Chronic Kidney Disease Causes and Risk Factors

Primary Causes of CKD

• Diabetes is one of the leading causes of CKD worldwide and is the primary cause of end-stage kidney disease (ESKD) in the United States, with diabetic kidney disease typically developing after a duration of 10 years in type 1 diabetes but may be present at diagnosis of type 2 diabetes, accounting for more than 30-40% of cases in many countries 1, 2, 3.
• Hypertension is one of the most frequent causes of CKD in developed countries, and can both cause kidney damage and result from kidney disease, creating a dangerous cycle that accelerates kidney function decline 3, 4.

Other Contributing Factors

• Glomerulonephritis is another significant cause of CKD, particularly in certain regions, with chronic glomerulonephritis and diabetes together accounting for more than 50% of CKD cases in China 3.
• Autosomal dominant tubulointerstitial kidney diseases can lead to progressive tubulointerstitial fibrosis and progression to end-stage renal disease 5.

Clinical Implications

• The American Diabetes Association recommends that patients with diabetes and hypertension should be regularly screened for CKD using urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) 1.
• The presence of CKD markedly increases cardiovascular risk and healthcare costs in patients with both type 1 and type 2 diabetes, according to the American Heart Association 6.

Diagnostic Considerations

• CKD is diagnosed by the persistent elevation of urinary albumin excretion (albuminuria), low eGFR, or other manifestations of kidney damage for at least 3 months, as stated by the National Kidney Foundation 4, 6.
• Screening for albuminuria can be most easily performed by urine albumin-to-creatinine ratio (UACR) in a random spot urine collection, recommended by the American Diabetes Association 1.

Prevention and Management

• The American Diabetes Association recommends the use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to reduce CKD progression and cardiovascular events in people with diabetes and CKD 2.
• Individuals should be referred for evaluation by a nephrologist if they have continuously increasing urinary albumin levels, continuously decreasing eGFR, or if the eGFR is <30 mL/min/1.73 m², as suggested by the National Kidney Foundation 7.

Chronic Kidney Disease with Normal Sized Kidneys

Primary Causes with Normal Kidney Size

• Diabetic Kidney Disease (DKD) typically presents with normal-sized kidneys despite progressive kidney damage, particularly common in type 2 diabetes where kidney size is initially preserved despite declining function, as noted by the American College of Radiology 8, 9
• Minimal Change Disease can cause significant proteinuria and kidney dysfunction while maintaining normal kidney morphology on imaging, according to the Mayo Clinic Proceedings 9
• Primary Focal Segmental Glomerulosclerosis (FSGS) can cause progressive CKD with normal-sized kidneys, especially in early stages, as reported by the Mayo Clinic Proceedings 9
• Polycystic Kidney Disease can cause kidney function decline with relatively normal-appearing kidneys in early stages, as stated by the Mayo Clinic Proceedings 9

Other Causes with Normal Kidney Size

• Infiltrative Disorders can maintain kidney size while reducing function, as noted by the Journal of the American College of Radiology 8

Diagnostic Considerations

• Ultrasound findings of normal-sized kidneys do not exclude CKD, particularly in diabetic nephropathy and infiltrative disorders, as reported by the Journal of the American College of Radiology 8
• Kidney biopsy may be necessary to definitively diagnose the cause of CKD when kidneys appear normal on imaging, with up to 30% of patients with diabetic kidney disease having other causes of CKD on kidney biopsy, according to the Mayo Clinic Proceedings 10, 9
• Laboratory evaluation shows that persistent albuminuria (UACR >30 mg/g) for at least 3 months is a key marker for CKD even with normal kidney size, and eGFR <60 mL/min/1.73 m² for at least 3 months confirms CKD regardless of kidney size, as stated by Diabetes Care 11, 11

Management Considerations

• Optimal blood pressure management is crucial in all forms of CKD, regardless of kidney size, as recommended by the American College of Physicians, based on guidelines from the Annals of Internal Medicine 12
• Nephrology referral should be considered when GFR <30 mL/min/1.73 m², confirmed significant proteinuria, or rapid decline in eGFR despite normal kidney size, as suggested by the Annals of Internal Medicine 12

CKD Presentation with Normal Corticomedullary Differentiation

Early-Stage CKD Characteristics

• Stages 1 and 2 CKD can maintain normal corticomedullary differentiation (CMD) because these stages are defined by the presence of kidney damage with normal or only mildly decreased GFR (≥60 mL/min/1.73 m²), meaning structural architecture remains largely intact, according to the American Journal of Kidney Diseases 13, 14
• Patients in Stage 1 have GFR ≥90 mL/min/1.73 m² with evidence of kidney damage, while Stage 2 patients have GFR 60-89 mL/min/1.73 m², both of which can show preserved CMD on imaging, as reported by the American Journal of Kidney Diseases 13, 14

Diagnostic Approach

• The American Journal of Kidney Diseases recommends measuring both eGFR and UACR at baseline, as CKD can be diagnosed by either abnormality regardless of imaging findings 13, 14

CKD Development and Progression in Uncontrolled Type 2 Diabetes

Key Timeline Distinctions and Risk Factors

• In uncontrolled type 2 diabetes, approximately 20-40% of patients will develop microalbuminuria within 10-15 years, with progression to more advanced stages occurring in 80-90% of those with microalbuminuria, according to the American Diabetes Association 15
• The American Journal of Kidney Diseases suggests that uncontrolled hypertension dramatically accelerates progression, with GFR decreasing at rates greater than 10 mL/min/year in those with poorly controlled hypertension and macroalbuminuria 16
• The Kidney International guideline recommends that screening must begin immediately upon diagnosis of type 2 diabetes, rather than waiting, due to the high risk of CKD being present at the time of diagnosis 17, 18

Clinical Implications for Screening and Management

• The Diabetes Care guideline recommends that screening for type 2 diabetes must begin at diagnosis, with annual measurement of both urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR), as studies show that 6.5% of newly diagnosed type 2 diabetes patients already have urinary albumin concentration greater than 50 mg/L, and 28% already have hypertension at diagnosis 15, 17, 18, 19, 20
• The American Journal of Kidney Diseases notes that reduced eGFR without albuminuria is becoming increasingly common in both type 1 and type 2 diabetes, meaning CKD can present without the traditional albuminuria progression pathway 16

Chronic Kidney Disease (CKD) Management and Prevention

Primary Etiologic Factors

• The American Heart Association suggests that uncontrolled systolic blood pressure can accelerate the rate of GFR deterioration to 4-8 mL/min per year, particularly in patients with coexistent renal disease 21
• Approximately 70% of individuals with elevated serum creatinine have hypertension, making it the dominant risk factor in this population, according to the American Heart Association 21
• The presence of cerebrovascular accident in a patient's history strongly suggests long-standing, poorly controlled hypertension with end-organ damage, as indicated by the American Heart Association 21
• The American Diabetes Association states that prediabetes significantly increases the risk of developing diabetic kidney disease, with approximately 20-40% of patients with diabetes eventually developing CKD 22
• The combination of prediabetes with hypertension and mixed hyperlipidemia creates a metabolic syndrome phenotype that dramatically accelerates CKD progression, as reported by the National Kidney Foundation 23

Clinical Implications for Diagnosis

• The American Diabetes Association recommends measuring both estimated GFR (eGFR) and urinary albumin-to-creatinine ratio (UACR) immediately, as CKD can be diagnosed by either abnormality 22
• CKD is defined as eGFR <60 mL/min/1.73 m² or presence of albuminuria (UACR ≥30 mg/g) persisting for at least 3 months, according to the American Heart Association 21

Management Priorities

• The American Diabetes Association recommends targeting blood pressure <130/80 mmHg in patients with CKD, particularly those with albuminuria ≥300 mg/g 24
• The American Heart Association strongly recommends ACE inhibitors or ARBs for patients with UACR ≥300 mg/g and/or eGFR <60 mL/min/1.73 m² 22, 24
• The National Kidney Foundation indicates that statin therapy is indicated for cardiovascular risk reduction in all CKD patients 23

Common Pitfalls to Avoid

• The American Diabetes Association advises against discontinuing ACE inhibitors or ARBs for minor increases in serum creatinine (<30%) in the absence of volume depletion 22
• The American Heart Association warns against combining ACE inhibitors with ARBs, as this increases adverse events without additional benefit 24

Chronic Kidney Disease Causes and Risk Factors

Introduction to CKD Causes

• Nephrotoxin exposure, including nonsteroidal anti-inflammatory drugs, heavy metals, agrochemicals, and contaminated drinking water, can cause CKD, according to the American Diabetes Association 25

Demographic and Genetic Risk Factors

• Older age increases CKD risk, as stated by the American College of Physicians 26
• Family history of kidney disease is highly important, as noted by the American College of Physicians 26
• Obesity is a risk factor for CKD development, according to the American College of Physicians 26
• Family history of kidney disease is a significant risk factor, as also mentioned by the American College of Physicians 27
• Older age is a strong risk factor for CKD, as also stated by the American College of Physicians 27

Nephrology Referral Indications

• The American Diabetes Association recommends referring to nephrology when eGFR <30 mL/min/1.73 m², or when there are continuously increasing urinary albumin levels, or continuously decreasing eGFR 28

Investigations for eGFR 42 (CKD Stage 3b)

Confirm CKD Diagnosis and Chronicity

• The Kidney International guideline recommends reviewing historical eGFR measurements to determine if kidney dysfunction has persisted >3 months, which is required to confirm CKD diagnosis rather than acute kidney injury 29
• For patients with unclear or <3 months duration, the Kidney International guideline suggests repeating serum creatinine and eGFR within 2-4 weeks to distinguish CKD from AKI 29
• The Kidney International and Diabetes Care guidelines recommend measuring UACR on a random spot urine sample immediately, as albuminuria classification is essential for risk stratification and treatment decisions 29, 30, 31

Determine Underlying Cause

• The Kidney International guideline recommends evaluating the clinical context systematically to identify the etiology of kidney disease, as this guides treatment 29
• The Diabetes Care guideline suggests identifying nephrotoxic exposures including NSAIDs, lithium, calcineurin inhibitors, and aminoglycosides 30
• The Kidney International guideline recommends looking for hematuria, pyuria, or casts that suggest glomerulonephritis or other primary kidney diseases 29

Screen for CKD Complications

• The Diabetes Care guideline recommends systematic screening for complications at eGFR 42 (stage G3b), including serum electrolytes, hemoglobin, serum calcium and phosphate, intact PTH, and 25-hydroxyvitamin D 30, 32
• The Diabetes Care guideline suggests monitoring blood pressure and weight, and assessing for edema, orthopnea, and signs of fluid retention 30, 32

Risk Stratification and Monitoring Frequency

• The Kidney International and Diabetes Care guidelines recommend that the combination of eGFR and albuminuria determines progression risk and monitoring intensity 29, 31
• The Diabetes Care guideline suggests monitoring frequency based on risk stratification, with moderate risk patients (eGFR 42 with UACR <30 mg/g) monitored 2 times per year, high risk patients (eGFR 42 with UACR 30-300 mg/g) monitored 3 times per year, and very high risk patients (eGFR 42 with UACR >300 mg/g) monitored 4 times per year and referred to nephrology 31

Nephrology Referral Indications

• The Diabetes Care guideline recommends referring to nephrology if any of the following are present, including uncertainty about etiology or atypical features suggesting non-diabetic kidney disease, and difficulty managing CKD complications 30, 31

Common Pitfalls to Avoid

• The Kidney International guideline recommends not relying on serum creatinine alone, and always calculating eGFR using validated equations (CKD-EPI 2021) 29
• The Kidney International and Diabetes Care guidelines recommend not skipping albuminuria testing, as eGFR and UACR provide independent prognostic information for cardiovascular events, CKD progression, and mortality 29, 30

Laboratory Monitoring for CKD Stage 3b

Essential Baseline and Monitoring Labs

• The National Kidney Foundation recommends measuring complete metabolic panel including sodium, potassium, chloride, and bicarbonate to screen for metabolic acidosis, hyperkalemia, and other electrolyte abnormalities in patients with CKD stage 3b 33, 34
• The Kidney Disease: Improving Global Outcomes (KDIGO) guideline suggests that parathyroid hormone (PTH) levels should be measured in patients with CKD stage 3, as PTH begins to rise when eGFR falls below 60 mL/min/1.73m², and evidence of bone disease may be present at CKD stage 3 35

Special Considerations for Potassium Monitoring

• The American Journal of Kidney Diseases recommends monitoring potassium levels in patients with CKD stage 3b, as potassium laboratory measurements have inherent variability, with diurnal and seasonal variation, and differences between plasma versus serum samples 33, 34
• The Kidney International journal suggests that if initiating medications that affect potassium, such as RAS inhibitors or MRAs, potassium should be rechecked within 2-4 weeks 36
• The National Kidney Foundation recommends monitoring potassium at 1 month after initiation of nonsteroidal MRA and then every 4 months 33, 34, 37

Chronic Kidney Disease Risk Factors and Screening

Demographic and Genetic Risk Factors

• Older age (>60 years) is a well-established risk factor for CKD, with prevalence increasing substantially with advancing age, according to the American Journal of Kidney Diseases and Annals of Internal Medicine 38, 39
• Family history of chronic kidney disease is highly significant, with individuals reporting a family member with kidney failure having increased prevalence of hypertension, diabetes, and earlier stages of CKD, as stated by the American Journal of Kidney Diseases and Annals of Internal Medicine 38, 39

Screening Recommendations

• The American Journal of Kidney Diseases recommends that all persons should be assessed during routine health encounters to determine if they are at increased risk for CKD based on clinical and sociodemographic factors, and target populations for screening include patients with diabetes, hypertension, age >60 years, family history of chronic kidney disease, and racial/ethnic minorities 38, 39, 40
• The American Journal of Kidney Diseases suggests measuring both estimated GFR (eGFR) and urinary albumin-to-creatinine ratio (UACR) immediately, as CKD can be diagnosed by either abnormality, and using UACR measurement instead of urine dipstick 40
• CKD is defined as eGFR <60 mL/min/1.73 m² OR presence of albuminuria (UACR ≥30 mg/g) persisting for at least 3 months, according to the American Journal of Kidney Diseases 40

Management of CKD with GFR 60-90 mL/min/1.73 m²

Confirm CKD Diagnosis

• The American Journal of Kidney Diseases recommends measuring urinary albumin-to-creatinine ratio (UACR) immediately on a random spot urine sample to confirm CKD Stage 2 diagnosis, as it requires evidence of kidney damage in addition to mildly decreased GFR 41, 42
• CKD is diagnosed only if UACR ≥30 mg/g OR other markers of kidney damage persist for ≥3 months alongside GFR 60-89 mL/min/1.73 m², according to the American Journal of Kidney Diseases and Kidney International 41, 42

Blood Pressure Management

• The American College of Cardiology recommends target blood pressure <130/80 mmHg for all CKD patients regardless of stage, as stated in the Mayo Clinic Proceedings and Diabetes Care 43, 44, 45
• For patients with UACR 30-299 mg/g (moderately increased albuminuria) AND hypertension, the American Diabetes Association recommends initiating either an ACE inhibitor or ARB, as stated in Diabetes Care 45
• For patients with UACR ≥300 mg/g (severely increased albuminuria), ACE inhibitor or ARB therapy is strongly recommended regardless of blood pressure level, according to Diabetes Care 44, 45

Cardiovascular Risk Reduction

• The American Journal of Kidney Diseases recommends initiating statin therapy for cardiovascular risk reduction, as CKD patients have 5-10 times higher cardiovascular mortality risk than progression to end-stage kidney disease 46

Identify and Treat Underlying Causes

• The American Diabetes Association recommends optimizing glucose control and considering SGLT2 inhibitors with demonstrated kidney and cardiovascular benefits if eGFR ≥20 mL/min/1.73 m² for diabetic patients 45

Monitoring Frequency

• The Kidney International and Diabetes Care recommend annual monitoring of eGFR and UACR for CKD Stage 2 with low risk (UACR <30 mg/g) 42, 45
• The Diabetes Care recommends increasing monitoring to 2 times per year for moderate risk (UACR 30-300 mg/g) and 3-4 times per year for high risk (UACR >300 mg/g) 45

Nephrology Referral Indications

• The Diabetes Care recommends considering nephrology referral for continuously increasing albuminuria despite optimal management, difficulty managing CKD complications or resistant hypertension 44, 45

Screening for Chronic Kidney Disease in Adults

Risk-Based Screening Approach

• The American College of Physicians recommends screening for CKD immediately in all adults with diabetes, hypertension, age >60 years, family history of kidney disease, cardiovascular disease, or obesity using both eGFR and UACR 47, 48
• Adults with hypertension should be screened during chronic disease management, as 91% of CKD patients have hypertension and the combination dramatically accelerates kidney damage, according to the American Journal of Kidney Diseases 48, 49
• Mandatory screening groups include adults age >60 years, with a prevalence of CKD that increases substantially with age 47, 48, 49, 50
• The American College of Physicians also recommends screening for adults with cardiovascular disease, as 46% of CKD patients have atherosclerotic heart disease 48

Appropriate Screening Tests

• The National Kidney Foundation recommends measuring both eGFR and urinary albumin-to-creatinine ratio (UACR) on a random spot urine sample, as both provide independent prognostic information 47, 48

When NOT to Screen

• The US Preventive Services Task Force found insufficient evidence for universal screening in asymptomatic adults without risk factors, as the risk of CKD and subsequent adverse outcomes is small in this population 47, 50, 51, 52
• The American College of Physicians recommends against routine screening for asymptomatic adults without risk factors, as the risk of false positives and potential harms from medications without proven benefit outweigh the benefits 47, 48, 50, 51

Evaluation of Chronic Kidney Disease with Normal‑Sized Kidneys

Significance of Normal Kidney Size

• Normal kidney length (≥ 9 cm) usually indicates that the disease is in an early stage before substantial fibrosis and atrophy develop【53】.
• A normal‑sized kidney does not rule out advanced chronic kidney disease, especially in diabetic nephropathy and infiltrative disorders; size alone provides limited information about severity or etiology【54】.

Confirming CKD Diagnosis and Establishing Chronicity

• CKD is diagnosed when either an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² or a urinary albumin‑to‑creatinine ratio (UACR) ≥ 30 mg/g persists for at least three months【55】【53】.
• Chronicity should be verified by reviewing prior eGFR/creatinine trends, previous urinalysis results, and relevant medical history; if the duration is unclear, repeat testing in 2–4 weeks is recommended to differentiate CKD from acute kidney injury【53】.
• A single abnormal eGFR or UACR measurement must not be interpreted as chronic disease without confirming persistence over time【53】.

Determining the Underlying Cause

Clinical History

• A long‑standing history of diabetes (typically > 10 years for type 1, may be present at diagnosis for type 2) raises suspicion for diabetic kidney disease【53】.
• Hypertension is present in roughly 70 % of patients with elevated creatinine, making hypertensive nephrosclerosis a common etiology【53】.
• A family history of kidney disease suggests possible genetic disorders such as Alport syndrome, thin basement membrane disease, or APOL1‑related nephropathy【53】.
• Systemic manifestations such as rash, arthritis, or hearing loss point toward vasculitis or hereditary conditions like Alport syndrome【54】.

Laboratory Evaluation

• Hepatitis B and C serologies should be obtained when an infectious etiology is considered【54】【53】.
• Autoimmune work‑up—including complement levels (C3, C4), antinuclear antibody, ANCA, and anti‑GBM antibodies—helps identify glomerulonephritis【54】【53】.
• Serum and urine protein electrophoresis with immunofixation and serum free‑light‑chain assays are recommended to exclude monoclonal gammopathies (e.g., multiple myeloma, MGRS)【53】.

Indications for Kidney Biopsy

• KDIGO 2024 guidelines endorse kidney biopsy as a safe and appropriate diagnostic tool when the underlying cause is uncertain or when results will influence management【55】【53】.
• Specific biopsy indications in patients with normal‑sized kidneys include:
  
  • Diabetic individuals with atypical features (e.g., absence of diabetic retinopathy, short disease duration, rapid eGFR decline, active urinary sediment, or nephrotic‑range proteinuria without retinopathy)【53】.
  • Suspicion of primary glomerulonephritis (hematuria with proteinuria, active sediment)【53】.
  • Nephrotic syndrome (UACR > 3000 mg/g with hypoalbuminemia and edema)【53】.
  • Rapidly progressive loss of kidney function【53】.
  • Persistent diagnostic uncertainty despite comprehensive evaluation【53】.

Nephrology Referral

• KDIGO 2024 recommends referral to a nephrologist when any of the following are present:
  
  • eGFR < 30 mL/min/1.73 m²【55】.
  • UACR ≥ 300 mg/g with ongoing increase in albuminuria despite optimal therapy【55】.
  • An eGFR decline > 5 mL/min/1.73 m² per year【55】.
  • Unclear etiology or atypical clinical features【55】.
  • Difficulty managing CKD complications (e.g., anemia, mineral‑bone disorder, resistant hypertension, hyperkalemia)【55】.
  • Consideration of kidney biopsy to clarify diagnosis【55】.

Diabetes as the Predominant Cause of Chronic Kidney Disease and End‑Stage Renal Disease

Epidemiology

• Diabetes accounts for roughly 40 %–50 % of all cases requiring dialysis or kidney transplantation worldwide, making it the leading cause of chronic kidney disease (CKD) and end‑stage renal disease (ESRD)【56】【57】.
• In the United States and other developed nations, diabetic kidney disease (DKD) is the single most common cause of kidney failure, representing about 40 % of new ESRD cases in the U.S. and ~50 % globally【56】【57】【58】.
• Among U.S. patients with ESRD, 66 %–86 % have a diagnosis of diabetes, with the exact proportion varying by age and racial/ethnic group【57】.

Diabetes Type‑Specific Contributions

• Type 2 diabetes contributes to over half of diabetic patients who start dialysis, reflecting its far greater prevalence compared with type 1 diabetes【58】.
• Although both types can lead to DKD, type 1 diabetes patients with sustained micro‑albuminuria have an 80 % chance of progressing to overt nephropathy within 10–15 years, and about 50 % develop ESRD within several subsequent years if untreated【58】.

Population‑Specific Risk Factors

• Native American, Hispanic (especially Mexican‑American), and African‑American individuals with type 2 diabetes face substantially higher risks of progressing to ESRD than non‑Hispanic white counterparts【58】.
• Overall, 20 %–40 % of people with diabetes develop evidence of nephropathy, but the proportion progressing to ESRD is lower in type 2 diabetes than in type 1 diabetes【56】【58】.

Mortality and Survival Outcomes

• The presence of DKD raises 10‑year all‑cause mortality from 11.5 % (diabetes without kidney disease) to 31 % (diabetes with kidney disease); cardiovascular disease is the leading cause of death rather than renal failure itself【59】.
• Among ESRD patients on hemodialysis, those with diabetes have the poorest adjusted survival: approximately 55 % survive 3 years and 40 % survive 5 years after dialysis initiation【57】.

Recent Trends and Impact of Therapeutic Advances

• The contribution of diabetes to overall ESRD prevalence has begun to moderate in recent years, likely reflecting improved management through renin‑angiotensin system blockade and newer glucose‑lowering agents【60】.

CKD Stage G2 Diagnosis and Epidemiology

Diagnostic Criteria

• The American College of Cardiology (ACC) and the American Society of Transplantation state that CKD Stage G2 is diagnosed only when both an eGFR of 60–89 mL/min/1.73 m² and evidence of kidney damage (urinary albumin‑to‑creatinine ratio ≥ 30 mg/g, hematuria, structural abnormalities on imaging, or biopsy‑proven disease) persist for at least 3 months. This dual‑criterion approach prevents misclassification of acute kidney injury as chronic disease. [@2, @1]

Confirmation of Kidney Damage

• The ACC recommends confirming kidney damage through albuminuria testing before labeling a patient with CKD Stage G2, and calls for aggressive cardiovascular‑risk reduction and treatment of underlying causes to prevent progression to advanced kidney disease. Early identification of albuminuria provides independent prognostic information for cardiovascular events, CKD progression, and mortality. [@1]

Role of Diabetes in CKD

• Diabetes is responsible for 30–40 % of CKD cases; screening for diabetes in patients with suspected CKD should be performed using hemoglobin A1c ≥ 6.5 %, fasting plasma glucose ≥ 126 mg/dL, or a 2‑hour oral glucose tolerance test ≥ 200 mg/dL (as outlined in the Circulation guidelines). Early detection allows timely glycemic control, which is essential for slowing CKD progression. [@3]