The effect of parathyroidectomy compared to non-surgical surveillance on kidney function in primary hyperparathyroidism: a nationwide historic cohort study

Background Patients with primary hyperparathyroidism (pHPT) and impaired kidney function (estimated glomerular filtration rate (eGFR) < 60 mL/min) are offered parathyroidectomy (PTX) to protect them from further complications. Surprisingly, two recent uncontrolled cohort studies have suggested a further decrease in kidney function following PTX. We aimed to examine the effects of PTX compared to non-surgical surveillance on kidney function in pHPT patients. Methods Historic cohort study. From the Danish National Patient Registry (NPR) and major medical biochemistry laboratories in Denmark, we identified 3585 patients with biochemically confirmed pHPT among whom n = 1977 (55%) were treated with PTX (PTX-group) whereas n = 1608 (45%) were followed without surgery (non-PTX group). Baseline was defined as time of diagnosis and kidney function was re-assessed 9–15 months after PTX (PTX group) or 9–15 months after diagnosis (non-PTX group). Results At follow-up, eGFR had decreased significantly in the PTX- compared to the non-PTX-group (median − 4% vs. − 1%, p < 0.01). Stratification by baseline eGFR showed that the decrease was significant for those with a baseline eGFR value of 80–89 and > 90 mL/min, but not for those with lower eGFR values. Findings did not differ between patients with mild compared to moderate/severe hypercalcemia. However, after mutual adjustments, we identified baseline levels of calcium, PTH, and eGFR as well as age and treatment (PTX vs. no-PTX) as independent predictors for changes in kidney function. Conclusion Compared to non-surgical surveillance, PTX is associated with a small but significant decrease in kidney function in pHPT patients with an initial normal kidney function.

Lymphatic Reconstruction in Kidney Allograft Aggravates Chronic Rejection by Promoting Alloantigen Presentation

Chronic rejection of the renal allograft remains a major cause of graft loss. Here, we demonstrated that the remodeling of lymphatic vessels (LVs) after their broken during transplantation contributes to the antigen presenting and lymph nodes activating. Our studies observed a rebuilt of interrupted lymph draining one week after mouse kidney transplantation, involving preexisting lymphatic endothelial cells (LECs) from both the donor and recipient. These expanding LVs also release C-C chemokine ligand 21 (CCL21) and recruit CCR7+ cells, mainly dendritic cells (DCs), toward lymph nodes and spleen, evoking the adaptive response. This rejection could be relieved by LYVE-1 specific LVs knockout or CCR7 migration inhibition in mouse model. Moreover, in retrospective analysis, posttransplant patients exhibiting higher area density of LVs presented with lower eGFR, severe serum creatinine and proteinuria, and greater interstitial fibrosis. These results reveal a rebuilt pathway for alloantigen trafficking and lymphocytes activation, providing strategies to alleviate chronic transplantation rejection.

Application of machine learning techniques to understand ethnic differences and risk factors for incident chronic kidney disease in Asians

IntroductionChronic kidney disease (CKD) is increasing in Asia, but there are sparse data on incident CKD among different ethnic groups. We aimed to describe the incidence and risk factors associated with CKD in the three major ethnic groups in Asia: Chinese, Malays and Indians.Research design and methodsProspective cohort study of 5580 general population participants age 40–80 years (2234 Chinese, 1474 Malays and 1872 Indians) who completed both baseline and 6-year follow-up visits. Incident CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in those free of CKD at baseline.ResultsThe 6-year incidence of CKD was highest among Malays (10.0%), followed by Chinese (6.1%) and Indians (5.8%). Logistic regression showed that older age, diabetes, higher systolic blood pressure and lower eGFR were independently associated with incident CKD in all three ethnic groups, while hypertension and cardiovascular disease were independently associated with incident CKD only in Malays. The same factors were identified by machine learning approaches, gradient boosted machine and random forest to be the most important for incident CKD. Adjustment for clinical and socioeconomic factors reduced the excess incidence in Malays by 60% compared with Chinese but only 13% compared with Indians.ConclusionIncidence of CKD is high among the main Asian ethnic groups in Singapore, ranging between 6% and 10% over 6 years; differences were partially explained by clinical and socioeconomic factors.

Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach

Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6–12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6–12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.

Impact of Renal Function on Effectiveness and Safety Associated With Low Dose Dabigatran in Non-valve Atrial Fibrillation Patients After Catheter Ablation

Aim: The purpose of this study is to compare the effectiveness and safety of 110 mg dabigatran in non-valve atrial fibrillation (NVAF) patients with different eGFRs.Methods: We conducted a single-center retrospective cohort study to investigate the effectiveness and safety of 110 mg dabigatran for NVAF patients between January 2017 and December 2018 based on the eGFR category.Results: A total of 560 NVAF patients who treated with 110 mg dabigatran were included for analysis. In 12 months, the Kaplan-Meier survival curves indicated that the lower eGFR subgroups were more likely to experience thrombosis, bleeding, and cumulative events earlier (P = 0.021 for thrombosis; P = 0.026 for bleeding; P = 0.001 for cumulative events). Gastrointestinal bleeding occurred more frequently in the moderate group than in other groups (6.94% in the moderate group vs. 1.54% in the mild group vs. 1.22% in the normal group, P = 0.028). By multivariate analysis, chronic kidney disease (P = 0.043; OR = 4.273, 95% CI 1.043–17.543) and diabetes mellitus (P = 0.023; OR = 2.194, 95% CI 1.114–4.323) were independent predictors of the composite endpoints. A positive linear relationship was observed between eGFR levels and occurrence rate of thrombosis and bleeding under anticoagulation patients with 110 mg dabigatran (R2 = 0.432 and R2 = 0.784, respectively).Conclusions: Impaired renal function was associated with decreased safety and increased thrombosis risks in NVAF patients taking low dose dabigatran.

Upregulated PD-1 Signaling is an Important Antagonist to Glomerular Health in Aged Kidneys

Kidney aging and its contribution to disease and its underlying mechanisms are not well understood. With an aging population, kidney health becomes an important medical and socioeconomic factor. We previously showed that podocytes isolated from aged mice exhibit increased expression of Programed Cell Death Protein 1 (PD-1) surface receptor and its two ligands (PD-L1, PD-L2). PDCD1 transcript increases with age in micro-dissected human glomeruli, which correlates with lower eGFR, and higher segmental glomerulosclerosis and vascular arterial intima to lumen ratio. In vitro studies in podocytes demonstrate a critical role for PD-1 signaling in cell survival and induction of a Senescence-Associated Secretory Phenotype (SASP). To prove PD-1 signaling is critical to podocyte aging, aged mice were injected with anti-PD-1 antibody (aPD-1ab). Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life-span of podocytes, but not parietal epithelial, mesangial or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrate that anti-PD-1 treatment improved the health-span of podocytes. It restored the expression of canonical podocyte genes, transcription factors and gene regulatory networks, increased cellular metabolism signatures and lessened SASPs. These results suggest a critical contribution for increased PD-1 signaling towards both kidney and liver aging.

Early life factors in relation to albuminuria and estimated glomerular filtration rate based on cystatin C and creatinine in adults from a Swedish population-based cohort study

Background Early life factors influence the number of nephrons a person starts life with and a consequence of that is believed to be premature kidney ageing. Thus, we aimed to identify early life factors associated with cystatin C and creatinine-based estimated glomerular filtration (eGFR) rate equations and urine -albumin-to-creatinine ratio after a follow-up of 46–67 years. Methods The study included 593 Swedish subjects without diabetes mellitus from the Malmo Diet Cancer Cohort. Perinatal data records including birth weight, gestational age, placenta weight and maternal related risk factors were analysed. eGFR was determined by Chronic Kidney Disease Epidemiology (CKD-EPI), the Lund-Malmö revised and Caucasian, Asian, Paediatric, and Adult (CAPA) equations. Postnatal growth phenotypes were defined as low (≤ 0) or high (> 0) birth weight z-score, or low (≤ median) or high (> median) body mass index at 20 years of age. Results In women, lower birth weight was associated with lower eGFR (CAPA; CKD-EPI cystatin C). Birth weight z-score predicted adult albuminuria specifically in men (OR 0.75, 95% CI [0.58; 0.96]). Women with high birth weight z-score and low BMI at 20 years had lower eGFR (CAPA; CKD-EPI cystatin C; p = 0.04). Men with high birth weight z-score and high BMI at 20 years had lower risk for albuminuria (OR 0.35, 95% CI [0.12; 0.93]). Conclusions Lower birth weight, prematurity and postnatal growth curve have a potential sex- specific effect of early exposure to an adverse environment on lower cystatin C-based eGFR and albuminuria later in life. Cystatin C compared to creatinine -eGFR equations shows a higher ability to detect these findings. Graphic abstract

Poly-IgA Complexes and Disease Severity in IgA Nephropathy

Background and objectives: Poly-IgA immune complex formation and glomerular deposition play a key role in IgA nephropathy. Our study sought to develop a new methodology for one-step serological detection of poly-IgA levels. Design, setting, participants, and measurements: A novel ELISA method using recombinant CD89 as 'capturing' probe was established for detecting poly-IgA immune complex in the plasma. We applied semiquantitative measurements of these poly-IgA indices in patients recruited at Peking University First Hospital with IgA nephropathy or other kidney disease types, as compared to healthy controls. The longitudinal trend of the poly-IgA index, together with the association with pathological parameters and treatment responses were evaluated. Finally, we analyzed the molecular composition of poly-IgA complexes in patients by mass spectrometry. Results: Recombinant CD89-mounted ELISA plates specifically captured plasma poly-IgA. The levels of poly-IgA immune complex (26.7, IQR 17.1-42.6 units/ml) in IgA nephropathy were significantly higher than those in healthy (15.5, IQR 10.7- 20.0 units/ml; P<0.001), or non-IgA nephropathy disease controls (14.8, IQR 10.5-21.9 units/ml; P<0.001). Higher levels of poly-IgA immune complex were associated with lower eGFR and worse kidney outcome. Accuracy parameters and concordant statistics showed good discrimination between IgA nephropathy and healthy controls based on poly-IgA index levels (AUC, 0.78; 95% CI, 0.72-0.83; P<0.001), significantly outperforming galactose deficient-IgA1 levels (AUC, 0.70; P=0.05). Corticosteroid and immunosuppressant treatments lowered poly-IgA indices. Following a recombinant CD89-directed workflow in conjunction with mass spectrometry, we also analyzed the molecular compositions of IgA immune complex in IgA nephropathy patients. Conclusions: Higher level of recombinant CD89-bound poly-IgA immune complex was associated with the severity of the disease, as well as treatment response to steroids and immunosuppressants.

Renal Outcome of IgM Nephropathy: A Comparative Prospective Cohort Study

Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by diffuse deposits of IgM in the glomerular mesangium. However, its renal prognosis remains unknown. We compared renal outcomes of IgMN patients with those of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or mesangial proliferative glomerulonephritis (MsPGN) from a prospective observational cohort, with 1791 patients undergoing native kidney biopsy in eight hospitals affiliated with The Catholic University of Korea between December 2014 and October 2020. IgMN had more mesangial proliferation and matrix expansion than MsPGN and more tubular atrophy and interstitial fibrosis than MCD. IgMN patients had decreased eGFR than MCD patients in the earlier follow-up. However, there was no significant difference in urine protein or eGFR among all patients at the last follow-up. When IgMN was divided into three subtypes, patients with FSGS-like IgMN tended to have lower eGFR than those with MCD-like or MsPGN-like IgMN but higher proteinuria than MsPGN-like IgMN without showing a significant difference. The presence of hypertension at the time of kidney biopsy predicted ≥20% decline of eGFR over two years in IgMN patients. Our data indicate that IgMN would have a clinical course and renal prognosis similar to MCD, FSGS, and MsPGN

The association of urine osmolality with decreased kidney function and/or albuminuria in the United States

Background Decreased kidney function is commonly caused by hypovolemia. When hypovolemic, the kidney reabsorbs water resulting in concentrated urine. Osmolality is a measure of urine concentration which is more objective than self-reported fluid intake. It has a positive association with hypovolemia. However, it remains controversial whether osmolality is associated with decreased kidney function and/or albuminuria. Methods We conducted a cross-sectional analysis of the 2009–2012 National Health and Nutrition Examination Survey, a standardized survey in the U.S. population. Participants aged 18–70 years old with random urine osmolality were included. Osmolality was categorized as quartiles. Decreased kidney function was defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 and albuminuria was defined by albumin-to-creatinine ratio ≥ 30 mg/gm. We performed multivariable regression via four sequential models. Results Our study sample included 7,373 participants. The mean age was 42.9 ± 0.4 years. Overall, 51.4% were male and 67.3% were white. The mean osmolality was 603.8 mOsm/kg and 629.1 mOsm/kg in those with and without decreased eGFR and/or albuminuria, respectively. The number of cases was 610 (6.7%). The prevalence from the lowest to highest quartiles of osmolality was 116 (6.2%), 213 (8.6%), 179 (7.5%), and 102 (4.3%), respectively (p-value for trend = 0.02). The relationship between osmolality and eGFR appeared nonlinear. After adjustment for demographic, social, cardiovascular, and dietary risk factors, there was no significant association of osmolality quartiles with decreased eGFR and/or albuminuria (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.56, 1.07). In sensitivity analyses, osmolality ≥ 500 mOsm/kg was associated with lower eGFR (adjusted ß -1.13, 95% CI -1.98, -0.28). In pre-specified subgroup analyses, osmolality had a statistically significant negative correlation with eGFR among individuals with eGFR ≥ 60 mL/min/1.73m2, but a positive correlation among those with eGFR < 60 mL/min/1.73m2 (adjusted ß -0.19, 95% CI -0.36, -0.01 versus adjusted ß 0.50, 95% CI 0.05, 0.96; p-value for interaction = 0.016). Conclusions Higher osmolality was significantly associated with lower eGFR among adults with eGFR ≥ 60 mL/min/1.73m2 Future research should examine the relationship between osmolality and change in kidney function over time among adults with normal eGFR.