On examination he looks pale, his blood pressure is 98/68 mmHg and his pulse rate is 89 beats/min. His heart sounds are normal, but there are bilateral crackles on auscultation of the chest and he has pitting lower limb oedema. The results of laboratory investigations are given below. The 24-h urine protein is 9 g/day. Which one of the following is the most likely cause of his underlying proteinuria?
| Value | Reference range | |
|---|---|---|
| Haemoglobin (g/L) | 102 | 135–180 |
| White cell count (cells/L) | 8.7 × 109 | 4–10 × 109 |
| Platelet count (cells/L) | 185 × 109 | 150–400 × 109 |
| Sodium (mmol/L) | 140 | 134–143 |
| Potassium (mmol/L) | 4.3 | 3.5–5.0 |
| Creatinine (μmol/L) | 135 | 60–120 |
| Albumin (g/L) | 15 | 35–45 |
A. AA amyloidosis
B. AL amyloidosis
C. BPP (β protein precursor) amyloidosis
D. Cystatin C amyloidosis
E. Mesangiocapillary glomerulonephritis
15. In developed countries, which one of the following bone disorders is most frequent in patients receiving maintenance haemodialysis?
A. Osteitis fibrosa cystica
B. Adynamic bone disease
C. Osteomalacia
D. Dialysis-related amyloidosis
E. Aluminium bone disease
16. A 28-year-old woman presents with nausea and vomiting and is found to have a platelet count of 60 × 109 cells/L (150–450 × 109 cells/L), haemoglobin of 87 g/L (115–165 g/L) and creatinine of 285 μmol/L (60–100 μmol/L). Which one of the following is consistent with a diagnosis of atypical haemolytic uraemia syndrome?
A. Markedly suppressed ADAMTS13 activity in blood
B. Stool culture positive for Shiga toxin-producing Escherichia coli (STEC)
C. A mutation in the gene encoding factor H
D. A mutation in the gene encoding ADAMTS13
E. A normal haptoglobin level
17. Which one of the following is NOT a risk factor for contrast-induced acute kidney injury?
A. Congestive heart failure
B. Metformin
C. Multiple myeloma
D. Non-steroidal anti-inflammatory drugs
E. Sepsis
18. Which one of the following anti-hypertensive medications should NOT be used in patients with pre-eclampsia?
A. Nifedipine
B. Methyldopa
C. Irbesartan
D. Labetalol
E. Hydralazine
19. A 26-year-old woman received a living donor kidney transplant from her aunt 2 years prior to her current presentation. Her post-transplantation course was complicated by one episode of cellular rejection. Her graft function is stable with serum creatinine 92 μmol/L. She is taking tacrolimus 2 mg twice daily, mycophenolate 500 mg twice daily and prednisolone 5 mg daily. She is not taking other medications. Her BP is 110/60 mmHg. Her spot urine protein-to-creatinine ratio is 0.1. She is very keen to start a family and plan for pregnancy. What would you do with her immunosuppression?
A. Change tacrolimus to cyclosporine
B. Change mycophenolate to sirolimus
C. Change mycophenolate to azathioprine
D. Stop prednisolone
E. Continue the current immunosuppression drugs
20. A 54-year-old man on regular haemodialysis presents with lower back pain and fever. You request a magnetic resonance imaging (MRI) study of the spine, but request that gadolinium not be used during the test because of concern about:
A. Contrast-induced nephropathy
B. Nephrogenic systemic fibrosis
C. High incidence of allergy reaction to gadolinium among patients on haemodialysis
D. Heavy metal toxicity
E. Systemic sclerosis
21. What is the most important risk factor for the development of post-transplant lymphoproliferative disorder (PTLD) in solid organ transplantation?
A. Kidney transplantation as opposed to other solid organ transplants
B. Epstein–Barr virus status mismatch between recipient and donor
C. Use of the monoclonal anti-CD52 antibody, alemtuzumab
D. Use of sirolimus
E. Previous infection with cytomegalovirus (CMV)
22. A 56-year-old man is admitted to the intensive care unit because of severe sepsis due to ascending cholangitis. This is complicated by acute kidney injury. Which one of the following is an indication for commencement of renal replacement therapy?
A. Oliguria, urine 0.3 mL/kg/h
B. Urea of 19 mmol/L
C. Pericardial rub
D. Serum creatinine of 400 μmol/L
E. Urinary sodium of <20 mmol/L
23. A 48-year-old man presents with severe right-sided loin pain radiating to the scrotum. A computed tomography scan demonstrates a 4-mm distal ureteric calculus. Which one of the following treatments has been shown to increase the chances of stone passage?
A. Frusemide
B. Tamsulosin
C. Atenolol
D. Intravenous saline
E. Thiazide diuretics
24. A 48-year-old man with IgA nephropathy received his first renal transplant 3 years ago. His post-transplant course was complicated by an episode of acute cellular rejection that was successfully treated with three doses of methylprednisolone. His current graft function is reflected by a serum creatinine of 145 μmol/L (70–120 μmol/L). His medications include tacrolimus, mycophenolate and prednisolone. He presented with a 3-week history of epigastric pain. Endoscopy revealed a gastric lesion and the histology confirmed Epstein–Barr virus associated post-transplantation lymphoproliferative disorder. The computed tomography scans of his head, chest and abdomen revealed no other lesion. Which is the best initial treatment for this patient?
A. Immunosuppression should be withdrawn
B. Immunosuppression should be reduced
C. Immunosuppression should be maintained at its current levels and rituximab should be started
D. Immunosuppression should be reduced and valganciclovir started
E. Immunosuppression should be reduced and gastrectomy should be performed
25. Which one of the following treatment modalities achieves the best long-term survival outcome in patients with hepatorenal syndrome?
A. Terlipressin
B. Norepinephrine (noradrenaline)
C. Continuous renal replacement therapy
D. Liver transplantation
E. Transjugular intrahepatic portosystemic shunts
26. A 38-year-old woman presented with bilateral red eyes, which was diagnosed as anterior uveitis. This was treated with topical steroids and improved. One month later, she represented with acute deterioration of her renal function (creatinine 250 μmol/L, reference range: 60–100 μmol/L). Moderate proteinuria (1.5 g/24 h) and urine eosinophilia were detected. There are no significant dysmorphic red blood cells or casts in the urinary sediment. Renal ultrasound showed both kidneys were normal in size and appearance. She had a percutaneous renal biopsy. What is the biopsy likely to show?
A. Membranous nephropathy
B. Minimal change disease
C. Tubulointerstitial nephritis
D. Focal and segmental glomerulosclerosis
E. IgA nephropathy
Theme: Glomerulonephritis (for Questions 27–31)
A. Alport disease
B. Goodpasture disease
C. Idiopathic membranous nephropathy (MN)
D. Immunoglobulin A nephropathy
E. Membranoproliferative glomerulonephritis (MPGN)
F. Minimal change disease (MCD)
G. Primary focal segmental glomerulosclerosis (FSGS)
H. Rapidly progressive glomerulonephritis
For each of the following scenarios, select the most likely type of glomerulonephritis that is involved.
27. Which glomerulonephritis is most likely to rapidly recur in a renal allograft?
28. When a patient presents with nephrotic syndrome, which type of causative glomerulonephritis is associated with the greatest risk of a venous thrombotic event?
29. Which glomerulonephritis is associated with selective cyclo-oxygenase 2 (COX-2) inhibitor use?
30. In which glomerulonephritis are anti-phospholipase A2 receptor (anti-PLA2R) antibodies commonly detected?
31. A 45-year-old man presents with microscopic haematuria and proteinuria for investigation. His serum creatinine is 196 μmol/L. His histopathology (H&E, immunofluorescence and electron microscopy) is shown below. What is the most likely diagnosis?
Renal biopsy: Haematoxylin and Eosin (Hand E) staining
Renal biopsy: immunofluorescence with anti-IgG
Renal biopsy: electron microscopy
Answers
Basic Science
1. Answer E
Nephrotic syndrome is associated with hypoalbuminaemia and peripheral oedema. Hepatic cholesterol and lipoprotein synthesis are increased in nephrotic syndrome, hence an elevated total and low-density lipoprotein cholesterol level is seen. Glomerular filtration barrier is disrupted, leading to proteinuria. Nephrotic syndrome is associated with hypercoagulability from increased hepatic synthesis of coagulation factors (e.g. fibrinogen) and loss of regulatory factors (anti-thrombin III, protein C and protein S) in urine. Renal vein thrombosis complicates all forms of nephrotic syndrome, especially membranous nephropathy. Nephrotic syndrome is associated with increased susceptibility to infection, particularly to Gram-positive bacteria, especially Streptococcus pneumoniae. This might be caused by urinary loss of IgG and complement, and impaired cellular immunity.
Nephrotic syndrome is associated with hypoalbuminaemia and peripheral oedema. Hepatic cholesterol and lipoprotein synthesis are increased in nephrotic syndrome, hence an elevated total and low-density lipoprotein cholesterol level is seen. Glomerular filtration barrier is disrupted, leading to proteinuria. Nephrotic syndrome is associated with hypercoagulability from increased hepatic synthesis of coagulation factors (e.g. fibrinogen) and loss of regulatory factors (anti-thrombin III, protein C and protein S) in urine. Renal vein thrombosis complicates all forms of nephrotic syndrome, especially membranous nephropathy. Nephrotic syndrome is associated with increased susceptibility to infection, particularly to Gram-positive bacteria, especially Streptococcus pneumoniae. This might be caused by urinary loss of IgG and complement, and impaired cellular immunity.
2. Answer A
Clinical studies have suggested that the degree of podocytopenia predicts the progression of diabetic kidney disease (Jefferson et al., 2011). Podocyte proliferation is a feature of collapsing glomerulopathy. Foot process effacement is seen in minimal change disease. Podocytes may respond to immune complex-mediated injury by producing inflammatory mediators and oxidative injury is a prominent feature in membranous nephropathy. Expression of slit diaphragm proteins are altered in nephrotic disorders, leading to loss of slit diaphragm integrity and protein permeability. Podocytes can undergo programmed cell death or apoptosis. When podocytes are lost by detachment or apoptosis and are not replaced by adjacent viable podocytes, this leads to podocytopenia and ultimately to a leaky glomerular filtration barrier.
Clinical studies have suggested that the degree of podocytopenia predicts the progression of diabetic kidney disease (Jefferson et al., 2011). Podocyte proliferation is a feature of collapsing glomerulopathy. Foot process effacement is seen in minimal change disease. Podocytes may respond to immune complex-mediated injury by producing inflammatory mediators and oxidative injury is a prominent feature in membranous nephropathy. Expression of slit diaphragm proteins are altered in nephrotic disorders, leading to loss of slit diaphragm integrity and protein permeability. Podocytes can undergo programmed cell death or apoptosis. When podocytes are lost by detachment or apoptosis and are not replaced by adjacent viable podocytes, this leads to podocytopenia and ultimately to a leaky glomerular filtration barrier.
Jefferson, J.A., Nelson, P.J., Najafian, B., and Shankland, S.J. (2011). Podocyte disorders: Core Curriculum 2011. Am J Kidney Dis 58, 666–677.
3. Answer D
Prognostic risk factors for progression of idiopathic membranous nephropathy include:
A high proportion of patients with idiopathic MN have circulating antibodies to the M-type phospholipase A2 receptor (PLA2R), a transmembrane protein located on podocytes (Beck and Salant, 2010).
Prognostic risk factors for progression of idiopathic membranous nephropathy include:
- Greater degree and duration of proteinuria
- Impaired kidney function at presentation
- Hypertension
- Male sex and age more than 50 years
- Non-Asian race
- Biopsy features of glomerulosclerosis, stage III/IV disease, tubulointerstitial fibrosis.
A high proportion of patients with idiopathic MN have circulating antibodies to the M-type phospholipase A2 receptor (PLA2R), a transmembrane protein located on podocytes (Beck and Salant, 2010).
Beck, L.H., Jr. and Salant, D.J. (2010). Membranous nephropathy: recent travels and new roads ahead. Kidney Int 77, 765–770.
4. Answer D
There are five types of arterial calcification:
Vascular calcification in CKD involves major disturbance of the calcium phosphate homeostasis and reductions in serum fetuin and pyrophosphate levels. In terms of pathobiology, vascular smooth muscle cell (VSMC) apoptosis and osteochondrogenic metaplasia is driven by hyperphosphataemia, worsened by iatrogenic hypoparathyroidism and low-turnover bone disease. Whilst antecedent diabetes mellitus, hypertension, dyslipidaemia and the metabolic syndrome continue to contribute to arteriosclerosis, hyperphosphataemia, reduced klotho expression and impaired soft-tissue calcification defences are key pathophysiological components of this condition.
Klotho is a putative ageing suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific for FGF-23 (Thompson and Towler, 2012). Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone–kidney–parathyroid control of phosphate and calcium. Klotho−/− mice display premature ageing and chronic kidney disease-associated mineral and bone disorder (CKD-MBD)-like phenotypes mediated by hyperphosphataemia and remediated by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1α-hydroxylase, vitamin D receptor or NaPi-cotransporter). CKD can be seen as a state of hyperphosphataemia-induced accelerated ageing associated with klotho deficiency. Humans with CKD experience decreased klotho expression as early as stage 1 CKD; klotho continues to decline as CKD progresses, causing FGF-23 resistance and provoking large FGF-23 and parathyroid hormone increases, and hypovitaminosis.
Vascular calcium phosphate deposition elicits an inflammatory response which has a downstream effect of vascular mineralisation. Therefore, patients with CKD face the ‘perfect storm’ of vascular calcification.
There are five types of arterial calcification:
- Calcific aortic valve disease
- Atherosclerotic intimal calcification
- Arterial medial calcification
- Vascular calcification of chronic kidney disease (CKD; also known as CKD-mineral bone disease)
- Calcific uraemic arteriopathy (CUA; also known as calciphylaxis).
Vascular calcification in CKD involves major disturbance of the calcium phosphate homeostasis and reductions in serum fetuin and pyrophosphate levels. In terms of pathobiology, vascular smooth muscle cell (VSMC) apoptosis and osteochondrogenic metaplasia is driven by hyperphosphataemia, worsened by iatrogenic hypoparathyroidism and low-turnover bone disease. Whilst antecedent diabetes mellitus, hypertension, dyslipidaemia and the metabolic syndrome continue to contribute to arteriosclerosis, hyperphosphataemia, reduced klotho expression and impaired soft-tissue calcification defences are key pathophysiological components of this condition.
Klotho is a putative ageing suppressor gene encoding a single-pass transmembrane co-receptor that makes the fibroblast growth factor (FGF) receptor specific for FGF-23 (Thompson and Towler, 2012). Klotho is expressed in kidney distal convoluted tubules and parathyroid cells, mediating the role of FGF-23 in bone–kidney–parathyroid control of phosphate and calcium. Klotho−/− mice display premature ageing and chronic kidney disease-associated mineral and bone disorder (CKD-MBD)-like phenotypes mediated by hyperphosphataemia and remediated by phosphate-lowering interventions (diets low in phosphate or vitamin D; knockouts of 1α-hydroxylase, vitamin D receptor or NaPi-cotransporter). CKD can be seen as a state of hyperphosphataemia-induced accelerated ageing associated with klotho deficiency. Humans with CKD experience decreased klotho expression as early as stage 1 CKD; klotho continues to decline as CKD progresses, causing FGF-23 resistance and provoking large FGF-23 and parathyroid hormone increases, and hypovitaminosis.
Vascular calcium phosphate deposition elicits an inflammatory response which has a downstream effect of vascular mineralisation. Therefore, patients with CKD face the ‘perfect storm’ of vascular calcification.
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