![Diagnostic assessment of anaemia [NICE2011]
Consider investigating and managing anaemia
in people with CKD if:
− Hb level falls to 11 g/dl or less (or 10.5 g/dl
or less if younger than 2 years)
or
− develop symptoms attributable to
anaemia (such as tiredness, shortness of
breath, lethargy and palpitations)
• The correction to normal levels of Hb with
ESAs is not usually recommended in people
with anaemia of CKD
• Typically maintain the aspirational Hb
range between:
Population Hb range
Adults, young people &
children > 2 yrs
10 and 12 g/dl
Children < 2 yrs 9.5 and 11.5 g/dl
– Do not wait until Hb levels are outside the
aspirational range before adjusting treatment,
for example, take action when Hb levels are
within 0.5 g/dl of the range’s limits](https://image.slidesharecdn.com/chrocinrenalfailureupdateondiagnostictests-190224122750/75/Chronic-renal-failure-update-on-diagnostic-tests-22-2048.jpg)
Uploaded byDr. Rajesh Bendre
Chronic renal failure update on diagnostic tests
Chronic kidney disease (CKD) is defined by kidney damage or a glomerular filtration rate (GFR) below 60 ml/min for over three months, with a rising prevalence in India posing future healthcare challenges. Diagnostic evaluation includes various urine and blood tests to assess kidney function and disease progression, along with novel biomarkers and risk prediction equations for better patient management. Recent guidelines emphasize early diagnosis, monitoring, and timely planning for renal replacement therapy to manage CKD effectively.
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Chronic renal failure update on diagnostic tests
- 1. Update on Diagnostictests in Chronic Renal Disease DR RAJESH V BENDRE MD(Path), DNB(Path), DPB
- 2. Chronic Renal Disease-Introduction CKD is defined as - Structural or functional abnormalities of the kidneys for >3 months, as manifested by either: 1. Kidney damage, with or without decreased GFR, as defined by ◦ Pathologic Abnormalities ◦ Markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging tests 2. GFR <60 ml/min/1.73 m2, with or without kidney damage In India, there is a rising incidence of chronic kidney disease that is likely to pose major problems for both healthcare and the economy in future years. The prevalence of CKD was observed to be 17.2% with ~6% have CKD stage 3 or worse. Recently estimated age-adjusted incidence rate of ESRD is 229 per million population (pmp), and >100,000 new patients enter renal replacement programs annually. Epidemiology & risk factors of chronic kidney disease in India – results from the SEEK (Screening & Early Evaluation of Kidney Disease) study. Singh et al. BMC Nephrology 2013, 14:114
- 3. Classification of CKDby Diagnosis Diabetic Kidney Disease Glomerular diseases (autoimmune diseases, systemic infections, drugs, neoplasia) Vascular diseases (renal artery disease, hypertension, microangiopathy) Tubulointerstitial diseases (urinary tract infection, stones, obstruction, drug toxicity) Cystic diseases (polycystic kidney disease) Diseases in the transplant (Allograft nephropathy, drug toxicity, recurrent diseases, transplant glomerulopathy)
- 4. Progression of CKDafter Diagnosis
- 5. CKD – Evaluation-Markers for Kidney Damage Basic Screening- Complete blood count (CBC), basic biochemistry panel with calculation of renal function, urinalysis, Urine protein/creatinine ratio Serum phosphate, 25-(OH) vitamin D, alkaline phosphatase, & intact PTH to screen for evidence of renal bone disease. Underlying Pathologic Disease specific Screening- • Serum and Urine protein electrophoresis, serum and urine free light chains: Screen for a monoclonal protein possibly representing multiple myeloma • Antinuclear antibodies (ANA), dsDNA antibody: Screen for systemic lupus erythematosus • Serum complement,C3,C4: Results may be depressed with some glomerulonephritides • C-ANCA and P-ANCA: Positive findings helpful in diagnosis of Wegener granulomatosis & microscopic polyangitis • Anti–GBM antibodies: screen for underlying Goodpasture syndrome • Hepatitis B & C, HIV, VDRL serology: for associated glomerulonephritides • Renal Biopsy– for Evidence of glomerular disease without diabetes & Sudden onset of nephrotic syndrome or glomerular hematuria
- 6. Basic Biochemistry- Creatinine& eGFR The medical care of patients with CKD focuses on the following: ◦ Delaying or halting the progression of CKD through early diagnosing and treatment of underlying pathologic disease & the manifestations of CKD ◦ Timely planning for long-term renal replacement therapy In February 2014, the Canadian Society of Nephrology released new guidelines with following recommendations- ◦ Delaying dialysis in CKD patients without symptoms until their glomerular filtration rate (eGFR) drops to 6 mL/min/1.73 m2 or until the first onset of a clinical indication (which includes symptoms of uremia, fluid overload, and refractory hyperkalemia or acidemia). ◦ Close monitoring should begin when eGFR reaches 15 mL/min/1.73 m2. Additional factors that may affect dialysis initiation include patient education and modality selection, the severity of existing uremic symptoms, and the rate of renal function decline
- 7. Creatinine & eGFR Oneof the most common reasons for a nephrology consult is an elevated creatinine. An elevation in the serum creatinine concentration usually reflects a reduction in the glomerular filtration rate (GFR). There are various causes of factitious elevation of creatinine. They can be broadly grouped into increased production of creatinine, interference with the assay and decreased tubular secretion of creatinine.
- 8. M Thorp. AnApproach To The Evaluation Of An Elevated Serum Creatinine. The Internet Journal of Internal Medicine. 2004 Volume 5 Number 2. Creatinine & eGFR
- 9. Creatinine & eGFR Renalfunction calculation in adult patients- Modification of Diet in Renal Disease (MDRD) Study equation used to calculate GFR. This equation does not require a patient's weight. However, underestimates the measured GFR at levels > 60 mL/min/1.73 m2. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is more accurate than the MDRD Study equation overall and across most subgroups and that it can report estimated GFRs that are at or > 60 mL/min/1.73 m2. Renal function calculation in pediatric patients- GFR in children is calculated using the Schwartz formula. An updated equation includes cystatin C is also available. Limitations- These formulas may overestimate GFR, with change in methods used to measure creatinine, hence following consistently with one laboartory & method(IDMS traceable) is important. Both the CKD-EPI and MDRD equations underestimated GFR in patients with type 2 diabetes.Accuracy was 67% for the CKD-EPI equation and 64% for the MDRD equation.
- 11. Urine SedimentAnalysis- Akin toLiquid Renal Biopsy The urine sediment examined by bright field microscopy under both low and high power without staining. For accurate characterisation of cellular elements in urine several staining techniques were developed. Dinda et al developed a simple supravital stain using crystal violet and safranin O, which is effective in differentiating various cell type including eosinophils and various casts. This Supravital stain overcomes artefactual changes due to drying & fixation as with other stains, definitely useful in doubtful cases routinely. Active urinary sediment is defined as >5 RBCs & >5 WBCs per HPF and/or cellular casts, which where not existing previously. These findings further correlated with degree of proteinuria becomes an important diagnostic & prognostic tool in patients with chronic renal disease, in both primary(eg. glomerulonephritis) & secondary(eg. Lupus nephritis).
- 12. Hematuria- normal individualsdo occasionally excrete RBC’s in the urine. Widely accepted 3-5 RBC’s/hpf as upper limit of normal. Microscopic examination for RBC’s is used as a diagnostic test, distinguishing between haematuria of glomerular origin and haematuria of urinary tract is of importance. • Using phase contrast microscopy (PCM)- Dysmorphic RBCs look different from normal RBCs since they can have holes through them, protrusions, or both & when present often associated with presence of RBC casts. By definition there should be atleast two different populations of RBCs identified. • Method to identify dysmorphic RBC’s described by Dinda et al, using supravital staining and looking for G1 cells (RBC’s which are doughnut shaped with one or more blebs). Once stained these cells can be identified by both bright field microscopy and PCM with equal sensitivity and specificity. There is a wide range of cut off values for dysmorphic red cells reported in the literature to be used to distinguish between glomerular and non-glomerular pathology. However most widely accepted cut off point is > 20% of dysmorphic red cells for diagnosing glomerular haematuria with supravital stain and bright field microscopy, a specificity of 82-92.8% and sensitivity of 88- 91.1%. Urine Sediment Analysis-
- 13. Future- Urinary Sediment-New Biomarkers- Proteins, chemokines profiling
- 14. Clinical scenario StudymRNA in urinary cells Key findings Primary Glomerular disease and Chronic kidney disease Szeto et al. Nephrin/podocin Both increase in proteinuric glomerulonephritis Szeto et al. TGF-β1 Correlation with GFR and the degree of tubulointerstitial scarring MCP-1 Correlation with the degree of glomerulosclerosis Lupus Nephritis Chan et al. TGF-β1 High expression in active disease; correlation with SLEDAI score and with the histologic activity index MCP-1 High expression in active disease, correlation with the degree of glomerulosclerosis and the SLEDAI score Chan et al. IFNγ High expression in active disease; correlation with SLEDAI score and the SLEDAI renal score IL-2 High expression in active disease Avihingsanon et al. IP-10 CXCR3 TGF-β VEGF High expression in class IV LN; reduction with therapy Renal Allograft Li et al. Perforin Granzyme B High expression in allograft acute rejection Kotsch et al. Granulysin High expression in allograft acute rejection Ding et al. CD103 High expression in allograft acute rejection Tatapudi et al. IP-10 CXCR3 High expression in allograft acute rejection Muthukumar et al. FOXP3 High expression in allograft acute rejection Mas et al. TGF-β1 High expression in CAN The urinary sediment beyond light microscopic examination Studies investigating the cellular content of specific mRNAs in the urinary sediment Future- Urinary Sediment- immune profiling
- 16. Interpretation Explanation Marker ofkidney damage Spot urine albumin-to-creatinine ratio >30 mg/g or spot urine total protein-to-creatinine ratio >200 mg/g for >3 months defines CKD Clue to the type (diagnosis) of CKD Spot urine total protein-to-creatinine ratio >500- 1000 mg/g suggests diabetic kidney disease, glomerular diseases, or transplant glomerulopathy. Risk factor for adverse outcomes Higher proteinuria predicts faster progression of kidney disease and increased risk of CVD. Effect modifier for interventions Strict blood pressure control and ACE inhibitors are more effective in slowing kidney disease progression in patients with higher baseline proteinuria. Hypothesized surrogate outcomes and target for interventions If validated, then lowering proteinuria would be a goal of therapy. Importance of Proteinuria in CKD
- 17. Early Diagnosis &Monitoring for CKD- GFR & Albuminuria
- 18. Kidney failure risk- Prediction Equations The kidney failure risk equations were developed in patients with CKD stages G3-G5 has now been validated in more than 700,000 individuals spanning 30 + countries worldwide. The four and eight variable equations accurately predict the 2 and 5 year probability of treated kidney failure (dialysis or transplantation) for a potential patient with CKD Stage 3 to 5. Determining the probability of kidney failure may be useful for patient triage, management of disease with timely dialysis and counselling for kidney transplant. Prospective trials evaluating the utility of this instrument for clinical decision making are in progress. Tangri N, Grams ME, Levey AS et al Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis. JAMA. 2016;315(2):1-11. Equations include following parameters- • Four variable (age, gender, eGFR, Urine albumin) & • Eight variable (age, gender, eGFR, Urine albumin, serum albumin, serum phosphorus, serum bicarbonate, serum calcium) equations For patients with CKD Stage 3, predicted 5-year risk of kidney failure • 0-5 % as low risk, • 5-15 % as intermediate risk, & • > 15 % as high risk
- 19. Feedback Loops inSecondary Hyperparathyroidism- Ca++ Decreased Vitamin D Receptors and Ca-Sensing Receptors PTH Bone Disease Fractures Bone pain Marrow fibrosis Erythropoietin resistance Serum P PTH Systemic Toxicity CVD Hypertension Inflammation Calcification Immunological 25D 1,25D Calcitriol Renal Failure
- 20. Pathology and Diagnosisof Bone Turnover in CKD From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th Edition., 2008 American Society for Bone and Mineral Research Laboratory values KDOQI Recommen d. Grading KDIGO Recommend. Grading iPTH (pg/mL) 150 to 300 Evidence Suggested range 2 to 9 x ULN 2C Corrected Ca (mg/dL) 8.4 to 9.5 Opinion Suggested to maintain in the normal range 2D P (mg/dL) 3.5 to 5.5 Evidence Suggested to lower toward the normal range 2C CaxP (mg2/dL2) <55 Evidence Not suggested to direct clinical practice N/A
- 21. Pathology and Diagnosisof Bone Turnover in CKD Phosphorus Goal = Normal Calcium Calcification represents the highest risk Detect with x-ray/ultrasound Restrict Calcium in 1. Hypercalcemia 2. Calcification 3. Low PTH 4. ADBD PTH Evaluate PTH in context of hyperP, hypoCa, vitamin D deficiency Marked changes should trigger treatment changes Especially, in event of hypocalcemia Treat the trends: Treat P and Ca to normal, PTH to Goal KDIGO International Clinical Practice Guidelines KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130
- 22. Diagnostic assessment ofanaemia [NICE2011] Consider investigating and managing anaemia in people with CKD if: − Hb level falls to 11 g/dl or less (or 10.5 g/dl or less if younger than 2 years) or − develop symptoms attributable to anaemia (such as tiredness, shortness of breath, lethargy and palpitations) • The correction to normal levels of Hb with ESAs is not usually recommended in people with anaemia of CKD • Typically maintain the aspirational Hb range between: Population Hb range Adults, young people & children > 2 yrs 10 and 12 g/dl Children < 2 yrs 9.5 and 11.5 g/dl – Do not wait until Hb levels are outside the aspirational range before adjusting treatment, for example, take action when Hb levels are within 0.5 g/dl of the range’s limits
- 23. Anaemia Pathway: diagnosis Isanaemia due to CKD? • Consider other causes if eGFR ≥60 ml/min/1.73m2 Consider treating anaemia when: • Hb falls to ≤ 11 g/dl (or ≤10.5 g/dl if younger than 2 years), or • symptoms attributable to anaemia develop Determine iron status: Iron deficiency anaemia: • diagnosed when serum ferritin < 100 μg/l in stage 3 CKD & above. •Functional iron deficiency defined by: • serum ferritin > 100 μg/l and either % hypochromic red cells > 6% (if test available), or transferrin saturation < 20% Iron correction should maintain: • serum ferritin > 200 μg/l • transferrin saturation > 20% (unless ferritin> 800 μg/l) • % hypochromic red cells < 6% (unless ferritin>800 μg/l) Review iron dose: • when serum ferritin reaches 500 μg/l (should not rise above 800 μg/l) Optimise iron status: • before or when starting ESAs, before deciding whether to use ESAs in non-dialysis patients
- 24. Functional iron deficiency(FID) Functional iron deficiency (FID) is a state in which there is insufficient iron incorporation into erythroid precursors in the face of apparently adequate body iron stores, as defined by the presence of stainable iron in the bone marrow together with a serum ferritin value within normal limits R e t i c u l o c y t e h e m o g l o b i n content (CHr) is a measurement of hemoglobin inside the reticulocyte. It correlates directly with the functional availability of iron in the marrow CHr constitutes the most valuable screening tool for identifying iron deficiency (ID) with or without anaemia. Decreased CHr (cutoff value of 25 pg/cell) stands for accurate d i a g n o s i s o f f u n c t i o n a l i r o n deficiency with sensitivity of 94% & specificity of 80%
- 25.
- 26. Genetic Testing inNephrology Nephrology Syndrome Panel Target genes- NGS, Multiplex PCR, Microarray Technologies aHUS/TMA/C3 Glomerulopathy (13 genes) ADAMTS13, C3, CD46, CFB, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE ,THBD Alport Syndrome (3 genes) COL4A3, COL4A4, COL4A5 Bartter Syndrome (5 genes) ATP6V1B1, BSND, CA2, CASR, CLCNKA Nephrotic Syndrome & Focal Segmental Glomerulosclerosis (34 genes) ACTN4, ADCK4 (COQ8B), ANLN, APOL1, ARHGAP24, ARHGDIA, CD2AP, COL4A3, COL4A4, COL4A5, COQ2, COQ6, CRB2, CUBN, EMP2, INF2, ITGA3, ITGB4, LAMB2, LMX1B, MEFV, MYH9, MYO1E, NEIL1, NPHS1, NPHS2, PDSS2, PLCE1, PTPRO, SCARB2, SMARCAL1, TRPC6, TTC21B, WT1 Cystic Disease and Nephronopthisis (23 genes) AHI1, CEP290, GLIS2, INVS, IQCB1, NEK8, NPHP1, NPHP3, NPHP4, RPGRIP1L, TMEM67, TTC21B, XPNPEP3, BICC1, CRB2, EYA1, HNF1B,PAX2, PKD1, PKD2, PKHD1, SIX5, UMOD Polycystic kidney (5 genes) BICC1, PKD1, PKD2, NOTCH2, PKHD1 Renal tubular acidosis (5 genes) ATP6V0A4, ATP6V1B1, CA2, EHHADH, HNF4A Inherited renal diseases are estimated to cause 50% of pediatric chronic renal failure (CRF) and 20% of adult CRF A significant proportion of these patients with nephrotic syndrome (NS) suffer from steroidresistant NS. Establishing the underlying genetic defect and inheritance pattern also allows family member testing to identify at-risk relatives.
- 27. CKD - Summary CKDpatients are asymptomatic for long periods, hence basic simple tests like serrum creatinine with eGFR, Albuminuria & Urinary sediment analysis are the key in early diagnosis & followup of CRF patients Associated Diabetes & Hypertension are major risk factor for rapid progression to disease, hence early therapeutic intervention will prolong the adverse outcome.