COVID-19 and the Kidney: Should Nephrologists Care about COVID-19 rather than Maintaining Their Focus on Renal Patients?

Clinical Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread globally from late 2019, reaching pandemic proportions. Epidemiology: The related disease, COVID-19, exacerbates and progresses due to patients' abnormal inflammatory/immune responses, widespread endothelial damage, and complement-induced blood clotting with microangiopathy. COVID-19 manifests mainly as a respiratory illness. In cases of severe viral pneumonia, it may lead to acute respiratory distress syndrome, respiratory failure, and death. Challenges: Many extrapulmonary manifestations commonly occur, and a substantial proportion of patients with severe COVID-19 exhibit signs of kidney damage. Clinically, kidney involvement ranges from mild/moderate proteinuria and hematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT). The pathophysiologic mechanisms of kidney damage and AKI in patients with COVID-19 remain unclear but are known to be multifactorial. Current knowledge implies direct SARS-CoV-2-dependent effects on kidney cells (tubular epithelial cells and podocytes) and indirect mechanisms through the systemic effect of viral infection secondary to the critical pulmonary illness and its management. Prevention and Treatment: Standard-of-care strategies apply, as there is no specific evidence to suggest that COVID-19 AKI should be managed differently from other types in severely ill patients. If conservative management fails, RRT should be considered. The choice of RRT approaches and sequential extracorporeal therapies depends on local availability, resources, and expertise. The focus should now be on the long-term follow-up of COVID-19 patients, especially those who developed kidney injury and dysfunction. This represents an opportunity for integrated multidisciplinary research to clarify the natural history of COVID-19 renal sequelae and the best therapeutic interventions to mitigate them.

Association of Proteinuria and Hematuria with Acute Kidney Injury and Mortality in Hospitalized Patients with COVID-19.

INTRODUCTION: Acute kidney injury (AKI) is strongly associated with poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19), but data on the association of proteinuria and hematuria are limited to non-US populations. In addition, admission and in-hospital measures for kidney abnormalities have not been studied separately. METHODS: This retrospective cohort study aimed to analyze these associations in 321 patients sequentially admitted between March 7, 2020 and April 1, 2020 at Stony Brook University Medical Center, New York. We investigated the association of proteinuria, hematuria, and AKI with outcomes of inflammation, intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and in-hospital death. We used ANOVA, t test, χ2 test, and Fisher's exact test for bivariate analyses and logistic regression for multivariable analysis. RESULTS: Three hundred patients met the inclusion criteria for the study cohort. Multivariable analysis demonstrated that admission proteinuria was significantly associated with risk of in-hospital AKI (OR 4.71, 95% CI 1.28-17.38), while admission hematuria was associated with ICU admission (OR 4.56, 95% CI 1.12-18.64), IMV (OR 8.79, 95% CI 2.08-37.00), and death (OR 18.03, 95% CI 2.84-114.57). During hospitalization, de novo proteinuria was significantly associated with increased risk of death (OR 8.94, 95% CI 1.19-114.4, p = 0.04). In-hospital AKI increased (OR 27.14, 95% CI 4.44-240.17) while recovery from in-hospital AKI decreased the risk of death (OR 0.001, 95% CI 0.001-0.06). CONCLUSION: Proteinuria and hematuria both at the time of admission and during hospitalization are associated with adverse clinical outcomes in hospitalized patients with COVID-19.

Prevalence of Kidney Injury and Associations with Critical Illness and Death in Patients with COVID-19.

BACKGROUND AND OBJECTIVES: Coronavirus disease 2019 is spreading rapidly across the world. This study aimed to assess the characteristics of kidney injury and its association with disease progression and death of patients with coronavirus disease 2019. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective study. Two representative cohorts were included. Cohort 1 involved severe and critical patients with coronavirus disease 2019 from Wuhan, China. Cohort 2 was all patients with coronavirus disease 2019 in Shenzhen city (Guangdong province, China). Any kidney injury was defined as the presence of any of the following: hematuria, proteinuria, in-hospital AKI, or prehospital AKI. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria. The primary outcome was death at the end of follow-up. The secondary outcome was progression to critical illness during the study period. RESULTS: A total of 555 patients were enrolled; 42% of the cases (229 of 549) were detected with any kidney injury, 33% of the cases (174 of 520) were detected with proteinuria, 22% of the cases (112 of 520) were detected with hematuria, and 6% of the cases (29 of 520) were detected with AKI. Of the 29 patients with AKI, 21 cases were recognized as in-hospital AKI, and eight were recognized as prehospital AKI. Altogether, 27 (5%) patients died at the end of follow-up. The death rate was 11% (20 of 174) in patients with proteinuria, 16% (18 of 112) in patients with hematuria, and 41% (12 of 29) in the AKI settings. Multivariable Cox regression analysis showed that proteinuria (hazard ratio, 4.42; 95% confidence interval, 1.22 to 15.94), hematuria (hazard ratio, 4.71; 95% confidence interval, 1.61 to 13.81), and in-hospital AKI (hazard ratio, 6.84; 95% confidence interval, 2.42 to 19.31) were associated with death. Among the 520 patients with noncritical illness at admission, proteinuria (hazard ratio, 2.61; 95% confidence interval, 1.22 to 5.56) and hematuria (hazard ratio, 2.50; 95% confidence interval, 1.23 to 5.08) were found to be associated with progression to critical illness during the study period. CONCLUSIONS: Kidney injury is common in coronavirus disease 2019, and it is associated with poor clinical outcomes. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_09_18_CJN04780420.mp3.

Successful management of COVID-19 and associated coagulopathy in a patient with durable left ventricular assist device.

Patients with durable left ventricular assist devices pose special problems for management in the setting of COVID-19 infection. We describe the successful management of a 44-year-old man with severe COVID-19 infection and HeartMate 3 left ventricular assist device. His course was complicated by cytokine storm and COVID-19-associated coagulopathy. We describe our institutional protocol for managing COVID-19 infection in patients on mechanical circulatory support, focusing on the need for a thoughtful, multidisciplinary approach.

Impact of extended infusional mesna prophylaxis on the incidence of BK viruria and hemorrhagic cystitis following post-transplantation cyclophosphamide and CTLA4Ig-based haploidentical transplantation.

Hemorrhagic cystitis (HC) has been reported with increased frequency following post-transplantation cyclophosphamide (PTCy)-based haploidentical hematopoietic cell transplantation (HCT) along with a strong association with BK viruria. We prospectively evaluated the incidence of BK viruria and HC in 115 patients (median age 20 years, 2-65) undergoing PTCy-based haploidentical HCT with (n = 71) or without (n = 44) CTLA4Ig. HC prophylaxis consisted of a continuous infusion of mesna 30 min prior and 48 h post-PTCy. The overall incidence of BK viruria was 65.7%. None with BK viruria < 104 copies/ml developed clinical symptoms (n = 65). The incidence of BK viruria ≥ 104 copies/ml was 7.1% (n = 8) and 75% developed HC. The incidence of HC was 5.4% at a median of 30 days. Both BK viruria ≥ 104 copies/ml and HC were strongly associated with acute GVHD (p < 0.001). A higher NRM was observed in those with BK viruria ≥ 104 copies/ml, related to GVHD and its complications (41.7% vs 12.6%, p = 0.04). The incidences of acute GVHD, vis-à-vis, overall BK viruria, BK viruria ≥ 104 copies/ml, and HC, tended to be lower in patients receiving CTLA4Ig. Thus, extended infusional mesna, coupled with significant reduction in alloreactivity along with possible preservation of antiviral immunity associated with the use of CTLA4Ig, was probably responsible for a much lower incidence of BK viruria and resultant HC than reported previously following PTCy-based haploidentical HCT.

Neutropenia and renal dysfunction due to intravesical cidofovir for virus-associated hemorrhagic cystitis after kidney and allogenic hematopoietic stem cell transplantations.

We present a patient with virus-associated hemorrhagic cystitis who underwent kidney and allogenic hematopoietic stem cell transplantations (allo-HSCT). Six months post-allo-HSCT, adenovirus hemorrhagic cystitis occurred, which has been in remission after a single dose of intravesical cidofovir. This might cause prolonged neutropenia and nephrotoxicity, suggesting cidofovir absorption in the blood.

Renal manifestations of dengue viral infection.

Dengue-related renal manifestations such as proteinuria, hematuria in the absence of thrombocytopenia, rhabdomyolysis, and acute kidney injury (AKI) are not uncommon. There is relatively sparse data on the renal manifestations of dengue viral infection (DVI). Hence, a retrospective study was conducted to investigate the incidence, characteristics, and clinical outcome of DVI with renal manifestations. A total of 2416 patients were admitted to our hospital with the diagnosis of dengue fever during the study period from 2012 to 2015. Data were collected from the electronic medical records and were analyzed retrospectively. The disease severity was classified according to the World Health Organization criteria. The renal manifestations were divided into AKI and non-AKI groups using AKI Network (AKIN) criteria. Proteinuria was defined as urinary protein >1+ (30 mg/dL) by dipstick test. A total of 218 patients were found to have proteinuria (9.56%). Most of the patients [135 (58.44%) with renal manifestations] were aged between 15 and 30 years. Comorbid conditions including diabetes mellitus, hypertension, and ischemic heart disease were seen in 10 (4.31%), 11 (4.76%), and six (2.59%) patients, respectively. Nephrotic-range proteinuria was seen in five patients (2.16%). AKI was seen in 82 patients (3.4%); 58 (70.73%) had AKIN-I, 19 (23.17%) had AKIN-II, and five patients (6.09%) had AKIN-III. Death occurred in 11 patients (39.28%) with AKI. The incidence of renal manifestations (proteinuria, hematuria, and AKI) is high at 9.59% among patients with dengue, and those with AKI had significant morbidity, mortality, longer hospital stay, and poor renal outcomes. Our findings suggest that AKI in dengue is likely to increase health-care burden that underscores the need for clinician's alertness to this highly morbid and potentially fatal complication for optimal prevention and management.

The relationship between skin rash and outcome in dengue.

BACKGROUND & OBJECTIVES: Dengue fever (DF) is a common cause of acute febrile illness. Skin involvement is seen in more than half of the patients. This study was aimed to compare the clinical profile and outcome in DF patients with or without skin involvement. METHODS: This study included all the patients with DF from the acute febrile illness database of a tertiary care health centre in south India. These patients were further subgrouped into SP and SN (skin involvement positive and negative) based on the presence and absence of skin rash. Differences in clinical presentation, laboratory parameters, disease course, morbidity and outcome among patients with DF with or without skin rash were recorded and analysed statistically. RESULTS: In total 387 patients (>16 yr) with DF were enrolled into the study. Among these 55 patients had evidence of skin rash. Presence of history of overt bleeding (OR = 4.96, p = 0.027) including gum bleeding (OR = 1.17, p = 0.23), epistaxis (OR = 5.52, p = 0.04), and haematuria (OR = 6.41, p = 0.01) were more among patients with SP as compared to SN. The SP patients were found to have lower levels of platelets during the disease course. Patients with SP had a higher percentage of platelet transfusion which was statistically significant. There was no difference in organ dysfunction and mortality among both the groups. INTERPRETATION & CONCLUSION: Cutaneous involvement, though common, is not pathognomonic and can help in dengue diagnosis. Adult patients with skin rash can develop worsening thrombocytopenia requiring platelet transfusion. However, there are limited data to suggest that such patients have a worse outcome and higher mortality.

[Surgical treatment of severe, refractory hemorrhagic cystitis following allogeneic hematopoietic stem cell transplantation: a report of 17 patients].

Objective: To investigate the clinical effect and safety of surgical treatment for severe, refractory hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Patients with severe HC, who were admitted to Peking University Institute of Hematology from January 2010 to December 2015, were enrolled in this study.All patients were refractory to medical managements and received bladder surgery including mucous electrocoagulation and/or selective transcatheter arterial embolization. Results: A total of 17 patients with severe HC (grade Ⅲ, n=5; grade Ⅳ, n=12) received surgical treatment, including 11 embolization and 18 mucous electrocoagulation.The median time from allo-HSCT to surgery was 107 d (46-179 d) and 75 d after HC.Eight patients only received embolization.Four patients only received mucous electrocoagulation.Five patients were given combined embolization and electrocoagulation.HC was cured in 11 patients, improved in 1 patient, which corresponded to a response rate of 70.6% and complete remission rate of 64.7%.Five patients didn't respond to these methods.In patients with response, macroscopic hematuria disappeared 3 to 10 days after treatments whereas microscopic hematuria vanished after 25 to 32 days.Both procedures were well tolerated and no severe adverse effects were observed. Conclusion: Surgery of bladder mucous electrocoagulation and/or selective arterial embolization are safe and effective for severe HC.

[Significance of Urological Surgical Treatment for Viral Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation].

This study investigated the significance of urological surgical intervention for viral hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 1, 024 patients underwent allo-HSCT at our medical center between January 2006 and July 2014. In the 6 patients (0.58%) who required urological surgical treatment for viral HC, we retrospectively analyzed patient characteristics and outcomes. Two patients underwent nephrostomy for bilateral hydronephrosis due to bladder tamponade. One of these patients showed no improvement in renal function, graft versus host disease worsened and he died on postoperative day (POD) 5. The other patient displayed improved renal function but hematuria did not improve, and total cystectomy was required. To control bleeding, we performed transurethral electrocoagulation (TUC) on 3 patients, and total cystectomy was performed on 2 patients. All 3 patients who underwent TUC had BK virus HC. Two of these patients experienced marked improvement in hematuria from immediately after surgery. Hemostasis was only temporary in the other patient, who eventually died due to septicemia on POD 24. The 2 patients who underwent total cystectomy had adenovirus HC. Both experienced secondary hemorrhage postoperatively and required further surgery. Eventually, one died due to postoperative bleeding on POD 1, and one died due to postoperative pneumonia on POD 57. Urological surgical treatment for HC was effective in some cases, but the ultimate outcome greatly depends on the general condition of the patient and treatment of the underlying hematological disorder. TUC may be considered for HC (particularly BK virus HC), but total cystectomy (especially inaden ovirus HC) should be avoided.

Detection and quantification of bovine papillomavirus type 2 in urinary bladders and lymph nodes in cases of Bovine Enzootic Hematuria from the endemic region of Azores.

Bovine Enzootic Hematuria (BEH) is a disease with a severe impact on production indexes and characterized by the development of bovine urinary bladder tumors, particularly in the Azores archipelago. The purpose of this study was to investigate and quantify BPV2 tissue distribution in bovine urinary bladder tumors, normal bladders, and iliac lymph nodes of cattle from the Azores. A real-time PCR system targeting the L1 gene was developed and allowed for the specific detection of the virus. BPV2 DNA was detected in a large proportion of the samples tested, both from neoplastic and healthy tissues, indicating that this virus is very prevalent in the bovine population of the Azores. Moreover, all types of tissues tested were positive, confirming a wide viral distribution within the infected animal. Bovine cutaneous papillomas sampled from Portuguese mainland dairy cattle were used as controls. Viral load ranged between 2.2×10(4) copies/cell in the skin papillomas, and 0.0002 copies/cell in the urinary bladders tumors from the Azores. This is the first report presenting quantitative data on BPV2 infection in bovine urinary bladder lesions from the Azores. This approach will provide a useful tool to evaluate the role of BPV2 not only in the pathogenesis BEH but also in cell transformation mechanisms.

Antibodies to BK virus in children prior to allogeneic hematopoietic cell transplant.

BK virus (BKV) is associated with kidney and bladder disease after hematopoietic cell transplantation (HCT) but less is known about the seroprevalence of pre-transplant antibodies to BKV in children. We measured BKV IgG antibody titers in 36 children before HCT. BKV IgG antibodies were detected in all 36 patients, with 28/36 (77.8%) developing BK viremia in the first 100 days. Pre-HCT BKV IgG antibody titers >1:40,960 were protective against later BK viremia ≥10,000 copies/ml. The seroprevalence of antibodies to BKV is high in children undergoing HCT and post-transplant BK viremia, which is associated with bladder and kidney injury, is common.

[Hemorrhagic cystitis due to adenovirus in a renal transplant recipient: the first reported case in black Africa in a setting of a very beginning of a kidney transplantation program and review of the literature]. / Cystite hémorragique à adénovirus chez le transplanté rénal: à propos d'un premier cas en Afrique noire survenu dans un tout débutant programme de greffe rénale et revue de la littérature.

Viral infections are an important complication of transplantation. Polyomavirus are the commonest viruses that infect the renal allograft. Herpes virus nephropathy has also been described. In the past 15 years, adenovirus nephritis has emerged as a potentially life-threatening disease in renal transplant patients in developed countries. Most of the papers devoted to adenovirus nephritis are reported cases. The fate of such patients in resources-limited countries is not known. Herein, we describe the clinical, biological and prognostic findings of a black African transplanted patient with adenoviral hemorrhagic cystitis. This case is the very first of its kind reported in black Africa in a setting of a start of a renal transplantation pilot project. The patient is a 54-year-old man admitted at the nephrology service for gross haematuria and fever occurred 1 month after kidney transplantation. The diagnosis of adenoviral hemorrhagic cystitis has been suspected because the patient has displayed recurrent conjunctivitis and gastroenteritis well before transplantation, which was then confirmed by the real-time polymerase chain reaction performed on the blood. Conservatory measures associated with immunosuppression reduction have permitted the discontinuation of haematuria. This case has been discussed in regard of the epidemiology, the diagnosis, the treatment, the evolution and the prognosis of the adenoviral infection in the renal transplant patient. A review of the literature has been performed subsequently.

Choreito formula for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (P = .018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P = .037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P = .0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT.

Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany.

Human infection with Puumala virus (PUUV), the most common hantavirus in Central Europe, causes nephropathia epidemica (NE), a disease characterized by acute kidney injury and thrombocytopenia. To determine the clinical phenotype of hantavirus-infected patients and their long-term outcome and humoral immunity to PUUV, we conducted a cross-sectional prospective survey of 456 patients in Germany with clinically and serologically confirmed hantavirus-associated NE during 2001-2012. Prominent clinical findings during acute NE were fever and back/limb pain, and 88% of the patients had acute kidney injury. At follow-up (7-35 mo), all patients had detectable hantavirus-specific IgG; 8.5% had persistent IgM; 25% had hematuria; 23% had hypertension (new diagnosis for 67%); and 7% had proteinuria. NE-associated hypertension and proteinuria do not appear to have long-term consequences, but NE-associated hematuria may. All patients in this study had hantavirus-specific IgG up to years after the infection.

Effective treatment of severe BK virus-associated hemorrhagic cystitis with leflunomide in children after hematopoietic stem cell transplantation: a pilot study.

Leflunomide, an immunosuppressant with antiviral activity, was used to treat 5 children with severe BK virus-associated hemorrhagic cystitis after hematopoietic stem cell transplantation. Without severe side effects, BK viral loads in blood and urine decreased significantly after leflunomide treatment. Compared with 7 historical controls, duration of BK virus-associated hemorrhagic cystitis was significantly shorter in patients receiving leflunomide therapy (P < 0.01).

Successful hyperbaric oxygen therapy for refractory BK virus-associated hemorrhagic cystitis after cord blood transplantation.

BK virus-associated hemorrhagic cystitis (BKV-HC) is a common and major cause of morbidity in recipients of allogeneic hematopoietic stem cell transplantation. A 32-year-old woman developed severe BKV-HC on day 24 after cord blood transplantation (CBT). Despite supportive therapies - such as hyperhydration, forced diuresis, and urinary catheterization - macroscopic hematuria and bladder irritation persisted for over a month. Hyperbaric oxygen (HBO) therapy at 2.1 atmospheres for 90 min per day was started on day 64 after CBT. Macroscopic hematuria resolved within a week, and microscopic hematuria was no longer detectable within 2 weeks. Hematuria did not recur after 11 sessions of HBO therapy, and no significant side effects were observed during or after treatment. HBO therapy could thus be useful in controlling refractory BKV-HC after CBT.