A Short (selective) History of Models of the Urine Concentrating Mechanism

• Presentation of the problem

• Landmarks leading up to the present work

  • 1951: Kuhn et al
  • 1972: Stephenson and Kokko & Rector
  • 1987: Lemley & Kriz
  • 1991: Wexler, Kalaba, & Marsh
  • 1995: Thomas & Wexler
  • 1998: Wang & Thomas et Thomas
  • 2003: Hervy & Thomas

Presentation of the problem

Since the work of Hargitay & Kuhn and Wirz, Hargitay, & Kuhn in 1951, we have known of the steep, cortico-papillary osmolality gradient in the internal medulla and its importance for the urine concentrating mechanism. According to Hargitay & Kuhn's Hairpin Countercurrent Hypothesis, a small local driving force (the "single effect") can explain a large global gradient thanks to countercurrent multiplication.

Although the basic application of this hypothesis was proven in the late 50s by in vivo micropuncture, the question of the single effect operating in the inner medulla remains open.

We present here a brief history of this question. Please note that this account makes no pretense at presenting a complete history of models of the urine concentrating mechanism. We recount here just one narrow path towards the model presented in these pages (Hervy and Thomas, 2003, Am. J. Physiol. Renal 284:F65-F81).

For further reading on other new and current ideas about this subject, see some fascinating new data on the heterogeneity of water and solute permeabilities along the thin descending limbs (Pannabecker et al. 2004) and a modelling study that explores possible new modes for the concentrating mechanism based on this new data (Layton et al. 2004). See also (Knepper, et al. 2003) and (Dwyer & Schmidt-Nielsen 2003) on the possible role of pelvic peristalsis.

Landmarks

1951: Kuhn and collaborators

In 1951, Hargitay & Kuhn were the first to propose a model of the urine concentrating mechanism based on countercurrent exchanges among multiple parallel tubes functioning in countercurrent fashion. (see figure).

They suggested, among other possibilities, that the primary driving force, or "single effect", might be active salt transport out of the ascending limbs of Henle, a suggestion later confirmed for the thick ascending limbs of the outer medulla.

However, by the late sixties the possibility of active transport of salt from the thin ascending limbs within the inner medulla had become controversial, which raised once more the question of the single effect for the inner medullary region.

1972: Stephenson and Kokko & Rector

In 1972, Stephenson and Kokko & Rector published, in the same issue of Kidney International, a hypothesis according to which the accumulation of NaCl towards the tip of the papilla in the passive inner medulla could be accomplished thanks to inner medullary recycling of a second solute, urea.

According to this "passive hypothesis", as it is called, the massive dumping of urea from the terminal portions of the collecting ducts during antidiuresis serves as intersititial, or "external", osmoles. By osmosis, this interstitial urea could draw water from the descending limbs of Henle (DHL), thereby concentrating its solutes, and, in particular, raising the luminal concentration of NaCl.

For this idea to work, the urea permeability of the DHL must be very low. Permeability measurements by in vitro microperfusion in rabbit tubules supported this possibility, but micropuncture results (from rat and hamster) clearly indicated that there was significant urea entry along the descending limb. This apparent conflict was later shown (especially by Imai's laboratory) to be species-related, and it was found that kidneys that concentrate well have higher, instead of lower, urea permeability of the inner medullary DHL.

It thus became necessary to search once more for the inner medullary single effect.

(see the exhaustive review by Stephenson (1992) for a rich account of the many central core models (including Layton's cascading nephrons in the IM) and progressively more detailed inclusion of medullary anatomical features (Chandhoke, Knepper, Saidel...))

1987: Lemley & Kriz

In 1987, Lemley & Kriz published an article reviewing the features of renal anatomy and physiology judged at the time to be relevant for the concentrating mechanism. They put together a synthesis based on considerations of the 3-dimensional aspects of, especially, the outer medulla (vascular bundles...) and known tubule permeabilities and micropuncture results. Based on this synthesis, they specified probable recycling paths for salt, urea and water in the different medullary regions. This amounted to specification of what might be called a "discursive" model. At the time, numerical techniques were not able to include the 3D aspects of this vision of the inner medulla in order to test quantitatively the conclusions reached by Lemley & Kriz on the basis of their discursive hypothesis. This challenge was soon taken up in the laboratory of Donald Marsh.

1991: Wexler, Kalaba, & Marsh

In 1991, Wexler, Kalaba & Marsh published a 3D mathematical model based on the morphological details specified by Lemley & Kriz [see above]. Their study showed that it is clearly important to take into account the vascular bundle structure of the inner stripe of the outer medulla, since this model successfully predicted an inner medullary osmotic gradient even with all permeabilities within two standard errors of published measurements. Nonetheless, several details were subsequently called into question (Han et al. 1992, Jen & Stephenson), and it eventually became clear that even consideration of the 3D anatomy is insufficient to explain the steep gradients observed. As with the earlier "flat" models, the WKM models are also highly sensitive to the DHL urea permeability, a qualitative mismatch with physiological data.

1995: Thomas & Wexler

In 1995, Thomas & Wexler explored an idea that had been briefly evoked in the early sixties (Ullrich, other labs...), namely, a possible role for interstitial "external" osmoles other than NaCl and urea. Using the 3D WKM model, we found that if there were about 100 mOsm of some osmoles other than NaCl and urea in the IM interstitium, then the model predicted a virtually physiological osmotic gradient that was much less sensitive to the urea permeability of DHL. At just about the same time, the same idea was also explored in an ideal, analytical central core model by Jen & Stephenson (1994). Their results suggested that even smaller concentrations might suffice. Unfortunately, no one had a suggestion at the time as to possible candidate solutes.

1998: Wang, Thomas, & Wexler

In 1998, Wang, Thomas, & Wexler published a new version of the WKM 3D model with improved agreement with literature on outer medullary anatomy and permeability data. (cf. opposite). The same year Thomas gave a detailed analysis of the water and solute recycling paths this model predicts and compared these quantitative model predictions with the discursive suggestions of (Lemley & Kriz [see above]). In addition to providing a clearer idea of the behavior of the global hypothesis underlying the model (i.e., as near as possible to the synthesis provided by Lemley & Kriz), it became obvious that although these models account more accurately for the contribution of vascular bundles and other such "3D" features, they still fail to provide an adequate explanation for the osmotic gradient of the inner medulla.

2003: Our Model (Hervy & Thomas, 2003) grew from this background.

Click on the "our model" link in the title bar for a detailed description of the model presented in this website.