This month I will focus in on some intriguing medication induced renal complications. The first one is another one of those “you know” moments from nephrology fellowship almost 40 years ago today. I had a mid 30-year-old business executive who had a 20 year history of diabetes that had been neglected. She presented with far advanced chronic renal failure with a creatinine of 8+ mg/dL. She had no obvious uremic symptoms. Her volume was well maintained on no diuretic therapy. Her blood pressure came under prompt control with simple antihypertensive medications. She had a vascular access placed when a 4 antigen matched sister declined to be a kidney transplant donor. She was on the kidney transplant list for exactly 1 day when she received a deceased donor kidney. The waiting me was somewhat shorter at that time than it is today. Following transplantation, the patient developed delayed graft function. At that time, Washington University Medical Center was doing nuclear medicine scans to identify transplant rejection. The imaging study suggested rejection. She was placed on enhanced immunosuppression therapy. Renal function did not improve. Repeat renal imaging revealed obvious transplant obstruction. It was last time I would believe a nuclear medicine scan for the diagnosis of rejection. Following relief of obstruction renal function promptly improved back to normal levels with creatinine approximately 1 mg/dL. In the postoperative period following relief of obstruction, the patient developed clinically obvious deep venous thrombosis of one of her legs. She was placed on Heparin infusion, with the plan to transition to Coumadin therapy. She then spontaneously developed severe hyperkalemia with potassium level in excess of 8 mEq/L, despite improving renal function, normal volume status, normal glucose levels, normal bicarbonate levels, no obvious medications known at the time (no CNI were available yet) to contribute to renal potassium retention. I asked my program director “what on earth could be the cause of this unexplained hyperkalemia?” The response was “you know” (No, I really didn’t know), if you incubate zona glomerulosa cells in adrenal culture media with Heparin, aldosterone production is markedly diminished. This is simply a functional hypo-aldosterone state. Stop Heparin, advance Coumadin, maintain adequate volume, give Florinef if you want, this will all get better. Yep, it all came true. Yikes!! My program director was quoting the data from adrenal cell culture incubation media, to explain an unrecognized (to me) cause of hyperkalemia.
The anti-aldosterone effect of Heparin had been surmised in the late 1950s. Back-to-back articles by Schlatmann and Cejka in Lancet 1960 confirmed that Heparin inhibited aldosterone effect in humans. Follow-up articles by Schlatmann and Conn in JCEM a few years later again showed that Heparin inhibited aldosterone production-release.
Another article by Dodd in American Journal of Medicine in 1964 again confirmed the finding of hypo-aldosteronism associated with Heparin use.
In a truly landmark article by O’Kelly in JCEM 1983 showed that frank mineralocorticoid deficiency could be seen with routine Heparin use in patients where limitations in the renin-angiotensin aldosterone system existed (diabetes-established CKD). While I was unaware that prior studies had shown the association of Heparin with hypo-aldosteronism, this paper occurred a couple years after this sentinel event described above.
Finally a thorough review of the topic was published in American Journal of Medicine by Oster in 1995.
Today, Heparin is included in all review articles on medication induced hyperkalemia. Now…. you have the rest of thestory.
Nephrology Fellowship 