Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest under drastically different clinical pictures. The most dramatic presentation of the four congenital acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a distinct, long-term degenerating condition with specific pathological and clinical features, for which a satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms possibly intervening in causing renal damage in AHPs are different: among others, δ-aminolevulinic acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses, and the known clinical features of renal involvement in acute hepatic porphyrias.

A Rare Case: IgG4-Related Chronic Inflammatory Disease with Kidney Involvement

IgG4 related disease is an immune-mediated chronic inflammatory disease. It is a multisystemic disease that can lead to retroperitoneal fibrosis with involvement of the pancreas, glands, thyroid, lymph nodes, etc. and characterized histopathologically by lymphoplasmocytic cell infiltration. We evaluated a patient diagnosed with IGG4 related disease impaired kidney function.

Translational research approaches to study pediatric polycystic kidney disease

Polycystic kidney diseases (PKD) are severe forms of genetic kidney disorders. The two main types of PKD are autosomal recessive and autosomal dominant PKD (ARPKD, ADPKD). While ARPKD typically is a disorder of early childhood, patients with ADPKD often remain pauci-symptomatic until adulthood even though formation of cysts in the kidney already begins in children. There is clinical and genetic overlap between both entities with very variable clinical courses. Subgroups of very early onset ADPKD may for example clinically resemble ARPKD. The basis of the clinical variability in both forms of PKD is not well understood and there are also limited prediction markers for disease progression for daily clinical life or surrogate endpoints for clinical trials in ARPKD or early ADPKD.As targeted therapeutic approaches to slow disease progression in PKD are emerging, it is becoming more important to reliably identify patients at risk for rapid progression as they might benefit from early therapy. Over the past years regional, national and international data collections to jointly analyze the clinical courses of PKD patients have been set up. The clinical observations are complemented by genetic studies and biorepositories as well as basic science approaches to elucidate the underlying molecular mechanisms in the PKD field. These approaches may serve as a basis for the development of novel therapeutic interventions in specific subgroups of patients. In this article we summarize some of the recent developments in the field with a focus on kidney involvement in PKD during childhood and adolescence and findings obtained in pediatric cohorts.

Isolated Renal Hydatid Cyst in a 6-Year-Old Boy: A Case Report

Hydatid cyst (HC) is a parasitic infection transmitted by oral ingestion of Echinococcus granulosus eggs. Isolated kidney involvement is extremely rare. It is even less common in children. We present a case of isolated renal HC in a 6-year-old boy from Şanlıurfa, southeast Turkey who complained of abdominal pain and distension. Cystectomy was performed with a flank incision using the extraperitoneal approach. No recurrence was detected in the postoperative 6-month follow-up. There are not enough data about the efficacy of medical treatment in renal HC. Therefore, medical treatment should be considered pre- and post-operatively to prevent dissemination, rather than being used as a primary treatment. Kidney-sparing surgery should be the first choice in patients with isolated renal HC. However, nephrectomy is recommended for nonfunctioning kidneys, large cysts thought to be connected with the collecting system, and cysts with suspicious tumor. In societies where HC disease is endemic, renal HC should be considered in children with cysts located in kidney, even if the indirect hemagglutination test is negative.

Kidney Dysfunction and Its Progression in Patients Hospitalized Duo to COVID-19: Contribution to the Clinical Course and Outcomes

The disease caused by coronavirus SARS-CoV-2 (COVID-19) can affect almost all organs of the human body, including kidneys. We conducted a one-center study to comprehensively analyze the effects of kidney involvement on the course and outcomes in patients hospitalized with COVID-19, depending on the estimated glomerular filtration rate (eGFR) at admission. Out of the 1958 patients, 1342 (68.54%) had eGFR ≥ 60 mL/min/1.73 m2 (group A) and 616 (31.46%) had eGFR < 60 mL/min/1.73 m2 (group B). Group B was additionally divided into subgroups B1, B2, and B3 based on eGFR. We found that mortality rates during hospitalization, as well as after 90 and 180 days, were much higher in group B than group A. The highest mortality was observed in the B2 subgroup with eGFR of 15–29. The mortality of B patients was associated with comorbidities, respiratory dysfunction, immunological impairment, and more frequent development of AKI. AKI had a negative impact on patients’ survival, regardless of the initial renal function. At discharge, 7.4% of patients had serum creatinine levels 30% higher, or more, as compared to admission. The disease course and outcomes in COVID-19 patients are associated with baseline eGFR; however, AKI during hospitalization is a more significant predictor of poor prognosis regardless of the initial renal function.

Kidney Function, Age, and Education as Contributors to Depression and Anxiety in Juvenile Systemic Lupus Erythematosus

Juvenile systemic lupus erythematosus (JSLE) is diagnosed in children younger than 18 years of age. Depression and anxiety are common, but not well understood in JSLE. We investigated the clinical and psychological factors associated with the psychological manifestations of JSLE. Twenty-nine JSLE patients were recruited for the study. Patients completed surveys evaluating their psychological status and perceptions about their health. Medical records were used to obtain laboratory results. The JSLE patient population was compared with adult-onset SLE (ASLE) patients and unaffected controls. Kidney involvement was associated with depression in the JSLE patients. The BUN levels, BUN/creatinine ratio, and leukocyturia were all significantly associated with depressive symptoms. Multivariate analysis found that the BUN/creatinine ratio was the most predictive value for both depression and anxiety. Depressive symptoms in JSLE were less pronounced than in ASLE, although anxiety was not different. Age and education are likely to be protective against depression in the JSLE patients. These findings may indicate that symptomatology is an important indicator of whether the patient needs psychiatric care.

COVID-19 in Elderly Patients with Acute Kidney Injury

Objective: Coronavirus disease 2019 (Covid 19) started in China in December 2019 and spread all over the world, is more progressive in patients who are elderly and with chronic diseases. Especially kidney involvement affects the survival of patients. In this study, we analyzed Covid 19 patients who developed acute kidney injury treated in our unit, retrospectively. Matherials: The clinical and laboratory data of 610 patients who hospitalized due to Covid 19 pandemic between 01.06.2020 and 30.06.2021 in the intensive care and other clinics of our hospital evaluated from the records, retrospectively. One hundred-fourty patients diagnosed with AKI according to the criteria of KDIGO (Kidney Disease Global Outcomes). The patients divided into two groups as KDIGO stage 1 and 2, 3. Results: The median age in both groups was 70 (35-92) and 73 (35-90) years. Approximately seventy percent of them were over 65 years old. Almost all of the patients had hypertension. Most of the patients were using angiotensin converting enzyme inhibitors (ACE inh) or angiotensin receptor blockers (ARB) (84%). AKI was present at the time of admission (61.9%) in the KDIGO 1 group and at the time of hospitalization (64.3%) in the KDIGO 2, 3 group. The mortality rate was higher in stage 2-3 AKI patients (35.7%). Ferritin and fibrinogen levels were high in the KDIGO 2, 3 group, while lymphocyte levels were low. Conclusion: AKI can be seen at the time of admission and during treatment in patients who are hospitalized and treated due to Covid 19. Covid 19 is more mortal in patients with advanced AKI.

The Pattern of Organ Responses Varies in Patients with Systemic Light-Chain Amyloidosis and Heart or Kidney or Heart and Kidney Involvement Who Achieve Deep Hematologic Responses

Introduction: In systemic light-chain amyloidosis (AL) aberrant clonal free immunoglobulin light chains (FLC) misfold and deposit in vital organs causing severe dysfunction (Nat Rev Dis Primers 2018;4:38). With anti-plasma cell therapy that reduces or eliminates the involved FLC (iFLC), defined organ responses can occur (N Engl J Med 2021;385:46, Blood Rev 2019;37:100581, Leukemia 2017;31:136, Blood 2014;124:2325). We asked whether the timing of individual organ responses may be influenced by the number of organs involved at diagnosis; therefore we evaluated the pattern of responses in patients with the two most commonly involved organs (heart, kidney) who achieved deep hematologic responses to therapy (CR=complete response, VGPR=very good partial response)(J Clin Oncol 2012;30:4541). We examined whether the rate of and time to organ response varied in patients with only heart or kidney or heart and kidney involvement, and whether the depth of hematologic response impacted the pattern of organ response. Methods: We performed a retrospective analysis AL patients diagnosed by tissue biopsy between 2007-2019 who had heart and/or kidney involvement at diagnosis and achieved hematologic CR/VGPR with treatment. Mann-Whitney was used to compare rates of organ responses and log-rank tests were applied to compare times to organ response among the subgroups as well as overall survival (OS) differences based on iFLC responses and on organ responses. Results were considered to be significant if two-sided P-value was less than or equal to 0.05. Results: We identified 111 patients with a median age of 62.5 years (range, 40-80) who met these criteria, 65 of whom (59%) were male. Cardiac involvement only was present in 34 (30.6%), renal involvement only in 31 (28.0%), and both cardiac and renal involvement in 46 (41.4%). Table 1 highlights patient characteristics. The median OS for the entire cohort was 112 months (95% CI 100-NA). The overall cardiac response rate was 62.5%, with a median time to response of 8 months (range, 1-73 months). Overall renal response rate was 67.1% with a median time to response of 10 months (range, 1-57 months). Log-rank analysis showed a significant difference in the OS based on post treatment iFLC levels (&lt;10 vs. 10-20 vs. &gt;20 mg/L) as we have previously described (Am J Hematol 2021;96:E20). Patients with kidney involvement only had significantly improved overall survival (OS) compared to those with cardiac involvement only (p=0.05), as expected. However, there was no difference in the OS of patients with cardiac only vs. cardiac and renal involvement (p=0.58), while there was a trend towards shorter OS in patients with cardiac and renal vs renal (p=0.09). The lower iFLC levels achieved post-treatment influenced cardiac response rate (p=0.07), and significantly impacted renal response rate (p&lt;0.01). For patients with cardiac involvement, iFLC responses did not have a significant impact on time to cardiac response, whereas for patients with renal involvement, faster responses were noted in those achieving lower iFLC levels (p=0.017) (Figure 1). There was no significant difference in time to cardiac response between patients with cardiac only vs. cardiac and renal involvement (p=0.93) whereas patients with renal only vs cardiac and renal involvement had a faster time to renal response (medians 14 (range, 10-29) vs 43 (13-not reached) months, p=0.018) (Figure 2). Conclusion: In AL patients with renal involvement who achieve CR/VGPR with treatment, post-treatment iFLC levels and co-presence of cardiac involvement play significant roles in the timing of renal responses. In AL patients with cardiac involvement who achieve CR/VGPR, post-treatment iFLC levels but not the co-presence of renal involvement influences the rate of cardiac response but neither influences the timing. These differences may be due to organ-specific factors such as proteomic adaptations or relative iFLC toxicity or complex cardio-renal hormonal interactions. Further hypothesis-driven study of these differences is warranted in this era of new and effective anti-plasma cell therapies. Figure 1 Figure 1. Disclosures Comenzo: Prothena Biosciences: Consultancy, Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding.

Initial Clinical Presentation and Predictors of Thrombotic Thrombocytopenic Purpura in Quebec

Thrombotic microangiopathies (TMA) constitute a group of life-threatening diseases of different aetiologies characterized by similar symptoms. The compilation of comprehensive data related to the initial clinical presentation of TMA is challenging due to their rare occurrence. The objective of this study was to assess and determine the predictive value of the clinical presentation of patients with a suspected TMA episode, subsequently confirmed as thrombotic thrombocytopenic purpura (TTP), compared with non-TTP TMA by taking advantage of the centralized ADAMTS-13 testing in Quebec. All ADAMTS-13 activity and antibody titration were performed at CHU Saint-Justine (CHUSJ). Measurements and patient demographics (from April 2012 to December 2019) were extracted from the Laboratory Information System of the CHUSJ. Patients with presumed TMA were classified into TTP when ADAMTS-13 activity was ≤10%, or suspicion of TMA other than TTP (non-TTP TMA) when ADAMTS-13 activity was &gt;10%. Clinical presentation was obtained through a survey form received with each plasma sample and containing information related to prior episodes of TMA, underlying conditions (pregnancy, cancer, infection, transplant, medication, other), clinical symptoms (fever, neurological signs, abdominal signs), and biological parameters (hemolytic anemia, thrombocytopenia). Statistical analyses were performed with IBM SPSS 26.0. The study was approved by the Research Ethics Committee of CHUSJ. A total of 2081 requests for ADAMTS13 testing were received during the study period, in 846 different individuals with suspected TMA: 147 patients (17%) had a confirmed TTP and 699 had a suspected non-TTP TMA. Clinical and biological characteristics associated with TMA suspicion were available for 105 TTP and 470 non-TTP TMA patients (68% of subjects). More than half of patients with TTP (55%; 48/87) had neurological signs at presentation compared to one third of patients (33%; 124/375) with non-TTP TMA (p=0.0001). There were no significant differences regarding fever and abdominal signs between the 2 groups (p=0.383 and p=0.355 respectively). Anemia and thrombocytopenia were reported in 92% (80/87) and 93% (86/92) of TTP patients compared to 74% (291/396) and 83% (352/426) of non-TTP TMA patients (p=0.0002 and p=0.009, respectively). Underlying conditions were reported in 62% (287/460) of non TTP-TMA patients compared to 35% (34/97) of TTP patients (p&lt;0.0001). Kidney involvement was documented in 20% (91/460) of non-TTP TMA and 7% (7/98) of TTP (p=0.003). Transplantation tended to be more often reported in non-TTP TMA (11%;58/560 versus 4%;4/98 in TTP; p=0.079). Pregnancy or postpartum was found in 11% (29/267) of females with non-TTP TMA and 5% (3/57) of females with TTP (p=0.232). Infections were present in 15% (68/462) of non-TTP TMA and 14% (14/98) of TTP (p=0.912). Drug associated TMA was reported in 15% (70/461) of non-TTP TMA and 9 % (9/98) of TTP (p=0.123). Cancers were documented in 16% (74/462) of non-TTP TMA and 9% (9/98) of TTP (p=0.084). When addressing the odds of TPP according to the clinical presentation, patients with neurological signs were at higher risk to be diagnosed with TTP compared to those who did not have neurological signs (odds ratio, 2.52; IC95%, 1.51 to 4.20; p&lt;0.001). Thirty percent of patients presenting with neurological signs had TTP compared to 14% presenting without neurological signs. Conversely, the risk to be diagnosed with TTP was lower in the setting of transplantation (odds ratio, 0.32; IC95%, 0.11 to 0.92; p=0.015). Indeed, among patients who have had a transplantation 7% were diagnosed with TTP, while 93% had non-TTP TMA. Finally, the risk of TPP was also lower in patients with TMA and concomitant kidney-related issue (OR=0.31; IC95%: 0.14 to 0.69; p=0.004) as among patients presenting with renal disorders, 93% were not subsequently diagnosed with TTP. In conclusion, the centralization of ADAMTS-13 activity testing in one reference center has enabled to determine the predictive value of clinical characteristics associated with TPP in comparison to other types of TMA for the entire province of Quebec, Canada. This study provides useful insight for caregivers and paves the way to the establishment of a provincial registry of TMA patients. Figure 1 Figure 1. Disclosures Lapeyraque: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rivard: Bayer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees. Bonnefoy: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.