COVID-19-Associated Acute Kidney Injury and Quantified Protein Catabolic Rate: A Likely Effect of Cytokine Storm on Muscle Protein Breakdown.

RATIONALE & OBJECTIVES: Previously we reported a cohort of patients with coronavirus disease 2019 (COVID-19)-associated acute kidney injury (AKI) with striking biochemical evidence of tissue breakdown in the absence of apparent rhabdomyolysis. We sought to quantify the extent of tissue catabolism in similar patients. STUDY DESIGN: During acute peritoneal dialysis (PD) in patients with COVID-19-associated AKI, we measured urea Kt/V adequacy and calculated the daily urea nitrogen generation rate while quantifying daily protein intake. SETTING & POPULATION: We did calculations in 8 patients with COVID-9-associated AKI undergoing acute PD at Mount Sinai Hospital in New York City. As a comparator, we obtained urea kinetic parameters from our database of ambulatory patients receiving maintenance PD. EXPOSURE OR PREDICTORS: 8 patients with COVID-19-associated AKI undergoing acute PD. OUTCOMES: Urea nitrogen generation rate in relation to daily protein intake. ANALYTICAL APPROACH: Urea nitrogen generation rate from urea kinetics was related to measured daily dietary protein intake in these patients and we compared it with this relationship in ambulatory maintenance PD patients for whom both parameters were calculated from urea kinetics. RESULTS: Urea nitrogen generation rate in patients with AKI was 10.2 ± 5 g/d, which is more than 2-fold higher than for stable outpatients receiving maintenance PD (4.7 ± 3 g/d) despite similar dietary protein intake (74.8 ± 11 vs 67.2 ± 29 g/d, respectively). This strongly suggests endogenous protein breakdown, probably from muscle. Urea nitrogen generation rate in these patients with AKI corresponds to 315 g/d of ongoing muscle breakdown and cumulative 2.5 kg of muscle breakdown during the early course of AKI. LIMITATIONS: Small number of participants and assumptions in comparing urea nitrogen generation rate with protein intake. CONCLUSIONS: In highly catabolic patients, an endogenous source of urea generation such as muscle protein breakdown seems to be the most likely explainable cause for our findings. This is the first study that we are aware of to quantify the degree of endogenous protein breakdown induced by COVID-19-related cytokine storm.

Acute Kidney Injury in Hospitalized Patients with COVID-19.

IMPORTANCE: Preliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID)-19 patients and is associated with worse outcomes. AKI in hospitalized COVID-19 patients in the United States is not well-described. OBJECTIVE: To provide information about frequency, outcomes and recovery associated with AKI and dialysis in hospitalized COVID-19 patients. DESIGN: Observational, retrospective study. SETTING: Admitted to hospital between February 27 and April 15, 2020. PARTICIPANTS: Patients aged ≥18 years with laboratory confirmed COVID-19 Exposures: AKI (peak serum creatinine increase of 0.3 mg/dL or 50% above baseline). Main Outcomes and Measures: Frequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aOR) with mortality. We also trained and tested a machine learning model for predicting dialysis requirement with independent validation. RESULTS: A total of 3,235 hospitalized patients were diagnosed with COVID-19. AKI occurred in 1406 (46%) patients overall and 280 (20%) with AKI required renal replacement therapy. The incidence of AKI (admission plus new cases) in patients admitted to the intensive care unit was 68% (553 of 815). In the entire cohort, the proportion with stages 1, 2, and 3 AKI were 35%, 20%, 45%, respectively. In those needing intensive care, the respective proportions were 20%, 17%, 63%, and 34% received acute renal replacement therapy. Independent predictors of severe AKI were chronic kidney disease, systolic blood pressure, and potassium at baseline. In-hospital mortality in patients with AKI was 41% overall and 52% in intensive care. The aOR for mortality associated with AKI was 9.6 (95% CI 7.4-12.3) overall and 20.9 (95% CI 11.7-37.3) in patients receiving intensive care. 56% of patients with AKI who were discharged alive recovered kidney function back to baseline. The area under the curve (AUC) for the machine learned predictive model using baseline features for dialysis requirement was 0.79 in a validation test. CONCLUSIONS AND RELEVANCE: AKI is common in patients hospitalized with COVID-19, associated with worse mortality, and the majority of patients that survive do not recover kidney function. A machine-learned model using admission features had good performance for dialysis prediction and could be used for resource allocation.

Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis.

BACKGROUND: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. OBJECTIVE: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. METHODS: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. RESULTS: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. CONCLUSION: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.

Revision of the Failed Thumb Carpometacarpal Arthroplasty.

PURPOSE: To evaluate the outcome of revision surgery for failed thumb carpometacarpal (CMC) arthroplasty. METHODS: We retrospectively analyzed 32 patients with failed thumb CMC arthroplasty. The primary reason for revision was pain caused by metacarpal subsidence. Revision surgery included soft tissue interposition and distraction pinning to address the metacarpal subsidence. Additional ligament reconstruction was performed in patients with thumb instability. Eight patients required additional metacarpophalangeal joint fusion for concomitant joint hyperextension. Eleven required additional partial excision of the trapezoid for concomitant scaphotrapezoidal joint arthritis. All patients were evaluated clinically and radiographically. RESULTS: Mean follow-up was 57 months (range, 24-121 months). Pain levels evaluated by visual analog scale were significantly reduced in all patients after revision surgery. Mean grip strength and key pinch strength significantly increased. Twenty-seven patients achieved good functional results; those for 5 patients were fair. CONCLUSIONS: This study showed that revision surgery with distraction pinning and soft tissue interposition with or without ligament reconstruction was an effective treatment for failed CMC arthroplasty of the thumb. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Elvitegravir/cobicistat/emtricitabine/tenofovir DF in HIV-infected patients with mild-to-moderate renal impairment.

In HIV-1-infected treatment-naive patients with mild-to-moderate renal impairment [creatinine clearance (CrCl): 50-89 mL/min], elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB, n = 33) achieved high rates of virologic success (78.8%; 95% confidence interval: 61.1% to 91.0%) and was well tolerated through week 48. Four patients discontinued study drug due to an adverse event and none due to proximal renal tubulopathy. As expected, decreases in CrCl were noted as early as week 2, after which they stabilized. The renal safety profile of STB in patients from this study is consistent with the long-term experience in a large number of patients with CrCl ≥70 mL/min.

Discontinuation of tenofovir disoproxil fumarate for presumed renal adverse events in treatment-naïve HIV-1 patients: meta-analysis of randomized clinical studies.

BACKGROUND: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected and noninfected patients. This meta-analysis explored the frequency of discontinuation attributed to renal adverse events (AEs) in randomized, controlled clinical studies that used TDF-containing regimens for ART-naïve, HIV-infected patients. METHODS: A literature search of 4 electronic databases through October 31, 2013 was utilized. RCTs included were limited to randomized, prospective, comparative design in ART treatment-naïve adults with HIV-1 infections receiving ART. Studies included trials containing TDF treatment regimens, with or without a non-TDF control group. Study design, follow-up, size of study population, treatment group, patient demographics, number of patients exposed to TDF or non-TDF control, baseline characteristics, investigator-defined criteria for renal AEs, and number of discontinuations due to a presumed renal AEs were extracted. RESULTS: Twenty-one clinical studies met the selection criteria. Treatment duration ranged from 48 to 288 weeks. Renal AEs led to study drug discontinuation in 44 of 10,129 patients exposed to TDF (0.43%; 95% CI, 0.32%-0.58%) and 2 of 2,013 patients exposed to non-TDF-containing regimens (0.10%; 95% CI, 0.01%-0.36%). In 5 randomized, controlled studies that included a non-TDF comparator, the estimated risk difference between the treatment groups (TDF vs non-TDF) was 0.50% (95% CI, 0.13%-0.86%; P = .007). CONCLUSIONS: In clinical studies using TDF-containing regimens, the rate of discontinuations due to renal AEs was low, but was slightly higher than in studies using non-TDF comparators.

Cardiovascular pathophysiology in chronic kidney disease: opportunities to transition from disease to health.

BACKGROUND: Chronic kidney disease (CKD) is common, and is associated with a high burden of cardiovascular disease. This cardiovascular risk is incompletely explained by traditional risk factors, calling attention to a need to better understand the pathways in CKD contributing to adverse cardiovascular outcomes. FINDINGS: Pathophysiological derangements associated with CKD, including disordered sodium, potassium, and water homeostasis, renin-angiotensin-aldosterone and sympathetic activity, anemia, bone and mineral metabolism, uremia, and toxin accumulation may contribute directly to progression of cardiovascular disease and adverse outcomes. CONCLUSION: Improving cardiovascular health in patients with CKD requires improved understanding of renocardiac pathophysiology. Ultimately, the most successful strategy may be prevention of incident CKD itself.

Impact of the CKD-EPI equation for estimating renal function on eligibility for cisplatin-based chemotherapy in patients with urothelial cancer.

BACKGROUND: Although a creatinine clearance (CrCl) of <60 mL/min, as calculated by the Cockroft-Gault (CG) equation, is a commonly used threshold for "cisplatin-ineligibility," the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has recently emerged as a more accurate method of estimating renal function. We sought to determine the impact of using the CKD-EPI equation for estimating renal function on cisplatin eligibility. METHODS: All patients pathologically diagnosed with muscle invasive and/or metastatic bladder urothelial carcinoma (T2-4, N or M positive) at Mount Sinai Medical Center between January 1, 2000, and January 27, 2011, were identified. For each patient, CrCl was estimated by using the CG equation and glomerular filtration rate (GFR) was estimated by using the CKD-EPI equation. The patients were considered cisplatin-ineligible if CrCl <60 mL/min or if GFR was <60 mL/min per 1.73 m(2). RESULTS: A total of 116 patients were included. The median CrCl estimated by CG was 58.93 mL/min, whereas the median GFR estimated by CKD-EPI was 64.67 mL/min per 1.73 m(2). When using the CG formula, 53% of our cohort was cisplatin ineligible, whereas 46% of the cohort was ineligible when using the CKD-EPI formula. The probability of deeming a patient ineligible when using the CG formula was 17% higher than the probability of deeming a patient ineligible when using the CKD-EPI formula: PR 1.17 (95% CI, 1.03-1.34); P = .0203. CONCLUSION: In our retrospective study, the CKD-EPI formula was less likely to deem a patient ineligible for cisplatin-based therapy compared with the CG formula. This finding was hypothesis generating, and prospective evaluation is necessary to determine the clinical relevance of using this more accurate method of renal function assessment in chemotherapy decision making.

APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy.

A chromosome 22q13 locus strongly associates with increased risk for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-1-associated nephropathy (HIVAN), and hypertensive ESRD among individuals of African descent. Although initial studies implicated MYH9, more recent analyses localized the strongest association within the neighboring APOL1 gene. In this replication study, we examined the six top-most associated variants in APOL1 and MYH9 in an independent cohort of African Americans with various nephropathies (44 with FSGS, 21 with HIVAN, 32 with IgA nephropathy, and 74 healthy controls). All six variants associated with FSGS and HIVAN (additive ORs, 1.8 to 3.0; P values 3 × 10(-2) to 5 × 10(-5)) but not with IgA nephropathy. In conditional and haplotype analyses, two APOL1 haplotypes accounted for virtually all of the association with FSGS and HIVAN on chromosome 22q13 (haplotype P value = 5.6 × 10(-8)). To assess the role of MYH9 deficiency in nephropathy, we crossbred Myh9-haploinsufficient mice (Myh9(+/-)) with HIV-1 transgenic mice. Myh9(+/-) mice were healthy and did not demonstrate overt proteinuria or nephropathy, irrespective of the presence of the HIV-1 transgene. These data further support the strong association of genetic variants in APOL1 with susceptibility to FSGS and HIVAN among African Americans.

Paraneoplastic glomerulopathy secondary to retroperitoneal sarcoma: a case report.

Glomerulopathy is a rare form of paraneoplastic disease. We present the second reported case of paraneoplastic glomerulopathy due to a retroperitoneal sarcoma. The patient presented with generalized edema and nephrotic syndrome. CT scan showed two large retroperitoneal masses. One large retroperitoneal mass was resected. Post-operatively, she developed kidney failure and biopsy showed minimal change disease. With steroid therapy, patient's symptoms went into remission. We hypothesize that minimal change paraneoplastic glomerulopathy developed due to damage from cytokines released from a T-cell mediated response to the malignancy.

HIV and CKD epidemiology.

Nephrologists can serve many important functions for HIV-infected patients, including identifying risks for developing kidney disease, detecting and diagnosing kidney disease, distinguishing antiretroviral-induced kidney injury from kidney disease in the setting of antiretroviral therapy, comanaging the clinical course and complications of CKD, and preparing patients for dialysis and/or transplantation. The epidemiology of kidney disease in HIV informs us for these functions by describing the natural history of disease, its frequent occurrence in high-risk communities, and its potential causes. Risk factors that drive CKD in HIV are black race, hypertension, diabetes, HIV viral replication with low CD4 cell counts, high viral load or acquired immune deficiency syndrome-defining conditions, and antiretroviral agents with nephrotoxic potential. The prevalence of these risk factors in any population determines the magnitude of the problem, which can range from as low as 2% to as high as 30%. Recent research focuses on kidney health in HIV. Important links between HIV viral replication and glomerular filtration rate, even in patients with normal kidney function, are now being reported. A review of these data provides the foundation for a better understanding of kidney disease and, hopefully, better treatment for patients with HIV.

Diminished benefits of drug-eluting stents versus bare metal stents in patients with severe renal insufficiency.

BACKGROUND: Since their introduction, the use of drug-eluting stents (DES) has increasingly become standard practice due to their decreased rates of in-stent restenosis and target lesion revascularization (TLR) rates in comparison to bare metal stents (BMS). However, these benefits have not been reproduced in patients with severe renal disease (SRD). This study compared TLR rates in patients with severe renal insufficiency treated with DES vs. BMS. METHODS: Between 2003 and 2006, we collected data on 6,220 consecutive patients receiving either DES or BMS. Both groups were similar in angiographic and clinical variables. TLR rates at 270 days and 1 year were then compared between patients receiving DES or BMS with varying creatinine clearance (CrCl). RESULTS: At 1 year after PCI, TLR rates were significantly lower for DES in patients with CrCl >60 (5 vs. 9.3%; p < 0.0001). However, in patients with CrCl <40 ml/min or on dialysis there was no significant difference in TLR rates for DES vs. BMS. CONCLUSION: While DES showed improved clinical outcomes in patients with normal and mildly impaired renal function, they showed no benefit over BMS in patients with moderate to severe renal insufficiency. Coupled with the possibly increased risk of late stent thrombosis with DES, BMS may be a more appropriate and safer stent in this population.

Cardiovascular risk factors in patients with chronic kidney disease.

Patients with chronic kidney disease have a higher burden of cardiovascular disease, which increases in a dose-dependent fashion with worsening kidney function. Traditional cardiovascular risk factors, including advanced age, diabetes mellitus, hypertension and dyslipidemia, have an important role in the progression of cardiovascular disease in patients who have a reduced glomerular filtration rate, especially in those with mild-to-moderate kidney disease. In patients with severe kidney disease, nontraditional or 'novel' risk factors, including inflammation, oxidative stress, vascular calcification, a prothrombotic milieu, and anemia, seem to confer additional risk. In this Review, we highlight factors that increase cardiovascular risk in patients with a reduced estimated glomerular filtration rate. In addition, we discuss therapeutic strategies for reducing cardiovascular risk in patients with kidney disease, whose unique atherosclerotic phenotype might require an approach that differs from traditional models developed in populations with normal kidney function. Therapeutic paradigms for patients with chronic kidney disease and cardiovascular risk factors must be evaluated in randomized trials, from which such patients have often been excluded.

Estimating glomerular filtration rate in patients with HIV infection.

Accurate markers of glomerular filtration rate in human immunodeficiency virus (HIV)-infected persons would be useful for early diagnosis of HIV-associated nephropathy and other glomerular diseases, and for identifying patients at high risk for subsequent declines in kidney function who also may develop cardiovascular disease or renal complications from antiretroviral agents or other therapies. Creatinine-based estimates of glomerular filtration rate have not been tested rigorously in HIV-infected persons. Their accuracy has been questioned in malnourished patients, with or without a wasting syndrome, and in those treated with anabolic steroids. Cystatin C level is increased in HIV, but more studies are needed to determine its association with kidney function, inflammation, and long-term outcomes.