Protected: A case of acute kidney injury due to ethylene glycol intoxication


In this article we describe a case of acute kidney injury caused by ethylene glycol intoxication which partially reversed after temporary hemodialysis treatment. The diagnosis was obtained after the patient’s clinical history and the finding of ethylene glycol in the blood, numerous intratubular crystals at renal biopsy, and the presence of large amounts of atypical – spindle-like and needle-like – calcium oxalate crystals in the urinary sediment.

Keywords: Ethylene glycol, acute kidney injury, urinary sediment, calcium oxalate crystals

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Protected: Combined extracorporeal CO2 removal and renal replacement therapy in a pregnant patient with COVID-19: a case report


Background. Pregnant women are at high risk of Coronavirus disease 2019 (COVID-19) complications, including acute respiratory distress syndrome. Currently, one of the cornerstones in the treatment of this condition is lung-protective ventilation (LPV) with low tidal volumes. However, the occurrence of hypercapnia may limit this ventilatory strategy. So, different extracorporeal CO2 removal (ECCO2R) procedures have been developed. ECCO2R comprises a variety of techniques, including low-flow and high-flow systems, that may be performed with dedicated devices or combined with continuous renal replacement therapy (CRRT).
Case description. Here, we report a unique case of a pregnant patient affected by COVID-19 who required extracorporeal support for multiorgan failure. While on LPV, because of the concomitant hypercapnia and acute kidney injury, the patient was treated with an ECCO2R membrane inserted in series after a hemofilter in a CRRT platform. This combined treatment reducing hypercapnia allowed LPV maintenance at the same time while providing kidney replacement and ensuring maternal and fetal hemodynamic stability. Adverse effects consisted of minor bleeding episodes due to the anticoagulation required to maintain the extracorporeal circuit patency. The patient’s pulmonary and kidney function progressively recovered, permitting the withdrawal of any extracorporeal treatment. At the 25th gestational week, the patient underwent spontaneous premature vaginal delivery because of placental abruption. She gave birth to an 800-gram female baby, who three days later died because of multiorgan failure related to extreme prematurity.
Conclusions. This case supports using ECCO2R-CRRT combined treatment as a suitable approach in the management of complex conditions, such as pregnancy, even in the case of severe COVID-19.

Keywords: pregnancy, COVID-19, lung-protective ventilation, hypercapnia, CO2 removal, acute kidney injury, continuous renal replacement therapy

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When a rear-end collision turns out to be a revelation: a case of IgG4 related kidney desease


IgG4 related renal disease represents a frequent manifestation of the wider IgG4 related disease, a fibroinflammatory disorder with a not fully understood etiology that affects several organs. Through the clinical case presented, we will focus attention on this pathology and on the diagnostic difficulties that may arise, and on the investigations necessary for the diagnosis. Finally, the main therapeutic options will be discussed.

Keywords: IgG4 related disease, IgG4 related kidney disease, fibroinflammatory disorders

Sorry, this entry is only available in Italian.


La malattia IgG4 relata (IgG4-RD) è un disordine clinico multi sistemico a carattere fibro-infiammatorio caratterizzato da: flebiti ostruttive, fibrosi retroperitoneale, lesioni tumor-like multiorgano ed infiltrato linfoplasmacellulare ricco di IgG4 spesso associati ad elevati livelli sierici di tali immunoglobuline [1]. La prima descrizione di questa condizione patologica avvenne nel 1961 quando Sarles et al. descrissero una forma di pancreatite in cui coesistevano un incremento delle IgG4 sieriche e la presenza di ipergammaglobulinemia [2].

Negli anni successivi il coinvolgimento delle IgG4 nell’eziopatogenesi di numerose condizioni cliniche è diventato sempre più evidente [3, 4], tanto che, a partire della prima decade degli anni duemila, è emersa in modo certo la correlazione tra questa sottoclasse di immunoglobuline e molteplici patologie dapprima considerate indipendenti (come sindrome di Mikulicz, tiroidite di Riedel, fibrosi mediastiniche, malattia di Ormond, pancreatite autoimmune di tipo I e colangite sclerosante) che, pertanto, sono state ridefinite come manifestazioni d’organo della IgG4 RD [59]. 

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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.

Keywords: granulomatosis with polyangiitis, ANCA-associated vasculitis, IgA nephropathy and granulomatosis with polyangiitis-overlap, rituximab

Sorry, this entry is only available in Italian.


La nefropatia a depositi mesangiali da IgA (IgAN) e la glomerulonefrite ANCA-associata sono nefropatie che solo raramente si presentano in concomitanza. A causa dell’esiguità dei dati attualmente disponibili in letteratura, la patogenesi, il trattamento e la prognosi di queste due malattie, presenti simultaneamente, non sono ad oggi ben definiti. La prevalenza di tale overlap è compresa tra lo 0,2% ed il 2% [14]. L’IgAN è la più comune glomerulopatia primitiva [5] con una prevalenza, calcolata sulla base della diagnosi istologica su biopsie renali, compresa tra il 3% ed il 16% [6, 7]. È interessante segnalare che uno studio autoptico su reni normali ha evidenziato come circa il 4,8% dei glomeruli sottoposti ad analisi istologica presentava depositi mesangiali ad IgA in assenza di storia di nefropatia nota [8]. Istologicamente la nefropatia ad IgA è caratterizzata da depositi mesangiali di IgA a cui possono essere associate IgG o IgM [911]. La glomerulonefrite ANCA-associata è caratterizzata da proliferazione extracapillare pauci-immune [12, 13]. A seguire riportiamo un caso di overlap di entrambe le forme istologiche con una successiva revisione dei dati disponibili in letteratura, confrontando i differenti quadri clinici, gli approcci terapeutici e le prognosi. 

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High-flow fistula: a problem not easy to handle


High-output cardiac failure is a well-known phenomenon of high-flow fistula in hemodialysis patients. The definition of “high flow” is varied and almost always connected to proximal arteriovenous fistulas (AVF).
High flow access is a condition in which hemodynamics is affected by a greater rate of blood flow required for hemodialysis and this can compromise circulatory dynamics, particularly in the elderly in the context of pre-existing heart disease.
High access flow is associated with complications like high output heart failure, pulmonary hypertension, massively dilated fistula, central vein stenosis, dialysis associated steal syndrome or distal hypoperfusion ischemic syndrome.
Although there is no single agreement about the values of AVF flow volume, nor about the definition of high‐flow AVF, there is no doubt that AVF flow should be considered too high if signs of cardiac failure develop.
The exact threshold for defining high flow access has not been validated or universally accepted by the guidelines, although a vascular access flow rate of 1 to 1.5 l/min has been suggested.
Moreover, even lower values may be indicative of relatively excessive blood flow, depending on the patient’s condition.
The pathophysiology contributing to this disease process is the shunting of blood from the high-resistance arterial system into the lower resistance venous system, increasing the venous return up to cardiac failure.
Accurate and well-timed diagnosis of high flow arteriovenous hemodynamics by monitoring of blood flow of fistula and cardiac function is required in order to stop this process prior to cardiac failure.
We present two cases of patients with high flow arteriovenous fistula with a review of the literature.

Keywords: Blood flow, cardiac failure, vascular access, hemodialysis

Sorry, this entry is only available in Italian.


Una insufficienza cardiaca ad alta gittata può essere la conseguenza di svariate condizioni patologiche quali anemia, sepsi, ipertiroidismo, beri beri. Un’altra causa nota, in alcuni pazienti emodializzati, può essere la presenza di una fistola arterovenosa (FAV) in relazione al notevole aumento del flusso dell’accesso vascolare con conseguente eccessivo carico di lavoro cardiaco, insufficienza cardiaca congestizia ed ipertensione polmonare [13].

Come è ben noto, la sindrome uremica è associata ad un aumento della morbilità e mortalità cardiovascolare; il rischio di morte in un paziente emodializzato con insufficienza cardiaca è del 33%, 46% e 57% rispettivamente a 12, 24 e 36 mesi dopo l’inizio della terapia dialitica secondo i dati del Renal Data System statunitense [4]. Un’insufficienza cardiaca congestizia può manifestarsi nel 25-50% dei pazienti emodializzati, in particolare nei pazienti con “fistola artero-venosa ad alto flusso”. 

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Possible vaccine-induced immune thrombotic thrombocytopenia in a patient with diabetes and chronic kidney disease or random association?


We report the case of a 75-year-old man who developed acute myocardial infarction 12 hours after the first dose of ChAdOx1 nCov-19 vaccine. The event was associated with a transient decrease of platelet count and the detection of anti-PF4 antibodies approximately 45 days after the event.
Vaccine-induced thrombotic thrombocytopenia (VITT) is characterized by the onset of venous or arterial thrombosis in temporal relationship to the administration of anti-Sars-Cov-2 viral vector vaccines (ChAdOx1 nCov-19 and Ad26.COV2.S), thrombocytopenia and the production of anti-PF4 antibodies. It occurs mainly at a young age, even if the median age is 54 years; it is often associated with thrombosis in atypical sites, such as the cerebral sinus.
Our reported case does not present all the diagnostic criteria of VITT. However, the close temporal relationship between ChAdOx1 nCov-19 vaccine administration, thrombosis, and concomitant anti-PF4 antibodies positivity makes the case suggestive of a possible slight form of VITT.

Keywords: Sars-CoV-2, chronic kidney disease, vaccine, ChAdOx1 nCov-19, vaccine-induced immune thrombotic thrombocytopenia, VITT

Sorry, this entry is only available in Italian.


Il virus Sars-CoV-2 è responsabile di una pandemia senza precedenti a livello mondiale, che ha causato quasi 300 milioni di infezioni, più 5 milioni di decessi [1] e gravi ripercussioni dal punto di vista sociale ed economico. Grazie a uno sforzo senza precedenti, solo dopo nove mesi dall’inizio della pandemia, sono stati resi disponibili diversi vaccini contro il virus Sars-CoV-2. In particolare, due di questi (Pfizer mRNABNT162b2 e Moderna mRNA-1273) utilizzano una tecnologia innovativa, basata su molecole di RNA messaggero che contengono le istruzioni per produrre temporaneamente la proteina “spike” del Sars-CoV-2.

Al contrario, altri due vaccini disponibili in Italia, ChAdOx1 nCov-19 (Astazeneca) e Ad26.COV2.S (Johnson & Johnson) sono basati su una tecnologia più tradizionale, che utilizza un vettore virale ad adenovirus per introdurre la proteina “spike” del Sars-CoV-2 nell’organismo e indurre la risposta anticorpale.

Nel febbraio 2021, dopo alcuni mesi dall’inizio della campagna vaccinale, sono stati segnalati i primi casi di trombosi atipiche, in particolare a livello del seno venoso cerebrale, insorte dopo 5-30 giorni dalla somministrazione di vaccini anti-Sars-CoV-2 a vettore virale [24]. I casi di trombosi si associavano alla comparsa di trombocitopenia e presenza di anticorpi anti-fattore 4 delle piastrine (anti-PF4); la nuova sindrome è stata denominata trombocitopenia trombotica immune indotta da vaccino (VITT) [2]. 

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Anti-angiogenic drugs and hypertension: from multidisciplinary collaboration to greater care


Anti-angiogenic drugs are widely used in cancer therapy. Their main targets of action are the vascular endothelial growth factor (VEGF) and its receptors (VEGF-R). Anti-angiogenic drugs are used to reduce the growth of the tumor and its metastases by acting on the phenomenon of tumor neo-angiogenesis. However, they are known for their side effects such as hypertension, acute kidney injury (AKI), and congestive heart failure.
Methods: retrospective study conducted on 57 consecutive patients known for ovarian cancer. Patients treated with Bevacizumab, as first-line, relapse, or maintenance treatment (2015-2022).
Results: according to FIGO staging, 98.2% (56 out of 57) of the patients in the study had third degree disease (G3). 49% of patients developed hypertension after starting Bevacizumab therapy (82% grade 2 according to CTCAE v.5). 89% of hypertensive patients started treatment and its management was multidisciplinary with nephrological consultation in 68% of cases. Only 3 out of 57 women discontinued treatment due to hypertension, and in only one of them it was not possible to restart it.
Conclusions: the evaluation of the patient by a multidisciplinary team (gynecologist and nephrologist) is essential to minimize the morbidity and mortality of patients, and to avoid the interruption of antineoplastic treatment.

Keywords: anti-angiogenic drugs, kidney injury, proteinuria, hypertension, ovarian cancer, multidisciplinary team

Sorry, this entry is only available in Italian.


I farmaci anti-angiogenici hanno lo scopo di prevenire e/o rallentare la crescita tumorale. Questi possono causare diversi effetti collaterali, tra i quali emerge l’ipertensione, definita nella Common Terminology Criteria for Adverse Events (CTCAE) come pressione arteriosa (PA) >140/90 mmHg o un aumento della pressione arteriosa diastolica (PAD) >20 mmHg rispetto al basale.

In questo lavoro, che vuole essere un percorso in questo complesso ambito onconefrologico, presentiamo dapprima il caso di una donna di 74 anni affetta da tumore dell’ovaio trattata con Bevacizumab che, a causa dello sviluppo di ipertensione, ha dovuto interrompere il trattamento, ripreso poi grazie alla valutazione della paziente da parte di un’equipe multidisciplinare (ginecologo e nefrologo). Vengono quindi riportati i risultati di uno studio retrospettivo su 57 pazienti consecutive trattate con Bevacizumab con lo scopo di verificare se e come la collaborazione interdisciplinare tra nefrologo e ginecologo fosse efficacie e funzionale: è stata valutata l’incidenza di ipertensione e proteinuria, se fosse stato richiesto consulto specialistico nefrologico e se fosse stato completato il trattamento. 

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Pediatric Minimal Change Disease and AKI following the Pfizer-BioNTech COVID-19 Vaccine: causal or incidental correlation?


The global coronavirus 2019 (COVID-19) pandemic required vaccination even in children to reduce infection.
We report on the development of acute kidney injury (AKI) and minimal change disease (MCD) nephrotic syndrome (NS), shortly after the first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech).
A 12-year-old previously healthy boy was referred to our hospital with complaints of peripheral edema and nephrotic range proteinuria.
Nine days earlier he had received his first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech).
Seven days after injection, he developed leg edema, which rapidly progressed to anasarca with significant weight gain. On admission, serum creatinine was 1.3 mg/dL and 24-hour urinary protein excretion was 4 grams with fluid overload.
As kidney function continued to decline over the next days, empirical steroid treatment and renal replacement therapy with ultrafiltration were started and kidney biopsy was performed.
Seven days after steroid therapy, kidney function began to improve, gradually returning to normal.
The association of MCD, nephrotic syndrome and AKI hasn’t been previously described following the Pfizer-BioNTech COVID-19 vaccine in pediatric population, but this triad has been reported in adults.
We need further similar case reports to establish the real incidence of this possible vaccine side effect.

Keywords: nephrotic syndrome, Acute Kidney Injury (AKI), SARS-CoV-2 vaccines, pediatric population


The global coronavirus 2019 (COVID-19) pandemic has shown an evolution in morbidity and mortality in the last years.
The advent of the vaccine has made it possible to modify the natural history of the disease as well as its transmission globally.
SARS-CoV-2 vaccines has good effectiveness with limited side effects and low rate of adverse event, among adults and pediatric population.
We describe a case on the development of acute kidney injury (AKI) with MCD nephrotic syndrome, shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech).


Case report

A 12-year-old previously healthy boy was referred to our hospital with complaints of peripheral edema and nephrotic range proteinuria.
He received his first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech) nine days before.
The first side effect was pain in the injection area.
He developed headache resistant to paracetamol seven days after injection, legs edema, which progressed to anasarca with significant weight gain from 65 kg to 76 kg.
On admission, blood pressure was 140/70 mmHg, and heart rate 80 beats/min.
Physical examination showed facial, upper and lower limbs and extremities edema, and evidence of ascites on POC ultrasound.
Previous laboratory test (13 months earlier) showed creatinine 0.78 mg/dL and negative protein urine test.
The patient and his family denied the use of non-steroidal anti-inflammatories and any other drugs-induced nephrotoxicity, before or after the vaccination.
Laboratory tests performed showed AKI with serum creatinine 1.3 mg/dL, serum urea nitrogen 85 mg/dL, albumin 2.2 g/dl, normal c3 and c4, negative ANA and ANCA testing. Molecular PCR test swab for SARS -CoV-2 was negative. Serology testing for HBV, HIV, HCV and SARS-CoV-2 was negative, but serology qualitative testing for SARS-CoV-2 for spike protein subunits S1 and S2 was positive for IgG. Urinalysis revealed proteins 185 mg/dL, β2 microglobulin 45 μg/L, and urinary sediment showed 10-15 red blood cells dysmorphic. Chest X-Ray was negative. The patient was admitted and intravenous infusion of human albumin (0,5 g/kg) was immediately administered; 24-hour urinary collection revealed proteinuria of 86 mg/m2/h.
In four days after the admission kidney function continued to decline: serum creatinine increased to 4 mg/dL and the patient developed fluid overload with dyspnea and oliguria resisted to furosemide, spironolakton and thiazide-diuretic. On day six renal replacement therapy (RRT) with ultrafiltration was started and kidney biopsy was performed. Light microscopy examination showed 11 glomeruli characterized exclusively by mild mesangial hypercellularity, tubular obstruction with cytoplasmic degeneration, and the presence of flaking elements in the lumen. Immunofluorescence was negative. Electron microscopy showed GBM with aspects of rehash, stretches of capillary wall with tortuous course, and aspects of collapse, swelling and extensive fusion of the pedicels and no electron-dense deposits. High-dose pulse intravenous steroids with 1 g of methylprednisolone (MEP) was given daily for three days, followed by oral PDN 60 mg daily. Seven days after the beginning of steroid therapy, kidney function began to improve with creatinine 1.82 mg/dL, albumin 3.2 g/dL, 24-hour urine collection for protein of 58 mg/m2/h, urine output increased, and renal replacement therapy was stopped after 5 sessions.
The patient was discharged in 15 days with a 10 kg weight loss, serum creatine 0.8 mg/dL, plasma albumin 3.1 g/dL, urinalysis showed no further proteinuria and protein-creatine ratio was 0.5. His blood pressure was well controlled. The patient continued oral PDN 60 mg daily for 4 weeks, and then taped down to 40 mg for 4 weeks. After 4 and 8 weeks of outpatient steroid therapy and on discontinuation at 12 weeks complete remission of nephrotic syndrome was maintained. Parents did not consent to the second vaccine dose.



Nephrotic syndrome is the most frequent glomerular disease in childhood. It is characterized by leakage of a large amount of proteins through the glomerular filter, leading to hypoalbuminemia, hyperlipidemia, decreased oncotic pressure, and edema. In overt forms, proteinuria exceeds 50 mg/kg/day or 40 mg/m2/h, and the urine protein/creatinine ratio is > 2 mg/mg [1].
Histological examination renal biopsy shows minimal change on light microscopy with negative immunofluorescence and unspecific electronic response. Whether MCD and focal segmental glomerulosclerosis are different entities or two extremes of the same disease is currently debated [2]. Anyway, data collected in past decades on the pathogenesis of NS show an immunologic dysfunction of both T and B cells, and also suggest podocyte’s direct role in activating cell pathways that cause proteinuria. Trigger events, such as viral infection, vaccination or allergens stimulate antigen-presenting cells (APCs) and activate T cells to induce cytokine release and B-cells to produce immunoglobulins. Several T-cell alterations have been described in NS: first of all, an imbalance between Th2 and Th1 Cell with an increase in production of Th2-specific interleukin 13 (IL-13), the reduction in frequency and function of T cells (T-regs) and the increase of Th17 cell activities. B cell pathway alterations have also been described, such as an increase in soluble form of CD23 (immunoglobulin-E receptor), a correlation between memory B cell repopulation and relapse after anti-CD20 therapy and circulating anti-CD40 autoantibodies. Moreover, the existence of other circulating permeability mediators (i.e. hemopexin, the soluble form of the urokinase-type plasminogen activator receptor, the cardiotrophin-like cytokine factor 1, and a hyposialylated form of the angiopoietin-like-4 glycoprotein) produced by abnormal T cell can directly affect podocytes and glomerular permeability barrier. In addition, podocytes can recognize microbial antigens by toll-like receptor (TLRs) and produce proteins leading to T-cells activation [3].
Throughout the literature, there are a lot of case reports that suggest a link between glomerular and autoimmune disease to immunization. MCD has been described after vaccinations against diseases such as meningitis C conjugate, influenza, hepatitis B, pneumococcus, diphtheria, tetanus, whooping cough, and measles. Moreover, some studies refer an increasing risk of relapsing subsequently vaccinations [410].
Additionally, evidence of temporal association between SARS-CoV-2 vaccinations and glomerular disease, including MCD with AKI and IgA nephropathy, is emerging in adults and in pediatric population [1113].
Nakawaza E. et al report the first case of nephrotic syndrome subsequent to BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A previously healthy 15-year-old Japanese boy presented proteinuria, hypertension, eyelid, and lower extremities edema 4 days after the first injection of vaccine. Evaluation for secondary glomerular disease was negative. Twenty-one days after vaccination, 60 mg of oral daily prednisolone was started. He achieved complete remission in 12 days without complications such as hypertension or acute kidney injury. Biopsy was not performed [14].
Pondtip J. et al describe in a healthy 14-year-old boy a nephrotic syndrome 5 days after the first injection of the SARS-CoV-2 BNT162b2 evolving in AKI (anuria and creatinine of 9 mg/dL) at day ten from vaccination. Secondary causes of glomerular disease were excluded. The patient received three daily doses of pulse methylprednisolone followed by oral prednisolone, 60 mg daily. He also received hemodialysis for 3 weeks. Light microscopy showed eighteen unremarkable glomeruli and diffuse tubular injury and interstitial inflammatory cell infiltration were noted. Immunofluorescence staining was negative. Electron microscopy showed diffuse foot process effacement, consistent with MCD [15].
Pella E. et al reported a case of an 18-year-old male adolescent who developed nephrotic syndrome eleven days after the first Pfizer-BioNTech injection. Diagnostic kidney biopsy showed no significant glomerular or tubular abnormalities in light microscopy with negative immunofluorescence and electronic picture referred to MCD. Treatment with methylprednisolone 48 mg daily was initiated and then tapered and leading to a complete remission six weeks later [16].
Our patient represents the second pediatric case reported of MCD subsequent to Pfizer-BioNTech vaccination. Differently we performed renal biopsy, despite not being recommended, because of the rapid decline of renal function and the need of hemodiafiltration. In addition to electronic picture of foot process effacement, on light microscopy we also found tubular obstruction and the presence of flaking element in lumen. We speculate that tubular involvement could be the cause of AKI.
All those cases showed typical clinical presentation characterized by vaccination, nephrotic syndrome, and AKI. In this report we described the first pediatric patient who experienced the same triad presented in adults; tubular edema with luminal obstruction and absence of significant glomerular change explained AKI evolution.
After vaccination, the vaccine’s antigen is presented to T-cells by dendritic cells resulting in activation of antigen-specific effector T cells, that peak between 7 and 14 days after vaccination.
It is not currently possible to establish whether the occurrence of AKI and MCD with nephrotic- syndrome is triggered by vaccination or completely random.
Vaccine-disease correlation is an exclusive diagnosis. Diagnosis is based on timing (7-14 days after vaccination) and exclusion of other triggers in the absence of conclusive means demonstrating a causal link.
We suggest that all patients who develop AKI and nephrotic syndrome following COVID-19 vaccine administration undergo renal biopsy in the immediately next days.
We suggest the use of steroids intravenously and subsequently per os with subsequent tapering down.
This therapeutic approach has proved to be useful as well as decisive in the case of our patient.
We await any other reports of similar cases to establish the true incidence of this possible important side effect of the vaccine.



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Role of physical exercise in an overlooked nutcracker syndrome occurred in a patient with diaphragmatic relaxation: a case report


Background: Nutcracker syndrome (NCS) is caused by extrinsic compression of the left renal vein (LRV), usually between the abdominal aorta (AA) and superior mesenteric artery (SMA). This rare disease includes symptoms such as hematuria, left flank pain or abdominal pain, varicocele in males, proteinuria, anemia, gynecological symptoms (dyspareunia, dysmenorrhea).
Case report: We report the case of a 48-year-old female patient, who experienced left abdominal colic after intensive physical exercise, finally resulting in a diagnosis of NCS. This abdominal pain was disabling for daily activities, it was controlled by analgesic drugs and led to hospital admissions. In-depth examinations were recommended to the patient to investigate the etiology of these attacks. A bad rotated and ectopic left kidney, which was located superior to the spleen, at the level of the left hemithorax base, was found due to the presence of a diaphragmatic relaxation in the posterior area, which caused an upward displacement of the kidney, part of the colon and omental fat. Because of the presence of a compression of the LRV by the SMA and the AA, the nephrologist diagnosed a NCS, presenting with abdominal pain following physical exercise, proteinuria and dysmenorrhea. Conservative treatment was chosen for the patient.
Conclusions: The patient was recommended to engage in a moderate and regular physical activity, avoiding acute and intense exercise: hypopressive abdominal gymnastics was suggested. The role of physical exercise in triggering painful attacks and its role in rehabilitation to prevent the same attacks was crucial for the patient.

Keywords: physical exercise, nutcracker syndrome, abdominal pain, diaphragmatic relaxation


Left renal vein entrapment syndrome, or nutcracker syndrome (NCS), is caused by extrinsic compression of the left renal vein (LRV), usually between the abdominal aorta (AA) and superior mesenteric artery (SMA) (anterior NCS), or, rarely, between AA and spinal column (posterior NCS) [1]. It is a rare disease with an unknown prevalence, occurring more frequently in females in their thirties and forties [2, 3]. Renal veins are large vessels anterior to the renal arteries, which flow into the inferior vena cava almost at right angles. The LRV is three times longer than the contralateral and it is posterior to the lienal vein and body of the pancreas. The vessel crosses the anterior surface of the AA, just inferior to the origin of the SMA. The left genital vein enters the LRV from below, while the left adrenal vein flows into it approximately at the level of the midline. A study enrolling 112 patients reported common NCS typical symptoms including hematuria (78.57%), left flank pain (38.39%), varicocele in males (35.71%), proteinuria (30.36%), and anemia (13.39%) [4]. Abdominal pain, gynecological symptoms (dyspareunia, dysmenorrhea), orthostatic hypotension, fatigue and infertility are also been described [5, 6]. Autonomic dysfunction symptoms such as hypotension, syncope, nausea and weight loss may occur [7]. Diagnosis must be reached by exclusion and by a stepwise approach including anamnesis, physical examination, instrumental methods such as doppler ultrasonography (DUS), computed tomography angiography (CTA), magnetic resonance imaging (MRI), venography, and intravascular ultrasound (IVUS) [3]. Table I shows clinical conditions to be considered in differential diagnosis with NCS.

Clinical conditions for differential diagnosis with NCS [3]
Pancreatic/retroperitoneal/renal tumor  



Para-aortic lymphadenopathy



Abdominal aortic aneurysm Left renal ptosis
Overarching testicular artery Lordosis
Fibrolymphatic tissue between the aorta and SMA Reduced retroperitoneal/mesenteric fat
High disposition of the LRV Gravid uterus compressing the renal vasculature
Table I: clinical conditions to be considered in differential diagnosis with nutcracker syndrome [3]. NCS: Nutcracker Syndrome; SMA: superior mesenteric artery; LRV: left renal vein

About imaging, a reno-caval pullback gradient ≥ 3 mmHg, a maximum flow velocity five times higher than normal values in the LRV passing the SMA compared to the renal hilum, or an angle less than 45 degrees between the AA and SMA on CTA or MRI are considered as diagnostic criteria [8]. Conservative treatment, endovascular treatment or open surgery approach depend on NCS symptoms and their severity. Physical activity is recommended by Health Authorities leading to a real health benefit for the body and regular exercise can mediate a protective effect, thanks to the stimulation of anti-inflammatory molecules and the reduction of visceral fat. Increased oxidative stress, weight and fat gain, low-grade systemic inflammation and risk of developing diseases such as type 2 diabetes, cardiovascular disease and some cancers are associated with physical inactivity [9]. The role of physical activity is undoubtedly positive in physiological and pathological conditions, but certainly the type of exercise and the workload should be personalized in light of the characteristics of the subject and his anamnesis. We report the case of a female patient, who experienced left abdominal colic after intensive physical exercise, finally resulting in a diagnosis of an anterior NCS (Figure 1).

CT shows the compression of the left renal vein
Figure 1: CT shows the compression of the left renal vein between the aorta and superior mesenteric artery in a patient affected by nutcracker syndrome. LRV: left renal vein, AA: abdominal aorta, SMA: superior mesenteric artery, IVC: inferior vena cava.


Case report

A 48-year-old woman, apparently in good health, suffered from left abdominal colic after practicing several hours of strenuous physical exercise. The woman practiced bodyweight aerobic exercises, gym exercises, and abdominal flexion and extension exercises several times a week. This abdominal pain was disabling for daily activities and was controlled by statim administration of analgesic drugs (e.g. intramuscular ketorolac) and also led to hospital admissions. The patient was within the normal weight range (BMI 20.74, normal range: 18.5-24,99) and suffered from pharmacologically controlled mild hypertension for about five years. In addition, the patient was suffering from anxious depressive syndrome and dysmenorrhea. Her therapy involved the use of nebivolol, olmesartan cilexetil and estradiol/progesterone. Routine blood chemistry tests had been performed multiple times and were normal. However, the latest analyses showed marked proteinuria (2 g/day) and an Escherichia Coli infection. Then antibiotic therapy was started, which led to the eradication of the infection; unfortunately, the episodes of abdominal colic increased their frequency. At this point, the patient underwent a urological examination, which suggested the possibility that a urinary calculosis could trigger the pain attacks, although not identifiable by ultrasound exams. The renal ultrasound, on the other hand, showed the ectopy of the left kidney displaced inferomedially about 1-2 cm superior to the umbilical scar. A therapy based on hydrochlorothiazide and food supplements based on Potassium Citrate, Magnesium, and Zinc was prescribed to stem the clinical picture, and a specific diet low in calcium was started. After two months since these dietary and therapeutic regimens have started, the frequency and intensity of abdominal colic remained unchanged. At this point, in-depth examinations were recommended to the patient to investigate the etiology of these attacks. First, the patient performed a chest and abdomen CT scan, which showed an asymmetry of the pulmonary fields due to a suspected left posterolateral hernia (Bochdalek’s hernia) with evidence of intestinal loops (Figure 2); in addition, there was a dislocation of both the spleen and the left kidney, which appeared to be badly rotated. The CT urography also showed a badly rotated and ectopic left kidney, which was located superior to the spleen, at the level of the left hemithorax base, due to the presence of a diaphragmatic relaxation in the posterior area which caused an upward displacement of the kidney, part of the colon and omental fat. Then the patient underwent a CT angiography which showed the presence of a compression of the LRV, due to a compression exerted by the SMA and the AA, reporting an angle of 30 degrees (normal value >45 degrees). The MRI also confirmed this anatomical picture. The nephrologist diagnosed a NCS, presenting with abdominal pain following physical exercise, proteinuria and dysmenorrhea. Conservative treatment was chosen for the patient, considering the syndromic picture and age. The patient was recommended to engage in a moderate and regular physical activity, avoiding acute and intense exercises; a dietary regimen was established aimed at the formation of an adipose panniculus that would restore normal anatomical relationships. The patient is continuing to be followed up periodically by the nephrologist, to ascertain the evolution of the case both from a clinical and laboratory point of view (at a six-month follow-up, the proteinuria was 0.4 g/day).

CT scan showed an asymmetry of the pulmonary fields
Figure 2: CT scan showed an asymmetry of the pulmonary fields due to a suspected left posterolateral hernia (Bochdalek’s hernia) with evidence of intestinal loops.



This article reports the case of a patient who didn’t show any specific multiple symptoms so that the diagnosis was delayed despite the patient had been followed several times from a clinical point of view. NCS was eventually diagnosed, a rare disease whose diagnosis is often unknown due to the low frequency of cases. Furthermore, the syndrome occurred in an equally particular and atypical case, given that the patient’s left kidney was ectopic and the topographical anatomy of the left abdomen was disturbed due to the presence of an infrequent anatomical defect of the diaphragm and suspected herniation of the viscera.

The diagnostic process was long and difficult also due to the absence of typical symptoms, such as hematuria [1]. The patient also was thin with a weight of only 62 kg and belonged to low limit of the normal BMI range. Among conservative treatments weight gain was recommended, because an increase in retroperitoneal adipose tissue has demonstrated to resolve NCS symptoms in 30% of cases by a reduction in LRV tension [10]. The abdominal colic was triggered by intense physical exercise, especially as a result of exercises that strained the abdominal muscles and increased intra-abdominal pressure. It is thanks to the physical exercise practiced by the patient that the painful symptoms were triggered, which prompted the patient to investigate the cause and the diagnostic process to be concluded. Some exercises increase intra-abdominal pressure such as abdominal exercises (e.g. sit-ups, curl-ups, crunches, double leg lifts, exercises on machines), weighted rotation exercises (e.g. seated medicine ball twists, suspended torso rotations, rotating planks) and planks on toes and its variations (e.g. planks with feet on ball or in suspension straps, planks on hands and toes and moving to elbows). In the scientific literature, it is known that intra-abdominal pressure associated with exercise can have a negative effect on pelvic floor muscle, even if the damage varies among activities and among women [11]. Repetitive, high-impact sports seem to expose females to the highest risk for urinary incontinence [12]. In a comparative in vivo study treadmill exercise determined an increase in intra-abdominal pressure causing inhibition of venous return by compression of the large abdominal veins [13]. On the other hand, it has always been known that physical exercise benefits patients with chronic renal disease by improving blood pressure and their maximal oxygen consumption level [14]. As also presented in our case, hypertension also appears among the symptoms of NCS. This symptom was reported in the case of NCS in a young Japanese woman by Hosotani et al. and in a 22-year-old Chinese man who showed left flank pain after activity [15, 16]. Our patient was used to performing intense physical exercise; therefore, it would be desirable not to upset her habits. To make sure that physical activity couldn’t trigger any attacks of abdominal pain, she should perform exercises at a moderate intensity, avoiding exertion. The most suitable training method for the patient could be hypopressive abdominal gymnastics (HAG), a global and systemic postural technique, which is becoming very well-known [17]. This training technique relaxes the diaphragm, reduces intra-abdominal pressure, and is already used for the treatment of abdominal diastasis in the postpartum period, urinary incontinence, pelvic prolapse and chronic low back pain. Caufriez, in the 80s, developed a training consisting of 33 hypopressive exercises to be performed in different postures (sitting, kneeling, quadrupedal and supine). Each exercise involved a hypopressive maneuver including a prolonged exhalation followed by apnea. During these exercises an intense and voluntary contraction of the inspiratory accessory muscles, such as the serratus anterior, the external intercostal, the scalene and the sternocleidomastoid, was performed, keeping the glottis closed (diaphragmatic suction). HAG produces direct activation of the transverse abdominal muscle, leading to a strengthening of the abdominal wall and stabilization of the spine [18]. The lumbar spine and hamstrings become more flexible and body posture reorganizes [19]. Clearly, in our case a conservative approach was chosen, but the patient needs a close follow-up that allows to monitor her conditions from a clinical and hemodynamic point of view.



The described case focuses on the difficulty of diagnosing a rare pathology such as NCS, which can only be recognized by differential diagnosis after excluding the most common causes of abdominal pain. Collateral symptoms must not be overlooked, and the patient’s physiological and pathological history must be taken into consideration. Physical exercise can always be recommended, even in pathological conditions such as in this case; obviously type, duration and intensity of physical exercise should be adapted to the general status of the patient. Furthermore, a balanced diet could also benefit the patient. In our case and in those under conservative treatment it is useful and necessary to carefully monitor the patients to follow the evolution of the pathology.



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PGNMID and anti-CD38 monoclonal antibody: a therapeutic challenge


Monoclonal gammopathy of renal significance (MGRS) designates disorders induced by a monoclonal protein secreted by plasma cells or B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form MGRS.

Until now, no guidelines to decide the best therapeutic approach to manage PGNMID exist, and most patients progress to End Stage Renal Disease (ESRD) without therapy. Recently, daratumumab has showed an acceptable improvement in proteinuria and renal function in patients with PGNMID.

We report the clinical outcome and the histological renal evolution and treatment complication of our patient, who was initially treated with a combination regimen including bortezomib, dexamethasone, and cyclophosphamide and then with anti-CD38 monoclonal antibody-based regimen.

Keywords: monoclonal gammopathy of renal significance, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, histological evaluation, pharmacological therapies, case report


Monoclonal gammopathy of renal significance (MGRS) designates disorders induced by a monoclonal protein secreted by plasma cells or B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. MGRS was defined by the Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012 [1] and is classified by the site of the dominant immunoglobulin deposition or even by the ultrastructural findings on renal biopsy. It is important to mention that while light chains and truncated heavy chains can affect all renal compartments, intact immunoglobulin molecules are limited to the glomerulus [12].

Renal damage due to nephrotoxic monoclonal immunoglobulin (MIg) or its light- or heavy-chain fragments include some disorders, such as cast nephropathy, amyloidosis, MIg deposition diseases, immunotactoid glomerulopathy, proliferative GN with monoclonal Ig deposits, light-chain proximal tubulopathy, and the rare entities of crystal-storing histiocytosis and crystalglobulinemia. C3 glomerulonephritis and Thrombotic Microangiopathy (TMA) due to dysregulation of the alternative complement pathway can be seen as a result of indirect mechanisms induced by immunoglobulins [2].

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of monoclonal gammopathy of renal significance (MGRS) often leading to end-stage kidney disease [3]. In 70% of cases no blood or bone marrow monoclonal immunoglobulins are detected [3].

In PGNMID, deposits are detected in the glomeruli, especially in mesangial and subendothelial space and occasionally in the subepithelial space [4]. In most patients, PGNMID is IgG3-driven, but it can also be IgA-driven or IgM-driven [5].

Plasma cell-derived PGNMID (usually IgG) is treated with bortezomib-based chemotherapy; B-cell-derived PGNMID is usually treated with a rituximab-based regimen [6]. The patients with PGNMID may have plasma cell clones that produce monoclonal proteins, which elicit inflammation. Recently daratumumab showed an acceptable improvement in proteinuria and renal function in patients with PGNMID [7].

Herein we report the clinical outcome and the histological renal evolution and treatment complication of our patient, who was initially treated with a combination regimen including bortezomib, dexamethasone, and cyclophosphamide and then with anti-CD38 monoclonal antibody.


Case report

We report the case of a 66-year-old white man with a history of JAK2 mutation-negative essential thrombocythemia, on cytoreductive therapy with anagrelide, who presented with proteinuria in the nephrotic range. At presentation urinalysis showed 40 RBCs/μL, albuminuria 100 mg/dl and proteinuria 4.3 gr/day. Serum creatinine was 1.8 mg/dL, calcium 8.7 mg/dl, hematuria with 40 RBC, serum immunofixation did not detect any abnormalities and protein electrophoresis showed hypogammaglobulinemia, IgG 508 mg/dl, negative Bence Jones and negative urine immunofixation revealed monoclonal IgA k (87 mg/24 h) and a mild increase in serum kappa free light chain with normal kappa/lambda ratio.

A kidney biopsy was performed (Figure 1) and showed a 30% of fibroepithelial crescent cell, 4% epithelia crescent cell and single fibrinoid necrosis. Immunofluorescence showed positive diffuse staining for IgA (3+), C3 (2+) and k-light chain (3+) involving the basal membrane in intramembranous and subepithelial region and the mesangium, with negative staining for λ-light chain and for heavy chain. The ultrastructural evaluation highlighted subendothelial and mesangial electron dense deposits. Therefore, we reached a diagnosis of proliferative glomerulonephritis with monoclonal IgA-kappa deposits without interstitial fibrosis, with mild tubular atrophy [7].

Figure 1: Renal Biopsy
Figure 1: Renal Biopsy. Photo A: electron microscopy, electron-dense deposits with focally variegated texture (without evidence of well-developed microtubules or fibrils) located in subendothelial area (original magnification ×14,000); photo B: electron microscopy: endocapillary hypercellularity filled by swollen endothelial cell, monocyte and neutrophil granulocyte (original magnification ×1900)

Bone marrow aspiration and biopsy with fluorescence in situ hybridization detected essential thrombocythemia with mild fibrosis MF-1 and presence of 8% κ-restricted plasma cells, considered as monoclonal gammopathy of undetermined significance (MGUS). Whole-body, CT bone scan showed erosive lesions of the temporal bone extended for 3 cm, non-ossifying fibromas (NOF) of the distal epiphysis of the right femur. Consequently, the diagnosis of MRGS was made and chemotherapy with CyBorD regimen (Bortezomib, Dexamethasone and cyclophosphamide) was started. The treatment schedule included 8 cycles of Bortezomib, Dexamethasone and cyclophosphamide with the following doses: cyclophosphamide 350 mg per os on days 1, 8, 15 + bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 15, 22 + dexamethasone 20 mg per os on days 1, 8, 15,22, each of these for 35 days.

Acyclovir, fluconazole and trimethoprim-sulfamethoxazole was added to the therapy as prophylaxis and after 4 weeks trimethoprim-sulfamethoxazole was withheld due to an allergic reaction.

After the first 4 cycles of therapy, a mild renal improvement was achieved. The serum creatinine decreased to 1.4 mg/dl with a partial reduction of proteinuria up to 3100 mg/24h and a reduction of monoclonal IgA k from 87 to 50 mg/24h. After 6 months of chemotherapy, osteolytic lesions on the sphenoid greater wing were detected on CT bone scan. After 8 cycles of CyBorD chemotherapy, at the 12th month of follow up: monoclonal IgA remained constant and under 50 mg/24h in urine immunofixation; serum free kappa light chain concentration was 32.9 mg/l and serum free light chain lambda was 14.7 mg/l (k/λ ratio = 2.2); a non-monoclonal component was detected in protein electrophoresis, while mild deterioration of renal function (cr: 2.3 mg/dl) without reduction of proteinuria was observed.

During the first 12 month of follow up no adverse effects related to the cytotoxic therapy were observed. At this time another evaluation with BMA and CT bone scan was programmed. The bone marrow aspirate and the biopsy were examined with light microscopy, immunohistochemistry, and flow cytometry, showing the presence of 10% κ-restricted plasma cells, considered as MGUS, with mild fibrosis MF-1. No new bone lesions were detected in the CT scan.

Based on radiological and histological findings, associated with progressive renal impairment (an increase of serum creatinine up to 4.1mg/dl with constant proteinuria nearly 4 gr/day), the second line treatment with Daratumumab-Lenalidomide plus Dexamethasone (D-Rd) was scheduled.

D-Rd regimen chemotherapy was started, despite the stable hematologic disease. The Daratumumab regimen consisted in an intravenous (IV) dose of 16 mg/kg once a week for 8 weeks, followed by the same dose once every 2 weeks plus lenalidomide and dexamethasone (for eight additional doses).

After one month of therapy with D-Rd regimen (4° administration) the patient was admitted to our hospital because of a rapidly progressive loss of renal function and nephrotic syndrome. Lower extremities petechiae were found on physical examination, with pitting edema in the lower limbs.

At admission, ultrasound examination evidenced the normal size of the inferior vena cava with a 40% collapsibility index, and mild bilateral pleural effusion; both kidneys had normal size and normal parenchymal thickness, with normal arterial and vein vascularization without hydronephrosis. Blood and urinary exams showed a progressive renal impairment with increase of creatinine up to 8.7 mg/dl and urea around 270-290 mg/dl, proteinuria increased to 5.5 gr/24h, Hb 8 gr/dl, albumin 1.9 gr/dl, calcium 6.9 mg/dl, magnesium1.3 mg/dl, sodiuria 47 mmol/l, creatinuria 114 mg/dl, procalcitonina 0.4 (normal range <0.5). They also evidenced normal complement C3 and C4 levels, negative cryoglobulins, and Ig levels 130 mg/dl. Protein electrophoresis detected monoclonal gammopathy IgAK 1.7%, 0.06 g/dl, negative rheumatoid factor; serum k free light chain concentration was 21.8 and lambda was 10.8 mg/l (k/λ ratio 2.01). Urinary immunofixation showed IgAk less than 50 mg/24h with microscopic hematuria and 300 mg/dl albuminuria. Skin punch biopsy was performed, revealing acute cutaneous vasculitis.

At this time, based on the deterioration of the renal function and despite the mild hematologic improvement during the first cycle of chemotherapy, ultrasound-guided percutaneous renal biopsy was performed again. The renal biopsy was examined with light microscopy and immunofluorescence. Light microscopy showed an increase of sclerosis up to 70%, 30% of fibroepithelial crescent cell and mild leucocyte interstitial infiltration. Immunofluorescence showed positive staining for IgA (2+) and C3 (1+) and k-light chain (2+) involving mesangial, subendothelial and intramembranous regions.

Given the rapidly progressive renal failure and the presence of fibroepithelial crescent cells in the renal biopsy, accompanied by acute cutaneous vasculitis, in a patient with IgA monoclonal gammopathy, the following renal rescue therapy was programmed: IV cyclophosphamide 500 mg once every 2 weeks for 4 doses adjusted for renal insufficiency and IV metilprednisolone 125/day for 3 days, followed by oral prednisone 50 mg with rapid tapering

On the other hand, the chemotherapy was continued with daratumumab IV at a dose of 16 mg/kg once weekly for 8 weeks, followed by 16mg/kg every two weeks for 8 weeks, plus oral dexamethasone 20 mg (only in the day of chemotherapy, withholding prednisone).

After nearly three weeks of therapy (after the 2nd administration of Daratumumab-dexamethasone and the 2 nd administration of cyclophosphamide) the patient was admitted because of fever, cough and hemoptysis. A CT scan at admission revealed extended consolidation diffused in the entire right lung lobe, characterized by ground glass opacities mixed with parenchymal consolidation and air bronchogram (Figure 2).

Figure 2: Pneumonitis before (A) and after (B) treatment

Serological assessment, sputum and blood cultures were done to identify the type of organism causing the infection and upon admission a broad-spectrum antibiotic therapy with meropenem and teicoplanin associated with a new triazole antifungal, voriconazole, was started. After one week of therapy, there was an improvement in the clinical symptoms. Therapy with voriconazole was continued because of positive serum aspergillus-specific antibody. On the other hand, CMV PCR exam resulted positive (58000 cp/ml) and antiviral therapy with IV ganciclovir (1.25 mg/kg/dose 3 times weekly) was started.

After roughly 7 days of antibiotic therapy, in consideration of the adequate reduction of systemic inflammatory markers with sustained renal failure (creatinine 8.4 mg/dl and urea 320 mg/dl), a central venous catheter (CVC) was inserted in the internal jugular vein and the patient underwent 6 hemodialysis sessions with the HFR Supra Bellco filter system to achieve an acceptable and persistent reduction of free light chains, as the effect of chemotherapy was still persisting.

After 22 days of hospitalization, as a result of febrile neutropenia, antibiotic therapy was continued and filgrastim (granulocyte colony-stimulating factor) was applicated subcutaneously. Suspecting that the neutropenia was induced by ganciclovir and in consideration of the negative PCR CMV test, the induction therapy was withheld. After a mild improvement of the renal function, the CVC was removed, and the creation of surgical arteriovenous fistulas (AVFs) was planned.

Following 4 days of granulocyte colony-stimulating factor therapy, the neutrophils count increased up to the normal range and the fever disappeared; therefore, maintenance therapy with oral valcyte was started and maintained for the following two weeks.

After nearly 35 days of hospitalization, Acinetobacter baumanii was found in sputum culture and was successfully treated with inhaled colistin at a dose of 1000000 UI three times a day for 5 days.

The patient was discharged with serum creatinine reduced from 8.4 mg/dl to 6 mg/dl and urea from 298 mg/dl to 150 mg/dl; CRP and procalcitonin were in the normal range, with negative cultural tests. One month after discharge, laboratory exams showed a further reduction of creatinine, down to 5.2 mg/dl, while urea remained steady around 150 mg/dl; CRP, procalcitonin and complete blood count were all in the normal range. The patient did not need hemodialysis and we decided to continue chemotherapy with Daratumumab-dexamethasone (Table I).

  Time Creatinine mg/dl ProteinuriaGr/ 24h SIF UIF SE KLC k/λ ratio IgG mg/dl
T0 Before treatment 1.8 3 neg IgAK 87mg/24h hypogammaglobulinemia 0.94
CyBorD T1 End of 1th cycle 1.89 3.2 neg IgAK:50.3 mg 24h hypogammaglobulinemia normal, without MC 0.9 508
T4 End of 4th cycle 1.4 2.5 neg IgAK<50 mg 24h hypogammaglobulinemia normal, without MC 1.02
T6 End of 6th cycle 2.1 4.2 neg IgAK<50 mg 24h hypogammaglobulinemia normal, without MC
T7 End of 7th cycle 2.05 4 neg IgAK<50 mg 24h hypogammaglobulinemia normal, without MC 28.16 mg/l 1.8 336
T8 End of 8th cycle 2.3 mg/dl 3.5 neg IgAK<50 mg 24h hypogammaglobulinemia normal, without MC 32.9 mg/l 2.2
2 month follow up 1th month 2.9 3.4 neg IgAK<50 mg 24h 35.05 1.6 362
2th month 4.4 5.9 MC IgAK IgAK<50 mg 24h MC 0.17 g/dl, 3.3 % 43 2.08 319
Anti CD38 monoclonal based chemotherapy T1 After 1th  cycle of D.Rd 6.8 4.4 MC IgAK IgAK<50 mg 24h MC 0.06 g/dl, 1.7 % 21 2.01 130
Second renal biopsy
T2 After 2 cycles of D-d and first administration of CYC 6.1 4.2 MC IgAK IgAK<50 mg 24h 17.3 1.2 91
1 month follow up without therapy 5.4 3.2 MC IgAK IgAK<50 mg 24h 11.3 0.9 540
Resumption of D-d after infection resolution
Table I: The disease progression (CyBorD: Bortezomib, Dexamethasone and cyclophosphamide; D-Rd: daratumumab-lenalidomide plus dexamethasone; SIF: serum immunofixation; UIF: urine immunofixation; SE: serum electrophoresis; KLC: kappa light chain)



The clinical presentation of kidney involvement in MGRS is ambiguous and, according to the IKMG recommendations, a kidney biopsy is mandatory for the correct diagnosis and management [1].

A peculiar aspect of MGRS is that kidney lesions are associated with low-grade plasma cell dyscrasias or lymphoproliferative disorders in the absence of multiple myeloma (MM) or other hematologic malignancies. PGNMID occurs specially is the sixth decade of life and is rarely seen in younger patients. Unlike other MGRS, abnormal monoclonal immunoglobulin in serum or urine or even in bone marrow is detected only in 30 % of the PGNMID [8].

Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody anti-CD38 cells [9]. Given the good results of daratumumab in the treatment of patients with refractory MM, it has recently been used in renal disease secondary to PGNMID. The hypothesis is that there is a correlation between kidney injury and monoclonal proteins produced by plasma cells. Therefore, removing the pathologic clone can result in a renal response [10].

Recently, Zand et al. have evaluated, in an open-label, phase 2 trial, daratumumab’s safety and efficacy in 11 adults with PGNMID. Daratumumab was administrated intravenously (16 mg/kg) once a week for 8 weeks, then every other week for eight additional doses. One patient did not complete the first infusion. During the 12-month follow up, six patients had a partial response, and four had a complete response. The trial concluded there was a significant improvement in proteinuria and a stabilization of kidney function in patients with PGNMID on daratumumab [7].

Until now, no guidelines to decide the best therapeutic approach to manage PGNMID exist, and most patients progress to End Stage Renal Disease (ESRD) without therapy [3, 11].

We have described a case of MGRS secondary to PGNMID treated at first with 8 cycles of CyBorD chemotherapy. After one year, monoclonal IgA remained constant, with a deterioration of renal function without reduction of proteinuria. At this time, considering both the findings in BMA and CT bone scan and the progressive renal impairment, we chose a second-line treatment with anti-CD38 monoclonal antibody, which showed good results according to a Mayo Clinic study

Unfortunately, during the first month of this second-line therapy (with daratumumab-lenalidomide-dexamethasone) the patient was hospitalized because of a rapidly progressive renal failure, despite stable hematologic disease. A second renal biopsy showed sclerosis in up to 70% of the glomeruli and 30% of fibroepithelial crescent cells. This was associated to acute cutaneous vasculitis, and the rescue therapy of choice included intravenous cyclophosphamide and oral prednisone; the treatment with daratumumab, without lenalidomide, was continued. Unfortunately, after three weeks, all therapies were withheld because of infective complications and sever febrile neutropenia.

The most common side effects associated with daratumumab are neutropenia (37%), thrombocytopenia (23%), anemia (16%), pneumonia (10%), infusion-related reactions (6%), upper respiratory tract infection (5%), and fatigue (5%) [12].

Some studies find daratumumab to be adequately safe, with an acceptable improvement in proteinuria during the first month of infusion. However, in the case we have described, severe pulmonary infection and life-threatening febrile neutropenia was observed within three months of therapy, with progressive renal impairment. It is possible that the severe pulmonary infection was detected because of the withholding of prophylaxis treatment with trimethoprim-sulfamethoxazole (due in turn to an allergic reaction), but it is also possible that the risk was increased by the association of anti-CD38 monoclonal antibody with alkylating agents. In our case, despite using the therapeutic regimen targeting plasma cell clones responsible for kidney injury, no improvement was achieved, even with the reduction of M-spike protein.



The management of PGNMID remains unclear, and treatment is based on expert consensus, depending on the underlying clone and the risk of renal impairment progression. While low-risk patients without detectable monoclonal disease are treated only with supportive care, chemotherapy is indicated for patients with monoclonal immunoglobulins and a high risk of renal impairment.

Histological evaluation guides all therapeutic decisions, according to the pattern and degree of kidney injury. Once MGRS is diagnosed, the collaboration between nephrology and hematology specialist is recommended to find the most adequate therapy.

The case we have described, of PGNMID with the presence of mild monoclonal IgA k in urine immunofixation, did not respond to first-line therapy with CyBorD regimen, nor to second-line regimen with Daratumumab (anti CD38). According to our experience, further research is needed to assess the management and outcome of PGNMID.



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