Electrolyte and Acid-Base Disorders in the Renal Transplant Recipient

Abstract

Kidney transplantation is the current treatment of choice for patients with end-stage renal disease. Innovations in transplantation and immunosuppression regimens have greatly improved the renal allograft survival. Based on recently published data from the Scientific Registry of Transplant recipients, prevalence of kidney transplants is steadily rising in the United States. Over 210,000 kidney transplant recipients were alive with a functioning graft in mid-2016, which is nearly twice as many as in 2005. While successful renal transplantation corrects most of the electrolyte and mineral abnormalities seen in advanced renal failure, the abnormalities seen in the post-transplant period are surprisingly different from those seen in chronic kidney disease. Multiple factors contribute to the high prevalence of these abnormalities that include level of allograft function, use of immunosuppressive medications and metabolic changes in the post-transplant period. Electrolyte disturbances are common in patients after renal transplantation, and several studies have tried to determine the clinical significance of these disturbances. In this manuscript we review the key aspects of the most commonly found post-transplant electrolyte abnormalities. We focus on their epidemiology, pathophysiology, clinical manifestations, and available treatment approaches.

Keywords: electrolytes; hypercalcemia; hyperkalemia; hypomagnesemia; hypophosphatemia; kidney transplant; metabolic acidosis; renal transplant.

Figure 1

(1) Trimethoprim inhibits the activity of ENaC in the late distal convoluted convoluted tubule and cortical collecting duct which decreases the electrical gradient for channels. (2) Tacrolimus and cyclosporine bind to FKBP and cyclophilin respectively forming complexes. These complexes inhibit calcineurin which is a phosphatase. Under normal conditions, calcineurin retrieve phosphate groups from different proteins including SPAK and WNKs. Inhibition of calcineurin allows for the phosphorylation of these kinases which activate NCC increasing sodium chloride reabsorption in the distal convoluted tubule. Increasing sodium reabsorption in this nephron segment decreases the delivery of sodium to more distal segments which in turn decreases the electrical gradient for potassium secretion via ROMK channels. (3) Activation of MR by aldosterone increases the activity of proteins associated with potassium excretion in the distal nephron including ENaC, ROMK, BK, and the Na+-K+-ATPase pump. In addition, calcineurin increases the expression of the mineralocorticoid receptor. In contrast, tacrolimus and cyclosporine, by inhibiting calcineurin, decrease the decrease the expression of the mineralocorticoid receptor with subsequent reduction in potassium Angiotensin converting enzyme inhibitors and angiotensin receptor blockers inhibit aldosterone with the subsequent reduction in potassium excretion. ENaC, epithelial sodium channel; ROMK, renal outer medullary potassium channel; FKBP, FK binding protein; SPAK, STE20/SPS1-related proline- and alanine-rich kinase; WNKs, with no-lysine kinases; NCC, sodium chloride cotransporter; MR, mineralocorticoid receptor; BK, big potassium channel. (A) Distal convoluted tubular cell. (B) Principal cell of collecting duct.

Figure 2

During times of acid load, type B intercalated cell converts to type Aintercalated cell to facilitate proton excretion. This process requires deposition of polymers of a protein called Hensin in the extracellular matrix. Cyclophilins are enzymes that assist in protein folding/oligomerization and are needed for polymerisation and deposition of Hensin. Cyclosporine by binding to and inhibiting the enzymatic activity of cyclophilin, prevents this adaptation of the intercalated cell from the bicarbonate secreting beta form to the acid secreting alpha form. V-ATPase, vacuolar type proton ATPase; AE, Anion exchanger 1.

Figure 3

In the distal convoluted tubule the final 10% of magnesium is reabsorbed in an active transcellular manner. The tubular epithelium in this part has a lumen-negative voltage. Apical reabsorption occurs via TRPM6, which can be stimulated via the basolateral EGFR. Kv1.1, an apically located potassium channel, establishes a favorable luminal membrane potential facilitating an increase in the driving force for magnesium reabsorption via TRPM6. At the basolateral membrane, magnesium is extruded via an unknown mechanism likely SLC41A1 transporter, which may be regulated by cyclin M2 acting as magnesium sensor. Magnesium extrusion depends on the sodium gradient, set by the Na+-K+-ATPase. The activity of the Na+-K+-ATPase is in turn dependent on potassium recycling via Kir4.1 channel. Tacrolimus and cyclosporine downregulate TRPM6 which is the major active transport protein in the distal tubule that is needed for reabsorption of magnesium. Cyclosporine also decreases the expression of EGF, and hence decreasing the expression of TRPM6. TRPM6, transient receptor potential melastatin type 6; Kv1.1, apical voltage-gated K channel 1.1; NCC, sodium chloride cotransporter; SLC41A1, solute carrier family 41 A1 Mg2+ transporter; Kir4.1, basolateral voltage-gated channel; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor.