How We Got Where We Are in Blood Pressure Targets.

PURPOSE OF REVIEW: While we started clinical trials evaluating the benefit of lowering systolic BP's >160 mm Hg and diastolic BPs of <130 mm Hg, the latest guideline suggests a target of <130/80 mm Hg in those with hypertension. This article summarizes exactly how we got to where we are looking over the last half-century. RECENT FINDINGS: Our understanding of systolic and diastolic blood pressure targets to improve cardiovascular outcomes has changed substantially over the past 5 decades. Regarding diastolic blood pressure targets to improve cardiovascular outcomes, initially the VA1 in 1967 had set the goal to <115 mmHg. Over time, several studies including the VA2, Hypertension Optimal Treatment (HOT), and United Kingdom Prospective Diabetes Study Group 38 (UKPDS38) highlighted even greater cardiovascular benefit with lower diastolic targets <80 mmHg, especially in diabetic patients. Of equal importance, multiple studies have focused the attention to systolic blood pressure targets. Starting in 1948 with the Framingham study, passing through the Systolic Hypertension in the Elderly Program (SHEP), Syst-Eur and Syst-China trials, all have set the systolic blood pressure goal <150 mmHg. Most recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed an improved cardiovascular outcome with a systolic blood pressure target <140 mmHg in patients with type 2 diabetes, while the Systolic Blood Pressure Intervention Trial (SPRINT) in non-diabetic patients moved it closer to 120 mmHg. There is "no one size fits all" when it comes to blood pressure targets to improve cardiovascular outcomes. To progress our understanding of individual blood pressure goals, future studies might develop a more standardized approach to highlight characteristics such as design and end point definitions while allowing clinical practitioners greater latitude to adapt guideline recommendations to individual patient characteristics and clinical needs.

Diffuse membranoproliferative glomerulonephritis with focal sclerosis and renal amyloidosis in an adult male with autosomal dominant dystrophic epidermolysis bullosa: a case report.

Previous reports of glomerular disease in adult patients with autosomal dominant dystrophic epidermolysis bullosa (EB) are limited and include post-infectious glomerulonephritis, IgA nephropathy, amyloidosis, and leukocytoclastic vasculitis. To our knowledge, membranoproliferative glomerulonephritis (MPGN) has not been described before. We report a case of a 39-year-old male with autosomal dominant dystrophic EB, presenting with bilateral leg swelling of one-week duration. There was no other significant past medical history. The physical examination was remarkable for scars and erosions over all body areas, with all extremities with blisters and ulcers covered, absent finger and toenails and bilateral lower extremity edema. Serum creatinine was 0.9 mg/dL, albumin 1.3 g/dL and urine protein excretion 3.7 g/24 h. Viral markers (hepatitis-B, C, and HIV), complement c3 and c4 levels and auto-immune antibody profile all remained negative or within normal limits. Renal ultrasound and echocardiogram were normal. Renal biopsy recovered 14 glomeruli, all with proliferation of mesangial and endothelial cells as well as an expansion of the mesangial matrix, focal segmental sclerosis and amorphous homogeneous deposits demonstrating apple-green birefringence under polarized light with Congo red stain. Our observation emphasizes the importance of recognizing MPGN and secondary amyloidosis in patients with EB, especially with the availability of newer treatment modalities.

Prevention of Intradialytic Hypotension in Hemodialysis Patients: Current Challenges and Future Prospects.

Intradialytic hypotension, defined as rapid decrease in systolic blood pressure of greater than or equal to 20 mmHg or in mean arterial pressure of greater than or equal to 10 mmHg that results in end-organ ischemia and requires countermeasures such as ultrafiltration reduction or saline infusion to increase blood pressure to improve patient's symptoms, is a known complication of hemodialysis and is associated with several potential adverse outcomes. Its pathogenesis is complex and involves both patient-related factors such as age and comorbidities, as well as factors related to the dialysis prescription itself. Key factors include the need for volume removal during hemodialysis and a suboptimal vascular response which compromises the ability to compensate for acute intravascular volume loss. Inadequate vascular refill, incorrect assessment or unaccounted changes of target weight, acute illnesses and medication interference are further potential contributors. Intradialytic hypotension can lead to compromised tissue perfusion and end-organ damage, both acutely and over time, resulting in repetitive injuries. To address these problems, a careful assessment of subjective symptoms, minimizing interdialytic weight gains, individualizing dialysis prescription and adjusting the dialysis procedure based on patients' risk factors can mitigate negative outcomes.

The link between bone and coronary calcifications in CKD-5 patients on haemodialysis.

BACKGROUND: Vascular calcifications are frequent in Stage 5 chronic kidney disease (CKD-5) patients receiving haemodialysis. The current study was designed to evaluate the associations between bone turnover/volume and coronary artery calcifications (CAC). METHODS: In 207 CKD-5 patients, bone biopsies, multislice computed tomography of the coronary arteries and blood drawings for relevant biochemical parameters were done. The large number of CKD-5 patients enrolled allowed separate evaluation of patients with CAC versus patients without CAC and adjustment for traditional and non-traditional risk factors for CAC. RESULTS: When all patients were analysed, associations were found between CAC and bone turnover, bone volume, age, gender and dialysis vintage. When only patients with CAC were included, there was a U-shaped relationship between CAC and bone turnover, whilst the association with bone volume was lost. In these patients, the relationship of CAC with age, gender and dialysis vintage remained. CONCLUSIONS: Beyond the non-modifiable risk factors of age, gender and dialysis vintage, these data show that bone abnormalities of renal osteodystrophy amenable to treatment should be considered in the management of patients with CAC.

Impact of kidney transplantation on functional status.

BACKGROUND AND AIMS: Functional capacity (FC) is known to affect morbidity and mortality in kidney transplantation. Despite this important role, little is known about the variables influencing post-transplant FC. Our study aims at identifying these crucial associations. METHOD: Our study included 16,684 renal transplant recipients (RTR). Patients had transplant between 1 September 2018 and 1 September 2019. Mild functional impairment was defined as those with a KPSS score > or = 80; moderate functional impairment was defined as those with a KPSS score between 50 and 70 and severe functional impairment was defined as those with a KPSS score < or =40. The outcome measured was FC at follow-up one-year post-transplant. Abnormal FC at follow-up was defined as those with KPSS score less than 80%. Normal FC at follow-up was defined as those with KPSS score equal or above 80%. Multivariate logistic regression was used to assess with the relationship between patient characteristics and abnormal functional status post-transplant. RESULTS: Three groups were identified; those with none-to-mild functional impairment at time of transplant (Group A; n = 8388), those who had moderate impairment at time of transplant (Group B; n = 7694) and those who had severe impairment at time of transplant (Group C; n = 602). Abnormal FC at one-year post transplant was present in 7.69%, 28.89%, 49.49% of patients in group A, B and C, respectively. Glucocorticoid withdrawal was associated with lower risk of developing abnormal FC post-transplant (OR = 0.75, p value = .02, 95% confidence intervals: 0.64 to 0.97), while recipient diabetes was associated with higher risk of abnormal FC (OR = 1.44, p value <.01, 95% confidence intervals: 1.20 to 1.74) in adjusted model. CONCLUSION: Kidney transplantation is associated with substantial improvement in all stages of FC in KTRs. Glucocorticoid withdrawal and diabetes mellitus are potentially modifiable factors of FC and merit further considerations during pre-transplant workup and post-transplant immunosuppressive therapeutic planning.Key messagesKidney transplantation is associated with substantial improvement in all stages of FC in KTRs.Glucocorticoid withdrawal and diabetes mellitus are potentially modifiable factors of FC and merit further considerations during pre-transplant workup and post-transplant immunosuppressive therapeutic planning.

Intact PTH combined with the PTH ratio for diagnosis of bone turnover in dialysis patients: a diagnostic test study.

BACKGROUND: Determination of parathyroid hormone (PTH) level is the most commonly used surrogate marker for bone turnover in patients with stage 5 chronic kidney disease on dialysis therapy (CKD-5D). The objective of this study is to evaluate the predictive value of various PTH measurements for identifying low or high bone turnover rate. STUDY DESIGN: Diagnostic test study. SETTINGS & PARTICIPANTS: 141 patients with CKD-5D from 15 US hemodialysis centers. INDEX TESTS: Intact PTH, PTH 1-84, and PTH ratio (ratio of level of PTH 1-84 to level of large carboxy-terminal PTH fragments). REFERENCE TEST OR OUTCOME: Bone turnover determined using bone histomorphometry. OTHER MEASUREMENTS: Demographic and treatment-related factors, serum calcium and phosphorus. RESULTS: Patients presented histologically with a broad range of bone turnover abnormalities. In white patients with CKD-5D (n = 70), PTH ratio <1.0 added to intact PTH level <420 pg/mL increased the positive predictive value for low bone turnover from 74% to 90%. In black patients (n = 71), adding PTH ratio <1.2 to intact PTH level <340 pg/mL increased the positive predictive value for low bone turnover from 48% to 90%. Adding PTH ratio >1.6 to intact PTH level of 340-790 pg/mL increased the positive predictive value for high bone turnover from 56% to 71%. LIMITATIONS: Because the research protocol called for carefully controlled blood specimen handling, blood drawing and routine specimen handling might be less stringent in clinical practice. By limiting study participation to black and white patients with CKD-5D, we cannot comment on the roles of intact PTH, PTH 1-84, and PTH ratio in other racial/ethnic groups. CONCLUSION: In black patients with CKD-5D, the addition of PTH ratio to intact PTH measurements is helpful for diagnosing low and high bone turnover. In white patients with CKD-5D, it aids in the diagnosis of low bone turnover.

Refractory ascites as a presenting feature of extramedullary plasmacytoma in an end-stage renal disease patient with HIV infection.

Refractory ascites as the only presenting feature of an extramedullary plasmacytoma complicating end-stage renal disease and HIV infection has not been described yet. We describe a case of a 39-year-old female with HIV-associated nephropathy manifesting with ascites formation after transition from peritoneal dialysis (PD) to hemodialysis (HD). Earlier on, she received cycler-assisted PD for 5 years uneventfully. A few weeks after HD transition, a striking refractory ascites developed requiring multiple paracenteses (5 - 7 L every second week). Serum protein electrophoresis showed hypoalbuminemia with only small amount of monoclonal IgG-κ at 0.30 g/dL. Serum immunofixation electrophoresis showed polyclonal immunoglobulins with polyclonal light chains. Both κ and λ light chains were increased, at 66.86 mg/dL (reference range: 0.33 - 1.94) and 18.55 mg/dL (reference range: 0.57 - 2.63), respectively, with a ratio of 3.6 (reference range: 0.26 - 1.65). However, an ascitic fluid analysis showed a marked increase in plasma cells with a κ : λ ratio greater than 5 : 1. Omental biopsy confirmed κ-restricted plasma cells. Multiple myeloma work-up with skeletal survey showed no evidence of focal osseous lesions, while bone marrow aspiration and biopsy also remained unremarkable. Accordingly, the diagnosis of omental extramedullary plasmacytoma with malignant ascites was confirmed. Conversion from PD to HD may unmask an underlying pathology favoring ascites formation.

PTH regulation of the human cytomegalovirus immediate-early gene promoter.

Secondary hyperparathyroidism and human cytomegalovirus (hCMV) seropositivity are highly prevalent in patients undergoing renal transplantation, and both are linked to the development of chronic allograft nephropathy (CAN). We investigated the hypothesis that parathyroid hormone (PTH) 1-84 regulates hCMV immediate-early gene (IEG) promoter activation in proximal renal tubular cells. PTH 1-84 enhanced hCMV IEG promoter (-548 to +92) activity in opossum kidney cells. Deletion analysis from the 5' end of the promoter localized the PTH 1-84 associated activity to the DNA sequence between -123 and -45. Mutation of an imperfect ATF/AP-1 DNA element within this region abrogated the PTH 1-84 effect and also strongly attenuated basal gene expression. Mobility shift analyses using this DNA element revealed that a member of the ATF-1 family was in the binding complex. In summary, we present evidence for a novel pathogenic role of PTH 1-84 in promoting hCMV immediate-early gene transcription.

Sclerostin and Dickkopf-1 in renal osteodystrophy.

BACKGROUND AND OBJECTIVES: The serum proteins sclerostin and Dickkopf-1 (Dkk-1) are soluble inhibitors of canonical wnt signaling and were recently identified as components of parathyroid hormone (PTH) signal transduction. This study investigated the associations between sclerostin and Dkk-1 with histomorphometric parameters of bone turnover, mineralization, and volume in stage 5 chronic kidney disease patients on dialysis (CKD-5D). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional study, 60 CKD-5D patients underwent bone biopsies followed by histomorphometry. Levels of sclerostin, Dkk-1, and intact PTH (iPTH) were determined in blood. RESULTS: Serum levels of sclerostin and iPTH correlated negatively. In unadjusted analyses, sclerostin correlated negatively with histomorphometric parameters of turnover, osteoblastic number, and function. In adjusted analyses, sclerostin remained a strong predictor of parameters of bone turnover and osteoblast number. An observed correlation between sclerostin and cancellous bone volume was lost in regression analyses. Sclerostin was superior to iPTH for the positive prediction of high bone turnover and number of osteoblasts. In contrast, iPTH was superior to sclerostin for the negative prediction for high bone turnover and had similar predictive values than sclerostin for the number of osteoblasts. Serum levels of Dkk-1 did not correlate with iPTH or with any histomorphometric parameter. CONCLUSIONS: Our data describe a promising role for serum measurements of sclerostin in addition to iPTH in the diagnosis of high bone turnover in CKD-5D patients, whereas measurements of Dkk-1 do not seem to be useful for this purpose.

Retinoic acid receptor gamma 2 interactions with vitamin D response elements.

The vitamin D receptor (VDR) typically binds DNA in a heterodimer complex with the retinoid X receptor (RXR) to direct repeat sequences separated by three base pairs, or vitamin D response elements (VDREs). A modified yeast one-hybrid screen was utilized to search for partner proteins capable of associating with the VDR on a repressor VDRE. Screening of a HeLa cell cDNA library revealed that retinoic acid receptor gamma 2 (RARgamma2) could specifically interact with VDREs, either in the presence or absence of the VDR. Importantly, the A-domain of RARgamma2 appeared to be crucial for this interaction as evidenced by the inability of RARgamma1 to affect reporter gene activity. Transfection data in COS-7 cells revealed the combination of both receptor ligands strongly attenuated transcriptional activation from an enhancer VDRE when RARgamma2 was co-transfected into these cells with the VDR. Furthermore, a VDR/RARgamma2 complex was detected in the mobility shift assay from nuclear extracts of transfected cells. Thus, the data highlight the novel ability of RARgamma2 to interact with VDREs and impact vitamin D activity, which would allow for additional fine-tuning of a transcriptional response depending on ligand availability and expression profile of these nuclear receptors in a given cell type.

Bone disease after renal transplantation.

In light of greatly improved long-term patient and graft survival after renal transplantation, improving other clinical outcomes such as risk of fracture and cardiovascular disease is of paramount importance. After renal transplantation, a large percentage of patients lose bone. This loss of bone results from a combination of factors that include pre-existing renal osteodystrophy, immunosuppressive therapy, and the effects of chronically reduced renal function after transplantation. In addition to low bone volume, histological abnormalities include decreased bone turnover and defective mineralization. Low bone volume and low bone turnover were recently shown to be associated with cardiovascular calcifications, highlighting specific challenges for medical therapy and the need to prevent low bone turnover in the pretransplant patient. This Review discusses changes in bone histology and mineral metabolism that are associated with renal transplantation and the effects of these changes on clinical outcomes such as fractures and cardiovascular calcifications. Therapeutic modalities are evaluated based on our understanding of bone histology.

Low bone volume--a risk factor for coronary calcifications in hemodialysis patients.

BACKGROUND AND OBJECTIVES: There is increasing evidence that altered bone metabolism is associated with cardiovascular calcifications in patients with stage 5 chronic kidney disease on hemodialysis (HD). This study was conducted to evaluate the association between bone volume, turnover, and coronary calcifications in HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional study, bone biopsies and multislice computed tomography were performed in 38 HD patients. Bone volume/total volume, activation frequency, and bone formation rate/bone surface were determined by histomorphometry and coronary calcifications were quantified by Agatston scores. RESULTS: Prevalence of low bone turnover was 50% and of low bone volume was 16%. Among the studied traditional cardiovascular risk factors, only age was found to be associated with coronary calcifications. Lower bone volume was a significant risk factor for coronary calcifications during early years of HD, whereas this effect was not observed in patients with dialysis duration >6 yr. Histomorphometric parameters of bone turnover were not associated with coronary calcifications. CONCLUSIONS: Low bone volume is associated with increased coronary calcifications in patients on HD.

Bone markers predict cardiovascular events in chronic kidney disease.

Recent studies have indicated a link between bone metabolism and cardiovascular events in patients with chronic kidney disease (CKD). CKD is a major health problem worldwide. This study evaluates the role of noninvasive markers of bone metabolism in predicting cardiovascular morbidity (coronary artery disease, peripheral vascular disease, stroke) and mortality in patients with mild to severe forms of CKD. In a prospective cohort study, 627 patients with CKD were screened. To focus on bone metabolism, traditional risk factors for cardiovascular events were excluded, and 135 patients with CKD stages 1-5 were followed for 4 yr. Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula. PTH (measured by four different assays), vitamin D 25 and 1,25, bone-specific alkaline phosphatase (BSALP), TRACP-5b, osteocalcin, serum collagen cross-link molecules, RANKL, and osteoprotegerin were determined. Predictors of cardiovascular events were evaluated by multivariable logistic regression, Kaplan-Meier survival, and Cox regression analysis. There were a total of 45 cardiovascular events (33%). Event rates were 5.6%, 29.1%, 45.2%, and 45.0% in CKD stages 1-2, 3, 4, and 5, respectively. In logistic regression, cardiovascular events were predicted only by (1) CKD stage (independent of age or sex; p < 0.001); (2) BSALP (p = 0.03); and (3) TRACP-5b (p = 0.04). Markers of bone formation (BSALP) and resorption (TRACP-5b) can serve as predictors of cardiovascular morbidity and mortality in CKD.