Renal involvement in paroxysmal nocturnal hemoglobinuria: an update on clinical features, pathophysiology and treatment

Kokoris, Styliani I.; Gavriilaki, Eleni; Miari, Aggeliki; Travlou, Αnthi; Kyriakou, Elias; Anagnostopoulos, Achilles; Grouzi, Elissavet

doi:10.1080/10245332.2018.1444563

Cited by 32 publications

(46 citation statements)

References 58 publications

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“…Our choice of erythrocytes as a model was due to erythrocytes being the most abundant component of blood compartments, and their relatively high vulnerability to osmotic lysis in comparison to nucleated cells. Moreover, intravascular hemolysis is a crucial event of diseases such as paroxysmal nocturnal hemoglobinuria (PNH) [ 33 ] or atypical hemolytic uremic syndrome (aHUS) [ 34 ], which are caused by malfunctions in the regulation of complement convertases. It is important to note that the risk of the development of complement-related diseases should be addressed in in vivo experiments in the animal model of B-cell malignancy, which we did not perform in this study.…”

Section: Discussionmentioning

confidence: 99%

Mutations resulting in the formation of hyperactive complement convertases support cytocidal effect of anti-CD20 immunotherapeutics

Felberg

Urbán

Borowska

et al. 2019

Cancer Immunol Immunother

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Anti-CD20 monoclonal antibodies (mAbs) rituximab and ofatumumab are potent activators of the classical complement pathway, and have been approved for the treatment of B-cell malignancies. However, complement exhaustion and overexpression of complement inhibitors by cancer cells diminish their therapeutic potential. The strategies of targeting membrane complement inhibitors by function-blocking antibodies and the supplementation with fresh frozen plasma have been proposed to overcome tumour cell resistance. We present a novel approach, which utilizes gain-of-function variants of complement factor B (FB), a component of alternative C3/C5 convertases, which augment mAb-activated reactions through a positive feedback mechanism called an amplification loop. If complement concentration is limited, an addition of quadruple gain-of-function FB mutant p.D279G p.F286L p.K323E p.Y363A (or selected single mutants) results in significantly increased complement-mediated lysis of ofatumumab-resistant tumour cells, as well as the complete lysis of moderately sensitive cells. Importantly, this effect cannot be achieved by further increasing ofatumumab concentration. Potentiation of cytotoxic effect towards moderately sensitive cells was less apparent at physiological serum concentration. However, an addition of hyperactive FB could compensate the loss of cytotoxic potential of serum collected from the NHL and CLL patients after infusion of rituximab. Residual levels of rituximab in such sera, in combination with added FB, were able to efficiently lyse tumour cells. We suggest that the administration of gain-of-function variants of FB can restore cytotoxic potential of complement-exhausted serum and maximize the therapeutic effect of circulating anti-CD20 mAbs. Electronic supplementary material The online version of this article (10.1007/s00262-019-02304-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Mutations resulting in the formation of hyperactive complement convertases support cytocidal effect of anti-CD20 immunotherapeutics

Felberg

Urbán

Borowska

et al. 2019

Cancer Immunol Immunother

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“…3 Other renal manifestations of PNH include chronic kidney disease (which is more common than AKI) and proximal tubular dysfunction due to iron toxicity. 4 What are the long-term therapeutic options? The only treatments for PNH are hematopoietic stem cell transplantation and eculizumab, a humanized xv QUIZ monoclonal antibody against C5 that inhibits terminal complement activation.…”

Section: Discussionmentioning

confidence: 99%

Acute Kidney Injury, Anemia, and Recurrent Dark Red Urine

Falcão

Colaço

Cruz

et al. 2019

American Journal of Kidney Diseases

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Case Presentation A 50-year-old man presented to the emergency department reporting dark-colored urine and diffuse abdominal pain. He reported two similar episodes in the previous four months but did not seek medical attention. Additionally, a week before, he had a flu-like syndrome for which he took a nonsteroidal anti-inflammatory drug. The patient's medical history was notable only for uninvestigated chronic mild thrombocytopenia. Glomerular filtration rate was normal three months earlier (serum creatinine, 0.89 mg/dL). Physical examination findings were unremarkable, except for mucocutaneous pallor. Laboratory tests revealed serum creatinine level of 7.8 mg/dL, hemoglobin level of 6.1 mg/dL, and platelet count of 127 × 10 3 /μL. Urinalysis showed heme (3+) but was negative for protein on dipstick, with the microscopic examination showing rare blood cells without cellular casts. Peripheral-blood smear showed mildly reduced platelet count and rare schistocytes. Other relevant laboratory values are presented in Table 1.

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“…AKI is mainly observed in hemolytic uremic syndrome but may also occur in thrombotic thrombocytopenic purpura [120][121][122]. Paroxysmal nocturnal hemoglobinuria (PNH) may cause both acute and chronic renal impairment via several pathophysiological mechanisms, mainly including the release of free heme and iron due to intravascular hemolysis and subsequent hemoglobinuria, Fanconi syndrome, and possibly subclinical microvascular thrombosis [123].…”

Section: Hyponatremia Related To Kidney Injury In Patients With Hematmentioning

confidence: 99%

Hyponatremia in Patients with Hematologic Diseases

Koumpis

Florentin

Hatzimichael

et al. 2020

JCM

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Hyponatremia is the most common electrolyte disorder in clinical practice and is associated with increased morbidity and mortality. It is frequently encountered in hematologic patients with either benign or malignant diseases. Several underlying mechanisms, such as hypovolemia, infections, toxins, renal, endocrine, cardiac, and liver disorders, as well as the use of certain drugs appear to be involved in the development or the persistence of hyponatremia. This review describes the pathophysiology of hyponatremia and discusses thoroughly the contributing factors and mechanisms that may be encountered specifically in patients with hematologic disorders. The involvement of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion and renal salt wasting syndrome (RSWS) in the development of hyponatremia in such patients, as well as their differential diagnosis and management, are also presented. Furthermore, the distinction between true hyponatremia and pseudohyponatremia is explained. Finally, a practical algorithm for the evaluation of hyponatremia in hematologic patients, as well as the principles of hyponatremia management, are included in this review.

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Renal involvement in paroxysmal nocturnal hemoglobinuria: an update on clinical features, pathophysiology and treatment

Abstract: Understanding the difficult but at the same time impressive mechanisms behind PNH remains a challenge for treating physicians.

Cited by 32 publications

References 58 publications

Mutations resulting in the formation of hyperactive complement convertases support cytocidal effect of anti-CD20 immunotherapeutics

Mutations resulting in the formation of hyperactive complement convertases support cytocidal effect of anti-CD20 immunotherapeutics

Acute Kidney Injury, Anemia, and Recurrent Dark Red Urine

Hyponatremia in Patients with Hematologic Diseases

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