For hundreds of years, or at least since I started to teach the kidney, it has been "understood" that NH₃ diffuses passively out of renal cells where it combines with H⁺ to become NH₄⁺ which is trapped in the urine because charged species cannot cross plasma membranes. Whilst this remains true and it is an important process in renal cells, recent work indicates that NH₃ metabolism and the production of HCO₃^- is a bit more complicated than that.

The good news is that the overall effect is unchanged. Renal cells, specifically those of the proximal tubule metabolise glutamine to make NH₃/NH₄⁺ which is eventually lost in the urine and by this process produce HCO₃^- to help regulate systemic pH

Most of the changes in our understanding and the increasing complexities that come from greater understanding emanate from the simple concept that both NH₃ and NH₄⁺ turn out to be good substrates for primary and secondary active transport processes better known for transporting other things. This will have the biggest impact on NH₄⁺ movement because, unlike NH₃, NH₄⁺ can't get across membranes unaided.

So, which transporters accomodate NH₄⁺ and make a contribution to renal NH₃/NH₄⁺ handling?

• The type 3 Na⁺ / H⁺ exchanger NHE-3
• K⁺ channels. In a dim light and at the molecular level, NH₄⁺ looks a lot like K⁺ and so fits through K⁺ channels.
• The Na⁺ - K⁺ - 2Cl^- cotransporter NKCC-2 (NH₄⁺ pretending to be K⁺)
• The Na⁺ - K⁺ ATPase (NH₄⁺ pretending to be K⁺)

In addition, NH₃/NH₄⁺ specific channels Amt (ammonia transporter) and methylamine permease (MEP) are well known in plants, bacteria and yeast and the rhesus blood group antigen (which is a glycoprotein found on erythrocyte membranes) has been identified as a member of the same family of proteins and it too transports NH₃/NH₄⁺. Various isoforms of these proteins are expressed in the kidney and one (RhCG) could contribute to NH₃ transport across the apical membrane of the collecting duct. Slightly bizarrely, knocking out these proteins does not seem to have much effect on renal NH₃ handling but it may have an impact on pH regulation.

What is really, really important then?

Probably NH₄⁺ transport out of the cells by the Na⁺ / H⁺ exchanger on the apical membrane of the proximal tubule cells. If you are really concentrating, then you might notice that NH₄⁺ can't mop up H⁺ in the urine because it has already combined with H⁺. Remember though that the H⁺ are themselves excreted by Na⁺ / H⁺ exchange. It really doesn't matter whether NH₄⁺ and H⁺ combine inside the cell and travel out together or combine outside the cell. The net effect is loss of H⁺ from the body in the urine and this is ultimately the key to manufacture of HCO₃^-.

The Na⁺ - K⁺ - 2Cl^- cotransporter lives in the apical membrane of the thick ascending limb of the loop of Henle where it is probably the most important mechanism for NH₄⁺ reabsorption.

The observation that NH₄⁺ travels through K⁺ channels is probably not that important because the electrochemical gradient for NH₄⁺ is directed into the cell and NH₄⁺ accumulation inside, for example proximal tubule cells which are manufacturing the stuff anyway, isn't an obviously help in NH₄⁺ transport into the urine.

However, intracellular NH₄⁺ accumulation in cells which don't themselves manufacture NH₄⁺, for example the inner medullary collecting duct cells may be very useful. There is evidence that the intracellular concentration NH₄⁺ from the medulla by the Na⁺ - K⁺ ATPase creates a concentration gradient for NH₄⁺ which drives NH₄⁺ from these cells into the urine.

The (greatly simplified) take home message

• Passive diffusion of NH₃ and trapping of NH₄⁺ in the urine is not sufficient explanation of renal NH₃/NH₄⁺ handling
• There are a whole load of channels and active transporters that can and do transport NH₃ and most significantly NH₄⁺
• NH₄⁺ is secreted into the urine in the proximal tubule, it is also concentrated in the medulla and excreted (again?) into the urine by the collecting duct
• NH₄⁺ is excreted in the urine and this excretion allows the manufacture of HCO₃^-
• It is going to be a while before we really understand what is going on

See the review by DavidWeiner and L. Lee Hamm in Annual Reviews of Physiology (2007) 69:317-40 for a much more thorough and accurate take on renal NH₃/NH₄⁺ handling.