Nephrology — Long Cases

10 Nephrology—Long Cases Desmond Yat-Hin Yap, Wai-Kei Lo, Kar-Neng Lai, and Daniel Tak-Mao Chan 10.1 Malaise and nausea (chronic kidney disease) History A 3l-year-old woman was referred from her family physician for management of uncontrolled hypertension. Six years ago, she was first noted to have hypertension and proteinuria during pre- employment check-up. She refused renal biopsy at that time, and subsequently defaulted follow-up. In the recent 1 month, she was bothered by facial puffiness which was worse in the early morning, and ankle swelling. She also experienced headache, malaise, and most recently, nausea. There was no urinary symptom. There was no intake of herbal medicine or analgesics. Physical examination She had café-au-lait complexion and mild ankle oedema. Fundoscopy revealed grade-3 hypertensive retinopathy. The blood pressure was 220/125 mmHg. Urine showed 3+ result on albustix. Her body weight was 55 kg. Investigations Blood tests showed: serum urea 23.1 mmo/L; creatinine S72 pmol/L; potassium 4.9 mmol/L; calcium 1.78 mmol/L;

128 Problem-Based Medical Case Management Case 10.1 phosphate 2.2 mmol/L; bicarbonate 21 mmol/L; albumin 32 g/L and haemoglobin 8.9 g/dL. with normochronic, normocytic red cells; 24-hour urine volume was 1.2 L, with creatinine concentra- tion 8,890 pmol/L and protein 3.3 g. Ultrasonography showed that her left and right kidneys were 7.6 and 8.0 cm in length respec- tively, with increased parenchymal echogenicity, loss of corti- comedullary differentiation, and no hydronephrosis. Questions 1. Did this lady have acute kidney injury or chronic kidney disease? She had chronic kidney disease. Supporting features are: — Presence of renal disease for several years. — Presence of uraemic complexion. — Ultrasonographic evidence of bilateral small kidneys with loss of corticomedullary differentiation. — Hypocalcaemia, hyperphosphataemia, and normochromic normocytic anaemia are more commonly found in chronic kidney disease. — Absence of identifiable causes of acute kidney injury, e.g., obstructive uropathy, nephrotoxic drug intake. « Her uncontrolled or accelerated hypertension might have added an acute element in the renal impairment, i.e., acute-on-chronic renal failure. 2. How will you assess renal function in this patient? * Renal function is indicated by the glomerular filtration rate (GFR), reflected by creatinine clearance which is calculated as follows: Creatinine clearance (mL/min) = [urine creatinine concentration x urine volume x 1,000] divided by [plasma creatinine concentration x 24 X 60], based on a 24-hour urine sample. In clinical practice, validated formulae such as the Cockcroft-Gault equation, Modification of Diet in Renal Disease (MDRD) formula, or the CKD-EPI formula can be used to calculate the estimated glomerular filtration rate (eGFR). More accurate methods to measure GFR include radioisotope

Case 10.1 Nephrology 129 tracer methods and inulin clearance, which are technically demanding and are thus used mainly for research purposes. + In patients with moderate to severe renal impairment, creati- nine clearance may overestimate renal function since under this setting creatinine is also secreted by the proximal tubule. Therefore, one can use the average of creatinine clearance and urea clearance, as a significant amount of filtered urea is pas- sively reabsorbed in the proximal tubule. Urea clearance (mL/min) = [urine urea concentration X urine volume x 1,000]/[plasma urea concentration x 24 x 60] Corrected GFR = [creatinine clearance + urea clearance] divided by 2. It is also a common practice to normalize these clearance values to body surface area (per 1.73 m?). ¢ The Cockcroft-Gault formula takes into account plasma creati- nine concentration, body weight, age, and gender: CrCl (in mL/min) = (140 — age) x lean body weight [kg] Plasma creatinine concentration [mg/dL] x 72 % 0.85 (if female) (The conversion factor for plasma creatinine concentration from mg/dL to umol/L is 88.4; the calculated CrCl for this patient is thus 10.98 mL/min.) The MDRD equation is more complex, taking into account plasma creatinine concentration, serum albumin concentration, blood urea nitrogen, age, gender, and race, to estimate the GFR. The CKD-EPI equation is based on the same four variables as the MDRD formula, but uses a different modelling method. The equation was reported to perform better than the MDRD formula, resulting in less bias in patients with higher GFR and a lower percentage of misclassification of CKD stages. 3. What are the long-term complications of this condition? Anaemia, renal bone disease, bleeding diathesis, metabolic disturbances (hyperkalaemia, hypocalcaemia, hyperphospha- taemia, hyperuricaemia, and metabolic acidosis), malnutrition, dyslipidaemia, cardiovascular morbidities (hypertension, heart failure, vascular and valvular calcifications), cerebrovascular

130 Problem-Based Medical Case Management Case 10.1 6. disease, dermatologic abnormalities (pruritus, skin pigmenta- tion, nail changes), defective immune responses and susceptibil- ity to infection, menstrual disturbance, and sexual dysfunction. ‘What accounts for the abnormal skin complexion? Coexistence of anaemia and retention of 8-melanocyte-stimulat- ing hormone, as well as pigment deposition (urochromogens). . What immediate treatment is required in this lady? Treatment of severe hypertension. What are the indications for emergency dialysis? Are they present in this patient? 7. Uncontrolled hyperkalaemia, acute pulmonary oedema with inadequate urine output, severe metabolic acidosis, uraemic pericarditis, severe uraemia, uraemic encephalopathy are the indications for emergency dialysis. None is present in this patient. What long-term treatment options are available for this patient’s renal failure? Treatment of accelerated hypertension may result in some improvement of renal function. It is likely that this patient will eventually require renal replacement therapy, in the form of peritoneal dialysis (the most prevalent form in Hong Kong is continuous ambulatory peritoneal dialysis), haemodialysis, or renal transplantation. Pitfalls and tips It is important to differentiate between acute kidney injury and chronic kidney disease, and to identify acute, potentially revers- ible, elements contributing to renal impairment in patients with chronic kidney disease (i.e., acute-on-chronic renal failure). History, physical examination, and investigations (blood tests and imaging) all help to make the differentiation. Creatinine clearance in patients with significant renal insuffi- ciency may result in overestimation of glomerular filtration rate. Establishing the original cause leading to progressive renal failure is not always possible, when patients present late with scarred end-stage kidneys.

Case 10.2 Nephrology 131 + A history of exposure to nephrotoxins (e.g., nephrotoxic drugs such as NSAIDs, some herbal medicine, radiological contrast) should be actively sought and further exposure prevented. » The decision whether to proceed with renal replacement therapy or to adopt a palliative approach and the choice between dif- ferent modes of renal replacement therapies require individu- alized consideration of a patient’s physical and psychosocial circumstances. 10.2 Polydipsia and ankle swelling (diabetic nephropathy) History A woman aged 64 years with a history of diabetes mellitus for 2 years and hypertension for over 5 years was admitted complain- ing of chest pain and shortness of breath. She was initially treated with an oral hypoglycaemic agent, which was stopped about a year ago because of deteriorating renal function. While she previ- ously had experienced polyuria and nocturia, she recently noticed a decrease in urinary frequency and progressive bilateral ankle swelling. Physical examination Her blood pressure was 160/95 mmHg. There was bilateral pitting ankle oedema and the jugular venous pressure was raised. Chest €xamination showed bilateral basal crackles and cardiomegaly. She also had diabetic retinopathy, with dot and blot haemorrhages. Urine sample showed 2+ proteinuria and no red cells. Questions L. What diabetic complications have developed in the patient? * The patient has diabetic retinopathy and most likely diabetic nephropathy, the latter leading to fluid overload. Diabetic

132 Problem-Based Medical Case Management Case 10.2 nephropathy is clinically defined by persistent proteinuria greater than 500 mg in a 24-hour urine sample in a patient with diabetes mellitus in the absence of other renal diseases. 2. What pathology may be found in the kidneys? » Excessive extracellular matrix deposition in the glomeruli resulting in mesangial expansion, thickening of the glomerular basement membrane, and diabetic glomerulosclerosis. Nodular glomerulosclerosis with typical Kimmelstiel-Wilson nodules may be observed. Ischaemic changes resulting from arteriolar hyalinosis are sometimes found. 3. What investigations should be performed in the patient? « The renal function of the patient should be assessed. Urinary protein excretion should be quantified. Urinalysis should be performed to exclude infection and other causes of kidney injury or parenchymal kidney diseases. « Ultrasonogram of the kidneys is useful to assess the renal size and morphology, and to exclude obstruction and other con- comitant lesions. 4. How should the blood pressure be controlled? » Blood pressure control is of key importance in patients with chronic kidney diseases including diabetic nephropathy. Either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers should be used as first line treatment in view of their reno-protective and proteinuria lowering effect. One must make sure that there is no renal artery stenosis and beware of hyperkalaemia. Calcium channel blockers, beta-blockers, and diuretics can be used as additional treatment. Pitfalls and tips « Diabetic nephropathy may complicate both type 1 and type 2 diabetes mellitus. Compared to type 1, a smaller proportion of type 2 patients progress to end-stage renal disease. However, the number of patients with type 2 diabetes mellitus is much higher than type 1 globally, and diabetic nephropathy now accounts for approximately 50% of all patients with end-stage renal failure with the majority of them having type 2 diabetes.

Case 10.3 Nephrology 133 + The apparent normal kidney size in patients with diabetic nephropathy may be deceptive, since nephromegaly is charac- teristic in the early phase of diabetic nephropathy. The kidneys may not appear small even when a patient has reached end- stage renal disease due to diabetic nephropathy. + Since diabetes mellitus is common, one should not assume dia- betic nephropathy when a patient with diabetes presents with renal abnormalities. The presence of haematuria, the absence of other diabetic microvascular complications such as retinopathy, an unusual clinical course such as sudden occurrence of heavy proteinuria, and concomitant clinical abnormalities should raise the suspicion whether there is another reason for the renal abnormalities and investigated accordingly. + Diabetic retinopathy is commonly associated with diabetic nephropathy. Patients with type 1 diabetes and nephropathy almost always have other signs of diabetic microvascular disease, such as retinopathy and neuropathy. The relationship between nephropathy and retinopathy is less predictable in type 2 diabetes. In approximately 70% of type 2 diabetic patients, nephropathy and retinopathy may coexist. * Oral hypoglycaemic drugs that are excreted via the kidneys should be avoided in patients with moderate or severe impair- ment of renal function, since continued use may precipitate severe prolonged hypoglycaemia. Biguanides must be avoided in the presence of moderate renal impairment since they can lead to life-threatening lactic acidosis. 10.3 A young man with gross haematuria (1A nephropathy) History A 39-year-old man with good past health presented with gross haematuria following 4 days of upper respiratory tract infection. P revious pre-employment check-up 5 years ago revealed border- line elevation of blood pressure of 130/90 mmHg and microscopic

134 Problem-Based Medical Case Management Case 10.3 haematuria. No further investigation or treatment was given then. There was no history of joint pain, skin rash or urine passage of stones. Upon admission, he was found to have impaired renal func- tion with a plasma creatinine of 135 umol/L, a creatinine clearance of 63 mL/min/1.73 m’, and urinary protein of 0.5 g/day. Abnormal microscopy was detected. Renal biopsy was performed percutane- ously under ultrasound guidance. Physical examination There were no uraemic signs, but urine showed 1+ albustix and numerous red cells. The blood pressure was 155/100 mmHg. Investigations There were normal serum complements, negative anti-nuclear factor, and anti-neutrophil cytoplasmic antibodies, normal serum IgG and IgM concentration, but serum IgA concentration was increased to 5.43 g/L (normal 0.70-3.86 g/L). Urine showed dys- morphic red cells and red cell casts. Questions 1. What is the characteristic pathological finding in IgA nephropathy" » IgA deposition in the mesangial areas with a staghorn pattern. Light microscopy usually shows mild mesangial proliferation. Electron-dense deposits are usually present in the mesangium on ultrastructural (EM) examination. 2. What is the typical clinical course of this disease? » IgA nephropathy usually runs a slowly, indolent, yet progres- sive course over a period of 2 to 3 decades. 3. What is the long-term prognosis of this disease? * 30% of these patients may develop end-stage renal failure within a follow-up period of 30 years.

Case 10.3 Nephrology 135 e n ¢ What is the immediate treatment? The blood pressure should be well controlled. . What is the mainstay of treatment? Low-salt and low-protein diet should be recornmended' Blockade of the renin-angiotensin system with either angio- tensin converting enzyme inhibitor or angiotensin II receptor antagonist lowers the blood pressure, reduces the proteinuria, and provides renal protection. . How is this condition related to Henoch-Schonlein purpura? Henoch-Schonlein purpura and IgA nephropathy have identi- cal renal pathology. Some nephrologists have considered them as different ends of the spectrum of a single pathologic entity. Other clinical features of Henoch-Schonlein Purpura such as arthralgia, abdominal pain, and skin rash are associated with leukocytoclastic vasculitis. These are not present in IgA nephropathy. Pitfalls and tips The use of urine microscopy to differentiate glomerular (dys- morphic red cells and red cell casts) from non-glomerular hae- maturia (normal red cells without casts) is extremely helpful in the approach and management of macroscopic haematuria. Patients with IgA nephropathy may have mild or no proteinuria. The association of repeated macroscopic haematuria with mucosal infection (such as the respiratory tract or the gastro- intestinal tract) is a characteristic feature of IgA nephropa- thy. This should not be confused with post-streptococcal glomerulonephritis. IgA nephropathy was previously amongst the conditions included in the “loin pain-benign haematuria syndrome”. The condition is not totally benign.

136 Problem-Based Medical Case Management Case 10.4 10.4 A young lady with ankle swelling (lupus nephritis) History A 22-year-old secretary presented with increasing ankle swelling for 3 weeks. She did not have other urinary symptoms such as polyuria, nocturia, gross haematuria, dysuria, or frequency. She felt generally unwell, but did not notice any skin rash or joint pain. She had good past health, and there was no family history of renal disease. She had consulted a private practitioner, who informed her that her blood pressure was elevated at 130/86 mmHg. She was given symptomatic treatment with a diuretic drug. Urine and blood tests showed microscopic haematuria, 1+ proteinuria by dipstix, serum creatinine level of 118 pmol/L, serum albumin level of 29 g/L, and positive anti-nuclear antibodies. Physical examination There was mild bilateral pitting ankle oedema and mild pallor. There was no fever, no palpable lymphadenopathy, no skin or joint abnormality. Her blood pressure was 142/90 mmHg. Questions 1. What is the clinical diagnosis and the most likely aetiologi- cal diagnosis? e Acute nephritic syndrome, most likely due to severe lupus nephritis. 2. In addition to those that had been done already, what are the most relevant investigations, and what are the expected findings? e 24-hour urine collection and urine protein-to-creatinine concen- tration ratio to confirm significant proteinuria and to quantify the level of proteinuria, which is important in monitoring the response to immunosuppressive treatment. Estimated glomeru- lar filtration rate or measurement of creatinine clearance by

Case 10.4 Nephrology 137 3. 24-hour urine collection is important to document the severity of renal impairment at baseline for future reference. In most patients the level of anti-double stranded DNA anti- bodies is high and C3 level is reduced during active disease. The level of C-reactive protein should be measured when it is suspected that the patient has concomitant infection. Ultrasonogram of the kidneys is indicated to exclude concomi- tant abnormalities (e.g., renal stone) and to confirm that the kidneys are not shrunken before proceeding to the investigation that yields a definitive diagnosis—percutaneous Kidney biopsy. The latter is likely to show lupus nephritis Class I (focal), IV (diffuse), or V (membranous), alone or in combination. What drugs are commonly used as immunosuppressive treatment of this condition? . 4. Corticosteroids with high initial dose followed by gradual taper- ing, combined with either mycophenolic acid or up to 6 months of intravenous or oral cyclophosphamide as initial immunosup- pressive regimen to induce disease remission, followed by low- dose corticosteroids combined with either mycophenolic acid or azathioprine for long-term maintenance to prevent disease flare. Anti-malarial such as hydroxychloroquine is recommended as adjunctive therapy since their use is associated with a reduced rate of disease flares. Apart from the underlying condition, what associated com- plications require attention (i.e., monitoring, prevention, and treatment)? These include complications of disease such as cerebral lupus, hypertension, hyperlipidaemia, complications of treatment such as drug-induced leucopaenia, infections including opportunistic infections, herpes zoster, mycobacterial infections, drug-induced adverse effects such as alopecia (cyclophosphamide), gonadal toxicity (cyclophosphamide), predisposition to malignancies (cyclophosphamide), gastrointestinal upset (cyclophosphamide and mycophenolic acid), and avoidance of pregnancy during active disease or when being treated with pregnancy-contrain- dicated medications.

138 Problem-Based Medical Case Management Case 10.5 Pitfalls and tips * Testing for hepatitis B surface antigen is advisable since HBsAg infection is endemic in many Asian regions and severe exacer- bation of hepatitis B can be precipitated by immunosuppressive medications. * Blood pressure must be well controlled since uncontrolled hypertension by itself can accelerate renal failure. * Normal clotting and haemostatic parameters (note that throm- bocytopenia can be a manifestation of active lupus) must be ensured before proceeding to kidney biopsy. * Persistent heavy proteinuria by itself predisposes to venous thrombosis, which can affect the venous system in the lower limbs or the renal vein. 10.5 Abdominal pain and peritoneal dialysis (PD) (PD associated peritonitis) History A 60-year-old woman with a history of type 2 diabetes developed end-stage renal failure due to diabetic nephropathy. She had been performing continuous ambulatory peritoneal dialysis (CAPD) herself, with three 2-1 exchanges per day, for 2 years. She also had diabetic retinopathy. She presented with acute diffuse abdominal pain a few hours ago. There was also nausea and mild diarrhea after onset of abdominal pain. Peritoneal fluid effiuent was noticed to be turbid and the effluent amount was noticed to be significantly less than usual. There was no fever. She lived alone and cared for herself. However, because of retinopathy, she could not read news- paper or watch television clearly. She took Glibenclamide 5 mg daily for her diabetes. Physical examination Her temperature was 37°C, and her blood pressure was 165/70 mmHg. Abdominal examination showed diffuse abdominal

Case 10.5 Nephrology 139 tenderness, with a Tenckhoff catheter in-situ. There was some pus and erythema at the exit site of the PD catheter. Questions 1. What condition is she suffering from? « Peritonitis in a patient treated with long-term peritoneal dialysis. 2. What are the diagnostic features of peritonitis complicating peritoneal dialysis? * Turbid peritoneal dialysis effluent, often with abdominal pain, with or without fever. The white cell count in the effluent PD fluid is usually higher than 100/mm’. 3. Does the absence of fever exclude peritonitis as the cause of her abdominal pain? * No. 4. What are the common organisms that may cause peritonitis complicating peritoneal dialysis? + Gram-positive organisms (e.g., coagulase-negative staphylo- coccus, followed by staphylococcus aureus) and gram-negative organisms (e.g., Escherichia coli, Klebsiella, Pseudomonas species) are the most common organisms. Less common causes include Mycobacterium tuberculosis, fungal species (e.g., Candida species), and atypical Mycobacteria. 5. What are the possible contributing factors for her peritonitis? * Poor eyesight or poor eye-hand co-ordination from her diabetic retinopathy predisposes her to contamination during dialysis exchanges; unhygienic home environment, exit site infection or tunnel track infection are possible contributing factors. 6. What is the treatment for PD associated peritonitis? * Antibiotics should be given intra-peritoneally (i.e., added to the PD fluid before inflow) immediately based on clinical diagno- sis. Do not wait for laboratory confirmation or culture result. 7. What is the antibiotic treatment regimen of choice before culture result is available? * The initial antibiotic treatment should cover both gram-positive and gram-negative organisms as both are common causative organisms. Vancomycin as the initial treatment is avoided for

140 Problem-Based Medical Case Management Case 10.5 fear of selecting vancomycin-resistant strains. Current empiri- cal antibiotic regimen is a combination of first-generation cephalosporin and an aminoglycoside in adjusted dosage. As an alternative the aminoglycoside can be replaced with a third- generation cephalosporin, which may help preserve residual renal function and avoid ototoxicity. The antibiotics may need to be changed when the PD fluid culture and microorganism sensitivity results are available. 8. Should she be continued on peritoneal dialysis during infection? * CAPD should be continued unless the peritonitis is refractory to treatment, which necessitates PD catheter removal. 9. What should be done if the peritonitis does not respond to antibiotic treatment? ¢ Adjust the antibiotic therapy according to culture result and sensitivity if appropriate. If peritonitis is refractory to treat- ment despite appropriate antibiotics, one should exclude intra-abdominal surgical conditions such as cholecystitis, appendicitis, and diverticulitis, and the PD catheter should be removed. The patient should be supported with haemodialysis and antibiotic treatment continued. Reinsertion of PD catheter can be attempted a few weeks after completion of antibiotic treatment in patients with no feature of intra-abdominal infection. 10. What is the chance of successful treatment of her peritonitis? * Success rate is over 90%. Success rate may be lower for gram- negative peritonitis. Fungal peritonitis requires PD catheter removal in addition to anti-fungal therapy. PD may continue during treatment of Mycobacterial peritonitis. 11. What is the effect of peritonitis on her blood sugar control? * Infection may aggravate hyperglycaemia, but the nausea and anorexia accompanying the peritonitis may also lead to reduced feeding and hypoglycaemia particularly in malnour- ished patients continued on diabetic medications.

Case 10.5 Nephrology 141 12. Ts oral hypoglycaemic therapy a good choice for her diabe- tes control? What are the other treatment options and route of administration of insulin? What are the pros and cons? « TInsulin is a better option than oral hypoglycaemic agents which may have a prolonged half-life in end-stage renal failure, with increased risk of hypoglycaemia.