Telomere Therapy for Chronic Kidney Disease

Figures & data

Figure 1. Telomeres, chronic kidney disease and pathophysiology overview.

As renal function decreases, there is an accumulation of urea, toxins and other waste products resulting in uremia. Uremia induces immune deficiency, oxidative stress and inflammation. Oxidative stress, inflammation and immune deficiency are associated with increased telomere attrition. Shorter telomeres predispose to kidney fibrosis and decrease the tissue repair capacity of the kidney in response to injury. This increases susceptibility to onset of CKD and exacerbates existing CKD.

CKD: Chronic kidney disease.

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Figure 2. Telomere shortening.

Due to the end replication problem, telomeres progressively shorten with each cell division.

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Table 1. Studies of associations between telomeres and chronic kidney disease.

Animal studies
Sample type	Main findings	Association	Source	Measurement method	Ref.
Uremic rats	Shorter cardiac TL correlates with expressed ROS in uremic rats. Treatment with antioxidant (vitamin C) increases TL and decreases ROS expression	Positive	Heart	Flow FISH^†	[45]
TERT and TERC knockout mice exposed to ischemia/reperfusion injury	TERT and TERC knockout significantly delayed renal recovery after ischemia/reperfusion-induced renal injury	Positive	Not specified	Not specified	[40]
Cats with CKD	Shorter kidney TL independently associated with CKD; no association between liver or skin TL and CKD. Liver telomerase activity highest in CKD group compared with other groups; no difference in kidney telomerase activity across groups	Positive	Kidney, liver, skin	qFISH^† TRAP assay^‡	[42]
Cyclosporine-induced nephrotoxic rats	Decreased kidney TL correlates with decline in renal function. Cyclosporine-induced oxidative stress could be responsible for renal telomere attrition and ensuing kidney senescence. Renal telomerase activity not affected by cyclosporine-A	Positive	Kidney	Southern blot (TRF analysis)^† TRAP assay^‡	[44]
TERT and Trf1 knockout mice	Trf1 deletion leads to development of kidney fibrosis. Telomerase-deficient mice treated with low-dose folic acid develop kidney fibrosis and severe kidney dysfunction	Positive	Kidney	qFISH^†	[33]
Telomerase knockout mice	Kidney injury results in shorter kidney TL in rats; recovery rate from injury is associated with TL	Positive	Kidney	qFISH^†	[39]
Rats with induced renal failure and myocardial infarction	Severe renal failure, but not mild renal failure, results in cardiac telomere attrition compared with control	Positive	Heart	qPCR^†	[41]
Cell lines
Cell type	Main findings	Association	Tissue source	Measurement method	Ref.
Human glomerular mesangial cells	High glucose environment promotes telomere attrition in kidney cells	Positive	Human glomerular mesangial cells	Southern blot (TRF analysis)^†	[64]
Human studies
Study population (sample size)	Main findings	Association	Tissue source	Measurement method	Ref.
Coronary heart disease patients (n = 954)	Decreased renal function associated with shorter baseline LTL and greater telomere attrition after 5-year follow-up; no longer significant after adjusting for age	Age-dependent	Leukocytes	qPCR^†	[69]
End-stage renal disease patients (n = 281)	Telomere attrition independently associated with end-stage renal disease. Decreased T-cell TL may explain uremia-associated immune deficiency in patients with loss of renal function	Positive	T-cells	Flow FISH^†	[46]
HD patients (n = 136)	Shorter PBMC TL associated with HD independent of age. HD patients with vitamin D supplementation had longer TL compared with untreated patients	Positive	PBMCs	Southern blot (TRF analysis)^†	[55]
Prevalent HD patients (n = 175)	LTL predicts mortality in CKD patients independent of age and gender	Positive	Leukocytes	qPCR^†	[54]
CKD patients (n = 222)	CKD associated with decreased PBMC TL. Telomerase activity not correlated with TL	Positive	PBMCs	qPCR^† TRAP assay^‡	[50]
Kidney transplant donors (n = 257)	LTL and intrarenal TL correlated; shorter TL not associated with renal function (eGFR) but with intrarenal arteriosclerosis	Positive	Leukocytes, kidney	qPCR^†	[66]
Kidney transplant recipients (n = 134)	5 years post-transplantation, intrarenal TL associated with renal arteriosclerosis, dependent on donor characteristics	Positive	Kidney	qPCR^†	[67]
Patients with cardiovascular risk factors (n = 766)	Shorter LTL associated with decreased renal function (eGFR); stronger correlation in non-CKD patients	Positive	Leukocytes	qPCR^†	[72]
CKD patients (n = 4926)	Shorter LTL in CKD patients associated with increased risk of mortality independent of kidney function	Age-dependent	Leukocytes	qPCR^†	[51]
Type 1 diabetes mellitus patients (n = 176)	Shorter LTL predicts incident microalbuminuria and diabetic nephropathy progression in Type 1 diabetes mellitus patients	Positive	Leukocytes	Southern blot (TRF analysis)^†	[60]
Type 2 diabetes mellitus patients (n = 691)	Shorter LTL independently predicts albuminuria progression in Type 2 diabetes mellitus patients with preserved renal function	Positive	Leukocytes	qPCR^†	[48]
Incident HD patients (n = 59)	Patients with increased leukocyte count had longer LTL after first year of dialysis. Patients with lower eGFR and higher albumin levels had higher telomere attrition	Positive	Leukocytes	qPCR^†	[47]
CKD and HD patients (n = 150)	Increased PBMC telomerase activity in CKD patients compared with control. Telomerase activity is highest in stage 5 CKD patients		PBMCs	TRAP assay^‡	[76]
CKD patients (n = 153)	Decreased PBMC telomerase activity and human TERT expression in CKD group compared with dialysis and control groups. Control group had highest telomerase activity		PBMCs	TRAP assay^‡ RT-qPCR^§	[77]
CKD patients (including dialysis and kidney transplantation patients) (n = 159)	CKD associated with leukocyte telomere attrition. Telomere attrition more pronounced in renal replacement therapy group compared with dialysis group after 1 year	Positive	Leukocytes	qPCR^†	[56]
Non-CKD patients with and without diabetes mellitus (n = 403)	LTL not associated with eGFR and urinary microalbumin-to-creatinine ratio in non-CKD patients	None	Leukocytes	qPCR^†	[74]
CKD patients (n = 10568)	Decreased LTL correlates with decreasing eGFR	Positive	Leukocytes	qPCR^†	[63]
Kidney transplant patients (n = 140)	T-cell TL shorter in end-stage renal disease patients compared with control; remains unchanged 1-year post kidney transplantation. Uremia-associated immunological aging not reversed by kidney transplantation	Positive	T-cells	flow FISH^†	[58]
Kidney transplant patients (n = 124)	Mycophenolic acid-treated patients have increased PBMC telomere attrition compared with mTOR inhibitor-treated patients	Positive	PBMCs	qPCR^†	[57]
Patients without CKD and CVD (n = 253)	TL independently correlated with albuminuria. Association between urea or creatinine and TL is age-dependent	Positive, age-dependent		qPCR^†	[73]
HD patients (n = 30)	HD patients have shorter PBMC TL associated with inflammation biomarkers	Positive	PBMCs	flow FISH^†	[53]
CKD patients with and without diabetes mellitus (n = 889)	Shorter LTL associated with CKD progression in active smokers and/or diabetes mellitus patients	Positive	Leukocytes	qPCR^†	[65]
CKD patients with and without diabetes mellitus (n = 4955)	Shorter LTL in CKD patients predicts cardiovascular disease incidence. Association between albuminuria or eGFR and TL is age-dependent	Age-dependent	Leukocytes	qPCR^†	[68]
CKD patients (n = 4955)	Patients with CKD for <6 months and >5 years had comparable LTL, longer than patients with CKD between 6 months and 5 years	Positive	Leukocytes	qPCR^†	[49]
End-stage renal disease patients on chronic HD (n = 66)	No significant difference in PBMC TL among end-stage renal disease patients and control. Patients on longer duration of HD had shorter TL	Positive	PBMCs	Southern blot (TRF analysis)^† TRAP assay^‡	[52]
Male patients with Type 2 diabetes mellitus (n = 84)	LTL associated with progression of kidney disease in Type 2 diabetes mellitus patients	Positive	Leukocytes	TRF analysis^†	[59]
HD patients (n = 81)	Telomerase activity decreased in PBMCs of HD patients; inversely correlated with duration of HD treatment		PBMCs	TRAP assay^‡	[78]
Chronic heart failure patients (n = 610)	LTL associated with declining renal function in chronic heart failure patients	Positive	Leukocytes	qPCR^†	[61]
Chronic heart failure patients (n = 866)	Shorter LTL associated with decreased renal function and may affect kidney’s ability to cope with metabolic changes in heart failure patients	Positive	Leukocytes	qPCR^†	[62]
Healthy participants (n = 609)	No association between LTL changes and renal function in healthy patients	None	Leukocytes	TRF analysis^†	[75]
Healthy participants (n = 139)	LTL reduces with age in healthy participants; correlates with eGFR	Positive	Leukocytes	Southern blot (TRF analysis)^†	[71]

† TL.

‡ Telomerase activity.

§ TERT/TERC expression.

CKD: Chronic kidney disease; HD: Hemodialysis; HPA: Hybridization protection assay; LTL: Leukocyte telomere length; PBMC: Peripheral blood mononuclear cell; qFISH: Quantitative fluorescence in situ hybridization; qPCR: Quantitative polymerase chain reaction; ROS: Reactive oxygen species; RT-qPCR: Real-time quantitative polymerase chain reaction; TL: Telomere length; TRAP: Telomeric repeat amplification protocol; TRF: Terminal restriction fragment.

Figure 3. Telomere therapies for chronic kidney disease.

Treatment possibilities include gene therapy using genes in the telomerase subunits TERT and TERC, proteins from the shelterin complex (TRF1, TRF2, TIN2, POT1, RAP1, TPP1) and other telomere maintenance genes, including PARN, CTC1, TCBA1, NHP2, RTEL1, NOP10, DKC1 and NAF1. Use of telomerase activators such as Astragalus membranaceus, Centella asiatica, oleanolic acid and maslinic acid can also be explored.

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