Stage 2 of Chronic Kidney Disease.

A person with stage 2 chronic kidney disease (CKD) has

kidney damage with a mild decrease in their glomerular filtration rate(GFR) of 60-89 ml/min.
There are usually no symptoms to indicate the kidneys aredamaged.

Stage 2 of Chronic Kidney Disease

A person with stage 2 chronic kidney disease (CKD) has kidney damage with a mild decrease in
their glomerular filtration rate (GFR) of 60-89 ml/min. There are usually no symptoms to indicate the
kidneys are damaged. Because kidneysdo a good job even when they’re not functioning at 100
percent, most people will not know they have stage 2 CKD. If they do find out they’re in stage 2, it’s
usually because they were being tested for another condition such as diabetes or high blood
pressure–the two leading causes of kidney disease.

Signs of stage 2 kidney disease

Other ways a person may discover they are in stage 2 CKD include:

 Higher than normal levels of creatinine or urea in the blood

 Blood or protein in the urine
 Evidence of kidney damage in an MRI, CT scan, ultrasound or contrast X-ray
 A family history of polycystic kidney disease (PKD)

Treating stage 2 kidney disease

Regular testing for protein in the urine and serum creatinine can show whether the kidney damage is
progressing. Living a healthy lifestyle can help slow progression of kidney disease. It’s
recommended that people in stage 2 CKD:

1. Eat a healthy diet

 Include a variety of grains (especially whole grains), fresh fruits and vegetables.
 Choose a diet that is low in saturated fat and cholesterol and moderate in total fats.
 Limit intake of refined and processed foods high in sugar and sodium.
 Choose and prepare foods with less salt or high-sodium ingredients.
 Aim for a healthy weight, consume adequate calories and include physical activity each day.
 Keep protein intake within a healthy level, as recommended by a renal dietitian.
 Consume vitamins and minerals as recommended by a doctor.
 Potassium and phosphorus are usually not restricted unless blood levels are above normal
2. Keep their blood pressure at a healthy level.
 125/75 for those with diabetes
 130/85 for non-diabetes and non-proteinuria
 125/75 for non-diabetes with proteinuria
3. Keep their blood sugar or diabetes under control.
4. Have regular checkups with their doctor and include a serum creatinine test to measure GFR.
5. Take medicines as prescribed by their doctor.
6. Exercise regularly.
7. Stop smoking.

Living with stage 2 kidney disease

There is no cure for kidney disease, but it may be possible to stop its progress or at least slow down
the damage. In many cases, the correct treatment and lifestyle changes can help keep a person and
their kidneys healthier longer.
If you would like to see a nephrologist (a doctor who specializes in the care of kidneys), you can use
DaVita's Find a Kidney Doctor tool to locate a nephrologist in your area.

ABSTRACT

In Brazil hypertension and type 2 diabetes mellitus are responsible for 60% of cases of end-
stage renal disease in renal replacement therapy. In the United States studies have identified
family clustering of chronic kidney disease, predominantly in African-Americans. A single
Brazilian study observed family clustering among patients with chronic kidney disease when
compared with hospitalized patients with normal renal function. This article aims to assess
whether there is family clustering of chronic kidney disease in relatives of individuals in renal
replacement therapy caused by hypertension and/or diabetes mellitus. A case-control study with
336 patients in renal replacement therapy with diabetes mellitus or hypertension for at least 5
years (cases) and a control matched sample group of individuals with hypertension or diabetes
mellitus and normal renal function (n = 389). Individuals in renal replacement therapy (cases)
had a ratio of 2.35 (95% CI 1.42-3.89, p < 0.001) versus the control group in having relatives
with chronic renal disease, irrespective of race or causative illness. There is family clustering of
chronic kidney disease in the sample studied, and this predisposition is irrespective of race and
underlying disease (hypertension or diabetes mellitus).

Key words: Chronic renal insufficiency; Hypertension; Diabetes mellitus; Heredity;

Epidemiology

Pathophysiology

Hypertension is an adverse factor in all progressiverenal diseases and seems especially so

in diabeticnephropathy. ... Increased systolic blood pressure further exacerbates
the disease progression to proteinuria and a decline in the glomerular filtration rate, leading to
end-stage kidney disease.

Practice Essentials
Diabetic nephropathy is a clinical syndrome characterized by the following [1] :
 Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on
at least 2 occasions 3-6 months apart
 Progressive decline in the glomerular filtration rate (GFR)
 Elevated arterial blood pressure (see Workup)
Proteinuria was first recognized in diabetes mellitus in the late 18th century. In
the 1930s, Kimmelstiel and Wilson described the classic lesions of nodular
glomerulosclerosis in diabetes associated with proteinuria and hypertension.
(See Pathophysiology.)
By the 1950s, kidney disease was clearly recognized as a common
complication of diabetes, with as many as 50% of patients with diabetes of
more than 20 years having this complication. (See Epidemiology.)
Currently, diabetic nephropathy is the leading cause of chronic kidney disease
in the United States and other Western societies. It is also one of the most
significant long-term complications in terms of morbidity and mortality for
individual patients with diabetes. Diabetes is responsible for 30-40% of all
end-stage renal disease (ESRD) cases in the United States. (See Prognosis.)
Generally, diabetic nephropathy is considered after a routine urinalysis and
screening for microalbuminuria in the setting of diabetes. Patients may have
physical findings associated with long-standing diabetes mellitus. (See Clinical
Presentation.)
Good evidence suggests that early treatment delays or prevents the onset of
diabetic nephropathy or diabetic kidney disease. This has consistently been
shown in both type1 and type 2 diabetes mellitus. (See Treatment and
Management).
Regular outpatient follow-up is key in managing diabetic nephropathy
successfully. (See Long-term Monitoring.)
Recently, attention has been called to atypical presentations of diabetic
nephropathy with dissociation of proteinuria from reduced kidney function.
Also noted is that microalbuminuria is not always predictive of diabetic
nephropathy. [2]Nevertheless, a majority of the cases of diabetic nephropathy
presents with proteinuria, which progressively gets worse as the disease
progresses, and is almost uniformly associated with hypertension.

Hypertension
 Glomerular and vascular changes:
o Elevated systemic blood pressures cause a hypertrophic response leading to intimal
thickening of the large and the small vasculature.
o The mechanisms are compensatory at first, but later lead to glomerular damage
 Global sclerosis – ischemic injury to the nephrons causes death
 Focal segmental sclerosis – glomerular enlargement for compensation of the loss of
nephrons in other areas of the kidney.
 Interstitial nephritis:
o The vascular and glomerular disease lead to tubular atrophy and an intense chronic
interstitial nephritis
 The intense chronic interstitial nephritis is thought be secondary to immunologic
processes against ischemia-mediated antigen changes on the tubular epithelial cell
surface.
 Chronically these changes lead to tubular and glomerular loss causing nephrons loss.
o With the death of some nephrons, less are available to maintain the GFR.
o Gradual decline in the GFR is noticed as the nephrons continue to die.

Diabetes – diabetic nephropathy

 Majority of the literature in the area is applied to the diabetic nephropathy patients based on data
hypothesized from the findings in animal models.
 Chronic hyperglycemiais thought to be the primary cause of diabetic nephropathy.
 o Unlike other tissues of the body, transmembrane glucose transporters (GLUT) receptors do
not facilitate intracellular glucose transport in the kidneys.
o This effect is mediated via a number of mechanisms including (i) glomerular hyperfiltration,
(ii) direct effects of hyperglycemia, and (iii) advanced glycosylation end products (AGE), and
(iv) cytokine secretion.
 Glomerular hyperfiltration:
o Glomerular hyperfiltration is mediated mainly via dilatation the afferent arteriole leading to a
rise in the GFR and the renal blood flow.
o This dilatation of the afferent arteriole is mediated by a number of mechanisms in diabetic
nephropathy:
 Hyperglycemia and high insulin-like growth factor-1 (IGF-1) concentrations (observed in
diabetic patients) – both are hypothesized to cause a rise in the GFR increasing renal
flow
 Hyperfiltration of glucose leads to augmented sodium-glucose transport in the proximal
convoluted tubule causing enhanced sodium transport
 Cause expansion of blood volume which leads to a rise in GFR
 The rise in proximal reabsorption also leads to a reduced distal fluid delivery which
activates the tubuloglomerular feedback with the renin-angiotensin system which
works to raise the GFR as well.
 Hyperglycemia and AGE:
o Hyperglycemia and AGE directly induce mesangial matrix production, cellular expansion and
apoptosis.
o The two have also been shown to increase basement membrane permeability to albumin.
 Cytokines:
o Elevations in vascular endothelial growth factor (VEGF), transforming growth factor beta
(TFG-β), and profibrotic proteins increase damage to the nephrons at different levels;
specific mechanisms are unclear.

Glomerulonephritis
 Glomerular injury takes place via inflammatory as well as non-inflammatory mechanisms in
different types of glomerulonephritides.
 Non-inflammatory injury:
o Common examples of this include the podocytopathies; minimal change nephrotic
syndrome/focal segmental glomerulosclerosis (MCNS/FSGS) and membranous
nephropathy(MN)
 A dramatic rise in the glomerular permeability without any evidence of inflammation on
light microscopy.
 Several cytokines such as IL-13 and members of the complement system C3, C5b-9
lead to glomerular basement membrane thickening, as well as podocyte damage,
apoptosis, detachment and excretion in the urine. This induces glomerular sclerosis.
 Inflammatory injury:
 o Common examples include post-streptococcal
glomerulonephritis (GN), membranoproliferative GN, Henoch-Schönlein
purpura (HSP), systemic lupus erythematosus (SLE), some forms of rapidly
progressive glomerulonephritis (RPGN), IgA nephropathy, hemolytic uremic
syndrome (HUS) and various vasculitides.
o This inflammatory injury has been found to be mediated by a number of mechanisms:
 Some members of the complement system such as C5a have been implicated in
inflammatory injury via inducing antibody deposition and activation and recruitment of
polymorphonuclear cells (PMNs); neutrophil, macrophage/monocyte, platelets and T-
cells.
 These cells produce oxidants and proteases that cause fibrin deposition, capillary wall
damage and produce proteinuria.
 Unlike podocyte targeting in non-inflammatory injury, disorders in which glomerular
endothelial and mesangial cells are principally involved exhibit a more dramatic
response to immune injury. This response is usually characterized by cell proliferation
and phenotype change, as well as readily visible structural changes in the renal biopsy.

Pathophysiology
Three major histologic changes occur in the glomeruli of persons with diabetic
nephropathy. First, mesangial expansion is directly induced by hyperglycemia,
perhaps via increased matrix production or glycation of matrix proteins.
Second, thickening of the glomerular basement membrane (GBM) occurs.
Third, glomerular sclerosis is caused by intraglomerular hypertension (induced
by dilatation of the afferent renal artery or from ischemic injury induced by
hyaline narrowing of the vessels supplying the glomeruli). These different
histologic patterns appear to have similar prognostic significance.
The key change in diabetic glomerulopathy is augmentation of extracellular
matrix. The earliest morphologic abnormality in diabetic nephropathy is the
thickening of the GBM and expansion of the mesangium due to accumulation
of extracellular matrix. The image below is a simple schema for the
pathogenesis of diabetic nephropathy.

Light microscopy findings show an increase in the solid spaces of the tuft, most
frequently observed as coarse branching of solid (positive periodic-acid Schiff reaction)
material (diffuse diabetic glomerulopathy). Large acellular accumulations also may be
observed within these areas. These are circular on section and are known as the
Kimmelstiel-Wilson lesions/nodules.
Immunofluorescence microscopy may reveal deposition of albumin, immunoglobulins,
fibrin, and other plasma proteins along the GBM in a linear pattern, most likely as a
result of exudation from the blood vessels, but this is not immunopathogenetic or
diagnostic and does not imply an immunologic pathophysiology. The renal vasculature
typically displays evidence of atherosclerosis, usually due to concomitant hyperlipidemia
and hypertensive arteriosclerosis.
Electron microscopy provides a more detailed definition of the structures involved. In
advanced disease, the mesangial regions occupy a large proportion of the tuft, with
prominent matrix content. Further, the basement membrane in the capillary walls (ie, the
peripheral basement membrane) is thicker than normal.
The severity of diabetic glomerulopathy is estimated by the thickness of the peripheral
basement membrane and mesangium and matrix expressed as a fraction of appropriate
spaces (eg, volume fraction of mesangium/glomerulus, matrix/mesangium, or
matrix/glomerulus).
The glomeruli and kidneys are typically normal or increased in size initially, thus
distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency,
wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).

In addition to the renal hemodynamic alterations, patients with overt diabetic

nephropathy (dipstick-positive proteinuria and decreasing glomerular filtration rate
[GFR]) generally develop systemic hypertension. Hypertension is an adverse factor in
all progressive renal diseases and seems especially so in diabetic nephropathy. The
deleterious effects of hypertension are likely directed at the vasculature and
microvasculature.
Evidence suggests that hypertension associated with obesity, metabolic syndrome, and
diabetes may play an important role in the pathogenesis of diabetic nephropathy.
Central obesity, metabolic syndrome, and diabetes lead to increased blood pressure.
Central obesity induces hypertension initially by increasing renal tubular reabsorption of
sodium and causing a hypertensive shift of renal-pressure natriuresis through multiple
mechanisms, including activation of the sympathetic nervous system and renin-
angiotensin-aldosterone system, as well as physical compression of the
kidneys. [3] Hypertension, along with increases in intraglomerular capillary pressure and
the metabolic abnormalities (eg, dyslipidemia, hyperglycemia) likely interact to
accelerate renal injury.
Similar to obesity-associated glomerular hyperfiltration, renal vasodilation, increases in
the glomerular filtration rate and intraglomerular capillary pressure, and increased blood
pressure also are characteristics of diabetic nephropathy. [4]Increased systolic blood
pressure further exacerbates the disease progression to proteinuria and a decline in the
glomerular filtration rate, leading to end-stage kidney disease.

Etiology
The exact cause of diabetic nephropathy is unknown, but various postulated
mechanisms are hyperglycemia (causing hyperfiltration and renal injury),
advanced glycation products, and activation of cytokines. Many investigators
now agree that diabetes is an autoimmune disorder, with overlapping
pathophysiologies contributing to both type 1 and type 2 diabetes; and recent
research highlights the pivotal role of innate immunity (toll-like receptors) and
regulatory T-cells (Treg). [5]
Glycemic control reflects the balance between dietary intake and
gluconeogenesis and tissue uptake or utilization through storage as glycogen
or fat and oxidation. This balance is regulated by insulin production from the β
cells in the pancreas. Insulin regulates serum glucose through its actions on
liver, skeletal muscle, and fat tissue. When there is insulin resistance, insulin
cannot suppress hepatic gluconeogenesis, which leads to hyperglycemia.
Simultaneously, insulin resistance in the adipose tissue and skeletal muscle
leads to increased lipolysis and reduction in disposal of glucose causing
hyperlipidemia in addition to hyperglycemia.
Evidence suggests that when there is insulin resistance, the pancreas is
forced to increase its insulin output, which stresses the β cells, eventually
resulting in β-cell exhaustion. The high blood glucose levels and high levels of
saturated fatty acids create an inflammatory medium, resulting in activation of
the innate immune system, which results in activation of the nuclear
transcription factors-kappa B (NF-κB), and release of inflammatory mediators,
including, interleukin (IL)–1β and tumor necrosis factor (TNF)–α, promoting
systemic insulin resistance and β-cell damage as a result of autoimmune
insulitis. Hyperglycemia and high serum levels of free fatty acids and IL-1 lead
to glucotoxicity, lipotoxicity, and IL-1 toxicity, resulting in apoptotic β-cell
death.
Hyperglycemia also increases the expression of transforming growth factor-β
(TGF-β) in the glomeruli and of matrix proteins, specifically stimulated by this
cytokine. TGF-β and vascular endothelial growth factor (VEGF) may
contribute to the cellular hypertrophy and enhanced collagen synthesis and
may induce the vascular changes observed in persons with diabetic
nephropathy. [6, 7] Hyperglycemia also may activate protein kinase C, which
may contribute to renal disease and other vascular complications of
diabetes. [8]
Familial or perhaps even genetic factors also play a role. Certain ethnic
groups, particularly African Americans, persons of Hispanic origin, and
American Indians, may be particularly disposed to renal disease as a
complication of diabetes.
It has been argued that the genetic predisposition to diabetes that is so
frequent in Western societies, and even more so in minorities, reflects the fact
that in the past, insulin resistance conferred a survival advantage (the so-
called thrifty genotype hypothesis).
Some evidence has accrued for a polymorphism in the gene for angiotensin-
converting enzyme (ACE) in either predisposing to nephropathy or
accelerating its course. However, definitive genetic markers have yet to be
identified. More recently, the role of epigenetic modification in the
pathogenesis of diabetic nephropathy has been highlighted. [9]
A study by Bherwani et al suggested that an association exists between
decreased serum folic acid levels and diabetic nephropathy. In the study,
which involved 100 patients with diabetes mellitus, including 50 with diabetic
nephropathy and 50 without it, multivariate logistic regression analysis
indicated that reduced folic acid levels increased the risk of diabetic
nephropathy by 19.9%. [10]