Overview of factors contributing to the
pathophysiology of progressive renal disease
Detlef O. Schlondorff1
1Renal Division, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
Some basic premises must be considered when validating
hypothesis about progression of renal disease. In an
accompanying series of five articles, specific aspects of
progression will be reviewed by experts in the field:
mechanisms of tissue and matrix remodelling; interstitial
fibrosis; the contribution of ischemia and hypoxia; the role
and type of the inflammatory infiltrate; and, finally,
Kidney International (2008) 74, 860–866; doi:10.1038/ki.2008.351;
published online 23 July 2008
KEYWORDS: progression of renal disease; hypoxia; interstitial fibrosis;
ischemia; glomerulosclerosis; matrix remodelling
BASIC CONSIDERATIONS CONCERNING PROGRESSION OF
Chronic progressive renal disease is characterized by
glomerulosclerosis, interstitial leukocyte infiltration, tubular
atrophy, and tubulointerstitial fibrosis.1Involvement of both
the tubulointerstitium and the glomeruli contributes to
progression and, hence, prognosis of all renal diseases.
Glomerular sclerosis may be associated with podocyte loss
with or without inflammatory and proliferative components.
In contrast, in the tubulointerstitial compartment, progres-
sive fibrosis is always associated with persistent sterile
inflammation. The latter is initiated by the generation of
soluble mediators in response to local cell stress and tissue
injury, resulting in the infiltration of leukocytes, and
subsequent secretion of various mediators by infiltrating
and resident bone marrow (BM)-derived cells, as well as
(see Figure 1). Together, these actions attempt to correct
and repair local tissue damage, but also result in the
activation of profibrotic cells, predominantly myofibroblasts,
and a local scar formation or fibrosis.1Fibrosis, in turn,
entails distortion of the intricate cellular architecture of the
nephron, initiating a vicious cycle and posing further
challenges to cellular homeostasis. As these considerations
apply to the process of fibrosis in any organ, hypotheses
about progressive fibrosis in renal disease should include
(1) the anatomical and physiological make-up of the kidney
and the nephron and
(2) the basic principles of the pathology of tissue injury and
One should keep in mind that a hypothesis and its
experimental support is limited by what we can measure. This
idea should be obvious when looking at the historical
development of renal pathology from gross anatomy and
histopathology to cellular, ultrastructural, molecular, and
genomic levels. What we can measure creates certain areas of
emphasis in research that may or may not reflect the
significance of the scientific question being asked. The
frequently quoted observation that tubulointerstitial changes
are the best predictors of renal function and prognosis may be a
case in point. Perhaps, the basis for this statement is founded
more in the pathologists’ capability to preferentially measure
and quantify changes in the tubulointerstitial space, which
progression of renal disease
& 2008 International Society of Nephrology
Received 22 April 2008; accepted 22 April 2008; published online
23 July 2008
Correspondence: Detlef O. Schlondorff, Renal Division, Department of
Medicine, Mount Sinai School of Medicine, One Gustave Levy Place, Box
1243, New York, New York 10029, USA. E-mail: email@example.com
Kidney International (2008) 74, 860–866
becomes neutralized, and that leukocytes at the site of tissue
injury disappear by either undergoing apoptosis or leaving
the site through blood or lymphatic vessels (reverse
migration). Furthermore, the extracellular matrix scaffold
must be remodeled to its original form and the parenchymal
cells must replace the lost cells in the original pattern. Under
these rare conditions, an early fibrotic process may be
reversible, as recently reported.23Unfortunately, this scenario
is the exception rather than the rule. Under most conditions,
disruption of the intricate tissue structure takes place,
so that repair can only occur in an incomplete manner,
that is with fibrosis. Depending on the degree of tissue
distortion resulting from the fibrosis and continued cell
stress, the process of repair may come to a relative standstill,
or damage will continue to progress relentlessly to renal
The advent of therapies that block the angiotensin system has
led to major advances in slowing the progression of most
forms of chronic renal diseases. Unfortunately, the therapeu-
tic benefits of interfering with the renin–angiotensin system
may approach their limits. Additional pathways of preventing
progression of renal diseases need to be studied. These
pathways could include preservation or growth of endothelial
cells and angiogenesis, preventing ischemia-hypoxia and their
detrimental responses, reducing or antagonizing reactive
oxygen species, interfering with TLRs and their endogenous
DAMP ligands, blocking or resolving proinflammatory and
profibrotic inflammatory infiltrates, altering the profibrotic
cytokine profile, enhancing removal of excessive matrix, and
reestablishing a favorable balance between apoptosis and cell
Finally, novel treatments aimed at the causes of the
different glomerular diseases, including that which targets
secondary tubolointerstitial involvement, need to be deve-
The author declared no competing interests.
This work was supported in part by a grant to D.S. from the NIH DK
1. Segerer S, Kretzler M, Strutz F et al. Mechanisms of tissue injury and repair
in renal diseases. In: Schrier R (ed). Diseases of the Kidney and Urinary
Tract. Lippincott, Philadelphia, 2007.
2. Shankland SJ. The podocyte’s response to injury: role in proteinuria and
glomerulosclerosis. Kidney Int 2006; 69: 2131–2147.
3.Ballermann BJ, Stan RV. Resolved:capillary endothelium is a major
contributor to the glomerular filtration barrier. J Am Soc Nephrol 2007; 18:
4.Kerjaschki D, Huttary N, Raab I et al. Lymphatic endothelial progenitor
cells contribute to de novo lymphangiogenesis in human transplants. Nat
Med 2006; 12: 230–234.
5.John R, Nelson PJ. Dendritic cells in the Kidney. J Am Soc Nephrol 2007;
6.Hostetter T. Hyperfiltration and glomerulosclerosis seminars. Nephrology
2003; 23: 194–199.
7.Baylis C, Brenner B. The physiological determinants of ultrafiltration. Rev
Physiol Biochem Pharmocol 1978; 80: 1–46.
8. Baumgartl H, Leichtweiss H-P, Lubbers DW et al. The oxygen supply of
the dog kidney: measurements of intrarenal pO2. Microvasc Res 1972; 4:
9. Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease.
Physiol Rev 2006; 86: 1133–1149.
10.Anders HJ, Schlondorff D. Toll-like receptors: emerging concepts in
kidney disease. Curr Opin Nephrol Hypertens 2007; 16: 177–183.
11.Anders HJ, Banas B, Schlondorff D. Signaling danger: toll-like receptors
and their potential roles in kidney disease. J Am Soc Nephrol 2004; 15:
12.Ferguson MWJ, O’Kane S. Scar-free healing:from embryonic mechanisms
to adult therapeutic intervention. Philos Trans R Soc London B 2004; 359:
13. Zandi-Nejad K, Eddy AA, Glassock RJ et al. Why is proteinuria an ominous
biomarker of progressive kidney disease? Kidney Int 2004; 65(Suppl 93):
14.Matzinger P. The danger model: a renewed sense of self. Science 2002;
15.Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4:
16.Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about
danger. J Leukoc Biol 2007; 81: 1–5.
17. Wu H, Chen G, Wyburn KR et al. TLR4 activation mediates kidney
ischemia/reperfusion injury. J Clin Invest 2007; 117: 2847–2859.
18.Lang A, Benke D, Eitner F et al. Heat shock protein 60 is released in
immune-mediated glomerulonephritis and aggravates disease: in vivo
evidence for an immunologic danger signal. J Am Soc Nephrol 2005; 16:
19. Seki E, De Minicis S, Osterreicher CH et al. TLR4 enhances TGF-b signaling
and hepatic fibrosis. Nat Med 2007; 13: 1324–1332.
20.Anders HJ, Vielhauer V, Schlondorff D. Chemokines and chemokine
receptors are involved in the resolution or progression of renal disease.
Kidney Int 2003; 63: 401–415.
21.Segerer S, Schlo ¨ndorff D. Role of chemokines for the localization of
leukocytes subsets in the kidney. Semin Nephrol 2007; 7: 260–274.
22.Wada T, Sakai N, Matsushima K et al. Fibrocytes:a new insight into kidney
fibrosis. Kidney Int 2007; 72: 268–273.
23.Remuzzi A, Gagliardini E, Sangalli F et al. ACE inhibition reduces
glomerulosclerosis and regenerates glomerular tissue in a model of
progressive renal disease. Kidney Int 2006; 69: 1124–1130.
Kidney International (2008) 74, 860–866
progression of renal disease
DO Schlondorff: Pathophysiology of progressive renal disease