Progression of chronic kidney disease : risk factors, sex differences and intervention

Background

Mortality and morbidity in pre-dialytic patients are substantial, including in people with mild to moderate chronic kidney disease (CKD). There are also unexplained sex-specific differences regarding prevalence, incidence, mortality and disease progression. Some studies suggest CKD is more prevalent in women, however the risk of kidney replacement therapy is higher for men. Explanations for this relationship includes unequal access to kidney replacement therapy, a faster progression in men, increased mortality in pre-dialytic stages among women and differences in monitoring and management. Diabetes is one of the leading causes of CKD, why adequate blood glucose control is a primary clinical goal for these patients. Broccoli sprout have a high content of glucoraphanin, a precursor of sulforaphane, which has been shown to decrease oxidative stress. Translational studies have shown that supplementation with broccoli sprout extract can improve metabolic control, but the effect in people with CKD remains uncertain. Hypoparathyroidism is a rare disease with unknown prevalence in Sweden and is a condition characterized by low level of parathyroid hormone. It can lead to severe and sometimes life-threatening hypocalcemia. Treatment therefore consists of calcium and vitamin D supplements, and introduced more recently, treatment with parathyroid hormone analogues. However, to what extent a regimen with high doses of calcium and vitamin D could cause kidney damage over time is not known.

Objective

The aim of study I was to investigate sex-specific differences in mortality and disease progression in patients with CKD stage 3b to 5, while study III explored differences between men and women in monitoring and management of people with CKD in a non-referred, general population. The aim of study II was to investigate the risk for CKD among people with hypoparathyroidism. Study IV investigated whether broccoli sprout extract could improve metabolic control in people with CKD and type 2 diabetes.

Methods and results

Study I used the Swedish Renal Registry-Chronic Kidney Disease (SRR-CKD). Incident patients with non-dialysis CKD 3b-5 identified between 2010 and 2018 were included. The outcomes of interest were sex-specific differences in time to CKD progression, death and repeated assessment of estimated glomerular filtration rate (eGFR). Of 26 279 incident cases, women had a lower risk for progression of CKD stage (SHR 0.88, 95% CI 0.85-0.92), mortality by any cause (SHR 0.90, 95% CI 0.85-0.94) and less steep decline of eGFR, compared to men.

Study II identified people with hypoparathyroidism through the Swedish National Patient Registry and Prescribed Drug Registry. A total of 1562 individuals with hypoparathyroidism and without prior CKD were included. The Total Population Registry was used to find matched controls. The outcomes of interest were time to a diagnosis with CKD and urolithiasis and incidence rates of hospitalization. Patient with hypoparathyroidism had an increased risk of CKD (HR 4.45, 95% CI 3.66-5.42) and were more likely to be hospitalized due to CKD (HR 3.49, 95% CI 2.84-4.30), compared to controls.

Study III used the Stockholm Creatinine Measurements Project, a repository of laboratory data in Region Stockholm between 2009 and 2017. A total of 227 847 individuals with at least one outpatient eGFR <60 ml/min/1.73m2 were included, exploring differences between men and women in diagnosis of CKD, provision of guideline-recommended therapy and monitoring of kidney function. Women were less likely to receive a diagnosis of CKD, being on statins or renin-angiotensin system inhibitors, despite the presence of indications. Also, women were less likely to be referred to a nephrologist (HR 0.46, 95% CI 0.43-0.48), despite fulfilling criteria for referral.

Study IV was a double-blind, placebo-controlled trial including people with CKD 3b-4 and type 2 diabetes. A total of 99 individuals were randomized to either broccoli sprout extract or placebo for 12 weeks. Metabolic control measured by fasting glucose, HbA1c, insulin and oral glucose tolerance test did not differ between treatment groups at the end of follow-up.

Conclusions

Men with CKD were more likely to progress to a more advanced CKD stage and had a steeper decline in eGFR, while women were less likely to receive a CKD diagnosis, have timely monitoring and to be referred to a nephrologist. Also, people with hypoparathyroidism had a markedly higher risk for developing CKD compared to controls. In the clinical trial, broccoli sprout extract did not improve metabolic control in people with CKD and type 2 diabetes.

List of scientific papers

I. Swartling O, Rydell H, Stendahl M, Segelmark M, Trolle Lagerros Y, Evans M. CKD Progression and Mortality Among Men and Women: A Nationwide Study in Sweden American Journal of Kidney Diseases, 2021;78(2):190-199
https://doi.org/10.1053/j.ajkd.2020.11.026

II. Swartling O, Evans M, Spelman T, Kamal W, Kämpe O, Mannstadt M, Trolle Lagerros Y, Björnsdottir S. Kidney Complications and Hospitalization in Patients with Chronic Hypoparathyroidism: A Cohort Study in Sweden Journal of Clinical Endocrinology and Metabolism, 2022;107(10):e4098-e4105
https://doi.org/10.1210/clinem/dgac456

III. Swartling O, Yang Y, Clase CM, Fu EL, Hecking M, Hodlmoser S, Trolle Lagerros Y, Evans M, Carrero JJ. Sex Differences in the Recognition, Monitoring, and Management of CKD in Health Care: An Observational Cohort Study Journal of the American Society of Nephrology, 2022;33(10):1903- 1914
https://doi.org/10.1681/asn.2022030373

IV. Avesani C, Swartling O, Rosengren AH, Heimbürger O, Svensson MK, Guron G, Segelmark M, Lundberg S, Jonsson A, Mörtberg J, Bratt O, Bonnevier U, Fernström A, Christensson A, Fontanive R, Evans M, Stenvinkel P, for the INITIATE Study Group No effect of broccoli sprout extract on glycemic control in patients with CKD and type 2 diabetes: A randomized clinical trial [Manuscript]