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Daniela Arias Rodriguez

Insulin in End-stage Renal Disease

Kidneys play an important role in the clearance of insulin. Sixty percent of the insulin renal clearance occurs through glomerular filtration and forty percent is removed from the blood vessels around the tubule. Insulin within the renal tubules enters tubular cells to be transported in lysosomes, which later insulin is metabolized to amino acids. At the end, less than one percent of filtered insulin is found in urine. Insulin renal clearance is 200 ml/min, which is higher than the normal GFR (120ml/min). Based on this clearance rate, the kidney breaks down 6 to 8 units of insulin per day, which represents 25% of pancreatic insulin production.  

How are insulin clearance, secretion and insulin tissue sensitivity affected in CKD? Insulin clearance: In patients with chronic kidney disease, insulin clearance is minimally affected until there is significant reduction in GFR. When the GFR is less than 15 to 20 ml/min, there is a significant reduction in insulin clearance, which is also affected by a decline in insulin metabolism by the liver. Because of the drop in insulin clearance in advanced renal disease, glucose tolerance improves in diabetic patients allowing for lower doses of insulin or even stopping insulin therapy in these patients. 

Insulin tissue sensitivity: In chronic kidney disease, nearly all patients with uremia develop insulin resistance. Build-up of uremic toxins or toxins and increase in parathyroid hormone are also believed to be responsible for the insulin resistance. Other mechanisms that can explain improper metabolism of glucose mediated by insulin include increased hepatic gluconeogenesis, decreased glucose uptake by liver/skeletal muscle and impaired glucose metabolism inside of the cells. 

Insulin secretion: its production is expected to increase in response to the insulin resistance. Although, contrary to what is expected, insulin secretion decreases in most cases causing a prominent impairment in glucose tolerance in these patients. Metabolic acidosis is one circumstance that can prevent insulin release in CKD. Moreover, increased levels of parathyroid hormones can prevent release of insulin from the pancreatic beta cells. Deficiency of calcitriol also seems to interfere with insulin secretion.

Gluconeogenesis in Liver Failure and ESRD 

Gluconeogenesis is the process by which the body produces glucose. This process occurs primarily in the liver, however, some production takes place in the kidney. Gluconeogenesis occurs when the body is deprived of energy storage (starvation or intense exercise). In this process, two molecules of pyruvate are required to form one molecule of glucose. 

In both liver failure and CKD, there is an impairment in gluconeogenesis causing hypoglycemia. In liver failure, this impairment results from the loss of normal liver function, while in the case of ESRD it occurs due to reduction of functioning renal mass. In acute liver failure, hypoglycemia occurs in 40%  of the patients mainly due to impaired gluconeogenesis and decreased glycogen storage in the liver. Aside from impaired gluconeogenesis, the development of spontaneous hypoglycemia seen in CKD can result from reduced caloric intake, impaired release of “counterregulatory hormone epinephrine,” hepatic disease and decreased metabolism of drugs that decrease plasma glucose. In these patients, glucose levels should be carefully monitored and treated with hypertonic glucose solutions to maintain glucose levels above 65 mg/dl. 

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Pulmonary Embolism and End-stage Renal Disease

There is a little information addressing this topic on UptoDate or Access Medicine. However, a few studies have found higher incidences of pulmonary embolism in patients with end-stage renal disease. Here, I provided a brief summary of three articles addressing this topic. The three articles concluded that patients with end-stage renal disease are at higher risk of developing pulmonary embolism. A combination of factors contribute to the hypercoagulable state in ESRD such as high levels of homocysteine, thrombin-antithrombin complex, fibrinogen, vWf and protein C dificiency, inducer of platelets aggregation during dialysis and use of erythropoietin. 

A cohort study on Taiwanese patients with end-stage renal disease and receiving long term dialysis found that dialysis patients have a 2 fold increased risk of developing pulmonary embolism and higher risk of death from PE than patients normal kidney function. Risk of developing PE was higher among patients receiving hemodialysis as compared to patients undergoing peritoneal dialysis. This study collected data on patients receiving dialysis between 1998 and 2010. Another cohort study examining the frequency of pulmonary embolism in patients with chronic kidney disease and end-stage renal disease found that the annual frequency of PE was 527, 204 and 66 per 100,000 people with ESRD, CKD and normal kidney function, respectively. It was found that the incidence of PE is 7.6 times higher among persons with ESRD as compared to persons with normal kidney function. This study used data from 2007 of the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample (NIS). This study explains that as patients progress to ESRD bleeding risk may be enhanced due to platelet dysfunction. However, the hypercoagulability seen in ESRD can be explained by several factors such as increased levels of homocysteine, thrombin-antithrombin complex, D-dimer, fibrinogen, vWf and protein C dificiency as well as use of erythropoietin. 

Another study on Taiwanese patients diagnosed with end-stage renal disease between January 1, 2004 and December 31, 2010  found that patients with ESRD have higher risk of developing DVT as compared to the general population. As we already know, deep vein thrombosis is a direct risk of pulmonary embolism. As compared to the general population, patients with ESRD have a 2.3  increased fold risk of developing DVT. This study explains that factors contributing to the thrombotic events seen in these patients include inducer of platelets aggregation during hemodialysis, elevated plasminogen activator inhibitor, increased Von Willebrand factor, oxidative stress, elevated homocysteine, fibrinogen, factors VII, VIII, and IX-XII, thromboplastin, and reduced protein C. Other related factors include administration of erythropoietin and blood transfusion. 

COVI19 and End-stage Renal Disease

Patients with existing medical issues such as diabetes, hypertension, cardiovascular disease, cancer, chronic lung disease, obesity, smoking including chronic kidney disease are at greater risk of developing a severe form of COVID- 19. There is little information about any relationship between COVI-19 and stage renal disease. However, patients with diagnosed or suspected COVID-19 can present with acute kidney injury. Acute kidney injury was reported in 25 to 29 percent of patients with severe infection or death patients according to observational data from Wuhan. Incidence of acute kidney injury on infected patients is close to five percent. In infected patients, kidney disease can present with hematuria, proteinuria or as acute kidney injury indicating higher risk of mortality. Patients with chronic kidney disease and hypertension are also at risk of developing severe forms of COVID-19. In a meta-analysis of 1389 patients, severe COVID infection was most common in patients with a current history of chronic kidney disease and hypertension. 

Sources

  • https://www-uptodate-com.york.ezproxy.cuny.edu/contents/coronavirus-disease-2019-covid-19-issues-related-to-kidney-disease-and-hypertension?search=covid%2019%20%20and%20esrd&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H3752979725
  • Pulmonary Embolism in Patients with CKD and ESRD. Gagan Kumar, Ankit Sakhuja, Amit Taneja, Tilottama Majumdar, Jayshil Patel, Jeff Whittle, and Rahul Nanchal, for the Milwaukee Initiative in Critical Care Outcomes Research (MICCOR) Group of Investigators, 2012. https://www.ncbi.nlm.nih.gov/pubmed/22837271
  • Increased risk of deep vein thrombosis in end-stage renal disease patients. Hsueh-Yi Lu1 and Kuang-Ming Liao, 2018. https://bmcnephrol.biomedcentral.com/track/pdf/10.1186/s12882-018-0989-z
  • Risk of pulmonary embolism in patients with end-stage renal disease receiving long-term dialysis. I-Kuan Wang,  Te-Chun Shen4, Chih-Hsin Muo, Tzung-Hai Yen  and Fung-Chang Sung, 2016. https://www.ncbi.nlm.nih.gov/pubmed/27448674

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