Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial.

INTRODUCTION: Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism. METHODS: PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m2. RESULTS: At week 52, over 95% (78/82) of participants remained enrolled in the OLE and of those, 86% maintained normocalcemia and 95% achieved independence from conventional therapy (no active vitamin D and ≤ 600 mg/day of calcium), with none requiring active vitamin D. Treatment with palopegteriparatide over 52 weeks resulted in a mean (SD) increase in eGFR of 9.3 (11.7) mL/min/1.73 m2 from baseline (P < 0.0001) and 43% of participants had an increase ≥ 10 mL/min/1.73 m2. In participants with baseline eGFR < 60 mL/min/1.73 m2, 52 weeks of treatment with palopegteriparatide resulted in a mean (SD) increase of 11.5 (11.3) mL/min/1.73 m2 (P < 0.001). One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide. CONCLUSION: In this post hoc analysis of the PaTHway trial, palopegteriparatide treatment was associated with significantly improved eGFR at week 52 in addition to previously reported maintenance and normalization of serum and urine biochemistries. Further investigation of palopegteriparatide for the preservation of renal function in hypoparathyroidism is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT04701203.

Chronic hypoparathyroidism is caused by inadequate parathyroid hormone (PTH) levels. Hypoparathyroidism is managed with conventional therapy (active vitamin D and calcium), but over time the disease itself and conventional therapy can increase the risk of medical complications including kidney problems. This study looked at how a new treatment for chronic hypoparathyroidism, palopegteriparatide (approved in the European Union under the brand name YORVIPATH^®), affects kidney function in adults in the PaTHway clinical trial. Participants were randomly assigned to receive palopegteriparatide or a placebo injection once daily along with conventional therapy. For both groups, clinicians used a protocol to eliminate conventional therapy while maintaining normal blood calcium levels. After 26 weeks, participants on placebo switched to palopegteriparatide. Ninety-five percent of participants were still enrolled in the PaTHway trial after 52 weeks. Of those, 86% had normal blood calcium levels and 95% did not need conventional therapy (not taking vitamin D and not taking therapeutic doses of calcium [> 600 mg/day]). After 52 weeks of treatment with palopegteriparatide, significant improvements were seen in a measure of kidney function called estimated glomerular filtration rate (eGFR). Improvements in eGFR from the beginning of the trial to week 52 were considered clinically meaningful for over 57% of participants. In participants with impaired kidney function at the beginning of the trial, eGFR improvements were even greater, and 74% of participants had a clinically meaningful improvement. These results suggest that palopegteriparatide treatment may be beneficial for kidney function in adults with chronic hypoparathyroidism, especially those with impaired kidney function.

Removal of common antimicrobial agents by sustained low-efficiency dialysis.

Adequate dosing of antimicrobials is paramount for treating infections in critically ill patients undergoing kidney replacement therapy; however, little is known about antimicrobial removal by sustained low-efficiency dialysis (SLED). The objective was to quantify the removal of cefepime, daptomycin, meropenem, piperacillin-tazobactam, and vancomycin in patients undergoing SLED. Adult patients ≥18 years with acute kidney injury (AKI) or end-stage kidney disease receiving one of the select antimicrobials and requiring SLED were included. Blood and dialysate flow rates were maintained at 250 and 100 mL/min, respectively. Simultaneous arterial and venous blood samples for the analysis of antibiotic concentrations were collected hourly for 8 hours during SLED (on-SLED). Arterial samples were collected every 2 hours for up to 6 hours while not receiving SLED (off-SLED) for the calculation of SLED clearance, half-life (t1/2) on-SLED and off-SLED, and the fraction of removal by SLED (fD). Twenty-one patients completed the study: 52% male, mean age (±SD) 53 ± 13 years, and mean weight of 98 ± 30 kg. Eighty-six percent had AKI, and 4 patients were receiving cefepime, 3 daptomycin, 10 meropenem, 6 piperacillin-tazobactam, and 13 vancomycin. The average SLED time was 7.3 ± 1.1 hours, and the mean ultrafiltration rate was 95 ± 52 mL/hour (range 10-211). The t1/2 on-SLED was substantially lower than the off-SLED t1/2 for all antimicrobials, and the SLED fD varied between 44% and 77%. An 8-hour SLED session led to significant elimination of most antimicrobials evaluated. If SLED is performed, modification of the dosing regimen is warranted to avoid subtherapeutic concentrations.

Determinants of the serum phosphate concentration in chronic kidney disease.

If Ccr is creatinine clearance and EP and TRP are rates of phosphate excretion and reabsorption, the serum phosphate concentration (Ps) is the sum of EP/Ccr and TRP/Ccr, i.e., the amounts of phosphate excreted and reabsorbed per volume of filtrate. At equilibrium, influx of phosphate into plasma determines EP, and EP/Ccr quantifies the contribution of phosphate influx to Ps. We used data obtained at 688 clinic visits of 387 patients to analyze the evolution of Ps in chronic kidney disease (CKD) stages G1 - 5 (dialysis excluded). EP/Ccr was calculated as (Pu×crs)/cru and TRP/Ccr as Ps-EP/Ccr (where u is urine, s is serum, and cr is creatinine). Means of these parameters were plotted against CKD stages, and correlations among variables were determined with regression analyses. In comparison to values in CKD stages G1 - 2, EP/Ccr rose and TRP/Ccr fell by the same amount in CKD G3a and G3b, and Ps did not change. In stages G4 and G5, EP/Ccr increased sharply, TRP/Ccr fell minimally, and Ps rose significantly. At estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73m2, TRP/Ccr was the principal determinant of Ps at eGFR < 45 mL/min/1.73m2, contributions of EP/Ccr and TRP/Ccr to Ps were comparable. Taken together, our results show that in CKD stages G4 and G5, the effect of phosphate reabsorption on Ps changes negligibly while that of phosphate influx increases dramatically. Because the tubular response to rising EP/Ccr is limited, maintenance of stable Ps in advanced CKD requires extreme reduction of phosphate influx into plasma. TRP/Ccr may define the lowest attainable Ps.

Recent Trends in Hypoparathyroidism-Related Inpatient and Emergency Department Admissions and Costs in the United States.

Hypoparathyroidism (HypoPT) is a rare disease associated with high morbidity. Its economic impact is not well understood. This retrospective, cross-sectional study used data from the United States-based National Inpatient Sample and the Nationwide Emergency Department Sample from 2010 to 2018 to quantify overall trends in number, cost, charges, and length of stay (LOS) for inpatient hospitalizations and number and charges for emergency department (ED) visits for HypoPT-related and for non-HypoPT-related causes. Additionally, the study estimated the marginal effect of HypoPT on total inpatient hospitalization costs and LOS as well as ED visit charges. Over the observed period, a mean of 56.8-66.6 HypoPT-related hospitalizations and 14.6-19.5 HypoPT-related ED visits were recorded per 100 000 visits per year. Over this period, the rate of HypoPT-related inpatient hospitalizations and ED visits increased by 13.5% and 33.6%, respectively. The mean LOS for HypoPT-related hospitalizations was consistently higher than for non-HypoPT-related causes. Total annual HypoPT-related inpatient hospitalization costs increased by 33.6%, and ED visit charges increased by 96.3%. During the same period, the annual costs for non-HypoPT-related hospitalizations and charges for ED visits increased by 5.2% and 80.3%, respectively. In all years, HypoPT-related hospital encounters resulted in higher charges and costs per individual visit than non-HypoPT-related encounters. The marginal effect of HypoPT on inpatient hospitalization costs and LOS, and on ED charges, increased over the period of observation. This study demonstrated that HypoPT was associated with substantial and increasing healthcare utilization in the United States between 2010 and 2018.

Association of Serum Calcium and Phosphate With Incident Cardiovascular Disease in Patients With Hypoparathyroidism.

The pathophysiological basis for the increased incidence of cardiovascular disease in patients with chronic hypoparathyroidism is poorly understood. To evaluate associations between levels of albumin-corrected serum calcium, serum phosphate, and calcium-phosphate product with the odds of developing cardiovascular events in patients with chronic hypoparathyroidism with ≥1 calcitriol prescription, we conducted a retrospective nested case-control study of patients who developed a cardiovascular event and matched controls without an event. The primary outcome was the instance of cardiovascular events. An electronic medical record database was used to identify 528 patients for the albumin-corrected serum calcium analysis and 200 patients for the serum phosphate and calcium-phosphate product analyses. Patients with ≥67% of albumin-corrected serum calcium measurements outside the study-defined 2.00 to 2.25 mmol/L (8.0 to 9.0 mg/100 ml) range had 1.9-fold higher odds of a cardiovascular event (adjusted odds ratio, 95% confidence interval 1.89, 1.10 to 3.25) compared with patients with <33% of calcium measurements outside the range. Likewise, patients with any serum phosphate measurements above 0.81 to 1.45 mmol/L (2.5 to 4.5 mg/100 ml) had 3.3-fold higher odds (3.26; 1.24 to 8.58), and those with any calcium-phosphate product measurements above 4.40 mmol2/L2 (55 mg2/dL2) had 4.8-fold higher odds of a cardiovascular event (95% confidence interval 1.36 to 16.81) compared with patients with no measurements above these ranges. In adult patients with chronic hypoparathyroidism, a cardiovascular event was more likely in those with a higher proportion of albumin-corrected serum calcium measurements outside 2.00 to 2.25 mmol/L (8.0 to 9.0 mg/100 ml) or any serum phosphate and any calcium-phosphate product measurements above the normal population range.

The risk of chronic kidney disease development in adult patients with chronic hypoparathyroidism treated with rhPTH(1-84): A retrospective cohort study.

OBJECTIVE: This study assessed the risk of developing chronic kidney disease (CKD) and decline in estimated glomerular filtration rate (eGFR) over a period of up to 5 years in adult patients with chronic hypoparathyroidism treated with recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) compared with a historical control cohort of patients not treated with rhPTH(1-84). DESIGN: Retrospective cohort study of patients with chronic hypoparathyroidism treated with rhPTH(1-84) derived from the REPLACE (NCT00732615), RELAY (NCT01268098), RACE (NCT01297309) and HEXT (NCT01199614, and its continuation study NCT02910466) clinical trials and a historical control cohort who did not receive PTH selected from an electronic medical record database. PATIENTS: One hundred and eighteen patients treated with rhPTH(1-84) and 497 patient controls. MEASUREMENTS: Incident CKD was defined as ≥2 eGFR measurements <60 ml/min/1.73 m2 ≥3 months apart during the study and a sustained eGFR decline of ≥30% from baseline. RESULTS: Over the 5-year period, Kaplan-Meier analyses showed that rhPTH(1-84)-treated patients had a significantly lower risk of developing CKD (log-rank p = .002) and a lower risk for a sustained eGFR decline ≥30% from baseline (log-rank p < .001) compared with patients in the control cohort. In adjusted analyses, patients in the rhPTH(1-84)-treated cohort had a 53% lower risk of developing CKD (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.25-0.87) and a 65% lower risk for sustained eGFR decline ≥30% from baseline (HR, 0.35; 95% CI, 0.13-0.89) compared with controls. CONCLUSIONS: Patients with chronic hypoparathyroidism treated with rhPTH(1-84) in long-term clinical trials had a significantly lower risk of developing CKD compared with patients in a historical control cohort not treated with rhPTH(1-84).

Association of Calcium and Phosphate Levels with Incident Chronic Kidney Disease in Patients with Hypoparathyroidism: A Retrospective Case-Control Study.

Objective: Reasons for the increased incidence of chronic kidney disease (CKD) in patients with chronic hypoparathyroidism are poorly understood. This study evaluated associations between levels of albumin-corrected serum calcium, serum phosphate, and calcium-phosphate product and the odds of CKD development in patients with chronic hypoparathyroidism. Design: A retrospective nested case-control study of adult patients with chronic hypoparathyroidism who had ≥1 prescription for calcitriol who developed CKD and matched controls who did not develop CKD were selected from the IBM® Explorys electronic medical record database. Patients. The study included a cohort of 300 patients for the albumin-corrected serum calcium analysis and 80 patients for the serum phosphate and calcium-phosphate product analyses. Measurements. We examined associations between albumin-corrected serum calcium, serum phosphate and calcium-phosphate product levels, and the risk of devloping CKD (defined as ≥2 outpatient estimated glomerular filtration values <60 mL/min/1.73 m2 occuring ≥3 months apart or ≥1 diagnostic code for CKD stages 3-5). Results: Individuals who had ≥67% of albumin-corrected serum calcium measurements outside, above, or below the study-defined range (2.00-2.25 mmol/L [8.0-9.0 mg/dL]) had 3.5-, 2.9-, and 2.7-fold higher odds of developing CKD (adjusted odds ratios [95% CI]: 3.46 [1.82-6.56], 2.85 [1.30-6.28], and 2.68 [1.16-6.15]), respectively, compared with patients who had <33% of albumin-corrected calcium measurements in those ranges. There was no association between developing CKD and having any serum phosphate measurements or any calcium-phosphate product measurements above normal population ranges. Conclusion: In adult patients with chronic hypoparathyroidism, a higher proportion of albumin-corrected calcium measurements outside of the 2.00-2.25 mmol/L (8.0-9.0 mg/dL) range was associated with higher odds of developing CKD.

Five-Year Estimated Glomerular Filtration Rate in Adults with Chronic Hypoparathyroidism Treated with rhPTH(1-84): A Retrospective Cohort Study.

INTRODUCTION: Chronic hypoparathyroidism is associated with higher risk of developing chronic kidney disease compared with the general population. This study evaluated changes in estimated glomerular filtration rate (eGFR) over a 5-year period in adult patients with chronic hypoparathyroidism treated with recombinant parathyroid hormone (1-84), rhPTH(1-84), compared with a historical control cohort of patients who did not receive rhPTH(1-84). METHODS: This retrospective cohort study included patients with chronic hypoparathyroidism treated with rhPTH(1-84) in the REPLACE (NCT00732615), RELAY (NCT01268098), RACE (NCT01297309), and HEXT (NCT01199614 and continuation study NCT02910466) clinical trials. A historical control cohort who did not receive parathyroid hormone but who had enrollment criteria similar to those for the clinical trials was selected from the IBM® Explorys electronic medical record database (January 2007-August 2019). Outcomes of interest were the annual rate of change in eGFR from baseline (i.e., eGFR slope) and the predicted eGFR change from baseline at years 1 through 5. RESULTS: The study comprised 72 adult patients with chronic hypoparathyroidism treated with rhPTH(1-84) and 176 control patients who did not receive rhPTH(1-84). Over 5 years, eGFR remained stable in the rhPTH(1-84) cohort, whereas eGFR declined at a rate of 1.67 mL/min/1.73 m2 per year in the control cohort (P < 0.001 for eGFR slope in the control cohort). At 5 years, predicted eGFR in the rhPTH(1-84) cohort increased from baseline by 1.21 mL/min/1.73 m2, whereas eGFR in the control cohort declined by 10.36 mL/min/1.73 m2, after adjusting for baseline variables. The difference in eGFR slopes between the cohorts over 5 years was 1.37 mL/min/1.73 m2 per year (95% CI 0.62-2.13; P < 0.001). CONCLUSION: Long-term treatment with rhPTH(1-84) was associated with stable eGFR compared with eGFR decline in the controls not treated with rhPTH(1-84). Preservation of renal function conferred by rhPTH(1-84) may benefit patients with chronic hypoparathyroidism by reducing risk of long-term renal complications.

Lower Risk of Cardiovascular Events in Adult Patients with Chronic Hypoparathyroidism Treated with rhPTH(1-84): A Retrospective Cohort Study.

INTRODUCTION: Patients with chronic hypoparathyroidism are at increased risk of cardiovascular disease. This study evaluated the risk of developing cardiovascular conditions over a period of 5 years in adult patients with chronic hypoparathyroidism treated with recombinant human parathyroid hormone (1-84), rhPTH(1-84), compared with a historical control cohort of patients not treated with rhPTH(1-84). METHODS: This retrospective cohort study comprised patients with chronic hypoparathyroidism treated with rhPTH(1-84) in the REPLACE (NCT00732615), RELAY (NCT01268098), and RACE (NCT01297309) clinical trials, and controls selected from the IBM® Explorys electronic medical record database (January 2007-August 2019) who did not receive parathyroid hormone but who had enrollment criteria similar to those for the clinical trials. Cardiovascular outcomes were the first diagnosis of cerebrovascular, coronary artery, peripheral vascular disease, or heart failure during the study period. RESULTS: We evaluated 113 adult patients with chronic hypoparathyroidism treated with rhPTH(1-84) and 618 control patients who did not receive rhPTH(1-84). Over the 5-year follow-up period, 3.5% of patients (n = 4) in the rhPTH(1-84) cohort had a cardiovascular event compared with 16.3% (n = 101) in the control cohort. Kaplan-Meier analysis demonstrated that patients in the rhPTH(1-84) cohort had lower risk of experiencing a cardiovascular event compared with patients in the control cohort (P = 0.005). Multivariable analyses adjusted for baseline variables showed that patients in the rhPTH(1-84) cohort had 75% lower risk for a cardiovascular event compared with patients in the control cohort (adjusted hazard ratio, 0.25 [95% CI 0.08-0.81]; P = 0.020). CONCLUSION: Long-term treatment with rhPTH(1-84) was associated with a lower risk of incident cardiovascular conditions compared with conventional therapy in patients with chronic hypoparathyroidism. Previous studies demonstrated that mineral homeostasis was maintained with lower use of calcium and active vitamin D when rhPTH(1-84) was added to conventional therapy. Future studies are needed to understand whether improved regulation of mineral homeostasis conferred by rhPTH(1-84) may provide long-term cardiovascular benefits to patients with chronic hypoparathyroidism.

Serum Low-Density Lipoprotein Cholesterol and Cardiovascular Disease Risk Across Chronic Kidney Disease Stages (Data from 1.9 Million United States Veterans).

In the general population, elevated low-density lipoprotein (LDL) cholesterol levels are an important risk factor for cardiovascular disease (CVD) and mortality; however, the association of LDL with mortality risk and cardiovascular events are less clear in chronic kidney disease (CKD). We sought to examine the relationship of LDL with mortality and rates of atherosclerotic cardiovascular disease (ASCVD) and non-atherosclerotic cardiovascular-related (non-ASCVD) hospitalizations across CKD stages. Our analytical cohort consisted of 1,972,851 United States veterans with serum LDL data between 2004 and 2006. Associations of LDL with all-cause and cardiovascular mortality across CKD stages were evaluated using Cox proportional hazard models with adjustment for demographics, comorbid conditions, smoking status, prescription of statins and non-statin lipid-lowering drugs, body mass index, albumin, high-density lipoprotein, and triglycerides. Associations between LDL and ASCVD and non-ASCVD hospitalizations were estimated using negative binomial regression models across CKD stages. The cohort consisted of 5% female, 14% Black, 29% diabetic, 33% statin-users, and 44% current smokers, with a mean patient age of 64 ± 14 years. Patients with high LDL (≥160 mg/dL) had a higher risk of all-cause and cardiovascular mortality as well as ASCVD and non-ASCVD hospitalization rates across all CKD stages compared with the reference (LDL 70 to <100 mg/dL). The associations with all-cause and cardiovascular mortality and ASCVD hospitalization rate were attenuated at higher CKD stages. These trends were reversed with amplification of the association of high LDL with non-ASCVD hospitalization at higher CKD stages. In conclusion, associations of LDL with mortality and both ASCVD and non-ASCVD hospitalizations are modified according to kidney disease stage.

Risk of Cardiovascular Conditions in Patients with Chronic Hypoparathyroidism: A Retrospective Cohort Study.

INTRODUCTION: In patients with chronic hypoparathyroidism disordered calcium homeostasis has been associated with risk of cardiovascular diseases, including cardiomyopathy, congestive heart failure, and arrhythmia; however, larger-scale studies are needed to examine these risks. This study evaluated the risk of cardiovascular conditions among patients with chronic hypoparathyroidism. METHODS: Adults with and without chronic hypoparathyroidism were selected from a medical insurance claims database in the USA from January 2007 to June 2017, and were followed for up to 5 years. Associations between chronic hypoparathyroidism and incident atrial fibrillation (AF), tachyarrhythmia, myocardial infarction (MI), coronary artery disease (CAD), heart failure (HF), stroke, cerebrovascular disease, peripheral vascular disease (PVD), and a combined cardiovascular endpoint of cerebrovascular disease, CAD, HF, and PVD were compared between cohorts using Kaplan-Meier analyses and unadjusted and adjusted Cox proportional hazards models. RESULTS: In 8097 patients with chronic hypoparathyroidism compared with 40,485 patients without, respectively, mean ± SD ages were 58.6 ± 16.3 and 47.3 ± 18.0 years, 76.2% and 54.4% were female, and 19.4% and 9.5% had the combination of cardiovascular findings at baseline. In adjusted analyses, patients with chronic hypoparathyroidism had significantly higher risk (adjusted hazard ratio and 95% confidence interval) of incident AF (1.72; 1.51-1.97), tachyarrhythmia (1.68; 1.32-2.14), MI (1.18; 1.01-1.38), CAD (1.39; 1.26-1.54), HF (1.64; 1.46-1.84), stroke (1.45; 1.31-1.62), cerebrovascular disease (1.48; 1.34-1.62), PVD (1.66; 1.51-1.81), and combined cardiovascular endpoint (1.63; 1.52-1.75), all P < 0.001 except P = 0.036 for MI, compared with patients without chronic hypoparathyroidism. CONCLUSIONS: This large retrospective cohort study showed that chronic hypoparathyroidism was associated with increased risk of incident cardiovascular conditions and arrhythmias. Results should be evaluated in light of limitations inherent to claims database analyses. Further studies are warranted to investigate reasons for these risks and to develop strategies for reducing cardiovascular conditions in patients with chronic hypoparathyroidism.

Efficacy of metformin monotherapy in US veterans with type 2 diabetes and preexisting chronic kidney disease stage 3.

AIM: To evaluate the glycaemic efficacy of metformin in people with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD3). PARTICIPANTS AND METHODS: This was a retrospective study including 145980 US veterans with T2D and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 who initiated metformin monotherapy between November 1999 and July 2017. Propensity-score-matched cohorts were generated based on baseline variables associated with CKD3 (eGFR 30-59 mL/min/1.73 m2 ) to evaluate the independent association between CKD3 and metformin discontinuation, the addition of a second hypoglycaemic agent, and changes in glycated haemoglobin (HbA1c) from baseline in those with and without CKD3. Associations were examined using the Kaplan-Meier method and multivariable regression models, adjusted for baseline and 12-month average metformin dose. RESULTS: The mean age of the entire cohort was 60.7 years, and 95% of the cohort were men, 21% were African American and 9% had CKD3. In the adjusted analyses, patients with CKD3 had a higher risk of metformin discontinuation or addition of a second hypoglycaemic agent, as compared with patients without CKD (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.19-1.26, and HR 1.26, 95% CI 1.13-1.40, respectively). Among metformin monotherapy users, there were no differences in the average HbA1c reduction from baseline to 12 or 24 months between patients with and without CKD3. CONCLUSIONS: Individuals with CKD3 and T2D were at increased risk of metformin monotherapy failure. However, the HbA1c-lowering efficacy of metformin was similar in patients with and without CKD3, highlighting that metformin is a valuable treatment option for newly treated individuals with T2D and CKD3.

Risk of Nephrolithiasis and Nephrocalcinosis in Patients with Chronic Hypoparathyroidism: A Retrospective Cohort Study.

INTRODUCTION: Chronic hypoparathyroidism managed with conventional treatment, comprising oral administration of calcium and active vitamin D, has been associated with renal complications, including nephrolithiasis and nephrocalcinosis. Further larger-scale studies are needed to examine these risks. This study evaluated the risk of nephrolithiasis and nephrocalcinosis in patients with chronic hypoparathyroidism. METHODS: A retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017. Included patients were those with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism over a maximum of 5-year follow-up. The main outcome measures were nephrolithiasis, identified by diagnosis codes or procedure codes for removing kidney stones, and nephrocalcinosis, identified by diagnosis codes. RESULTS: The nephrolithiasis analyses included 8097 adult patients with hypoparathyroidism and 40,485 adult patients without hypoparathyroidism. After excluding patients with a diagnosis of nephrocalcinosis at baseline, nephrocalcinosis analyses included 8051 patients with hypoparathyroidism and 40,466 patients without hypoparathyroidism. During 5 years of follow-up, patients with chronic hypoparathyroidism had significantly increased risk of nephrolithiasis and nephrocalcinosis in Kaplan-Meier analysis compared with patients without hypoparathyroidism (both P < 0.001). In the adjusted analyses, chronic hypoparathyroidism was associated with higher risks of nephrolithiasis (hazard ratio [HR], 1.81; 95% confidence interval [CI] 1.60-2.04) and nephrocalcinosis (HR, 6.94; 95% CI 4.41-10.92). A sensitivity analysis restricted to patients with at least one kidney imaging examination showed that 2.6% of patients (n = 59) with hypoparathyroidism and 0.5% of patients (n = 20) without hypoparathyroidism (ratio, 5.5; P < 0.001) developed nephrocalcinosis. CONCLUSIONS: This large retrospective cohort study showed a statistically significant and clinically meaningful increased risk of nephrolithiasis and nephrocalcinosis in patients who have chronic hypoparathyroidism compared with those who do not have chronic hypoparathyroidism.

Risk of Chronic Kidney Disease and Estimated Glomerular Filtration Rate Decline in Patients with Chronic Hypoparathyroidism: A Retrospective Cohort Study.

INTRODUCTION: Chronic hypoparathyroidism, treated with conventional therapy of oral calcium supplements and active vitamin D, may increase the risk of kidney complications. This study examined risks of development and progression of chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) decline in patients with chronic hypoparathyroidism. METHODS: A retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017 included patients with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism followed for up to 5 years. Main outcome measures were (1) development of CKD, defined as new diagnosis of CKD stage 3 and higher or ≥ 2 eGFR measurements < 60 ml/min/1.73 m2 ≥ 3 months apart, (2) progression of CKD, defined as increase in baseline CKD stage, (3) progression to end-stage kidney disease (ESKD), and (4) eGFR decline ≥ 30% from baseline. Time-to-event analyses included Kaplan-Meier analyses with log-rank tests, and both unadjusted and adjusted Cox proportional hazards models were used to compare outcomes between cohorts. RESULTS: The study included 8097 adults with and 40,485 without chronic hypoparathyroidism. In Kaplan-Meier analyses, patients with chronic hypoparathyroidism had higher risk of developing CKD and CKD progression and higher rates of eGFR decline (all P < 0.001). In multivariable Cox models adjusted for baseline characteristics, hazard ratios (95% confidence intervals [CIs]) were 2.91 (2.61-3.25) for developing CKD, 1.58 (1.23-2.01) for CKD stage progression, 2.14 (1.51-3.04) for progression to ESKD, and 2.56 (1.62-4.03) for eGFR decline (all P < 0.001) among patients with chronic hypoparathyroidism compared with those without hypoparathyroidism. CONCLUSION: Patients with chronic hypoparathyroidism have increased risk of development and progression of CKD and eGFR decline compared with those without hypoparathyroidism. Further studies are warranted to understand underlying mechanisms for the associations between chronic hypoparathyroidism and kidney disease.

Effect of intensive blood pressure on the progression of non-diabetic chronic kidney disease at varying degrees of proteinuria.

The ideal blood pressure (BP) target for renoprotection is uncertain in patients with non-diabetic chronic kidney disease (CKD), especially considering the influence exerted by pre-existing proteinuria. In this pooled analysis of landmark trials, we coalesced individual data from 5001 such subjects randomized to intensive versus standard BP targets. We employed multivariable regression to evaluate the relationship between follow-up systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CKD progression (defined as glomerular filtration rate decline by 50% or end-stage renal disease), focusing on the potential for effect modification by baseline proteinuria or albuminuria. The median follow-up was 3.2 years. We found that SBP rather than DBP was the primary predictor of renal outcomes. The optimal SBP target was 110-129 mm Hg. We observed a strong interaction between SBP and proteinuria such that lower SBP ranges were significantly linked with progressively lower CKD risk in grade A3 albuminuria or ≥0.5-1 g/day proteinuria (relative to SBP 110-119 mm Hg, the adjusted HR for SBP 120-129 mm Hg, 130-139 mm Hg, and 140-149 mm Hg was 1.5, 2.3, and 3.3, respectively; all p<0.05). In grade A2 microalbuminuria or proteinuria near 0.5 g/day, a non-significant but possible connection was seen between tighter BP and decreased CKD (aforementioned HRs all <2; all p>0.05), while in grade A1 albuminuria or proteinuria <0.2 g/day no significant association was apparent (HRs all <1.5; all p>0.1). We conclude that in non-diabetic CKD, stricter BP targets <130 mm Hg may help limit CKD progression as proteinuria rises.

Renal complications in patients with chronic hypoparathyroidism on conventional therapy: a systematic literature review : Renal disease in chronic hypoparathyroidism.

A systematic literature review was performed to summarize the frequency and nature of renal complications in patients with chronic hypoparathyroidism managed with conventional therapy. Methodology was consistent with the recommendations outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Peer-reviewed journal articles with specified medical subject heading terms were identified using the PubMed, EMBASE, and Cochrane databases. Data were extracted from eligible articles based on prespecified parameters for clinical outcomes of renal calcifications and disease. Because of the heterogeneity of the data, a meta-analysis could not be conducted. From 1200 potentially relevant articles, data were extracted from 13 manuscripts that reported data for ≥1 of the 19 predefined renal outcomes for ≥10 adult patients (n = 11 manuscripts) or pediatric patients (n = 2 manuscripts). The collective data provide evidence that adult and pediatric patients with chronic hypoparathyroidism and treated with conventional therapy (oral calcium and active vitamin D) had an increased risk of renal complications. The reported rate of nephrolithiasis was up to 36%, with the lowest rates in studies reporting shorter duration of disease. The rate of nephrocalcinosis was up to 38%. Some studies reported a combined nephrolithiasis/nephrocalcinosis outcome of 19% to 31%. Data for renal disease that encompassed a range of renal insufficiency to chronic kidney disease were reported in 10 articles; the reported rates ranged from 2.5% to 41%. In patients who receive long-term treatment with oral calcium and active vitamin D, chronic hypoparathyroidism may be associated with an increased risk of renal complications compared with the general population.

Systemic Bartonellosis Manifesting With Endocarditis and Membranoproliferative Glomerulonephritis.

Cat scratch disease caused by Bartonella species is mostly benign and self-limiting condition. Systemic infection is uncommon in immunocompetent host. We describe the case of a 66-year-old male who presented with sudden painless left eye blindness and brown-colored urine. Laboratory findings revealed progressively rising serum creatinine in association with nephrotic-range proteinuria at 7 g/day and glomerular hematuria on urinalysis. An echocardiogram demonstrated mitral and tricuspid valve vegetations despite multiple negative blood cultures. The left eye blindness was attributed to retinal artery occlusion from septic valvular embolus. Kidney biopsy showed membranoproliferative glomerulonephritis pattern of injury with "full house" pattern on immunofluorescent staining with subendothelial deposits on electron microscopy. Markedly elevated IgG (immunoglobulin G) titers for B henselae and B quintana were discovered. The patient had several cats at home. Kidney failure rapidly progressed to require hemodialysis. Once the diagnosis of systemic bartonellosis was confirmed, doxycycline (for 4 months) with rifampicin (for 3 months) were initiated. Repeat echocardiogram in 4 months demonstrated a resolution of valvular vegetations; however, the left eye blindness was permanent. In the present case the correct diagnosis of systemic bartonellosis allowed institution of appropriate antibiotic therapy and to also achieve a partial recovery of renal function and to discontinue hemodialysis.

Five-year Estimated Glomerular Filtration Rate in Patients With Hypoparathyroidism Treated With and Without rhPTH(1-84).

CONTEXT: Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone. OBJECTIVE: To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1-84) during a 5-year period. DESIGN/SETTING: A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1-84). PATIENTS: Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1-84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1-84) from the Geisinger Healthcare Database (01/2004-06/2016) composed the historical control cohort. INTERVENTIONS: The rhPTH(1-84) cohort (N = 69) received rhPTH(1-84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1-84). MAIN OUTCOME MEASURES: Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses. RESULTS: At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1-84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1-84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1-84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009). CONCLUSIONS: Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1-84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1-84).

Cinacalcet-Associated Resolution of Primary Hyperparathyroidism in a Patient With Normal Kidney Function.

Cinacalcet use is associated with risk of hypocalcemia; however, this risk has been mostly demonstrated in patients with chronic kidney disease. In this article, we describe a case of a 59-year-old male with primary hyperparathyroidism (PHPT), hypercalciuria, osteopenia, and normal kidney function who was started on cinacalcet for the management of recurrent hypercalcemia following prior unsuccessful parathyroidectomy. Within 6 months following cinacalcet commencement, he developed symptomatic and biochemical hypocalcemia requiring discontinuation of the medication and initiation of calcium supplementation. Over more than 3 years of follow-up, his calcium supplementation was gradually tapered off and then discontinued. He is presently eucalcemic and euparathyroid off calcium supplements while also demonstrating normalization of hypercalciuria and bone mineral density. These data indicate that our patient has experienced resolution of PHPT after brief exposure to cinacalcet. We recommend that low starting cinacalcet doses should be considered for treatment of hypercalcemia in patients with PHPT who underwent unsuccessful parathyroidectomy along with close clinical and biochemical follow-up.

A generic method for analysis of plasma concentrations
.

The purpose of this NephEd contribution is to introduce a generic method for analyzing plasma concentrations ([x]p). The method is applicable to substances that are filtered by glomeruli, reabsorbed or secreted by tubules, and excreted in urine. The equality from which the method follows states that the filtration rate of substance x is the sum of excretion and net reabsorption rates of x (Fx = Ex + TRx). If x is completely ultrafilterable, Fx = GFR[x]p, and [x]p = Ex/GFR + TRx/GFR. If creatinine clearance (Ccr) is substituted for GFR, Ex/Ccr simplifies to [x]u[cr]p/[cr]u, which can be calculated from measurements in simultaneous aliquots of serum and urine. TRx/Ccr is then deduced as [x]p - Ex/Ccr. The ratios Ex/Ccr and TRx/Ccr - the determinants of [x]p - quantify the amounts of x excreted and reabsorbed per volume of filtrate. If [x]p is abnormal, the generic method identifies which of the determinants is creating the abnormality. If [x]p is normal despite disruptive circumstances, e.g., a reduced GFR, the method elucidates the preservation of normalcy. Herein, we develop these concepts and illustrate their practical utility.