Mesenchymal stromal cell therapy compared to SGLT2-inhibitors and usual care in treating diabetic kidney disease: A cost-effectiveness analysis.

BACKGROUND AND OBJECTIVES: To simulate the cost-effectiveness of Mesenchymal Stromal Cell (MSC) therapy compared to sodium/glucose co-transporter 2 inhibitors (SGLT2i) or usual care (UC) in treating patients with Diabetic Kidney Disease (DKD). DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This Markov-chain Monte Carlo model adopted a societal perspective and simulated 10,000 patients with DKD eligible for MSC therapy alongside UC using a lifetime horizon. This cohort was compared with an SGLT2i alongside UC arm and a UC only arm. Model input data were extracted from the literature. A threshold of $47,000 per quality-adjusted life year and a discount rate of 3% were used. The primary outcome measure was incremental net monetary benefit (INMB). Sensitivity analysis was conducted to examine: parameter uncertainty; threshold effects regarding MSC effectiveness and cost; and INMB according to patient age (71 vs 40 years), sex, and jurisdiction (UK, Italy and Ireland). RESULTS: While MSC was more cost-effective than UC, both the UC and MSC arms were dominated by SLGT2i. Relative to SGLT2i, the INMB's for MSC and UC were -$4,158 and -$10,085 respectively indicating that SGLT2i, MSC and UC had a 64%, 34% and 1% probability of being cost-effective at the given threshold, respectively. This pattern was consistent across most scenarios; driven by the relatively low cost of SGLT2i and demonstrated class-effect in delaying kidney failure and all-cause mortality. When examining younger patients at baseline, SGLT2i was still the most cost-effective but MSC performed better against UC given the increased lifetime benefit from delaying progression to ESRD. CONCLUSIONS: The evidence base regarding the effectiveness of MSC therapy continues to evolve. The potential for these therapies to reverse kidney damage would see large improvements in their cost-effectiveness as would targeting such therapies at younger patients and/or those for whom SGLT2i is contra-indicated.

The impact of chronic kidney disease on developed countries from a health economics perspective: A systematic scoping review.

Chronic kidney disease (CKD) affects over 10% of the global population and poses significant challenges for societies and health care systems worldwide. To illustrate these challenges and inform cost-effectiveness analyses, we undertook a comprehensive systematic scoping review that explored costs, health-related quality of life (HRQoL) and life expectancy (LE) amongst individuals with CKD. Costs were examined from a health system and societal perspective, and HRQoL was assessed from a societal and patient perspective. Papers published in English from 2015 onward found through a systematic search strategy formed the basis of the review. All costs were adjusted for inflation and expressed in US$ after correcting for purchasing power parity. From the health system perspective, progression from CKD stages 1-2 to CKD stages 3a-3b was associated with a 1.1-1.7 fold increase in per patient mean annual health care cost. The progression from CKD stage 3 to CKD stages 4-5 was associated with a 1.3-4.2 fold increase in costs, with the highest costs associated with end-stage renal disease at $20,110 to $100,593 per patient. Mean EuroQol-5D index scores ranged from 0.80 to 0.86 for CKD stages 1-3, and decreased to 0.73-0.79 for CKD stages 4-5. For treatment with renal replacement therapy, transplant recipients incurred lower costs and demonstrated higher HRQoL scores with longer LE compared to dialysis patients. The study has provided a comprehensive updated overview of the burden associated with different CKD stages and renal replacement therapy modalities across developed countries. These data will be useful for the assessment of new renal services/therapies in terms of cost-effectiveness.

Chronic kidney disease, health-related quality of life and their associated economic burden among a nationally representative sample of community dwelling adults in England.

Chronic kidney disease (CKD) affects up to 15% of the adult population and is strongly associated with other non-communicable chronic diseases including diabetes. However, there is limited information on a population basis of the relationship between CKD and health-related quality of life (HRQoL) and the consequent economic cost. We investigated this relationship in a representative sample in England using the 2010 Health Survey for England. Multivariable Tobit models were used to examine the relationship between HRQoL and CKD severity. HRQoL was converted to quality adjusted life year (QALY) measures by combining decrements in quality of life with reductions in life expectancy associated with increased disease severity. QALYs were adjusted for discounting and monetised using the UK threshold for reimbursement of £30,000. The QALYs were then used in conjunction with forecasted prevalence to estimate the HRQoL burden associated with CKD among individuals with diabetes up to 2025. Individuals with more severe CKD had lower HRQoL compared to those with better kidney function. Compared to those with normal/low normal kidney function and stage 1 CKD, those with stage 2, stage 3 with albuminuria and stage 4/5 CKD experienced a decrement of 0.11, 0.18 and 0.28 in their utility index, respectively. Applying the UK reimbursement threshold for a QALY, the monetised lifetime burden of reduced HRQoL due to stage 2, stage 3 with albuminuria and stage 4/5 CKD were £103,734; £83,399; £125,335 in males and £143,582; £70,288; £203,804 in females, respectively. Utilizing the predicted prevalence of CKD among individuals with diabetes mellitus, the economic burden of CKD per million of individuals with diabetes is forecasted at approximately £11.4 billion in 2025. In conclusion, CKD has a strong adverse impact on HRQoL in multiple domains. The estimated economic burden of CKD among individuals with diabetes mellitus in the UK is projected to rise markedly over time.

Methods Used in Economic Evaluations of Chronic Kidney Disease Testing - A Systematic Review.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is high in general populations around the world. Targeted testing and screening for CKD are often conducted to help identify individuals that may benefit from treatment to ameliorate or prevent their disease progression. AIMS: This systematic review examines the methods used in economic evaluations of testing and screening in CKD, with a particular focus on whether test accuracy has been considered, and how analysis has incorporated issues that may be important to the patient, such as the impact of testing on quality of life and the costs they incur. METHODS: Articles that described model-based economic evaluations of patient testing interventions focused on CKD were identified through the searching of electronic databases and the hand searching of the bibliographies of the included studies. RESULTS: The initial electronic searches identified 2,671 papers of which 21 were included in the final review. Eighteen studies focused on proteinuria, three evaluated glomerular filtration rate testing and one included both tests. The full impact of inaccurate test results was frequently not considered in economic evaluations in this setting as a societal perspective was rarely adopted. The impact of false positive tests on patients in terms of the costs incurred in re-attending for repeat testing, and the anxiety associated with a positive test was almost always overlooked. In one study where the impact of a false positive test on patient quality of life was examined in sensitivity analysis, it had a significant impact on the conclusions drawn from the model. CONCLUSION: Future economic evaluations of kidney function testing should examine testing and monitoring pathways from the perspective of patients, to ensure that issues that are important to patients, such as the possibility of inaccurate test results, are properly considered in the analysis.

The need for improved identification and accurate classification of stages 3-5 Chronic Kidney Disease in primary care: retrospective cohort study.

BACKGROUND: Around ten percent of the population have been reported as having Chronic Kidney Disease (CKD), which is associated with increased cardiovascular mortality. Few previous studies have ascertained the chronicity of CKD. In the UK, a payment for performance (P4P) initiative incentivizes CKD (stages 3-5) recognition and management in primary care, but the impact of this has not been assessed. METHODS AND FINDINGS: Using data from 426 primary care practices (population 2,707,130), the age standardised prevalence of stages 3-5 CKD was identified using two consecutive estimated Glomerular Filtration Rates (eGFRs) seven days apart. Additionally the accuracy of practice CKD registers and the relationship between accurate identification of CKD and the achievement of P4P indicators was determined. Between 2005 and 2009, the prevalence of stages 3-5 CKD increased from 0.3% to 3.9%. In 2009, 30,440 patients (1.1% unadjusted) fulfilled biochemical criteria for CKD but were not on a practice CKD register (uncoded CKD) and 60,705 patients (2.2% unadjusted) were included on a practice CKD register but did not fulfil biochemical criteria (miscoded CKD). For patients with confirmed CKD, inclusion in a practice register was associated with increasing age, male sex, diabetes, hypertension, cardiovascular disease and increasing CKD stage (p<0.0001). Uncoded CKD patients compared to miscoded patients were less likely to achieve performance indicators for blood pressure (OR 0.84, 95% CI 0.82-0.86 p<0.001) or recorded albumin-creatinine ratio (OR 0.73, 0.70-0.76, p<0.001). CONCLUSIONS: The prevalence of stages 3-5 CKD, using two laboratory reported eGFRs, was lower than estimates from previous studies. Clinically significant discrepancies were identified between biochemically defined CKD and appearance on practice registers, with misclassification associated with sub-optimal care for some people with CKD.

Chronic kidney disease after nonrenal solid organ transplantation: a histological assessment and utility of chronic allograft damage index scoring.

BACKGROUND: It is proposed that chronic calcineurin inhibitor (CNI) nephrotoxicity has a central role in chronic kidney disease after nonrenal solid organ transplantation (NRSOT), although there are little data on renal histology in this setting. The aim of this study was to assess the histological features and renal outcomes of a cohort of patients with chronic kidney disease after NRSOT. METHODS: Renal biopsies of 62 NRSOT recipients were evaluated for histological diagnoses. Biopsies were graded for chronic allograft damage index parameters and for arteriolar hyalinosis. The sum of all chronic allograft damage index parameters and arteriolar hyalinosis scores was called chronic damage index. RESULTS: The biopsies were performed at a median of 4 (range: 0.3-15.9) years after NRSOT and at serum creatinine of 318±17.7 µmol/L (mean±standard deviation). Twenty-two (35.5%) biopsies showed predominant features of chronic CNI nephrotoxicity, 27 (43.5%) predominant features of hypertensive nephropathy, and 12 (19.3%) an alternative primary renal pathology. Twenty-four (38.7%) patients had progression to end-stage renal disease, at a median of 1.5 (0-10.1) years after biopsy and 6.9 (0.3-19.2) years after NRSOT. The risk of renal progression was associated with in situ damage measured by chronic damage index. CONCLUSIONS: Although CNI nephrotoxicity is an important cause of renal failure after NRSOT, many patients do not have overt histological evidence of CNI toxicity. Quantitative parameters of chronic damage can stratify renal prognosis.

Mortality prediction after kidney transplantation: comparative clinical use of 7 comorbidity indices.

OBJECTIVES: Despite comorbidity associated with chronic kidney disease, little data exist applying comorbidity scoring systems to renal transplant recipients. This study compared the performance of 7 established comorbidity scores in predicting mortality after kidney transplantation. MATERIALS AND METHODS: We retrospectively analyzed prospectively collected data from 2033 incident renal transplant recipients. Comorbidity was assessed at baseline, and the following scores were derived: Recipient Risk Score, Charlson Comorbidity Index, Age-adjusted Charlson Comorbidity Index, Modified End-Stage Renal Disease Charlson Comorbidity Index, Foley Score, Wright-Khan Index, and Davies Index. Cox models investigated the association of each comorbidity score with mortality; performance characteristics were tested using receiver operating characteristic curve analysis. RESULTS: Age-stratified Cox analyses showed the Recipient Risk Score-based model displayed the best fit, and receiver operating characteristic curve analysis showed the Recipient Risk Score demonstrated greatest predictive use (5-year mortality c-statistic: 0.787). The independent effect of age on mortality was demonstrated after analysis of scores not containing age as a component (the Charlson Comorbidity Index, the Modified End-Stage Renal Disease Charlson Comorbidity Index, the Davies Index); addition of age to these scores improved fit. CONCLUSIONS: Of the currently available comorbidity scores, the Recipient Risk Score demonstrated greatest use. This has implications for deceased-donor allocation algorithms, assessment of confounders in clinical research, and potentially, individual patient management.

Serum free light chain assessment in monoclonal gammopathy and kidney disease.

Abnormalities of immunoglobulin free light chains (FLCs) are frequently present in patients with monoclonal gammopathies and can cause kidney disease. The recent introduction of highly sensitive immunoassays that measure FLCs to levels below those present in normal individuals has provided a new tool for diagnosis and management in this setting. Here, we review the biology of FLC production in health and disease, and the utility of FLC immunoassays in the assessment of monoclonal gammopathies in kidney disease.

Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Monoclonal free light chains (FLC) frequently cause kidney disease in patients with plasma cell dyscrasias. Polyclonal FLC, however, have not been assessed in patients with chronic kidney disease (CKD) yet could potentially play an important pathologic role. This study describes for the first time polyclonal FLC in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A sensitive, quantitative immunoassay was used to analyze serum and urinary polyclonal FLC in 688 patients with CKD of various causes. RESULTS: Serum kappa and lambda FLC concentrations increased progressively with CKD stage (both P < 0.001) and strongly correlated with markers of renal function, including cystatin-C (kappa: R = 0.8, P < 0.01; and lambda: R = 0.79, P < 0.01). Urinary FLC concentrations varied significantly between disease groups (kappa: P < 0.001; lambda: P < 0.005) and also rose significantly with increasing CKD stage (both FLC P < 0.0001). Urinary FLC concentrations were positively correlated with their corresponding serum concentration (kappa: R = 0.63; lambda: R = 0.65; both P < 0.001) and urinary albumin creatinine ratio (kappa: R = 0.58; lambda: R = 0.65; both P < 0.001). The proportion of patients with abnormally high urinary FLC concentrations rose with both the CKD stage and the severity of albuminuria. CONCLUSIONS: This study demonstrates significant abnormalities of serum and urinary polyclonal FLC in patients with CKD. These data provide the basis for studies that assess the contribution of polyclonal FLC to progressive renal injury and systemic inflammation in patients with kidney disease.

Quantitative assessment of serum and urinary polyclonal free light chains in patients with type II diabetes: an early marker of diabetic kidney disease?

OBJECTIVE: Free light chains (FLCs) are bi-products of normal immunoglobulin synthesis and are predominately removed from the circulation by the kidneys. This study assessed polyclonal FLCs as a novel biomarker of early diabetic kidney disease. RESEARCH DESIGN/METHODS: Serum and urinary FLCs were assessed by the immunoassay Freelite, in white and South-Asian patients with type II diabetes recruited from the United Kingdom Asian Diabetes Study. RESULTS: The incidence of monoclonal proteins in this diabetic population was 1.9%. Type II diabetic patients had significantly raised concentrations of serum polyclonal FLCs before overt renal impairment developed (p < 0.001). Both kappa and lambda FLCs correlated with all tested markers of renal function; in particular cystatin-C: Spearman's coefficient (R) = 0.55 (p < 0.01) and R = 0.56 (p < 0.01), respectively. The South-Asian diabetic patients had higher serum polyclonal FLCs than Caucasian diabetic patients and this was independent of renal function. Urinary FLCs concentrations were raised in diabetic patients (p < 0.001). The majority (68%) of diabetic patients with normal urinary albumin:creatinine ratios (ACRs) had abnormal urinary FLC:creatinine ratios. Both kappa and lambda FLC concentrations correlated with urinary ACR: R = 0.32, p < 0.01 and R = 0.25, p < 0.01 respectively. CONCLUSIONS: Type II diabetic patients can have significantly raised concentrations of serum and urinary polyclonal FLCs before overt renal disease occurs. These novel findings provide the basis for future studies to assess whether polyclonal FLCs could provide a useful tool for early diagnosis of diabetic kidney disease.

Serum free-light chain removal by high cutoff hemodialysis: optimizing removal and supportive care.

In multiple myeloma the predominant cause of irreversible renal failure is cast nephropathy, secondary to excess kappa or lambda serum free light chains (FLCs). These molecules are efficiently cleared by hemodialysis (HD) using the Gambro HCO 1100 dialyzer. To optimize the removal of FLCs by this dialyzer we have studied the effect of dialyzers in series, dialyzer change, and hemodiafiltration in 14 patients with multiple myeloma and renal failure. The clearance rates of both kappa FLCs and lambda FLCs were significantly increased on two dialyzers from 19 (7.3-34)-15.3 (9-28) mL/min to 47 (17-79)-35.5 (20-57) mL/min, respectively. Clearance rates of both FLCs decreased over the course of the dialysis sessions (both P < 0.001). Changing the dialyzer during a HD session increased lambda FLC clearance rates (22.5 [6-41] to 37.6 [9-52] mL/min; P < 0.001) and decreased kappa FLC clearance rates (39.6 [9-72] to 19 [8-59] mL/min; P < 0.003). Ultrafiltration during HD increased the clearance rates of kappa FLCs (R 0.52, P < 0.01) but not lambda FLCs (R -0.25; P < 0.076). Hemodiafiltration increased the clearance rates of both kappa (19 [SD 6.8] to 32 [SD 9.8] mL/min) and lambda FLCs (15 [SD 7.8] to 20 [SD 7.7] mL/min). Albumin replacement requirements for 8 h of HD increased from 12 g for a single dialyzer to 45 g for two dialyzers in series (P < 0.001). Different protocols are required to optimize the removal of kappa and lambda FLCs in patients with myeloma and renal failure.