Patients With Renal Disease

Clearance of Toxins and Homeostasis

The kidneys serve to clear waste material from the bloodstream and maintain homeostasis of water, salt, and acid/base states. More than one-fifth of a person's cardiac output is delivered to the kidneys every minute, generating roughly 180 liters of filtrate every day. Only a small portion of this filtrate is excreted. This tight control is achieved by orchestrated structures called nephrons , the basic functional units of the kidney. Each nephron is composed of a highly differentiated vascular tuft, the glomerulus, which is entangled with a tubule that is lined by specialized epithelial cells arranged in a unique order. The glomeruli are in charge of filtering the blood through closely knit podocytes, which line the glomerular basement membrane and ensure that cellular elements as well as large macromolecules are not filtered. Renal tubules selectively re-absorb solutes and water, secrete toxins and acids, and concentrate the filtrate, resulting in a urine output that varies in volume and concentration according to one's daily intake of water and solutes. Levels of sodium, potassium, bicarbonate, calcium, phosphate, and magnesium are tightly maintained by these structures.

Volume Control

The ability of the kidneys to continuously filter a large blood volume each minute leads to its central role in controlling blood pressure. The juxtaglomerular apparatus detects states of hyper- or hypofiltration and either decreases or increases the filtration rate via activity of the renin-angiotensin system. The collecting duct can further fine-tune the body's volume status via the epithelial sodium channels (ENaK), which are regulated by aldosterone secretion that is triggered by a variety of stimuli (e.g., angiotensin II).

Endocrine Function

In addition to toxin clearance, electrolyte homeostasis, and volume status regulation, the kidneys also have an endocrine function. Interstitial fibroblasts within the kidney secrete erythropoietin in response to a decrease in oxygen tension in the blood, which stimulates bone marrow erythropoiesis. Aldosterone secretion by the adrenal glands maintains euvolemia as an end-result of renin secretion by the kidneys. Additionally, the kidneys activate vitamin D (via the 1-alpha-hydroxylase enzyme), which is important for calcium and phosphorus absorption from the gut, serotonin activation in the brain, and mediation of the cross-talk between the kidneys and the parathyroid glands.

All things considered—between toxin clearance, electrolyte homeostasis, blood pressure control, hypoxemia responsiveness, and vitamin D activation—it becomes clear that healthy renal function supports optimal brain function. Conversely, the presence of kidney disease should alert medical teams and consultants to the possibility of neuropsychiatric dysfunction.

Epidemiology and Risk Factors

Kidney disease is a major public health problem. According to the United States Renal Data System's (USRDS) last annual report, the overall prevalence of CKD in the general population is 14%, and the prevalence of ESRD is 0.2%. Obesity, hypertension, and diabetes are the most common risk factors for developing CKD. Genetics also play a role. For example, steroid-resistant nephrotic syndrome (SRNS), one of the most intractable kidney diseases, results from podocin mutations in about 25% of childhood cases and in 15% of adult cases. Additionally, autosomal dominant polycystic kidney disease (ADPKD) affects 1 in 1000 individuals and results from mutations in PKD1 and PKD2 that affect renal tubular cell differentiation.

Lithium and Kidney Disease

Widely and successfully used for the treatment of bipolar disorder, this alkali metal is known for its potential nephrotoxicity. Chronic lithium exposure is associated with an increased incidence of nephrogenic diabetes insipidus (NDI) and CKD; although both complications are uncommon, they are not rare. NDI results from lithium's inhibition of the translocation of aquaporin 2 to the apical membrane of the principal cell of the collecting duct, leading to decreased tubular permeability to water and the excretion of large volumes of dilute urine. The accompanying hypernatremia stimulates thirst and polydipsia. Lithium-induced CKD manifests as a slowly progressing (over decades) kidney dysfunction with pathologic features of chronic tubulo-interstitial nephropathy including interstitial fibrosis, tubular atrophy, and the development of microcysts. The duration of lithium treatment is a principal factor in the development of kidney disease. In a Swedish population-based study it was found that the prevalence of ESRD was increased in patients treated chronically with lithium and that the mean duration of lithium treatment in these patients was 23 years. Finally, lithium's narrow therapeutic window mandates frequent monitoring of lithium levels and educating patients about the risk of lithium intoxication. A recent Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) systematic review of lithium poisoning recommended that hemodialysis is warranted when renal function is impaired and the lithium level is >4.0 mEq/L, or in the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias (irrespective of the lithium level). Of note, although lithium is contraindicated in acute renal failure, it may be used with caution in CKD. In fact, some patients who have required renal transplantation because of lithium-induced nephrotoxicity decide, in consultation with their nephrologist and psychiatrist, to resume lithium post-transplantation since it is often the only effective medication for their bipolar illness.

Paradoxically, recent data suggest that lithium may have nephro-protective properties in several animal models of AKI. This is yet to be substantiated in clinical settings.