68 year old Joseph Hernandez, has been a patient of the practice for many years, he was diagnosed with type 2 diabetes 15 years ago, his blood sugar control has been reasonably good, his most recent HBA1c 9%. He developed hypertension 2 years ago, but his blood pressure has become increasingly difficult to control.
His renal function has been deteriorating over the last 2 years with his most recent glomerular filtration rate [GFR] being measured at 40 ml/min/1.73m²
History:
Physical:
Generally diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the setting of diabetes. Patients usually have physical findings associated with long-standing diabetes.
The key change in diabetic glomerulopathy is augmentation of extracellular material. The earliest morphologic abnormality in diabetic nephropathy is the thickening of the glomerular basement membrane (GBM) and expansion of the mesangium due to accumulation of extracellular matrix. Large acellular accumulations may be observed in the solid spaces of the tuft. These are circular on section and are known as the Kimmelstiel-Wilson lesions/nodules.
The glomeruli and kidneys are typically normal or increased in size initially, thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency.
The renal vasculature typically displays evidence of atherosclerosis, usually due to concomitant hyperlipidaemia and hypertensive arteriosclerosis.
Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy. First, mesangial expansion is directly induced by hyperglycaemia, perhaps via increased matrix production or glycosylation of matrix proteins. Second, GBM thickening occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by renal vasodilatation or from ischaemic injury induced by hyaline narrowing of the vessels supplying the glomeruli). These different histologic patterns have similar prognostic significance.
The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycaemia (causing hyperfiltration and renal injury), advanced glycosylation products, and activation of cytokines.
Relationship between serum creatinine and the glomerular filtration rate (GFR):
The inverse reciprocal relationship between GFR and serum creatinine shows that some individuals have a GFR as low as 30 – 40ml/min without serum creatinine rising out of the normal range. A normal GFR is 120 ± 25ml/min/1.73m².
Key points:
GFR is the rate at which fluid passes into nephrons after filtration, it measures renal excretory function. The normal range depends on the size of an individual, and should be corrected for surface area - typically 1.73 m²
GFR normal range = 120 ± 25ml/min/1.73m²
Clearance of a solute from plasma into urine equals GFR, if the solute is freely filtered and neither secreted into nor absorbed from the renal tubules.
Cockcroft and Gault (C&G) equation:
CrCl (C&G) = (140 – age) x lean body weight (kg) x (1.22 males or 1.04 females) / serum creatinine (μmol/l)
MDRD study equation:
CrCl = 186 x (creatinine in μmol/l/88.4)^-1.154 x (Age in years)^-0.203 x (0.742 if female) x (1.210 if black)
These equations do not perform well in unusual circumstances, such as extremes of body (and muscle) mass.
| Stage | Description | GFR (ml/min/1.73m²) | Action |
|---|---|---|---|
| 1 | Kidney damage² with normal or high GFR | ≥ 90 | Investigate, e.g. haematuria and proteinuria |
| 2 | Kidney damage with slightly low GFR | 60 – 89 | Renoprotection – blood pressure control, dietary modifications |
| 3 | Moderately low GFR | 30 – 59 | |
| 4 | Severe low GFR | 15 – 29 | Prepare for renal replacement therapy (if appropriate) |
| 5 | Kidney failure | < 15 or dialysis |
¹US National Kidney Foundation Kidney Disease Quality Outcomes Initiative classification of stages of chronic kidney disease
²Kidney damage means pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies or GFR < 60 ml/min/1.73m² for 3 months. Symptoms unusual until ≥ stage 3.
Chronic renal failure (CRF) refers to an irreversible deterioration in renal function which classically develops over a period of years. Initially, it is manifest only as a biochemical abnormality. Eventually, loss of the excretory, metabolic and endocrine functions of the kidney leads to the development of the clinical symptoms and signs of renal failure, which are referred to as uraemia.
Disturbances in water, electrolyte and acid-base balance contribute to the clinical picture in patients with CRF, but the exact pathogenesis of the clinical syndrome of uraemia is unknown. Many substances present in abnormal concentration in the plasma have been suspected as being 'uraemic toxins', and uraemia is probably caused by the accumulation of various intermediary products of metabolism.
Clinical features: Nocturia, due to the loss of concentrating ability and increased osmotic load per nephron, is often an early symptom. Patients may present with complaints which are not obviously renal in origin, such as tiredness or breathlessness. In end-stage renal failure (ESRF), patients appear ill and anaemic. They do not necessarily retain fluid, and may show signs of sodium and water depletion. There may be unusually deep respiration related to metabolic acidosis (Kussmaul's respiration), anorexia and nausea. Later, hiccoughs, pruritus, vomiting, muscular twitching, fits, drowsiness and coma ensue.
Physical signs: Yellow complexion, pallor, JVP raised in fluid overload or pericardial tamponade, pericardial friction rub, pulsus paradoxus in pericardial tamponade, 'brown line' pigmentation of nails, excoriation, bruising, peripheral neuropathy (absent reflexes, reduced sensation, paraesthesia, 'restless legs')
One or other of the following may be evident: dual lumen central venous catheter for dialysis access, arteriovenous fistulae for dialysis access, peritoneal dialysis catheter, scar to indicate transplanted kidney.
| Disease | Proportion of end-stage renal failure | Comments |
|---|---|---|
| Congenital and inherited | 5% | e.g. Polycystic kidney disease, Alport's syndrome (hereditary progressive nephritis and deafness) |
| Renal artery stenosis | 5% | |
| Hypertension | 5 – 25% | It is uncertain whether such variation is due to true racial differences or to differences in diagnostic labelling |
| Glomerular diseases | 10 – 20% | IgA nephropathy is the most common |
| Interstitial diseases | 5 – 15% | |
| Systemic inflammatory Diseases | 5% | e.g. SLE, vasculitis |
| Diabetes mellitus | 20 – 40% | Large racial and national differences exist |
| Unknown | 5 – 20% |
Commonly accepted criteria for initiating patients on maintenance dialysis include the presence of uraemic symptoms, the presence of hyperkalaemia unresponsive to conservative measures, persistent extracellular volume expansion despite diuretic therapy, acidosis refractory to medical therapy, a bleeding diathesis, and a creatinine clearance or eGFR below 10mL/min per 1.73m².
Haemodialysis relies on the principles of solute diffusion across a semi-permeable membrane. Movement of metabolic waste products takes place down a concentration gradient from the circulation into the dialysate. There are three essential components to haemodialysis; the dialyzer, the composition and delivery of dialysate and the blood delivery system.
Dialysate:
The haemodialysis procedure is targeted at removing both low- and high-molecular-weight solutes. The procedure consists of pumping heparinized blood through the dialyzer at a flow rate of 300 – 500 mL/min, while dialysate flows in an opposite counter-current direction at 500 – 800mL/min. It is usually carried out three times per week. Careful compliance with diet and fluid restrictions is required between treatments as recommended by a qualified dietitian experienced in the management of ESRD.
Peritoneal dialysis may be carried out as continuous ambulatory peritoneal dialysis (CAPD) in which two litres of a sterile, isotonic dialysis fluid are introduced through a permanent Silastic catheter into the peritoneal cavity and left in place for approximately 6 hours. During this time, metabolic waste products diffuse from peritoneal capillaries into the dialysate fluid down a concentration gradient. The fluid is then drained and fresh dialysis fluid introduced. The inflow fluid is rendered hyperosmolar by the addition of glucose; this results in net removal of fluid from the patient on each cycle (ultrafiltration). This cycle is repeated 3 – 5 times daily during which time the patient is mobile and able to undertake normal daily activities. Its long-term use may be limited by episodes of bacterial peritonitis and damage to the peritoneal membrane. Automated peritoneal dialysis (APD) is now widespread with a mechanical device performing the fluid exchanges during the night, leaving the person free, or with only a single exchange to perform, during the day. Diet and fluid is less restricted in CAPD compared to haemodialysis.