Mixed uremic osteodystrophy: an ill-described common bone pathology in patients with chronic kidney disease.

Renal osteodystrophy (ROD) starts early and progresses with further loss of kidney function in patients with chronic kidney disease (CKD). There are four distinct types of ROD based on undecalcified bone biopsy results. Adynamic bone disease and osteomalacia are the predominant forms of low bone turnover, while hyperparathyroid bone disease and mixed uremic osteodystrophy (MUO) are typically associated with high bone turnover. MUO is a prevalent but poorly described pathology that demonstrates evidence of osteomalacia on top of the high bone formation/resorption. The prevalence of MUO ranges from 5 to 63% among different studies. The pathogenesis of MUO is multi-factorial. Altered phosphate homeostasis, hypocalcemia, vitamin D deficiency, increased FGF-23, interleukins 1 and 6, TNF-α, amyloid, and heavy metal accumulation are the main inducers of MUO. The clinical findings of MUO are usually non-specific. The use of non-invasive testing such as bone turnover markers and imaging techniques might help to suspect MUO. However, it is usually impossible to precisely diagnose this condition without performing bone biopsy. The principal management of MUO is to control the maladaptive hyperparathyroidism along with correcting any nutritional mineral deficiencies that may induce mineralization defect. MUO is a common but still poorly understood bone pathology category; it demonstrates the complexity and difficulty in understanding ROD. A large prospective bone biopsy-based studies are needed for better identification as proper diagnosis and management would improve the outcome of patients with MUO.

Characteristics and outcomes of prisoners hospitalized due to COVID-19 disease.

BACKGROUND: Correctional facilities have faced unique challenges during the COVID-19 pandemic. A COVID-19 outbreak was reported in the Federal Medical Center (FMC) in Lexington, Kentucky, a prison for inmates requiring medical and mental care. The main objective of this study was to examine clinical characteristics and outcomes of prisoners vs. non-prisoners admitted to the hospital due to COVID-19 disease. MATERIALS AND METHODS: We did a retrospective, comparative cohort study of 86 consecutive COVID-19 patients admitted to the University of Kentucky hospital between March 1 and June 1, 2020. Among these, 37 patients were inmates from a single local FMC and 49 were non-inmates. RESULTS: Mean (SD) age of the cohort was 59.1 (14.5) years, 68.6% were male and 61.6% white. All inmates were men. No significant differences in age or race were observed between inmates and non-inmates. Hypertension (81%), obesity (62%), COPD/asthma (43%), diabetes (41%), coronary artery diseases (38%), and chronic kidney disease (22%) were among the most common comorbidities prevalent in inmates. Inmates had overall higher serum creatinine and C-reactive protein, more proteinuria, and lower platelet counts at the time of hospital admission when compared to non-inmates. Incidence of acute kidney injury (AKI) was more frequent in inmates (68 vs. 38% in non-inmates, p = 0.008). Overall, patients who developed AKI had higher acuity of illness with more requirement of ICU care and mechanical ventilation. Kidney replacement therapy (KRT) was provided to 12.8% of patients. Inpatient mortality occurred in 15.1% of patients and was not different in inmates vs. non-inmates (13.5 vs. 16.3%, p = 0.862). All survivors became independent of KRT, and ~ 1 of 10 survivors had a reduction of eGFR ≥ 25% from baseline by the time of discharge, which was more frequent in inmates vs. non-inmates, 15.6 vs. 2.4%, p = 0.042, respectively. CONCLUSION: Inmates represent a vulnerable population with prevalent comorbidity and susceptibility to COVID-19. When compared to non-inmates with COVID-19, inmates exhibited higher incidence of AKI and, for survivors, less kidney recovery by the time of hospital discharge. Surveillance of long-term sequela of COVID-19 is warranted in this susceptible inmate population.

The 2018 Banff Working Group classification of definitive polyomavirus nephropathy: A multicenter validation study in the modern era.

Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the Banff Working Group published a new 3-tier morphologic classification scheme derived from in-depth statistical analysis of a large multinational patient cohort. Here we report a multicenter "modern-era" validation study that included 99 patients with definitive PVN transplanted post January 1, 2009 and followed the original 2018 study design. Results validate the PVN classification, that is, the 3 PVN disease classes predicted clinical presentation, allograft function, and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks posttransplant [median], P = .004), and showed significantly better function at 24 months postindex biopsy (serum creatinine 1.75 mg/dl, geometric mean, vs class 2: P = .037, vs class 3: P = .013). Class 1 presented during long-term follow-up with a low graft failure rate: 5% class 1, vs 30% class 2, vs 50% class 3 (P = .009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24 months postdiagnosis; serum creatinine with persistence: 2.48 mg/dL vs 1.65 with clearance, geometric means, P = .018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis.

Effect of amphotericin B-deoxycholate (Fungizone) on the mitochondria of Wistar rats' renal proximal tubules cells.

Amphotericin B-deoxycholate (Fungizone [FZ]) is a widely used potent antimycotic drug in spite of its nephrotoxic effect via different mechanisms. The effect of FZ on renal cell bioenergetics is not clear. The current study evaluated the effect of FZ on the bioenergetics of albino rats' isolated renal proximal tubule cells (PTCs). The cytotoxic effect of FZ on the isolated renal cells was assessed by MTT and lactate dehydrogenase (LDH) assays. The effect of FZ on the PTCs uptake (OAT1 and OCT2) and efflux (P-gp and MRP2) transporters was evaluated. Then, the effect of FZ on mitochondria was assessed by studying complexes I-IV activities, lactate assay, oxygen consumption rates (OCR), and western blotting for all mitochondrial complexes. Moreover, the effect of FZ on mitochondrial membrane fluidity (MMF) and fatty acids composition was evaluated. Additionally, the protective effect of coenzyme q10 was studied. Outcomes showed that FZ was cytotoxic to the PTCs in a concentration and time-dependent patterns. FZ significantly inhibited the studied uptake and efflux tubular transporters with inhibition of the mitochondrial complexes activities and parallel increase in lactate production and decrease in OCRs. Finally, FZ significantly reduced the expression of all mitochondrial complexes in addition to significant increase in MMF and MMFA concentration. Coenzyme Q10 was found to significantly decrease FZ-induced cytotoxicity and transporters impairment in the PTC. FZ significantly inhibits bioenergetics of PTC, which may stimulate the cascade of cell death and clinical nephrotoxicity.

Pathogenesis and management of vascular calcification in CKD and dialysis patients.

Patients with chronic kidney disease (CKD) have a predisposition to develop vascular calcification due to dysregulated homeostatic mechanisms, which lead to an imbalance in the circulatory promoters and inhibitors of vascular calcification, leading to a net calcification stress. These factors promote ectopic calcification and induce vascular smooth muscle cells to undergo osteogenic differentiation and actively calcify the vascular media. The article summarizes clinically relevant pathogenic mechanisms of vascular calcification in patients with CKD and in dialysis patients and summarizes novel therapeutic interventions. In addition to the management of traditional cardiovascular risk factors, patients with CKD-mineral and bone disorder need close attention in the management of the mineral metabolism to prevent adverse effects on the bone and vascular compartments. This article reviews current evidence and therapeutic guidelines in the management of mineral metabolism in CKD and dialysis.

PTH assays in dialysis patients: Practical considerations.

Parathyroid hormone (PTH) 1-84 is the main biologically active hormone produced by the parathyroid cells. Circulating PTH molecules include the whole PTH 1-84 along with amino (N) and carboxyl (C) terminal fragments. While PTH is the best available noninvasive biomarker to assess bone turnover in dialysis patients, the biological roles of individual circulating PTH fragments are still not completely known. The understanding that there is an enormous variation in the target specificity of currently available PTH assays for different circulating forms of PTH has led to the evolution of assays from first to second then third generation. With a reduction in kidney function, there is a preferential increase in circulating C fragments and non-PTH 1-84 forms, resulting in a decrease in the ratio of PTH 1-84/non-PTH 1-84. However, there are also substantial differences in between-assay measurements, with several fold variations in results. Targets based on multiples of the upper limit of normal (ULN) should be used rather than PTH ranges using absolute iPTH values. To date, the second-generation PTH remains the most widely used assay. Current guidelines recommend following iPTH trends rather than absolute values. Herein, we highlight problems and challenges in PTH assays/measurements and their interpretations in dialysis patients.

Long-term outcomes and management considerations after parathyroidectomy in the dialysis patient.

Parathyroidectomy (PTX) remains an important intervention for dialysis patients with poorly controlled secondary hyperparathyroidism (SHPT), though there are only retrospective and observational data that show a mortality benefit to this procedure. Potential consequences that we seek to avoid after PTX include persistent or recurrent hyperparathyroidism, and parathyroid insufficiency. There is considerable subjectivity in defining and diagnosing these conditions, given that we poorly understand the optimal PTH targets (particularly post PTX) needed to maintain bone and vascular health. While lowering PTH after PTX decreases bone turnover, long-term changes in bone activity have been poorly explored. High turnover bone disease, usually present at the time a PTX is considered, often swings to a state of low turnover in the setting of sufficiently low PTH levels. It remains unclear if all low bone turnover equate with disease. However, such changes in bone turnover appear to predispose to vascular calcification, with positive calcium balance after PTX being a potential contributor. We know little of how the post-PTX state resets calcium balance, how calcium and VDRA requirements change or what kind of adjustments are needed to avoid calcium loading. The current consensus cautions against excessive reduction of PTH although there is insufficient evidence-based guidance regarding the management of chronic kidney disease - mineral bone disease (CKD-MBD) parameters in the post-PTX state. This article aims to compile existing research, provide an overview of current practice with regard to PTX and post-PTX chronic management. It highlights gaps and controversies and aims to re-orient the focus to clinically relevant contemporary priorities in CKD-MBD management after PTX.

Impact of human leukocyte antigen and calculated panel reactive antibody on BK viremia in kidney transplant recipients: A single-center experience and literature review.

BACKGROUND: The aim of this retrospective analysis was to investigate the effect of human leukocyte antigen (HLA) and calculated panel reactive antibody (cPRA) on BK virus activation as evidenced by BK viremia (BKV). PATIENTS AND METHODS: At our institution, 649 kidney transplant patients were screened for BKV from 2009 to 2017. Patients were considered to have BKV if they had >10 000 copies/mL of BK DNA in their blood. Donor and recipient HLA and cPRA, demographic, clinical and laboratory data, as well as immunosuppressive medications were collected. RESULTS: We identified 122 BK positive and 527 BK negative patients. Only 25% of the patients had cPRA of 20% or more, and 64% had more than three HLA-A, -B, and -DR mismatches. In both univariate and multivariate analyses, male gender, age, and maintenance of steroid therapy significantly increased the risk of BKV (P = 0.005, 0.005 and <0.001, respectively). The degree of cPRA and the individual HLA allele and HLA allele matching did not significantly affect BKV. CONCLUSION: Neither the degree of HLA mismatching nor cPRA appears to affect BKV. Moreover, no specific HLA allele, HLA allele matching, or cPRA were associated with BKV.

Serum bone markers in ROD patients across the spectrum of decreases in GFR: Activin A increases before all other markers
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INTRODUCTION: Renal osteodystrophy (ROD) develops early in chronic kidney disease (CKD) and progresses with loss of kidney function. While intact parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (1,25D), and fibroblast growth factor-23 (FGF-23) levels are usually considered the primary abnormalities in ROD development, the role of serum activin A elevations in CKD and its relationships to ROD have not been explored. The aims of this study were to evaluate serum activin A at different CKD stages, and to establish the relationships between activin A, bone biomarkers, and bone histomorphometric parameters. MATERIALS AND METHODS: 104 patients with CKD stages 2 - 5D underwent bone biopsies. We measured in the serum activin A, BSAP, DKK1, FGF-23, α-Klotho, intact PTH, sclerostin, TRAP-5b, and 1,25D. Biochemical results were compared across CKD stages and with 19 age-matched controls with normal kidney function. RESULTS: Median activin A levels were increased in all stages of CKD compared to controls from 544 pg/mL in CKD 2 (431 - 628) to 1,135 pg/mL in CKD 5D (816 - 1,456), compared to 369 pg/mL in controls (316 - 453, p < 0.01). The increase of activin A in CKD 2 (p = 0.016) occurred before changes in the other measured biomarkers. Activin A correlated with intact PTH and FGF-23 (r = 0.65 and 0.61; p < 0.01) and with histomorphometric parameters of bone turnover (BFR/BS, Acf, ObS/BS and OcS/BS; r = 0.47 - 0.52; p < 0.01). These correlations were comparable to those found with intact PTH and FGF-23. CONCLUSION: Serum activin A levels increase starting at CKD 2 before elevations in intact PTH and FGF-23. Activin A correlates with bone turnover similar to intact PTH and FGF-23. These findings suggest a role for activin A in early development of ROD.

Long term outcomes of patients transplanted for hepatocellular carcinoma with human immunodeficiency virus infection.

BACKGROUND: We aimed to study outcomes in HIV + patients with HCC in the US following Liver Transplantation (LT) using the UNOS dataset. METHODS: The database was queried from 2003 to 2016 for patients undergoing LT with HCC, HIV+, and HCC/HIV+. RESULTS: Out of 17,397 LT performed for HCC during the study period, 113 were transplanted for HCC with HIV infection (91 isolated livers). Patients transplanted for HCC/HIV+ were younger (55.54 ± 5.89 vs 58.80 ± 7.37, p < 0.001), had lower total bilirubin (1.20 vs 1.60, p = 0.042) significantly lower BMI (25.35 ± 4.43 vs 28.39 ± 5.17, p < 0.001) and were more likely to be co-infected with HBV (25.3% vs 8.2% p < 0.001) than those transplanted for HCC alone. HCC/HIV + patients were found to have a 3.8 fold increased risk of peri-operative mortality at 90 days after matching. HCC/HIV + recipients had 54% decreased long-term survival within the HCC cohort. Our initial analysis of overall graft and patient survival found significant differences between HCC/HIV and HCC/HIV + recipients. However, these variances were lost after case-matching. Recurrence and disease free survival were similar in HCC alone vs HCC/HIV + recipients. CONCLUSIONS: Our analysis suggests that excellent outcomes can be achieved in selected patients with HCC/HIV+.

Parathyroidectomy-A last resort for hyperparathyroidism in dialysis patients.

Despite advancements in the medical management of secondary hyperparathyroidism, parathyroidectomy is still necessarily in some patients. However, patients' selection, optimal surgical intervention and long-term outcome are still not well-defined and very challenging for the practicing nephrologists. In this manuscript we will attempt to answer several questions related to parathyroidectomy in dialysis patients. We will discuss the indications, the appropriate parathyroidectomy surgical techniques and current guidelines for parathyroidectomy. We will also discuss short- and long-term outcome and analyze the pros and cons of the procedure. It is readily apparent that the performance of parathyroidectomy in dialysis patients should be highly individualized.

Urinary calcium excretion and bone turnover in osteoporotic patients
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INTRODUCTION: It is well documented that patients with osteoporosis (OP) have high incidence of hypercalciuria (HC). However, the mechanism of HC in patients with OP is not well established. It is thought to be the result of high bone turnover (HBT) with excessive bone resorption. OP also frequently presents with low bone turnover (LBT). At this time, it is not clear whether OP with LBT is also associated with hypercalciuria. PURPOSE: The purpose of this study is to evaluate urinary calcium excretion in osteoporotic patients with HBT and LBT. MATERIALS AND METHODS: This is a retrospective study of 132 patients with osteoporosis who underwent bone biopsy at the University of Kentucky between January 2010 and December 2012. Based on bone biopsy results, patients were divided into HBT or LBT groups. Demographic data, medical history, bone mineral density, serum creatinine, calcium, phosphorus, estimated glomerular filtration rate (eGFR), filtered calcium load, fractional excretion of calcium and phosphorus, 25-hydroxy vitamin D levels, and 24-hour urinary calcium excretion and creatinine were obtained from the patients' medical records. Also, intact parathyroid hormone (iPTH), serum osteocalcin, bone-specific alkaline phosphatase, N-telopeptide of type I collagen, and urine pyridinium levels were measured. RESULTS: Hypercalciuria was present in approximately half of the patients in both the HBT and LBT groups. Patients with HBT OP were significantly younger than those with LBT OP (p = 0.013). There was no difference between HBT and LBT patients in 24-hour urinary calcium excretion, serum creatinine, calcium, phosphorus, eGFR, filtered calcium load, and fractional excretion of phosphorus. Mean values of serum osteocalcin and serum N-telopeptide of type I collagen were significantly lower in the LBT compared to the HBT group (p = 0.000 and 0.0152, respectively). There was a significant correlation between filtered calcium load and urinary calcium excretion in HBT patients but not in patients with LBT. Fractional excretion of calcium significantly correlated with urinary calcium excretion in both groups. There was no correlation between kidney function and 24-hour urinary calcium excretion. There was no correlation between dual-emission X-ray absorptiometry T-scores and 24-hour urinary calcium excretion. CONCLUSION: HC is frequently present in patients with OP regardless of the underlying bone turnover status. This may suggest the presence of a bone-derived renal calcium regulating factor(s). Further studies are needed to understand the exact mechanism and the potential consequences of HC in OP patients.
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Idiopathic Membranous Nephropathy: Diagnostic and Therapeutic Challenges.

BACKGROUND: In adults, membranous nephropathy (MN) is a major cause of nephrotic syndrome. While a majority of cases of MN are idiopathic, secondary forms can be seen in the setting of autoimmune disease, neoplasia, infection, and after being exposed to certain therapeutic agents. Both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections could cause MN. However, the effect of coexisting HIV and HCV infection on the spectrum and progression of kidney disease as well as the effect of MN treatment on HIV and HCV infection are not well known. METHODS: In this study, we describe a patient with hemophilia A and acquired HIV and HCV infections, a patient who developed severe nephrotic syndrome and for whom renal biopsy showed MN. RESULTS: Patient responded well to adrenocorticotropic hormone gel without adversely affecting HIV or HCV infections. CONCLUSION: Adrenocorticotropic hormone gel might be useful in the management of complex cases of idiopathic MN.

Thrombotic microangiopathy in systemic lupus erythematosus: efficacy of eculizumab.

Thrombotic microangiopathy (TMA) is a severe disorder with poor outcomes. The cause is unknown for many patients, although TMA is associated with connective tissue disorders, including systemic lupus erythematosus (SLE). While uncommon, TMA is one of the most serious complications of SLE and in many cases may be resistant to therapy. We report a patient with SLE complicated by TMA that was refractory to standard therapy but responded well to eculizumab, with continued remission after 1 year of follow-up. Eculizumab might be useful in the management of resistant cases of TMA caused by SLE.

Fibrillary glomerulonephritis masquerading as rapidly progressive glomerulonephritis with pseudo-linear glomerular basement membrane staining.

Fibrillary glomerulonephritis (FGN) is a rare disorder with poor renal prognosis. It is a heterogeneous disease associated with significant risk of end-stage renal disease (ESRD). Its etiology and pathogenesis have not been clearly identified. We report a case of a patient presenting with hypertensive crisis, nephrotic range proteinuria, and rapidly progressive glomerulonephritis (RPGN). The kidney biopsy demonstrates crescentic GN on light microscopy (LM) and strong pseudo-linear/globular glomerular basement membrane (GBM) staining for immunoglobulin G on immunofluorescence (IF), suggestive of anti-GBM disease. However, circulating anti-GBM antibodies were negative. Electron microscopy (EM) revealed fibrillary deposits in the GBM, confirming the diagnosis of FGN. Review of the literature revealed very few reported similar cases. It appears that severe hypertension and heavy proteinuria, while uncommon in anti-GBM disease, are consistent findings in RPGN form of FGN.

FGF-23 serum levels and bone histomorphometric results in adult patients with chronic kidney disease on dialysis.

BACKGROUND: Fibroblast growth factor-23 (FGF-23) is a hormone principally produced by osteocytes/osteoblasts. In patients with chronic kidney disease (CKD), FGF-23 levels are usually elevated and can reach up to 300 - 400 times the normal range. FGF-23 is regulated by local bone-related and systemic factors, but the relationship between circulating FGF-23 concentrations and bone remodeling and mineralization in CKD has not been well characterized. In the current study, we examined the relationship between FGF-23 levels and bone histomorphometry parameters in adult patients with renal osteodystrophy. MATERIAL AND METHODS: 36 patients on dialysis (CKD-5D) underwent bone biopsies after tetracycline double labeling. Blood drawings were done at time of biopsy to determine serum levels of markers of bone and mineral metabolism. RESULTS: Patients with high bone turnover had higher values of serum FGF-23 than patients with low bone turnover. FGF-23 levels correlated with activation frequency (ρ = 0.60, p < 0.01) and bone formation rate (ρ = 0.57, p < 0.01). Normal mineralization was observed in 90% of patients with FGF-23 levels above 2,000 pg/mL. Furthermore, FGF-23 correlated negatively with mineralization lag time (ρ = -0.69, p < 0.01) and osteoid maturation time (ρ = -0.46, p < 0.05) but not with osteoid thickness (ρ = 0.08, ns). Regression analysis showed that FGF-23 was the only independent predictor of mineralization lag time. FGF-23 correlated with cancellous bone volume (ρ = 0.38, p < 0.05) but did not predict it. CONCLUSION: Circulating FGF-23 concentrations may reflect alterations in ongoing bone formation along with active mineralization, but not exclusively in bone formation or mineralization. Abnormal mineralization lag time (> 100 days) was mainly seen in patients with FGF-23 levels less than 2,000 pg/mL, while very high levels of FGF-23 are associated with normal mineralization lag time.

Secondary Osteoporosis and Metabolic Bone Diseases.

Fragility fracture is a worldwide problem and a main cause of disability and impaired quality of life. It is primarily caused by osteoporosis, characterized by impaired bone quantity and or quality. Proper diagnosis of osteoporosis is essential for prevention of fragility fractures. Osteoporosis can be primary in postmenopausal women because of estrogen deficiency. Secondary forms of osteoporosis are not uncommon in both men and women. Most systemic illnesses and organ dysfunction can lead to osteoporosis. The kidney plays a crucial role in maintaining physiological bone homeostasis by controlling minerals, electrolytes, acid-base, vitamin D and parathyroid function. Chronic kidney disease with its uremic milieu disturbs this balance, leading to renal osteodystrophy. Diabetes mellitus represents the most common secondary cause of osteoporosis. Thyroid and parathyroid disorders can dysregulate the osteoblast/osteoclast functions. Gastrointestinal disorders, malnutrition and malabsorption can result in mineral and vitamin D deficiencies and bone loss. Patients with chronic liver disease have a higher risk of fracture due to hepatic osteodystrophy. Proinflammatory cytokines in infectious, autoimmune, and hematological disorders can stimulate osteoclastogenesis, leading to osteoporosis. Moreover, drug-induced osteoporosis is not uncommon. In this review, we focus on causes, pathogenesis, and management of secondary osteoporosis.