Progress in the area of diabetic kidney research leading to new therapeutics development
has been very limited. Indeed, no new medicines indicated for the treatment of chronic
kidney disease (CKD) have been approved since ARB's have become standard of care nearly
15 years ago. Several factors explain the limited progress including but not limited to;
a) animal and cell culture models do not recapitulate human DKD b) human genetic studies
so far have failed to identify reproducible genetic variants associated with DKD c) the
clinical manifestation of DKD is heterogeneous and might have even changed since the
original description d) DKD is a clinical diagnosis and it is not clear what percentage
of patients have histological disease.
Laboratory mice have served as invaluable tools to understand human disease development.
As mouse genetic tools became readily available, it enabled us to perform time and cell
type specific gene manipulation in animals to generate disease models and to understand
the contributions of specific pathways. Unfortunately, mouse models do not recapitulate
human diabetic kidney disease as animals develop only early DKD lesions; mesangial
expansion and mild albuminuria11. Most models do not develop arterial hyalinosis,
tubulointerstitial fibrosis and declining glomerular filtration rate (GFR); hallmarks of
progressive DKD. There are several fundamental differences in gene expression patterns
and physiology of human and murine kidneys. Such differences may explain the lack of
translatability between mice and humans of pharmacological approaches aimed at treating
DKD. This seems to be a general trend in other disease areas as well (for example
Alzheimer's disease), leading to a recent movement toward translational and clinical
research with increasing reliance on human samples.
Human genetic studies made paradigm-shifting observations in relatively rare monogenic
forms of kidney diseases (including polycystic kidney disease and focal segmental
glomerulosclerosis). Diabetic CKD on the other hand follows a complex polygenic pattern.
Currently, the most powerful method to define the genetics of complex diseases such as
DKD is genome wide association (GWAS), where associations between polymorphisms and the
disease state are tested. Prior studies indicate that for complex traits, such as DKD,
genetic polymorphisms that are associated with disease state are localized to the
non-coding region of the genome12,13. Moreover, the genetic architecture of diabetic
kidney disease has not been characterized and several large collaborations are currently
addressing this issue14. Thus, the next challenge is to define target genes, target cell
types and the mode of dysregulation caused by non-coding snips (SNPs15). Such studies
require large collection of human tissue samples from disease relevant organs.
Diabetic kidney disease (DKD) remains a clinical diagnosis. Subjects with CKD in the
presence of diabetes and albuminuria are considered to have diabetic nephropathy. Such
definition is used in clinical practice and in research studies including clinical
trials. Studies performed in 1980 provide the basis for the practice16,17. Investigators
stage DKD as a progressive disease, beginning with the loss of small amounts of albumin
into the urine (30-300mg/day; known as the stage of microalbuminuria, high albuminuria,
occult or incipient nephropathy), then larger amounts (>300mg/day; known as
macroalbuminuria, very high albuminuria or overt nephropathy), followed by progressive
decline in kidney function (eGFR), renal impairment and ultimately ESRD 17-19. This
paradigm has proved useful in clinical studies, especially in type 1 diabetes, for
identifying cohorts at increased risk of adverse health outcomes. However, boundaries
between stages of DKD are artificial and the relationship between urinary albumin
excretion and adverse health outcomes is log-linear in clinical practice. Indeed, the
American Diabetes Association recently abandoned staging of albuminuria (ACR) for a
more-straightforward [ACR >30 mg/g, (albuminuria present); ACR <30 mg/g (albuminuria
absent)] criterion. Moreover, many patients, and especially those with type 2 diabetes,
do not follow this classical course in modern clinical practice. For example, many
subjects with DKD do not manifest excessive urinary albumin loss20. Indeed, of the 28% of
the UKPDS cohort who developed moderate to severe renal impairment, half did not have
preceding albuminuria. In the Diabetes Control and Complications Trial (DCCT), of the 11%
patients with type 1 diabetes who developed an eGFR<60 ml/min/1.73m2, 40% never had
experienced overt nephropathy21. In addition, most patients with microalbuminuria do not
progressively exhibit an increase in urinary albumin excretion as in the classical
paradigm with treatment-induced and spontaneous 'remission' of albuminuria widely
observed22,23. Consequently, individuals with microalbuminuria may better be regarded as
being at increased risk of developing progressive renal disease (as well as
cardiovascular disease and other diabetic complications), rather than as actually having
DKD per se. While over the last 40 years it became evident that the original description
of DKD needs revision, no alternative criteria have emerged given the lack of solid data
on the correlation between histopathological (gold standard) DKD diagnosis and clinical
manifestations. It is also possible that, with the introduction of better glycemic
control and anti-renin (RAAS) blockade, the disease has evolved necessitating new
observational cohorts to understand the clinical disease course and manifestations.
Diabetic kidney disease presents with a variable rate of kidney function decline24. Data
from large observational cohorts indicate that GFR decline frequently does not follow a
linear course. Several groups are working on modeling GFR decline patterns in patients.
Such studies contributed to emphasizing patients termed as "rapid progressors". There is
no consensus definition for rapid progression. Many studies define rapid progressors as
patients with greater than 3 cc/year GFR decrease but alternative cut points such as even
10 cc/year has also been used. Identification and clinical characterization of rapid
progressors became the center of several large scale efforts as these are the patients
who would likely need intensive clinical management25. Furthermore recent post-hoc
analyses of the Diabetic Nephropathy (IDNT and RENAAL) studies indicate that clinical
trial outcomes are mostly driven by a small number of subjects with unusually rapidly
progressive GFR decline i.e. subjects that display characteristics of rapid progressors.
While investigators are still awaiting accurate descriptions, biomarker and clinical
descriptive studies have yielded several interesting observations. Albuminuria remains
one of the strongest risk factor for "FDA-approved" (hard) renal outcomes; doubling of
serum creatinine, dialysis or death. Indeed some of the latest studies indicate that
using a 4 or a 6 variable model, that includes albuminuria, age, sex, serum phosphate,
serum calcium and serum albumin has C-statistics score of 0.84-0.91 to predict ESRD
26,27. During the last years several new biomarkers have been identified that can
potentially identify patients who are at increased risk for rapid loss of kidney
function. For example blood and urinary levels of kidney injury molecule (KIM1) shows
promise to identify patients who are at risk for kidney function decline. Recently,
investigators showed that circulating levels of tumor necrosis factor receptor 1 and 2
levels can identify patients with rapidly declining renal function 28. While these
markers are generating increased interest; the critical questions remains; why do some
patients follow a rapid decline in kidney function?