolitis, respiratory failure, purpura, and rapidly progressive kidney failure (nephritic syndrome - serum creatinine 3 mg/dl) required the start of steroid therapy, according to EUVAS. The presence of florid crescents in 3 out of 6 glomeruli in the renal biopsy and the IgA positive immunofluorescence allowed to make a diagnosis of overlap of GPA and IgA nephropathy. Rituximab (RTX 375 mg/m² per week for 4 weeks) and plasma exchange (7 sessions) were added to steroid therapy. During follow-up, partial functional recovery was achieved after 4 months, whereas total regression, i.e. the absence of protein and red blood cells in urine sediment, was reached during the 4-years follow-up. The main therapy during the first 2 years of follow-up was RTX, followed by mycophenolate mofetil for the remaining 2 years.

The risks associated with percutaneous native kidney biopsies: a prospective study.

BACKGROUND: The known risks and benefits of native kidney biopsies are mainly based on the findings of retrospective studies. The aim of this multicentre prospective study was to evaluate the safety of percutaneous renal biopsies and quantify biopsy-related complication rates in Italy. METHODS: The study examined the results of native kidney biopsies performed in 54 Italian nephrology centres between 2012 and 2020. The primary outcome was the rate of major complications 1 day after the procedure, or for longer if it was necessary to evaluate the evolution of a complication. Centre and patient risk predictors were analysed using multivariate logistic regression. RESULTS: Analysis of 5304 biopsies of patients with a median age of 53.2 years revealed 400 major complication events in 273 patients (5.1%): the most frequent was a ≥2 g/dL decrease in haemoglobin levels (2.2%), followed by macrohaematuria (1.2%), blood transfusion (1.1%), gross haematoma (0.9%), artero-venous fistula (0.7%), invasive intervention (0.5%), pain (0.5%), symptomatic hypotension (0.3%), a rapid increase in serum creatinine levels (0.1%) and death (0.02%). The risk factors for major complications were higher plasma creatinine levels [odds ratio (OR) 1.12 for each mg/dL increase, 95% confidence interval (95% CI) 1.08-1.17], liver disease (OR 2.27, 95% CI 1.21-4.25) and a higher number of needle passes (OR for each pass 1.22, 95% CI 1.07-1.39), whereas higher proteinuria levels (OR for each g/day increase 0.95, 95% CI 0.92-0.99) were protective. CONCLUSIONS: This is the first multicentre prospective study showing that percutaneous native kidney biopsies are associated with a 5% risk of a major post-biopsy complication. Predictors of increased risk include higher plasma creatinine levels, liver disease and a higher number of needle passes.

Early Light Chains Removal and Albumin Levels with a Double Filter-Based Extracorporeal Treatment for Acute Myeloma Kidney.

Renal impairment in Multiple Myeloma (MM) represents one of the most important factors that influences patient survival. In fact, before the introduction of modern chemotherapy, less than 25% of patients with acute kidney injury (AKI) and MM who required dialysis recovered sufficient renal function to become independent from dialysis, with a median overall survival of less than 1 year. There are many other factors involved in determining patient survival. In this study we aimed to investigate the role of double filter-based extracorporeal treatment for removal of serum free light chains (sFLC) in acute myeloma kidney (AKI for MM) and to evaluate patient overall survival. All patients received Bortezomib-based chemotherapy and extracorporeal treatment for sFLC removal. For each session 2 dialyzers of the same kind were used. The dialytic dose was not related to the degree of renal function but to the removal of sFLC. The factors that have been found to be significantly associated with lower mortality were reduction of sFLC at day 12 and day 30, >50% reduction of sFLC at day 30, number of sessions and independence from dialysis. Among baseline characteristics, albumin level was statistically associated with the patients' outcome. Our analysis highlights the importance of the early treatment for removal of sFLC in AKI for MM. These results indicate that the early removal of sFLC can improve patient's outcome.

The Relationship between Timing of Pretransplant Kidney Biopsy, Graft Loss, and Survival in Kidney Transplantation: An Italian Cohort Study.

INTRODUCTION: Kidney biopsy is performed to assess if an extended criteria graft can be used for transplantation. It may be performed before or after cross-clamping during organ procurement. This study aims to evaluate whether the timing of biopsy may modify cold ischemia times (CIT) and/or graft outcomes. METHODS: Kidney transplants performed in our center from January 2007 to December 2017 were analyzed. Grafts with preimplantation kidney biopsy were included. Biopsies were performed during surgical back table (ex situ kidney biopsy [ESKB]) until 2012 and since then before the aortic cross-clamping (in situ kidney biopsy [ISKB]). To overcome biases owing to different distributions, a propensity score model was developed. The study population consists in 322 patients, 115 ESKB, and 207 ISKB. RESULTS: CIT was significantly lower for ISKB (730 min ISKB vs. 840 min ESKB, p value = 0.001). In both crude (OR 0.27; 95% confidence interval, 95% CI 0.12-0.60; p value = 0.002) and adjusted analyses (OR 0.37; 95% CI 0.14-0.94; p value = 0.039), ISKB was associated with a reduced odd of graft loss when compared to ESKB. DISCUSSION/CONCLUSION: Performing preimplantation kidney biopsy during the recovery, prior to the aortic cross-clamping, may be a strategy to reduce CIT and improve transplant outcomes.

Renal involvement in sarcoidosis: histological patterns and prognosis, an Italian survey.

BACKGROUND: Granulomatous interstitial nephritis in sarcoidosis (sGIN) is generally clinically silent, but in <1% causes acute kidney injury (AKI). METHODS: This Italian multicentric retrospective study included 39 sarcoidosis-patients with renal involvement at renal biopsy: 31 sGIN-AKI, 5 with other patterns (No-sGIN-AKI), 3 with nephrotic proteinuria. We investigate the predictive value of clinical features, laboratory, radiological parameters and histological patterns regarding steroid response. Primary endpoint: incident chronic kidney disease (CKD) beyond the 1°follow-up (FU) year; secondary endpoint: response at 1°line steroid therapy; combined endpoint: the association of initial steroid response and outcome at the end of FU. RESULTS: Complete recovery in all 5 No-sGIN-AKI-patients, only in 45% (13/29) sGIN-AKI-patients (p=0.046) (one lost in follow-up, for another not available renal function after steroids). Nobody had not response. Primary endpoint of 22 sGIN-AKI subjects: 65% (13/20) starting with normal renal function developed CKD (2/22 had basal CKD; median FU 77 months, 15-300). Combined endpoint: 29% (6/21) had complete recovery and final normal renal function (one with renal relapse), 48% (10/21) had partial recovery and final CKD (3 with renal relapse, of whom one with basal CKD) (p=0.024). Acute onset and hypercalcaemia were associated to milder AKI and better recovery than subacute onset and patients without hypercalcaemia, women had better endpoints than men. Giant cells, severe interstitial infiltrate and interstitial fibrosis seemed negative predictors in terms of endpoints. CONCLUSIONS: sGIN-AKI-patients with no complete recovery at 1°line steroid should be treated with other immunosuppressive to avoid CKD, in particular if males with subacute onset and III stage-not hypercalcaemic AKI.

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.

Preliminary experience of sequential use of normothermic and hypothermic oxygenated perfusion for donation after circulatory death kidney with warm ischemia time over the conventional criteria - a retrospective and observational study.

Donation after circulatory death (DCD) is a potential source of reducing organ demand. In Italy, DCD requires a 20-min no-touch period that prolongs warm ischemia and increases delayed graft function (DGF) risk and graft loss. We report here our preliminary experience of sequential use of normothermic regional perfusion (NRP), as standard procedure, and hypothermic oxygenated perfusion (HOPE), as an experimental technique of organ preservation, in 10 kidney transplants (KT) from five DCD Maastricht III with extensive functional warm ischemia time (fWIT) up to 325 min. During NRP, renal function tests were evaluated to accept organs which were retrieved according to standard fashion with biopsy. While waiting for pathology and cross-match results, organs were preserved with HOPE through pressure- and temperature-controlled arterial pulsatile flow. All grafts with Karpinski score ≤4 were used for conventional single KT with mean cold ischemia time of 584 ± 167 min and mean fWIT of 151 ± 132 min. At the end of HOPE, lactate levels increased significantly in all cases with DGF (P = 0.0095), which were 3/10 (30%). No primary nonfunctions were recorded, and all patients had sCr < 1.5 mg/dl at 6-month post-KT. NRP and HOPE for DCD may overcome fWIT limits safely, and lactate during HOPE predicts DGF.

Functional Abnormalities and Thyroid Nodules in Patients with End-stage Renal Disease.

BACKGROUND/AIM: Clinical and subclinical hypothyroidism is more common in patients with end-stage renal disease (ESRD) than in the general population. Patients with ESRD with hypothyroidism are more susceptible to cardiovascular disease, with an increased risk of mortality than those with normal thyroid function. Moreover, these patients have higher incidence of benign and malignant nodules. PATIENTS AND METHODS: This was a retrospective study on 2,147 patients with ESRD on the renal transplant waiting list between 2000 and 2015 aimed at identifying the presence of hypothyroidism and associated variables. RESULTS: Hypothyroidism was detected in 437/2,147 (20.3%) patients, 289 of them having the subclinical form. Cardiovascular disease and older age were significantly associated with hypothyroidism, and autosomal polycystic kidney disease was correlated to goiter (p<0.001). CONCLUSION: Thyroid abnormalities, particularly hypothyroidism with nodules, should be investigated in patients with ESRD on a waiting list for renal transplant to control cardiovascular complications and cancer risk.

Removal of free light chains in hemodialysis patients without multiple myeloma: a crossover comparison of three different dialyzers.

BACKGROUND: Immunoglobulin light chains are classified as middle molecule uremic toxins able to interact with B lymphocyte membranes leading to the activation of transmembrane signaling. The ensuing impairment of neutrophil function can contribute to the chronic inflammation state of uremic patients, and the increased risk of bacterial infections or vascular calcifications. The aim of this crossover observational study was to assess the difference in free light chain removal by three different hemodialysis filters in patients not affected by multiple myeloma. METHODS: Free light chain removal was compared in the polymethylmethacrylate (PMMA) membrane Filtryzer BK-F, the polyphenylene HFR17 filter and the conventional polysulfone filter F7HPS. Twenty chronic hemodialysis patients were enrolled: mean age was 67.7 ± 17.0 years, M/F = 14/6, dialysis vintage (months) 25.5 ± 32.0. The patients were randomized into two groups of treatment lasting 6 weeks each. The dialysis sessions checked were the midweek sessions and the blood was drawn at times 0, 120' and 240'. Kappa (k) and lambda (λ) light chain levels, ß2microglobulin (ß2M), C reactive protein (CRP) and albumin were checked. RESULTS: K light chain levels were 345.0 ± 100.0 mg/L, λ light chains were 121.4 ± 27.0 mg/L. The values of k light chains at times 120' and 240' were significantly lower with PMMA and HFR17 than those obtained with F7. The reduction ratio per session (RRs) for k light chains was 44.1 ± 4.3% with HFR17, 55.3 ± 3.4% with PMMA, 25.7 ± 8.3% with F7 (p = 0.018). The RRs for λ light chains was 30.3 ± 2.9% with HFR17, 37.8 ± 17.3% with PMMA, 14.0 ± 3.9% with F7 (p = 0.032). As to ß2M, RRs was 42.4 ± 3.2% with HFR17 vs. 33.9 ± 2.8% with PMMA vs. 6.3 ± 1.9% with F7 (p = 0.022). The three filters tested showed no differences in CRP or albumin levels. CONCLUSION: In terms of light chain and ß2M removal, the PMMA and on-line HFR filters are similar and both are significantly more effective than the F7 filter in chronic dialysis patients. TRIAL REGISTRATION: The present trial was registered retrospectively ( NCT02950389 , 31/10/2016).

Hematopoietic Cell and Renal Transplantation in Plasma Cell Dyscrasia Patients.

Gammopathies, multiple myeloma, and amyloidosis are plasma dyscrasias characterized by clonal proliferation and immunoglobulin overproduction. Renal impairment is the most common and serious complication with an incidence of 20-30% patients at the diagnosis. Kidney transplant has not been considered feasible in the presence of plasma dyscrasias because the immunosuppressive therapy may increase the risk of neoplasia progression, and paraproteins may affect the graft. However, recent advances in clinical management of multiple myeloma and other gammopathies allow considering kidney transplant as a possible alternative to dialysis. Numerous evidence indicates the direct relationship between hematological remission and renal function restoring. The combination of kidney and hematopoietic cell transplant has been reported as a promising approach to reestablish end-organ function and effectively treat the underlying disease. This review describes current protocols used to perform kidney transplantation in patients with plasma dyscrasias.

[Kidney Transplantation and inborn errors of metabolism]. / Trapianto renale nelle malattie da errori congeniti del metabolismo.

Inherited kidney diseases constitute at least 150 different disorders and they have an overall prevalence of about 6080 cases per 100,000 in Europe and in USA. At least 10% of adults and nearly all children who progress to renal-replacement therapy have an inherited kidney disease, representing the fifth most common cause of end-stage renal disease after diabetes, hypertension, glomerulonephritis, and pyelonephritis. These conditions include both structural and functional disorders, among which are counted diseases resulting from inborn errors of metabolism (IEM). Some inborn errors of metabolism primarily affect kidney and because of progress in renal replacement therapy, patients with inherited kidney disorders rarely die when their disease progresses and can live for many years. However, these patients often have compromised health with a poor quality of life. Renal transplantation offers a viable treatment option for those inborn errors of metabolism characterized by primary renal damage caused by dysfunction of a mutated protein, as in cystinuria. In this case, the indication to renal transplantation makes it possible to overcome the specific enzyme defect. However this option remains valid even when the genetic defect is expressed systemically and renal involvement is just one of the clinical manifestations of the disease, as in Anderson-Fabry disease, cystinosis, hereditary amyloidosis and primary hyperoxaluria. In these conditions, renal transplantation is combined with the liver (primary hyperoxaluria) or cardiac transplant (familial amyloidosis) improving the quality and life expectancy of patients.

[Kidney Transplantation and inborn errors of metabolism]. / Trapianto renale nelle malattie da errori congeniti del metabolismo.

Inherited kidney diseases constitute at least 150 different disorders and they have an overall prevalence of about 6080 cases per 100 000 in Europe and in USA. At least 10% of adults and nearly all children who progress to renal-replacement therapy have an inherited kidney disease, representing the fifth most common cause of end-stage renal disease after diabetes, hypertension, glomerulonephritis, and pyelonephritis. These conditions include both structural and functional disorders, among which are counted diseases resulting from inborn errors of metabolism (IEM). Some inborn errors of metabolism primarily affect kidney and because of progress in renal replacement therapy, patients with inherited kidney disorders rarely die when their disease progresses and can live for many years. However, these patients often have compromised health with a poor quality of life. Renal transplantation offers a viable treatment option for those inborn errors of metabolism characterized by primary renal damage caused by dysfunction of a mutated protein, as in cystinuria. In this case, the indication to renal transplantation makes it possible to overcome the specific enzyme defect. However this option remains valid even when the genetic defect is expressed systemically and renal involvement is just one of the clinical manifestations of the disease, as in Anderson-Fabry disease, cystinosis, hereditary amyloidosis and primary hyperoxaluria. In these conditions, renal transplantation is combined with the liver (primary hyperoxaluria) or cardiac transplant (familial amyloidosis) improving the quality and life expectancy of patients.

Importance of vascular calcification in kidney transplant recipients.

BACKGROUND: Kidney transplantation is the treatment of choice for chronic kidney disease (CKD), but in kidney transplant recipients (KTRs) cardiovascular events are the first cause of death with a functioning graft, ranging from 36 to 55%. The impact of vascular calcification (VC) on morbidity and mortality of KTRs is not appreciated enough nowadays. SUMMARY: This review summarizes 13 important studies on VC in KTRs, comparing the results with CKD and dialysis populations. We focused on VC evaluation and use of coronary artery calcification (CAC) and aorta calcification (AoC) scores. We also evaluated the influence of traditional and non-traditional progression risk factors. KEY MESSAGES: VC strongly predicts cardiovascular events and all-cause mortality in KTRs. VC assessment is important in KTRs and based essentially on multislice computed tomography or electron beam computed tomography recognition of lesions. Quantitative measurement of CAC and AoC scores is essential for a correct definition of the calcium burden before and after kidney transplant. Progression of CAC slows down but does not halt after kidney transplant. A variable association of both traditional and non-traditional risk factors is shown. There is a strong association between baseline CAC score and CAC progression. A significant improvement in secondary hyperparathyroidism after transplantation favorably affects the progression of CAC. Low 25(OH)D3 levels are an independent determinant of CAC progression. Diabetes is a risk factor for the presence of CAC in KTRs, but has not been independently associated with CAC progression. The data published on the use of immunosuppressive drugs as progression factors are few and inconclusive.

The impact of apoptosis and inflammation gene polymorphisms on transplanted kidney function.

BACKGROUND: The progressive deterioration of kidney allograft function leads in most cases to transplant failure. Polymorphisms in genes encoding for inflammatory and apoptosis molecules may be one possible explanation for interindividual differences in kidney transplant outcomes. The objective of our work was to identify the possible effect of interleukin 6 (IL-6), transforming growth factor beta 1 (TGFB1), and Fas on graft function. MATERIAL AND METHODS: A case-control study was carried out to assess potential associations between polymorphisms in inflammation- and apoptosis-related genes and the risk for chronic impairment of kidney graft function. The study included 376 cadaveric kidney recipients, 256 of them with stable graft function and 120 who experienced renal deterioration during the follow-up period of 2.6 ± 1.4 years. Genotyping of IL-6/G-174C, TGFB1/L10P, TGFB1/R25P, and Fas/G-670A polymorphisms was performed by PCR-RFLP and direct sequencing. RESULTS: Considering the single IL-6, TGFB1, and Fas polymorphisms, we found similar allelic and genotype frequencies between the 2 groups. To test the hypothesis of mutual effects of polymorphisms, multiple logistic regression was performed incorporating data for all the possible dual genotypic associations. The association of IL-6 high producer and Fas low producer genotype resulted in a protective effect against graft dysfunction (OR=0.79; 95% C.I.=0.72-0.86). CONCLUSIONS: This study did not find significant associations of apoptosis and inflammation gene polymorphisms with transplanted kidney function in Italian renal transplant recipients. However, our data seem to indicate that the carriage of IL-6 high producer/Fas low producer genotype has a protective effect against graft function loss.

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.