The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction

Abstract

There is an alarming global increase in the incidence of end-stage kidney disease, for which early biomarkers and effective treatment options are lacking. Largely based on the histology of the end-stage kidney and on the model of unilateral ureteral obstruction, current investigation is focused on the pathogenesis of renal interstitial fibrosis as a central mechanism in the progression of chronic kidney disease (CKD). It is now recognized that cumulative episodes of acute kidney injury (AKI) can lead to CKD, and, conversely, CKD is a risk factor for AKI. Based on recent and historic studies, this review shifts attention from the glomerulus and interstitium to the proximal tubule as the primary sensor and effector in the progression of CKD as well as AKI. Packed with mitochondria and dependent on oxidative phosphorylation, the proximal tubule is particularly vulnerable to injury (obstructive, ischemic, hypoxic, oxidative, metabolic), resulting in cell death and ultimately in the formation of atubular glomeruli. Animal models of human glomerular and tubular disorders have provided evidence for a broad repertoire of morphological and functional responses of the proximal tubule, revealing processes of degeneration and repair that may lead to new therapeutic strategies. Most promising are studies that encompass the entire life cycle from fetus to senescence, recognizing epigenetic factors. The application of techniques in molecular characterization of tubule segments and the development of human kidney organoids may provide new insights into the mammalian kidney subjected to stress or injury, leading to biomarkers of early CKD and new therapies.

Keywords: acute kidney injury; atubular glomeruli; chronic kidney disease; proximal tubule; unilateral ureteral obstruction.

Fig. 1.

Measurements of microdissected nephrons from patients with chronic Bright's disease (chronic kidney disease). Left, top: schematic normal and hypertrophied nephrons with the relative volume of glomerulus and tubular segments represented by the area of each segment. Virtually all of the adaptive growth is contributed by the proximal tubule. Left, bottom: relative proximal tubular diameter; represented by marks reflecting varying cross-sectional area along the length of the tubule. Representative hypertrophied and atrophied proximal tubular segments are compared with a normal one. Right: atubular glomerulus and aglomerular tubule. [Reproduced with permission from J. Oliver (128) and Wolters Kluwer.]

Fig. 2.

Number of papers containing the key words “unilateral ureteral obstruction” published between 1986 and 2015. Medline search was performed April 2016. There was a 10-fold increase in the annual number of publications between 1986 and 2015.

Fig. 3.

Microdissected human nephrons. A and B: glomerulus and proximal tubule from term neonate and adult, respectively. C: complete atrophic nephron from aging adult. D: complete hypertrophic nephron from aging adult. Arrows indicate glomeruli. [Reproduced with permission from J. Oliver (129; 132) and Wolters Kluwer.]

Fig. 4.

A: length of human proximal tubule from birth to 90 yr. Data are shown from measurements of microdissected nephrons from 105 cadavers undergoing routine necropsy, who had suffered acute death. Steady growth from birth to 20 yr is followed by a plateau and a gradual decline after the 3rd to 4th decade. Red box = 20–30 yr of age, peak reproductive years. B: lifetime risk for diagnosis of ESKD from birth to 90 yr, from Grams et al. (68). [Graphic representation of data in A reproduced with permission from Darmady et al. (33) and Wiley.]

Fig. 5.

Fractional distribution of glomerulotubular junction integrity in serial sections of glomeruli from patients with nephropathic cystinosis and diabetic nephropathy. Data are arranged by age group, with age range for patients in each diagnostic group. “Atubular glomeruli” are those with no tubular connection; “Tubular atrophy” indicates glomeruli connected to atrophic tubules; and “Normal” indicates glomeruli connected to normal tubules. DM, diabetes mellitus. Data were derived from Larsen et al. (97), Najafian et al. (117), and White et al. (186).

Fig. 6.

Progression of cystinosis in mouse and man. A: “swan neck deformity” of the proximal tubule in human cystinosis develops after 5 mo of age is shown: normal, cystinosis 5 mo, and cystinosis 14 mo. B: scheme showing nephron changes with age in murine and human cystinosis. Fanconi syndrome generally develops in the first 6 mo of life, with significant decrease in GFR by 2–5 yr, and renal failure in the 2nd decade. There is marked interindividual variability in the rate of progression of renal lesions, and treatment with cysteamine can significantly delay progression to renal failure. The evolution of renal lesions in the mouse is more gradual, with GFR decreasing only later in adulthood. The period of proximal tubular maturation extends through the first 6 mo in humans and the first 3 mo in the Ctns^−/− mouse; the “swan-neck lesion” is initiated in the first 3 mo in the mouse, and between 6 and 12 mo in humans. The development of irreversible renal lesions in both species includes loss of functional proximal tubular mass and the development of tubular atrophy, interstitial fibrosis, and formation of atubular glomeruli. Therapy should be directed to the early period of adaptation (potentially reversible changes) rather than the late (destructive) phase. [Reproduced with permission from Mahoney and Striker (107) and Springer, and Galarreta et al. (55).]